DD/BL - Unit 2

What is lipofuscin?

'wear and tear on cell' accumulation of lipid and protein. Usually remnant of former ROS damage.

What are the causes of permeability increase in endothelial vasculature in acute inflammation.

- Endothelial cells contract and leave gaps between them. - Endothelial cells are injured, die, detach - Transcytosis - transport through endothelial cells via vesicle.

What is the rate of cancer related deaths in americans?

1 in 5 die from cancer.

Describe the processes involved in and give clinical examples of collateral tissue damage associated with inflammation.

1) Damage to tissue surrounding infectious agent that is difficult to destroy. 2) Cleaning of necrotic tissue via inflammation can cause damage 3) Auto immune. Inflammation directed against host.

True or False 1) Celecoxib affects COX 2 in Platelets and vascular endothelial cells 2) Low dose Aspirin affects COX 1 only in platelets

1) FALSE - Celecoxib only affects COX 2 in endothelial cells 2) TRUE

What are the top 5 causes of death in cancer patients?

1) Infection 2) Organ Failure 3) Thromboembolism 4) Hemorrhage 5) Emaciation

Discuss management strategies for patients with innate immune disorders.

1) Infection Anticipation 2) Surgery 3) Antibiotics 4) G-CSF -> more neutrophils 5) Cytokine therapy 6) Marrow/HSC transplantation 7) Gene therapy EXPANDED> 1) Anticipation of infection and aggressive attempts to define the causative agent. 2) Surgical procedures for infected sites may be both diagnostic and therapeutic. 3) Prompt initiation of broad spectrum antibiotics covering a wide range of organisms, switching to specific coverage when microbial diagnosis is known. 4) For severe quantitative disorders of neutrophils, G-CSF may be used at a dose of 3 μg/kg/day to resolve the neutropenia (review from previous lecture). 5) Specific syndromes of neutrophil dysfunction may benefit from prophylactic antibiotics or cytokine therapy (e.g., INFγ for CGD). 6) Transplantation with hematopoietic stem cells has the capability to reconstitute neutrophil numbers and/or function. 7) Gene therapy: proof of concept studies has demonstrated reconstitution. Specific problems need to be resolved before a practical solution is achieved.

Describe the potential outcomes for ACUTE inflammation

1) It resolves - Short lived injury -> minimal tissue dmg -> regeneration. Here the tissue returns to essentially normal functioning 2) Becomes Chronic - Offending agent not removed. Prolonged inflammation or result in scarring 3) Scarring - If significant tissue damage or inability to regenerate then connective tissue fills the void. Limits function.

What are the major etiologies of cell injury?

1) Physical agents - trauma, heat, etc. 2) Chemical and drugs 3) Infection 4) Immunologic insults - autoimmune... 5) Genetic derangement - PKU, CF, etc.. 6) Nutritional imbalance - atherosclerosis, protein and vitamin deficiency, etc. 7) Hypoxia

What are the systemic effects of inflammation (also called acute-phase reaction)?

1) Pyrexia 2) Increase serum conc of acute-phase proteins 3) Leukocytosis: Leuk up in blood 4) Tachycardia, hypertension, hypohidrosis, rigors, chills, anorexia, somnolence, malaise

Describe the steps of recognition, phagocytosis, and killing/degradation involved in intracellular leukocyte activity.

1) Recognition/attachment - Either via specific receptors on leukocyte or via opsonin receptor on leukocyte. 2) Engulfment and formation of vacuole - like it sounds. 3) Killing/degradation of vacuolated material - phagosome fuses with lysosome containing ROS and bleach-like oxidizing agents that kill the phagocytosed microbe.

What is the effect of MMPs on the basement membrane?

1) degrades basement membrane 2) causes release of growth factors (e.g. VEGF) from ECM-sequestered pools.

A T-cell must:

1. Not recognize "self", that is, not bind so firmly to a self structure (MHC alone, or MHC loaded with a "self" peptide) that the T cell becomes activated; this would be autoimmunity. 2. Not recognize free antigen (which is antibody's job). 3. Recognize antigenic peptide plus self MHC.

What percent of heavy smokers develop lung cancer?

10%

A titer for IgG of a solution is measured to be 79. To what factor can the solution be diluted to and still be effective in its immunological activity?

1:79 dilution. 1 part solution, 78 parts water (diluting fluid).

