Fundamentals

Front 1

LOOK CLOSELY: This group of cytokines have a major role in what process of the body?

Back 1

Pro-inflammatory cytokines! (early reponses to infection)

Can also cause SYSTEMIC effects as seen here! Mobilize to get an immune response

Hint 1

MASSIVE MASSIVE INFLAMMATION

Front 2

LOOK CLOSELY: This group of cytokines have a major role in what process of the body?

Back 2

CYTOKINES FOR HEMATOPOESIS in immune cells differentiation

Hint 2

Front 3

LOOK CLOSELY: What do all these cytokines have in common? This group of cytokines have a major role in what process of the body?

Back 3

ADAPTIVE IMMUNE RESPONSE... helps with T1 and T2 helper cells

Front 4

LOOK CLOSELY: Whats the theme here? What do all these cytokines have in common?

Back 4

Cytokines synthesed by TH1 cells... focused on activation of macrophages to kill intracellular pathogens.

Front 5

LOOK CLOSELY: What do all these cytokines have in common?

Back 5

Cytokines secreted by TH2 helper cell help ANTYIBODY production... increases B cell proliferation. Fun fact: Cytokines secreted by Th2 cells known as "ANTI-INFLAMMITORY CYTOKINES"

Front 6

LOOK CLOSELY: What do all these cytokines have in common? What process in the body makes them so important

Back 6

Important for IMMUNE REGULATION

IL-10 and TGF-beta= STOP SIGNS

IL-7 and IL-15= Long Term memory

key for turning off immune response

Front 7

One cytokine can have many different effects... so what sort of chaos might happen if the IL-2 receptor were somehow mutated?

Back 7

So FCuked!! cant mount a sufficient immune response

Hint 7

Mutation of the gamma chain of IL-2 receptor also affects receptors for IL-4, IL-7, IL-9, IL-15. The gene for this “common gamma chain” is encoded on the X chromosome so males are most commonly affected. The result is a decrease in NK and T cells and nonfunctional B cells due to lack of T cell help. The deficiency is more severe than an IL-2 deficiency because multiple cytokines are affected.

Front 8

Looking at this list, which cytokines therapies could be used for treatment of malignancy, autoimmune diease, allergy and transplantation?

When would you want to ENHANCE immune response and when would you want to SUPRESS immune response? How could you do this?

Back 8

Front 9

Interferons (IFN) help protect against viral infections.

Type 1 = alpha and beta

Type 2= gamma

Which one is part of innate repsonse (made by most cells) and which one is more adaptive response (made by NK, Th1, and killer Tcells)?

Back 9

Type I (alpha/beta)= Innate

Type II (gamma)= KILLER/ adaptive

Hint 9

Front 10

What makes cytokines so AWESOME?!?! Can you think of examples of each?

Back 10

different cells, same cytokine= TGF-beta [monocytes, tcells, chondrocytes]

same cell, different cytokines= macrophages [TNF, CXCL8, IL1,IL6,IL12)]

Autocrine- T cell secreting IL2

Paracrine- INFgamma from Tcell activates macrpophage

pleiotropy - IL-2 [Tcell growth, Bcell antibody synthesis, increase NK cells]

Redundancy- IL-2, IL4, IL7, IL15 all T cell growth factors

Synergy- CD40 and INFgamma activating macrophage

Antagonisim- IL2 promotes growth... TGFbeta inhibits T cell growth

Hint 10

Low yield, but just cool what a difference cytokines can make

Front 11

What about the JAK/STAT pathway is so snazzy for cytokines?

Back 11

RAPID RESPONSE TO CYTOKINES

Front 12

What should these side effects SCREAM to you?

Back 12

CNS drugs= ANTI-muscarinic ACTIVITY

(aka anti-cholinergic side effects)

Hint 12

Front 13

Might save life during apocalypse... why is ATROPINE and PRALIDOXIME work as an antidote for nerve gas/ chemical warefare? (also works for poising from insecticides/ organophosphates?)

Back 13

These drugs are really POWERFUL Acholinestgerase inhibitors (meaning they UP and exacerbate the cholinergic effects (PNS) on the body)

Atropine is a powerful (ANTI-CHOLINERGIC) so it will help remove side effects (via comp. inhibition/ anatagonist) of a system overwhelmed with acetylecholine

pralidoxime- breaks up [nearly] irreversible bond between nerve agent phosphate and cholinesterase

Hint 13

Other irreversible Ach inhibitors (indirect cholinergics)

Front 14

Whats the difference between HYPEREMIA and CONJESTION?

