Unit 3 Flashcards
most common form SCID
X linked IL2 R gene
Most common mutation CF
delta F 508
What enzyme does newborn screening in CF pick up
Immunoreactive trypsinogen
Testing for lupus which is more sensitive vs specific
Anti nuclear AB - auto AB to nuclei cells.
98% peoplesystemic lupus have a positive ANA test * most sensitive. Also called immunofluorescent antinuclear antibody test.
Anti-double-stranded DNA antibody (anti-dsDNA) = specific ANA antibody found in about 30% of people SLE + less than 1% of healthy individuals * specific.
The presence of anti-dsDNA antibodies suggests more serious lupus, such as lupus nephritis (kidney lupus). When the disease is active, especially in the kidneys, high amounts of anti-DNA antibodies are usually present.
Use enzyme-linked immunosorbent assay (ELISA)
How chronic infection CF leads decreased lung funcion
o Chronic infection – launch Th17 response against extracellular bacteria. Repeating cycle of infection and neutrophilic inflammation develops. Neutrophil releases lysosomal enzymes + peroxidase. Increased vascular permeability + fluid build-up lungs increasing diffusion distance * limiting effective gas exchange. TGF-ß and endothelin, cause smooth muscle proliferation, intimal thickening, interstitial fibrosis.
o Cleavage of complement receptors CR1 and C3bi and immunoglobulin G (IgG) by neutrophil elastase (NE) results in failure of opsonophagocytosis * bacterial persistence. NE leads production (IL)–8 from epithelial cells and elastin degradation * persistence of inflammation and infection, structural damage, impaired gas exchange, and, ultimately, end-stage lung disease and early death. As chronic inflammation gets resolved get formation scar tissue each time * builds up which reduced lung function.
o Airway obstructed due build up mucus * harder exhale air * reduced FEV
o Struggle expel air quickly as airways could collapse during exhalation – breathe out slowly pursed lips positive pressure maintain airway patency.
Warm type haemolytic anemia
patho
Breakdown tolerance -IgG auto AB produced against rhesus antigen rbc
igG coat RBC binding Fc R receptor phagocytes - phagocytosis esp sleen as splenic macrophages best affinity FC region.
Repeated partial pahgocytosis - damages membrane - spherocyte
Cold type haemolytic anemia
patho
Breakdown tolerance- IgM auto AB against polysaccaride 1 antigen.
Form IC peripheries <37 - Igm binds anitgen low affinity. Igm fixes complement classical * when RBC enter warmer region igM detaches leaving complement bound - kupffer cells high affinity C3b extra vascular hemaolysis liver
Warm type haemolytic anemia testing
Blood film - leucoerthroblastic, poly chromatic spherocytes
+ve direct Ab test IgG C3d
postive coombs for IgG
Cold type haemolytic anemia testing
Blood film normocytic, poly chromatic spherocytes
+ve Cooms complement
Folate cycle
dUMP -> thymidylate via thymidylaye synthase. Thymine needed DNA synthesis.
erythropoesis
Multipotent heamatopoetic stem cell common myeloid progenitor pro-erthroblast basilic erthroblast polychromatic erthroblast Orthochromatic eryhtroblast/normoblast poly-chromatic erythrocyte/ reticulocyte erthyrocyte
Causes micro cytic anemia
Microcytic anaemia- > Hypo chromatic -> Iron deficiency, Thalassaemia, anaemia chronic disease, hyperthyroidism + lead poisoning
Clotting diseases with prolonged prothrombin time
Owen parahemophillia (factor 5 deficiency) Liver failure - deficiency gamma carboxylated coagulation factors - II (prothrombin), VII, IX and X.