What is the new FDA limit for mg of acetaminophen present in a combo drug (acetaminophen/opioid)

325 mg

What is the max recommended dose for Acetaminophen? What is the major concern in toxicity? What is its effect when combined with alcohol?

4g a day max. Major Concern is Hepatotoxicity EtOH - induces CYP2E1 activity which produces more of the toxic metabolite to liver. (Also ethanol directly agonizes liver disease)

How many kinds of helper and killer T cells are there? What are their signature surface markers?

5 helper and 1 killer. Helper: CD4 Killer: CD8

What percent of all T cells are Treg cells?

5%

Describe the mechanism of action, major toxicities, and resistance mechanisms for Antimetabolites? Give an example of one

5-Fluorourcil - Pyrimidine analog. Inhibits DNA synthesis -> Apoptosis. Toxicity - GI, myelosupression. Resistance mechanisms - Alterations in target enzyme (Thymiditylate synthase)

At what dose does Aspirin begin to become toxic?

6g

Of the total amount of thymocytes in the thymus, how many will pass the test and get exported?

<2%

At what neutrophil absolute count range is an adult considered at severe risk for infection (sepsis, pneumonia, etc)?

<250 ANC/uL

What amount of malignant neoplasms are caused by environmental factors?

>80+

What medication would you want to administer to a newborn with a failure to close its Ductus Arteriosus?

A COX 2 inhibitor. Prostaglandins keep the ductus arteriosus open. Induced COX 2 activity up regulates the amount of prostaglandin (PGE2) that maintains the patent ductus arteriosus.

What is celecoxib?

A COX-2 selective NSAID

What is classified as an 'embolus'?

A FREE FLOATING, intravascular mass of a solid, liquid or gas Most emboli are detached thrombi, or fragments of thrombi, called thromboemboli Other types of emboli include fat, atherosclerotic debris, gas bubbles, bone marrow, tumor fragments, amniotic fluid or foreign material.

What is a CTL cell?

A Killer T Cell (Cytotoxic T cell)

What is an opsonin? What are examples of opsonizing factors?

A factor that signals phagocytic cells to phagocytose the host cell. Opsonizing factors: IgG, C3b (complement system), collectins.

What is Arachidonic Acid (AA)?

A fatty acid that is cleaved off of membrane phospholipids in cells. It is transformed into a number of compounds that mediate inflammation and hemostasis

What is a Treg cell? What is its function? What can a deficiency in these lead to?

A form of T cell that acts to suppress the function of all other T-helper cells. Deficiency in Treg cells leads to autoimmune disorders.

What is gangrenous necrosis?

A form of coagulative (ischemic, lack of blood supply) necrosis involving multiple tissue layers.

What is the difference between a lymphokine and a cytokine?

A lymphokine is a cytokine secreted by a lymphocyte.

What is a neutrophil extracellular trap? What is it composed of? What is its purpose?

A method for leukocytes (neutrophils) to trap/degrade EXTRAcellular microbes/material. Neutrophils eject their chromatin in a scaffolding formation with embedded antimicrobial compounds Provides concentrated area of antimicrobial material that traps microbes

What is omeprozole? What does it do?

A proton pump inhibitor Inhibits the H+/K+-ATPase system found at the secretory surface of gastric parietal cells. (no pumping H+ into gastric space).

What is atherosclerosis? What causes it?

A specific form of arteriosclerosis in which an artery wall thickens as a result of invasion and accumulation of white blood cells (WBCs) (foam cell) and proliferation of intimal smooth muscle cell creating a fibrofatty plaque. Caused by an initial lesion, damage, infection.

What is a quiescent cell? What is an example?

A stable cell type that is not actively proliferating but can if it needs to. Hepatocytes (liver cells). Different than non-dividing cells that can not proliferate if needed (e.g brain)

What is prednisone?

A synthetic glucocorticoid

What is granulomatous inflammation?

A type of chronic inflammation characterized by aggregated of activated macrophages ('granuloma')

Describe the biosynthetic pathways for production of prostaglandins, prostacyclin, thromboxane, and leukotrienes, including the specific enzymes involved.

AA made from membrane phospholipids via Phospholipase A2 AA converted into either: - Prostaglandins, prostacyclin and thromboxane using COX1, COX2 enzymes OR - Leukotrienes using 5-LOX

Immature T-cell is the thymus are only exposed to the 'self' produced by thymus cells. How then do these cells mature to know self from other parts of the body before their release?