Back 14

HYPEREMIA
Active process in which arteriolar dilation lead to increased blood flow. Affected tissues typically turn red. Examples include sites of inflammation and skeletal muscle during exercise.

CONGESTION
- Congestion, the passive accumulation of blood within a tissue, is the result of impaired flow and usually occurs together with edema.
- The increased volume of blood results in increased hydrostatic pressures and fluid leakage.
- Two common examples of chronic congestion:
o Chronic pulmonary congestion: this often occurs in the setting of left ventricular heart failure. When the left ventricle cannot pump properly, blood ‘backs up’ in the lungs. Over time, this congestion results in changes in the lung parenchyma: alveolar walls become thickened and numerous macrophages are identified in alveolar spaces as they recycle iron from broken down red blood cells.
o Chronic hepatic congestion: this often occurs in the setting of right sided ventricular failure. In this case, blood backs up into the liver. Again, over time this process will lead to changes in the liver: the central regions of the hepatic lobules are affected most and the cells may degenerate with subsequent fibrosis.

Front 15

What are 4 conditions that can cause edema?

Back 15

Front 16

How would you describe the difference between petichiae and purpura? what causes difference b/w these two

Back 16

- Defects in primary hemostasis (platelet defects) often present with petechiae in the skin or mucosal surfaces.
- Defects in secondary hemostasis (coagulation factor defects) often present with bleeds in deep soft tissues or joints.
- Acute massive bleeding may result in hypovolemic shock and death
- Chronic or recurrent external blood loss (for example, through the gastrointestinal tract, genitourinary tract or gynecologic tracts) may result in iron loss and anemia.

Hint 16

o Hematoma: Accumulation of blood within a tissue
o Petechiae: Hemorrhages that are small (1-2mm) often involving skin or mucus membranes. Associated with decreased numbers of platelets, platelet dysfunction or less commonly, clotting factor abnormalities.
o Purpura: Slightly larger hemorrhages (> 3mm). Similar causes as petechiae or secondary to trauma, inflammation or increased vascular fragility.
o Ecchymoses: >1-2 cm, subcutaneous hemorrhages often associated with trauma. These bruises may change colors clinically as red blood cells are degraded and resorbed.
o Hemothorax: Accumulation of blood in pleural spaces
o Hemopericardium: Accumulation of blood in pericardial spaces often secondary to rupture of the aorta (from aortic aneurysm or trauma)
o Hemarthroses: Accumulation of blood in the joint space

Front 17

Be careful... burns can cause both hypovolemic shock or shock associated with systemic inflammation (formerly "septic shock"). What is the difference between these two types?

Back 17

Hint 17

What do they have in common.

Front 18

What are some complications of shock?

Back 18

Front 19

3 things make up hemostasis (vascular wall, platelets, and coag cascade) What are the events of normal hemnostasis after injury?

Back 19

1. Vasoconstriction:

2. Platelet activation

3. platelet aggregation

4. activation of coag cascade

5. stabilization of platelet plug

Front 20

Endothelium very important. What are some ANTITHROMBITIC PROPERTIES, and what are PROTHROMBITIC PROPERTIES? WHy do we give t-PA to people that are having a stroke?

Back 20

Antiplatelet- (1hemostasis)

Anticoagulant- (2dary hemostasis)

Fibrinolytic effects

Hint 20

Antithrombotic Properties
a.Antiplatelet factors
i. An intact endothelial prevents the subendothelial, extra-cellular matrix from coming into contact with platelets
ii. Prostacyclin: produced by endothelium, vasodilator and inhibitor of platelet aggregation
iii. Nitric oxide: Also produced by endothelium and inhibits platelet aggregation
iv. Adenosine diphosphatase: expressed on endothelial cells, degrades ADP and inhibits platelet aggregation
b. Anticoagulant effects
i. Heparin-like molecules- cofactors of antithrombin III (which inactivates thrombin and other factors)
ii. Thrombomodulin- binds to thrombin and becomes activated then in turn activates protein C.
1. Protein C: with the help of protein S, cleaves factors Va and VIIIa
2. Protein S: Produced by endothelium, acts as a co-factor for protein C
iii. Tissue factor pathway inhibitor: on surface of endothelium, inhibits activated tissue factor
c. Fibrinolytic effects
i. Tissue-type plasminogen activator (t-PA): produced by endothelium, helps to clear fibrin
B. Prothrombotic Properties
a. Platelet effects
i. Von Willebrand factor (vWF): produced by endothelium, enhances platelet adhesion to endothelium
b. Procoagulant effects
i. Tissue factor: stimulated by bacterial endotoxins or cytokines, activates extrinsic clotting cascade
c. Antifibrinolytic effects
i. Plasminogen activator inhibitors: produced by endothelia and suppress fibrinolysis