An essential cofactor for gamma-carboxylation is vitamin K,
Oculomotor n. parasympathetic component
Preganglionic neurons: midbrain (Edinger-Westphal nucleus)
Postganglionic neurons: Ciliary ganglion
Targets: Ciliary muscle & sphincter pupillae
Function: Accommodation of the lens, constriction of pupil
Facial nerve parasympathetic component
Preganglionic neurons: pons (superior salivatory nucleus)
Postganglionic neurons: pterygopalatine & submandibular ganglia
Targets: Lacrimal glands, submandibular gland, sublingual gland
Function: Increased secretion (tears and/or saliva)
Glossopharyngeal n. parasympathetic component
Preganglionic neurons: pons (inferior salivatory nucleus)
Postganglionic neurons: Otic ganglion
Target: Parotid gland
Function: Increased secretion
Vagus n parasympathetic component
Preganglionic neurons: medulla (Dorsal vagal motor nucleus)
Postganglionic neurons: within walls of viscera
E.g. enteric NS!
Target: Thoracic & abdominal viscera (up to the splenic flexure)
Function: Rest & digest
Pelvic splanchnic nerves
Preganglionic neurons: S2-S4
Postganglionic neurons: within walls of viscera
Target: Hindgut & pelvic viscera
Function: Peristalsis, glandular secretion, engorgement of erectile bodies, urination
Obstructive airway disease
Airflow obstruction due narrowing airways. Fev1 decreases much more FVC (same or drop slightly)* ratio drops.
Restrictive airway disease
Restrictive: Decreased lung volume – fibrosis. Not able create as great pressure difference due lack compliance * draw out smaller volume air. Fev1 and FVC drop by the same amount * ratio remains the same.
Pelvic pain line
Pain from viscera ‘above or in contact with inferior layer of parietal peritoneum’ travels via sympathetic splanchnic nerves
Pain from sub-peritoneal organs is conveyed via parasympathetic nerves
Pseudomonas virulence factors
Type 4 pilli
twitching motility + cell adhesion
LPS
Inflam signal + resistance phagocytosis
Type 3 secretion system
Injection toxins into host cells
Alginate
Slime layer + resistance IC + proteins
Flagellum
Motility + inflam signal
Phospholipse
Tissue invasion
Exoenzyme S/A
Inhibit elongation factors - kills
Sidophores
Iron sequesration + cell death
Elastase/protease
Tissue invasion
How siderphores allow iron sequestration
Siderophores are essential to iron sequestration in pseudomonas but in the process, they strip iron from human cells. Host cells need Fe for oxidative phosphorylation, siderophores are released from bacteria to scavenge Fe3+ from host cells – metabolic stress kills cell + iron sequestered into bacterium via transferrin. Neutrophil response – oxidative burst leads peroxide secretion from phagocytes. Fe3+ strips oxygen from peroxide * no damage to bacterium.
How does pseudomonas cause a respiratory tract infection in CF? 4 mark
o Initially pseudomonas adopts a non- mucoid phenotype, no biofilm formation, motile, cytotoxic with immunogenic LPS -> elicits strong IR.
o Normally bacteria eliminated by non-specific barrier defences – ventilation also have mucus trapping, defensin secretion + ciliary action- poor ventilation or entry bacteria increased by external devices infection occurs normally macrophages detect bacteria + drive inflammation. DC recruits Th17 help, neutrophils recruited + pathogen cleared.
o In CF patients produce excess/thick mucus that bacteria can live inside – mucus not removed by ciliary action * colonisation occurs + replication bacteria cannot be controlled.
o Once inside mucus pseudomonas changes its phenotype to a mucoid alginate secreting phenotype. Biofilm formation which is impenetrable to therapy, resorbs flagella, limited toxin production + this limit immune response as IS only encounter organisms if reach edges of mucus.
Risk factors for pseudomonas
o Failure immunity
o Structural defect
o Lack adequate ventilation
o Devices
How does the mucoid phenotype helps evade IS
How does the mucoid phenotype helps evade IS
o Biofilm prevents penetration of immune proteins + compounds. Lipid A of LPS binds less efficiently to TLR4 -reduced inflammation + reduced bacterial clearance leading to chronic infection with repeated flare ups.
o Increased neutrophil mediated damage respiratory epithelium, elastic + connective tissues. Neutrophils undergo NETosis form extracellular traps + neutrophil granule contents released. Wheeze, cough, mucus hyper-production -> bronchitis, bronchiectasis + pulmonary failure inevitable. Need antimicrobial therapy prevent colonisation + eliminate bacteria during flare ups.