AIRE genes - autoimmune regulator genes (AIRE genes) in thymic stromal cells cause these cells to make peptides that are from extra-thymic entities (liver, thyroid, adrenal, etc..) . This way the T-cells are exposed to them in advance of release.

On which cells is CD3?

ALL T cells.

Which MHC do T helper cells (T1, T2, T17) recognize? And T follicular helper cells? And Treg cells?

ALL are MHC 2

Describe the mechanism of anti cancer antibody agents. Give examples of these.

Ab - inhibit specific targets or signal immune system to kill certain targets (Ab binds tumor antigen) Rituxamib - Anti CD20 Trastuzumab/ Herceptin- Anti-Her2 breast cancer. Bevacizumab/Avastin- Anti-VEGF colon cancer

What does MC (mineralocorticoid) 'activity' relate to? How can this value be altered?

Ability to retain salt. Higher MC = Higher salt retention. Structural modifications to the GC molecule can inc/dec its MC ability.

What is hypohidrosis?

Abnormal sweat production in response to heat. Lack of sweat, unable to sweat normally.

Which should be avoided in hepatic dysfunction? Why? 1) Aspirin 2) Ibuprofen (Motrin, Advil) / Naproxen (Naprosyn, Aleve) 3) Celecoxib (Celebrex) 4) Acetaminophen (Tylenol)

Acetaminophen Metabolism of this causes a hepatotoxic metabolite. CYP2E1 (a CYP450 polymorphism) is involved in the metabolism of acetaminophen into a hepatotoxic metabolite.

Safest agent to treat musculoskeletal pain in patients with kidney dysfunction Aspirin Ibuprofen (Motrin, Advil) / Naproxen (Naprosyn, Aleve) Celecoxib (Celebrex) Acetaminophen (Tylenol)

Acetaminophen. Does not inhibit COX 1 or COX 2 in periphery.

What is the safest over-the-counter pain medication to recommend to patients with gastric ulcers 1) Aspirin 2) Ibuprofen (Motrin, Advil) / Naproxen (Naprosyn, Aleve) 3) Celecoxib (Celebrex) 4) Acetaminophen (Tylenol)

Acetaminophen. (Celecoxib works too, but its not OTC)

Safest agent for pain treatment in patients taking oral anticoagulants Aspirin Ibuprofen (Motrin, Advil) / Naproxen (Naprosyn, Aleve) Celecoxib (Celebrex) Acetaminophen (Tylenol)

Acetaminophen. No COX 2 inhibition in periphery. NOT Celecoxib because is pro-thrombotic, and if patient is on anti-coagulants, they are fighting platelet aggregation.

Where are acid and neutral proteases active?

Acid active at low pH: Lysosomes Neutral active at mid pH: Outside the cell (~7.4)

What is the role of the clotting factor XII in inflammation.

Activates the kinin system -> production of bradykinin -> increased vascular permeability, vascular dilation and pain

Which features are associated with chronic and acute DIC

Acute onset - Bleeding dominates Chronic - Thrombosis dominates

Describe the pathologic features of lung Adenocarcinoma along with associated mutations.

Adenocarcinoma - Cancer cells form primitive glands, production of mucin. Can form in areas of scars. K-Ras mutation.

What is the difference between an adenoma and an adenocarcinoma? What is the source tissue in these neoplasms?

Adenomas - benign Adenocarcinomas - malignant 'Adeno-' : Neoplasms of/from glandular tissues.

All of the following are strategies to minimize the development of HPA axis suppression with chronic corticosteroid therapy EXCEPT: Alternate-day administration of therapy Administration via topical or inhalation routes where possible Using the lowest dose of corticosteroid that adequately controls symptoms Administration of two-thirds of the daily dose in the morning and one-third in the late afternoon

Administration of two-thirds of the daily dose in the morning and one-third in the late afternoon

What is ACTH? What secretes it? What is its function?

Adrenocorticotropic hormone. Secreted by anterior pituitary Controls synthesis and secretion of glucocorticoids and androgens at the adrenal cortex.

The long-term administration of large doses of prednisone will cause the least reduction in the synthesis of which hormone? Cortisol Corticotropin (ACTH) Corticotropin-releasing hormone (CRF) Aldosterone Growth hormone

Aldosterone (cos is mineralocorticoid, controlled by renin-angiotensin system) Growth hormone ('can' be affected)

What are the metabolic effects of Cortisol?