Front 21

Thrombus: Formation of a blood clot in uninjured vasculature or in a vessel with minor injury (or a pathologic disease).

What are the three things that can lead to a thrombus? (VIRCHOWS TRIAD)

Back 21

Factors involved in thrombosis: VIRCHOW TRIAD
1. Endothelial injury
2. Abnormal blood flow (stasis or turbulence)
3. Hypercoagulability

Hint 21

Endothelial Injury
- Important factor (alone can cause thrombosis)
- Especially important in arterial circulation
- May initiate thrombosis with physical injury or if it is dysfunctional.
- Examples of physical injury:
o Atherosclerotic plaque
o Inflammatory vascular injury (vasculitis)
- Dysfunctional injury:
o Hypertension
o Bacterial endotoxins

Abnormal Flow
- Normal flow is laminar: platelets flow centrally, separated from the endothelium by peripheral flowing plasma
o Stasis: Slow flow or no flow; largely contributes to venous thrombosis
o Turbulence: Irregular flow, largely contributes to arterial thrombosis
- Mechanisms of stasis and turbulence in thrombosis:
o Allow platelets to come into contact with endothelium
o Prevent dilution of activated clotting factors
o Retard inflow of clotting factor inhibitors
o Promote endothelial cell activation

Hypercoagulability: Alteration of the coagulation pathways that predisposes to thrombosis.
o Contributes less frequently to thrombotic states than other factors
o Causes may be primary or secondary
General points:
o Inherited causes of hypercoagulability should be considered in young patients (less than 50 years) who present with a thrombus and in patients with thrombosis in unusual sites.
o May contribute to both venous (common) and arterial (less common) thrombi.

Front 22

What is the difference between venous, arterial and mural thrombi.... what are complications of each?

Back 22

Arterial Thrombus
- Firmly attached, frequently superimposed on an atherosclerotic plaque and usually occlusive.
- Gross: gray, white
- Microscopic: Composed of alternating areas/laminations of platelets, fibrin and red blood cells. Some degenerating leukocytes may be present.

Venous Thrombus
- Attached to vessel wall
- Gross: more red in appearance
- Microscopic: composed largely of erythrocytes

Mural Thrombus
- Thrombi forming adjacent to and attached to the wall of a structure, such as the heart.
- Often have finding similar to arterial thrombi.
- Due to hypomotility or injury to the wall
- *Small thrombi may form on the cardiac valves

Hint 22

Front 23

The 5 different types of embolisims: Thromboembolisim--> pulmonary embolus, systemic thromboembolisim, air, fat, amniotic fluid. Which ones are the scariest? What are the complications of each? What is most common? Which one can happen with SEVERE ortho trauma? Which ones could cause a stroke?

Back 23

difference in stoke... one may be athlerosclerosis... one may be from the heart (embolisim breaking off)

Hint 23

Thromboembolism: Pulmonary Embolus
- Venous thrombus (originating in the femoral vein most commonly) that potentially occludes small or large branches of pulmonary artery.
- Very common entity that occurs in a variety of clinical settings in both men and women.
- Predisposing factors include: those associated with hypercoagulability and immobility (particularly post-operative period, long plane rides etc)
- Clinically, there is a spectrum. Small occlusions may be clinically silent, large ones may cause chest pain. An embolus at the bifurcation (referred to as a saddle embolus) is fatal. The diagnosis is confirmed with a CT.