How pseudomonas has developed antimicrobial resistance (natural feature of overdose)
o Hydrophobic penicillins (Penicillin V, flucloxacillin) + glycopeptides cannot enter outer membrane channels
o Hydrophilic penicillins (Amoxicillin) + cephalosporins can enter but chromosomally encoded beta-lactamases degrade them
o Constantly expressed outer membrane efflux pumps pump protein synthesis inhibitors + folate antagonists out cell (Macrolides, Tetracyclines, Trimethoprim + Fusidate)
Mucoid phenotype in psedomonas
Alginate secreting Biofilm formation Resorb flagella Limited toxin production limits IR -
Productive cough CF
Lack CFTR reduced chloride secretion increases sodium + water absorption - lowers water content mucus lining respiratory epithelium - isotonic dehydrated mucus
defective mucocilliary action accumulation secretion obstruct bronchi + bronchitis triggering cough reflex
How Pseudomonas acquires resistance
Chromosomal mutation. Activation of existing resistance genes. Uptake of genetic material from other organisms
Acquired resistance Pseudomonas
o De-repression chromosomal ESBL + plasmid-acquired beta-lactamases (NDM1) OR carbapenemases (KPC) degrade ceftazidime, tazobactam + meropenem
o Overexpression multi- drug efflux pumps actively remove fluoroquinolones (ciprofloxacin), aminoglycosides (gentamicin) + carbapenems
o Changes in drug targets (topoisomerases + small ribosomal subunits) prevent fluoroquinolone + aminoglycoside binding -> expression 16s rRNA methylation enzymes + expression altered topoisomerase enzymes.
What is pseudomonas
Pseudomonas aeruginosa is a Gram-negative, oxidase-positive, non-fermenting bacillus
What pseudomonas relations
Acinetobacter, Burkholderia and Stenotrophomonas
atopy
Atopy (genetic tendency to develop allergic disease). 40% in Caucasian populations. Atopic have higher levels IgE + Eosinophils in blood. Due polymorphism of many genes. MHC II -> enhanced presentation of allergen peptides. TRC alpha chain -> enhanced recognition of allergen peptides. Il-4R -> increased Il-4 signalling. Il-4 -> variation Il-4 protein expression. FceRI -> IgE binding. Chromosome 5 genes for Il-4,3,5,9,12,13 + GM-CSF involved isotope switching, eosinophil survival + mast cell proliferation.
Genetic factors asthma
HLA DR/Q
Polymorphisms ADAM33
Chromosome 5q
Atopic asthma
Atopic asthma
Most common type – type 1 hypersensitivity reaction. Allergic sensitisation + patients’ family hx asthma + high serum IgE.
Stress induced asthma
Stress induced Initially At catecholamine -> bronchodilation. Long periods of exposure catecholamines, their receptors become downregulated * effects less severe. Reduction in catecholamine sensitivity reduces immune cell regulation, as T and B lymphocytes possess adrenergic receptors, so catecholamines can regulate IL-4, IL-5 and IL-13 expression, histamine release from mast cells and recruitment + activation of eosinophils.
Cold induced asthma
Cold/ exercise induced Airway cooling - dehydration of the fluid lining respiratory epithelium. Drying of the airways increased blood flow (hyperemia) -> oedema + bronchoconstriction.
Exercise induced asthma, symptomatic 5-15 minutes after exercise, as catecholamine release during exercise helps with bronchodilation.
Drug induced
Drug induced 3-5%, NSAID + Aspirin sensitivity -> Drugs inhibit AA pathway inhibit production prostaglandins. Prostaglandin E inhibits enzymes generate leukotrienes * inhibit this get upregulation leukotrienes -> bronchoconstriction.
Urticaria (hives) + typical asthmatic symptoms.