All things that are related to stress and the need for fast energy (more glucose, food for krebs, ETC) See pic.

Define alloantigen

Alloantigen - an antigen present in some but not all individuals of the same species, as those in different human blood groups.

Explain the rationale for alternate day therapy and the necessity for tapered withdrawal following chronic therapy with glucocorticoids.

Alternate day - Still get inflammatory suppression while leaving the hypothalamus-pituitary-adrenal axis less suppressed. Tapered - When chronic administation, adrenal gland rendered weak, must taper off so adrenal gland can slowly re-strengthen.

What is a mitogen?

An antigen that binds and causes cells to non-specifically divide.

Relate the therapeutic uses of NSAIDs (analgesia, anti-inflammation) to their dosage. What constitutes high, low, and intermediate dosages?

Analgesia and Antipyretic - Intermediate Anti-Inflammatory - High (only IBU and ACET, not ASA) Anti Thrombogenesis - Low Low • Ibuprofen - not listed • Acetylsalicylic acid/Acetaminophen - 80-300mg/day Intermediate • Ibuprofen - 200-400 prn • Acetylsalicylic acid/Acetaminophen - 500 - 1000 mg prn High • Ibuprofen - up to 3200 mg/day • Acetylsalicylic acid/Acetaminophen - 3000 - 5000 mg/day

Give an example of a disease whose incidence is tightly linked to a particular HLA allele. Speculate on the mechanism which might explain the linkage.

Ankylosing spondylitis - autoimmune disease of the axial skeleton (insertions of tendons into bone, and fibrous joints of spine) with chronic inflammation. In severe cases vertebrae can fuse together. People that have the HLA-B27 allele are 90 times more likely to get it. The thought is that an antigen that resembles the HLA-B27 allele triggers immune response that cross-reacts with endogenous HLA-B27 (MHC I).

Discuss major treatment strategies including growth factors for treating neutropenia.

Antibiotics. G-CSF used to increase neutrophil production

What is an APC? What are three examples of these?

Antigen presenting cell. Macrophages, Dendritic cells, and B-Cells

What are the common causes of defective leukocyte function? What is the result of defective leukocyte function?

Aplastic Anemia - via chemotherapy Diabetes Genetic disorders - Chédiak-Higashi syndrome, phagosomes and lysosomes do not fuse.

Describe the two pathways (and their characteristics) that irreversible damage is resolved in cellular response

Apoptosis and Necrosis. See pic

Explain why cancer is much more common in the elderly compared to young adults.

Apparently this learning objective is really complex and is not answered directly by the materials we were given. If you know the answer please let me know. (and no, its not just due to collection of mutations over a life time, thats been disproven (right here at CU) as the sole cause)

What is fat necrosis?

Areas of fat destruction. Usually following lipase release from pancreas following acute pancreatic infection or trauma.

What vascular structure is the primary location of dilation involved in the increase of blood flow to capillary beds

Arterioles.

What is the difference in clinical presentations between carcinomas located in the ascending and descending colon?

Ascending - No symptoms till large size. Stool is still liquid here and can pass easily. Descending - constipation, obstruction. Stool is solid here, easy to block.

How long does aspirin's anti-platelet effect last? How long does other NSAID's effects on platelets last?

Aspirin: Remember inhibition in permanent, so aspirin's effects last as long as the lifetime of a platelet. 4-7 days Other NSAIDs: 2 days. Is reversible.

What is the most common cause of arterial thrombi?

Atherosclerosis. Thrombi form near or on top of atherosclerotic plaques. Can also form near gas bubbles. (Causes: injected or the bends)

What are some examples of immune mediated diseases characterized by chronic inflammation?

Auto immune - Chrons, Lupus Allergic - Asthma

What is neoplasia? What is its root cause?

Autonomous and progressive cell growth. Cause: Non-lethal genetic damage.

Fun question: Cells divide, then stop dividing after a certain amount of divisions (~50) thereby 'aging' the cells as they stick around in a non-proliferative fashion. This stage is called senescence, something that is largely avoided if you can turn on telomerase in a controlled fashion (among other things). No reason we can not simply regenerate all tissue continuously right? What is the proposed theoretical life span (avg and max) of a human if cellular senescence is avoided?