Systemic thromboembolism
- Most systemic thromboemboli arise from mural thrombi in the heart.
- Can also arise from aortic aneurysms or valvular vegetations
- Can travel to a wide variety of sites including intestines, kidney, spleen and extremities
- Consequences vary but may result in tissue infarction

Fat Embolus
- Uncommon, usually involves fat (that is a normal component of the bone marrow) and often, other elements of the bone marrow that become dislodged during severe trauma (with several fractures) or burns, during orthopedic surgery or during particularly rigorous CPR (with fracture of sternum).
- May or may not cause symptoms.
- Fat embolism ‘syndrome’ (includes the following) may result in death:
o Pulmonary insufficiency
o Neurologic symptoms (irritability, confusion, seizures)
o Anemia (red blood cells aggregate and hemolyze)
o Thrombocytopenia (platelets attach to the fat, and are removed)
o Pathogenesis involves both mechanical and biochemical injury and the syndrome may have an element of DIC.

Air Embolus
- Bubbles caused by gas in the circulation (in excess of 100cc) may cause obstruction and occlusion.
- Decompression sickness: occurs when deep sea divers are exposed to sudden changes in atmospheric pressure.
- Gas emboli may cause ischemic injury in many tissues acutely/chronically.
- Treatment involves chambers that allow for slow decompression.

Amniotic Fluid Embolus
- Uncommon complication of normal pregnancy during labor or the immediate post-partum period.
- Result of infusion of amniotic fluid (and some fetal tissue such as squames from the skin or hairs) into the maternal circulation via tears in fetal membranes or rupture of uterine veins.
- Sudden onset of dypsnea, confusion, seizure, hypotension.
- High mortality and often associated with DIC.

Front 24

What are classic examples of RED infarcts? White infarcts?

Back 24

Red: So-called because they are hemorrhagic and typically occur in the following settings.
- Venous occlusions
- Dual circulation
- Previously congested tissues
- Re-perfusion
*Classically, pulmonary and bowel infarcts are examples of red infarcts.

White: Occur in organs with end-artery circulation (heart, spleen, kidney)

*Most infarcts (either type) tend to be wedge-shaped with a hyperemic border and slightly irregular outlines.

Hint 24

dominant feature is necrosis- in all areas this is COAGULATIVE NECROSIS... [EXPECT FOR THE BRAIN!!!! BRAIN IS LIQUIFACTIVE NECROSIS]

Front 25

Which drug (norepi or epi) are selective for everything EXCEPT B2 RECEPTORS!! ? What does this mean for the body clinically

Back 25

Low does of epi, get relaxation
Large does of epi, get contraction, why???? There are more alpha 1 recpetors than beta 2.

Hint 25

Front 26

WHat the eff is going on here?

Back 26

no idea

Front 27

What types of G proteins do all of these receptors have.... what is the ultimate result?

Back 27

Front 28

Why are catecholamines ineffective as an oral dose? Why is it always with a needle?? ow

Back 28

The location of COMT is mainly extraneuronal, (gut, liver, kidney, brain) this renders catecholamines ineffective oraly, since they are METABOLIZED before absorption even occurs

Hint 28

Front 29

Why is Adderall (amphetamines) so powerful in increasing release of catcecholamines? What does it do extra?

Back 29

Hint 29

Front 30

Why is NOREPINEPHRINE the only drug where total peripheral resistance goes UP instead of down?

Back 30

norepi (at physiologic levels) can't activate beta-2 receptors in the body!

Front 31

What the hell is going on at norepi here?

Back 31

Increase in CONTRACTABILITY of heart, INCREASE in SV but causes HR to go DOWN so NO CHANGE IN CARDIAC OUTPUT

(Does not involve medulla, all neurally mediated compensation mechanisims happen, baroreceptor reflex engaged)

Hint 31

Front 32

In the above table, would the presence of ATROPINE change the effects of NE on cardiac output? How? By what mechanisim?

Back 32

Yes! By blocking muscarinic receptors, atropine would block baro-receptor induced vagus stimulation and would therefore increase the heart rate, therefore cardiac output would increase. What about with epi?

Hint 32

Norepinephrine – stimulates alpha-1, alpha-2 and beta-1>>> beta2)
Limited clinical use due to its rapid reuptake, and its potent vasoconstrictive effects. However, it is useful in septic shock and other severe hypotensive states (e.g., anesthesia) because, even though it doesn’t increase cardiac output very much, the increased cardiac force and BP increase perfusion pressure without increasing heart rate.

Front 33

What are therapeutic effects of direct adrenergenic agonists? When would this be useful?

Back 33