Early phase asthma
Early phase response - sensitization
o Inhaled allergens get across mucosal layer taken up DC, presented T-helper cells inducing exaggerated Th2 response to harmless environmental antigen.
o Th2 produces Il-4 -> stimulate proliferation + differentiation plasma cells + IgE production. Il-13 -> stim mucus secretion from bronchial submucosal glands + IgE from plasma cells.
o Plasma cell produced IgE binds to Fc on submucosal mast cells BUT by this time the antigen has already been cleared.
o Second exposure to antigen the ready and waiting mast cells react immediately, releasing granule contents with immediate affects. Allergen binds mast cell bound IgE immunoglobins cross linking Fc receptors triggering degranulation + release;
- Leukotrienes -> bronchoconstriction, increased vascular permeability and oedema and increased mucus secretion (B4 recruits immune cells, C4, D4, E4 bronchoconstrict)
- Histamine -> potent bronchoconstrictor
- Prostaglandin D2 -> bronchoconstriction and vasodilation (causing oedema)
Late phase asthma
o Th2 -> IL-5 activates locally recruited eosinophils into airways which bond IgE immunoglobins through Fc receptors which cross linked bound to allergen. Eosinophils release eosinophil cationic protein + major basic protein -> damages cells respiratory tract + leukotrienes -> oedema + further bronchial constriction.
o Chemokines produced T + epithelial cells recruit more T cells, eosinophils + basophils. Epithelial release eotaxin = chemokine for eosinophils.
Chronic inflammation -> bronchial hyperresponsiveness to histamine, cold air, sulphur dioxide and AMP. mediated by high levels IgE * airways more responsive to contractile stimuli.
Epithelial shedding from chronic inflammation exposes subepithelial tissues to inflammatory mediators + sensitises nerves * altered neural control of the airways. Airway obstruction due muscular bronchoconstriction, acute oedema and mucus plugging.
Characteristics early phase asthma
bronchoconstriction, increased mucus production and increased vascular permeability and oedema, leading to symptoms of wheezing, chest tightness and breathlessness.
Mast cell contents activate subepithelial vagal receptors, triggering acetylcholine release from vagal efferents that directly induces smooth muscle contraction through muscarinic receptors.
Why is breathlessness worse at night asthma
Airway obstruction due bronchoconstriction + mucus plugging * respiratory muscles need work harder to generate a negative intrapulmonary pressure for inspiration. Muscle fatigue -> lead to breathlessness. Inability to draw in air-> bronchoconstriction.
Increased exposure to allergens at night; cooling of the airways; being in a reclined position leading to pooling of secretions worsens airway obstruction at night * breathlessness.
Cortisol peaks in the early morning hours, leading to increased inflammation
What is asthma
Chronic disorder conducting airways caused immunological reaction marked episodic bronchoconstriction due increased airway sensitivity variety stimuli, inflammation bronchial walls + increased mucus secretion. Flare ups IgE mediated type I hypersensitivity reaction Allergen specific IgE AN bind mast cells via Fc receptor. When antigen binds to IgE the Cross linking of IgE induces degranulation of mast cells), following exposure environmental allergen in genetically predisposed person.
Response to b2 agonist in asthma, COPD and restrictive
Asthma >15% response
COPD <15%
No response restrictive
Changes in airway remodeling
Sub epithelial fibrosis Increase SM mass Goblet + mucus gland hyperplasia Angiogenesis Loss cartilage integrity Inflammation Epithelial alteration
What do neutrophils release
Granules - cellular proteases, elastase, proteinase 3 + cathepsin - tissue damage
Functional alpha 1 antitrypsin deficiency
Oxidative injury allows inactivation native antiproteases