Avg: 1200 years old Max: 25,000 years old

Compare and contrast the antigen receptors of T and B cells

BOTH: have V(D)J regions, multiple chains, 3 per CDR regions per chain (alpha only has V and J, similar to light chain) DIFFERENT: TCR have 2 chains and Ab have 4, Transmembrane chains are not identical in TCR and are identical (H chains) in Ab.

What is shock? What can it cause?

BP or Blood volume not adequate to perfuse tissues. Leads to widespread cellular hypoxia, can lead to global cell death.

What do the TLR generally respond to? What do they activate?

Bacteria, virus', infections. Activate: TLR stimulated → transcription factors → mediators of inflammation and anti-microbial products

Describe the process of pyrexia induction starting with bacterial infection and ending at body temperature increase. Complete mechanism along with all factors involved.

Bacterial exogenous pyrogens such as lipopolysaccharide (LPS) induce leukocytes (macrophages) to make TNF and IL-1 which increase levels of cyclooxygenases that convert Arachidonic Acid into prostaglandins. In the hypothalamus the prostaglandins, especially PGE2, stimulate the production of neurotransmitters, which function to reset the temperature set point at a higher level. Exogenous pyrogen -> Endogenous pyrogen -> Inc Cyclooxygenase -> Inc prostaglandins -> inc neurotransmitters -> body set-temp increased.

What factors attract and activate neutrophils?

Bacterial products IL-8 C5a LTB4

How do you 'grade' neoplasms?

Based on the histologic grade of the neoplasm pertaining to differentiation of cells. - Low grade - more differentiation, and more like original tissue - High grade - Less differentiation, less like original tissue.

What are the four main groups of NSAIDs and their characteristics?

Based on: Selectivity: COX-1 or COX-2 Inhibition: Reversible or irreversible Aspirin is IRREVERSIBLE for BOTH (and the only irreversible) tNSAIDS are REVERSIBLE for BOTH Celecoxib -> COX 2 Acetaminophen -> COX 2 (CNS)

Why does scarring impair tissue function?

Because damage can not be repaired and normal tissue cells replaced by mostly collagen. Loss of function due to replacement of normal/functional cells with collagen. (Ex, Liver Cirrhosis)

Why do NSAIDs also result in undesirable side effects?

Because prostaglandins also mediate many other bodily functions.

Discuss how T cells selected to recognize "self + X" also recognize foreign MHC (allorecognition).

Because they have already been selected to recognize ONLY the endogenous MHC as the 'ok' MHC. The recognition of foreign MHC is a chance cross-reaction.

Why do CTL only see MHC 1 - antigen combos?

Because they need to monitor ALL cells for infection, not just Antigen presenting cells.

Why does Na+ reabsorption in the kidney (in left heart failure) cause an osmotic pressure DECREASE in peripheral blood ?

Because though the blood is gaining Na+/H2O, it is not reabsorbing anything else. Proteins in blood are therefore diluted and osmotic pressure drops (fluids leave vessels for tissues)

What is a leiomyoma?

Benign neoplasm of smooth muscle tissue.

What is the most common form of neoplasm?

Benign skin tumors. Basal cell carcinomas (yes, name implies malignancy/cancer but is considered benign due to its activity)

Benign neoplasms generally do NOT progress to malignancy. However, an important exception was noted here. What was it?

Benign, but premalignant neoplasms (eg: COLONIC ADENOMA)

Describe the gross features of benign and malignant neoplasms.

Benign: - Encapsulated, non invasive - No necrosis Malignant: - Invasive into adjacent tissue - Necrosis common

Describe the microscopic features of benign and malignant neoplasms.

Benign: - More differentiation - Low turnover, apoptosis/mitosis - Cells similar - Tumor/Surrounding tissue boundary maintained. Malignant: - Variable differentiation - High turnover, apoptosis/mitosis - Cells visibly not similar - Tumor/Surrounding tissue boundary destroyed, invasive

What is hemorrhage?

Blood outside the vasculature

Describe Toll-like receptors and the inflammasome and their role in inflammation.