Part lung affected emphysema
Acinus - respiratory bronchiole, alveolar ducts + alveolar
Symptoms COPD
Cough worse morning - productive colorless sputum
Breathlessness 6th decade life due reduction FVC
Wheezing
Severe Tachypnoea -rapid shallow breathing Acc respiratory muscles Cyanosis Elevated JVP
Examination
Hyperinflation
decreased breath sounds
prolonged expiration
Obstructive lung disease
obstruction due narrowing airways - fev1 decreases more fvc * ratio drops
Restrictive lung disease
DECREASED LUNG VOLUME - fibrosis. not able create great pressure differnece due lack compliance * draw smaller volume air
Fev1/ FVC drop by same amount * ratio remains the same
how to episodic asthma symptoms become persistent with time
Persistent mucous inflammation - up regulation nerves vessels + glands in resp tract -> increased responsiveness allergens + environmental irritants (epitope spreading)
-> patient sensitive wide range stimuli * episodic symptoms become persistant
Lung mechanism of compensation
Physiological shunting and hypoxic vasoconstriction - area capillary not getting ventilated vasocontricts and blood shunts to area well ventilated
If physiological dead space- get bronchocontriction and reduced surfactant - diverts to areas well perused alveoli
Type I and type II respiratory failure
Type I hypoxaemic respiratory failure - Localized mismatching ventilation/perfusion ratio
Po2 low Pco2 normal/low
Type II hypercapnic respiratory failure - large portion lung pneumothroax - global reduction in flow of air to alveoli or blood to pulmonary capillaries
po2 low pco2 high
Role kidney and liver in chronic acidosis
liver decrease urea production and increase glutamine production
Kidney up regulates glutamine dehydrogenase + PEPCK which catalyze breakdown glutamine into ammonium and bicarbonate ions
Where is glutamine taken up
PCT
Glutamine to glucose steps
Glutamine alpha ketoglutarate oxaloacetate Phosphoenolypyruvate Glucose + bircarbonate (3 bircarbonate excreted into interstium along with Na+)
kidneys response to chronic alkalosis
Decrease plasma bicarbonate
Increase number and activity type b intercalated cells in collecting duct -> secrete HCO3 into tubule lumen
Mechanism Warfrin
Competively inhibits vit K reductase needed activate vit k into usable forms by body. reduce synthesis vit K dependent clotting factors
II, VII, IX X
Mechanism Heparin
Binds + activated antithrombin III which activates it against 11, IX, X and slightly XII
Unfractionated inactivates throbin and factor X
LMWH only inactivates factor X
dalteparin
Steps clotting
Vascular spasm Platlet plug formation Coagulation Clot refraction + repair Fibrinolysis
Endo cells release…. to prevent clotting normally
NO2/ PGI2 -> NATURALLY INHIBIT PLATELET PREVENT BINDING
Heparin sulfate on surface which bonds AT III which degrades clotting factors II, IX X
thrombomodulin of surface which binds Thrombin (II)
Which activates protein C which degrades V and VIII
Stages vascular spasm
Endo injury constrict BV prevent Blood loss
Endo cells injured -> endothelin activates intracell PIP2 mechanism contraction
Direct injury Sm- myogenic mechanism -> contraction
Chemokines/pro inflam cytokines activate nociceptors - pain reflex contraction
Parasympathetic cranial nerves
oculomotor, facial, glossopharyngeal and vagus nerves, which are also known as cranial nerves
III, VII, IX and X
SIRS
Body wide response involving inflam mediators can be caused when infections reach bloodstream.
Infection BS, TNF alpha binds R endo cells. Momocytes detect pathogens PRR, complemnt R + Fc R. monocytes initiate pro inflam cytokine responce.
Dissemination increase fever HR CRP + WCC
SIRS to Sepsis
TNF alpha activated eno cells release TF (activates coagulation cascade - hypoperfusion other areas + ROS direct organ damage) and NO drives vasodialtion + capillary leakage.
TNF alpha also activates neutrophils - produce TNF alpha. Activated neutrophils form NETS
SIRS to septic shock
Increase TF hypercoagualtion, depletion clotting factors increased anticoagulation
TNF alpha, CXCL8 + NO casue vasodilation - fluid loss into tissues - oedema (LUNGS + CSF) hypoperfusion + BP rapdil drops
SEPTIC SHOCK - low BP/MAP
Bacteria cause sepsis
Esherichia coli (gram neg) Stapylococcus aureus (gram = +ve)
Bacteria cause meningitis
GBS E-coli Staph aureus Strep pneu Neisseria meningitis
qSOFA
presence doc/suspected infection with organ dysfunction + qSOFA 2+ = sepsis
RR >20
CNS altered mentation
SBP <100mmHg
CARS
compensatory anti inflam response syndrome
If ongoing septic shock and IR run out of immune cells * pathogen no longer being present switch anti inflam responce
Increase TGF B + IL-10
Decrease TNF alpha, CXCL8 + NO
body assumes infection is over
SOFA
sequential organ failure assessment for sepsis - SIRS presence infection with SOFA >2 = SEPSIS
Looks at respiratory, coagulation, liver, CNS + renal
Community acquired pneumonia
Strep. pneu
Amoxicillin
Community acquired UTI
E- coli
Trimethoprim
Catheter associated UTI
Gram neg
E- coli
kleibsiella spp
Gentamycin
Hospital acquired pneumonia
Staph aureus
Pseudomonas
tazocin
ECG trace PE
S1Q3T3 McGinn white sign
When does gallop heart rhythm happen
Diastole
Brief study development AS plaque
Endothelium dysfunction + high amounts circulating LDL
Increase LDL deposit intima + oxidised
Oxidised LDL activate eno cells which upregulate receptors bind leukocytes
Adhesion leukocytes allow monocyte + t cell entry - monocytes differentiate into macrophages as moves into tunica intima.
Macrophages take in oxLDL + become foam cells
Foam cells promote migration SMC from tunica media- intima + SMC proliferation.
SM proliferation - heightened synthesis collagen * hardening AS plaque.
Foam cells die - release lipid contents.
Plaque grows + pressure - rupture.
Thrombosis + coagulation impede blood flow
ANP
Stretch atria causes drop BP
Decrease GFR, decrease resorption Na+, inhibit release renin, aldosterone = ADH
MI
Irreversible necrosis heart muscle secondary prolonged ishemia due imbalance O2 supply + demand often caused plaque rupture thrombus formation in left anterior decending artery * reduction blood supply to ant wall left ventricle.
Which cell type release synovial fluid
type B
Pathophysiology OA
Initial articular cartilage damage - chondrocyte switches repair cartilage, makes less proteoglycans + more type II collagen. Then switches increase type I collagen. Type I doesn’t interact proteoglycan same way + decrease elasticity. Over years chondrocytes became exhausted and apoptose.
Weak cartilage - flake off into cartilage space = JOINT MICE
Type A cells clear joint mice - attracting lymphocytes + macrophages - release pro inflam cytokines - synovitis
Fibrilations form - cracks on articular smooth surface
Cartilage wears away until rubs bone - bone eburnation
Osteophytes - hebardens + bouchards nodes
Rickets pathophysiology
Deficiency Vit D, hypocalceamia, increase plasma Ca, decrease plasma P. bone formation as compensation - abnormal mineralization due lack calcium and phosphate. If at growth plate = rickets. If bone matrix = osteomalacia.
Anemia in inflam states
Il-6 binds to IL-6 receptors on liver cells increasing hepcidin expression. Hepcidin interacts with ferroportin causing internalisation into enterocytes, inhibiting iron mobilisation from cellular stores. TNF alpha also opposes action of EPO which reduces erythropoiesis. Reduced RBC formation and reduces iron availability reduces amount Oxygen that is transported around body causing anaemia and fatigue.
High risk strains HPV
HPV 16,18,31,33,45
HPV genital warts
6,11
HPV cutaneous warts
1-4
HPV oral infections
13+ 32
What is target HPV virus
Stratum basale keratinocytes
Whats the trigger to switch off E2 in HPV and then l1/2 promotor switches on
keratinisation of cell + de-condensation of nucleus
HPV mechanism of immune evasion
E5 blocks MHC I peptide loading * inhibits NK recognition
E6 blocks expression chemokines MIP1alpha and cxcl8
IFN prvented being transcribed by E7
Once inside cell E6 inhibits expression TLR -9
What is the role of HPV E7
HPV E7 binds Rb + mimics phosphorylation
E2F drives cyclin E expression
What is the role of HPV E6
Decreases Rb causes increase p53
HPV E6 binds p53 stopping expression CDK1
Measles virus 8 proteins
Early non structural proteins
Nucleocapsid - contains + stabilises RNA
Virulence protiens p/v/c immune evasion
Late proteins structural proteins
Matrix - form + stabilize lipid envelope upon release cell
Fusion - virulence determinant allows syncytia formation
Haemaglugutinin major adhesion
Polymerase - replicates neg sense RNA * protein synthesis.
Receptors blood vessels
Alpha 1 vasoconstriction
Beta 2 vasodilation
Alpha I preferentially activated high adrenaline concentrations
Receptors in the eye
Miosis - pupillary constrictor muscle sphincter
Parasympathetic M3
Mydriasis- pupil dilator muscles radial. Alpha 1 sympathetic
4 ways kidney stabilizes blood pressure -long term
o Myogenic intrinsic -Increase BP, increase stretch SM, increase cytosolic calcium, aa constricts + reduction renin section
o Tubuloglomerular intrinsic – Increase BP, increase GFR, Increase Na+ uptake macula densa cells stim adenosine release, triggers vasoconstriction aa + inhibits renin secretion from granular cells
o Extrinsic - Drop BP detected baroreceptors, increase sympathetic firing, increase noradrenaline, increase proximal tubule Na/H exchange.
o Extrinsic RAAS- Angiotensin II, arteriolar vasoconstriction, increase thirst, Na= appetite, increase Na/H+ exchange, aldosterone secretion (increases Na= reabsorption from principal cells distal nephron)
o ANP- secreted atrial myocytes response increase BP, decrease proximal na transport vasodilation A>E
o Adrenal cortex release aldosterone
Mechanism of NO release
The glycocalyx transduces information on shear stress (flow-induced vasodilatation)
Activation of intracellular protein kinase B (PKB)
PKB phosphorylates endothelial nitric oxide synthase (eNOS) ↑eNOS activity
↑ NO production in endothelial cells which then diffuses freely through cell membranes to act locally in VSMCs due to its very short half-life
NO activates guanylate cyclase in VSMCs ↑cGMP production Protein kinase G (PKG) activation:
Inhibition of MLCK ↓ Ca2+ sensitivity.
Phosphorylation of phospholamban disinhibition Ca2+-ATPase pumps ↑ Ca2+ expulsion + sequestration
Activation of sarcolemma K+ channels hyperpolarisation opening probability of voltage-gated Ca2+ channels Ca2+ influx
NOD 2 hypothesis for crohns
- Loss of function of NOD2 leads to reduced α-defensins, reduced recognition in macrophages and dendritic cells and bacteria thrive
- NOD2 enhances autophagy in endothelial cells clearing bacteria. Without this the bacteria build up . Also associated with reduced α-defensins
- NOD2 negatively regulates TLR signalling reducing inflammatory cytokine release. Mutations cause deregulated TLR signalling and excessive inflammation. TLR induces IL-12 and pro-inflammatory cytokines. Tips the balance towards Th1 and Th17 induction
Coeliac mechanism
Gluten transits the epithelial cells and is altered by tissue transglutaminases into it’s peptide gliadin. Could be as a result of an infection e.g. rotavirus
Dendritic cells take up the antigen and drive a TH1 response.
IFNγ activates macrophages and drives inflammation
TTG complexed with gliadin can be recognised by B cells which with T cell help produce antibodies to gliadin TTG perpetuating inflammation
Damage and inflammation can drive IL-15 release by the epithelial cells and activate NK and CD8 responses
NSTEMI
ST segment appears depressed
Partial occlusion coronary vessel - depolarization drom sub endocardium first as last per-fused - depolarization towards +ve - positve deflection - baseline shift upwards towards +ve value * ST segment appears depressed
STEMI
Complete occlusion coronary artery - transmural ishemia - depolrization from ishemic to healthy tissue - directiondepol away electrode - neg deflection - shift baseline down towards neg value * ST segment appear elevated
Risk factor lupus
HLA DR3/2
defects C1q
virus
UV
Role CFTR in respiratory vs pancreas vs sweat ducts
Respiratory - secretes cl- and inhibits ENAC
Pancreas- SLC2 pumps HCO3 out and Cl- in
Sweat ducts - active resorption chloride + activates ENAC- resorption both sodium + chloride.