Both are receptors that, once activated, mediate or promote inflammation and recruitment/activation of leukocytes. TLR: Inside and on the outside of cells. Recognize variety of material from microbes. Once active it activates transcription factors of proteins that mediate inflammation, interfere with action of infectious agents (interferons) and promote lymphocyte activation. Inflammasome: Recognize microbial material and debris from dead cells (e.g ATP). Activates caspase 1 which activates Interleukin 1B (IL-1B) which recruits leukocytes to come and clean up dead cells.

Distinguish Class I and Class II histocompatibility antigens

Both class I and class II antigens are glycoproteins composed of two polypeptide chains. Class I - consist of an allelically variable chain associated with an invariant chain called beta2-microglobulin. Class II - Consist of two chains both of which are variable.

Identify what histological feature defines "invasion."

Breaking through basement membrane.

What is the central compliment factor? List three pathways and their triggers that lead to the formation of this central factor.

C3 convertase 1 Classical: fixation of C1 to antigen-antibody complexes 2 Alternative: microbe cell wall components combine with plasma proteins (factors B, D) 3 Lectin: plasma lectin binds microbial mannose and stimulates classical pathway

What is the key factor in the complement system that leads to the formation of the membrane attack complex

C3 convertase: cleaves C3 into C3a and C3b. C3b binds C3 convertase to form C5 convertase which leads to the C5-C9 assembly of the MAC.

How is C5 convertase formed and what does it do?

C3b merges with C3 convertase to form C5 convertase, which initiates C5b-9 formation (the MAC)

Which factor of the compliment system plays a part in the chemotaxis of a leukocyte that has performed diapedesis and is in the extravascular space?

C5a - Chemotactic, especially for phagocytes and neutrophils

Which complement factors increase leukocyte endothelial adhesion

C5a, C4a, C3a

What is the function of CD4 and CD8 in cell activation? Where do they bind?

CD4 binds MHC 2 and CD8 binds MHC 1. They do NOT bind at the antigen-holding cleft of MHC but rather at the base of the MHC. CD4 and CD8 transduce activating signal but their primary mechanism is to greatly increase binding affinity between the T cell and target cell

What factor is involved in extravasation and how?

CD44, adhesion molecule (normally expressed by T-cells) cancer cells use this to increase adhesion to the epithelial wall prior to extravasation.

Which NSAIDs inhibit COX1? and COX2?

COX 1 - Aspirin and traditional NSAIDs (ibu, naproxen, etc.) COX 2 - ALL NSAIDs (though Acet inhibits COX 2 selectively in the CNS)

Compare COX 1 and COX 2 inhibitors regarding risk to kidney function

COX 1 inhibitor = COX 2 inhibitor Both are bad. Best to avoid NSAIDs with patients having kidney problems.

What is the primary difference between COX 1 and COX 2 expression?

COX 1 is always expressed to maintain baseline. COX 2 has induced activity.

What are the effects of prostaglandins on the Kidney?

COX 1 products (constitutive) • Inc Renal blood flow -> promotion of diuresis COX 2 products. (induced) • Adaptation to stresses via maintenance of RBF • Most critical in elderly - deteriorating renal function

What are the functions of CRP, Fibrinogen, and SAA?

CRP and SAA - adhere to cell walls and may act as opsonins. Fibrinogen - binds red blood cells causing them to form stacks that quickly form sediments

Which surface marker do CTL cells have and which MHC do they specifically recognize? And Th cells? Which part of the MCH do they bind?

CTL - CD8, MHC I Th - CD4, MHC II They bind the base of the MHC protein. (TCR bind the tips ('bowl' and antigen)

Describe the process of CTL activation

CTL activation requires direct contact with antigen-bearing DC and IL-2 (secreted by Th1 cells).

What two primary types of T cell emanate from the thymus?

CTL and Th0

What are the two classes of chemokines and their basic functions?

CXC and CC CXC: Chemotactic for neutrophils CC: Chemotactic for a variety of cells.

What is the surface marker for a Tfh cell? What dose this marker do?

CXCR5 It can be acquired by a Th1 or Th2 cell. It allows them to migrate to the follicle.

What is the function of IL-12?

CYTOKINE that pushes Th0 cells to differentiate into Th1 cells.

What are some of the non-genetic etiologies of cancer?

Cancer can be considered an infectious disease (viral origin, (e.g.. HPV -> Cervical cancer)

If cancer is a series of genetic mutations leading to uncontrolled proliferation, why do we treat it with drugs that induce more genetic mutations?

Cancer cells are closer to their apoptotic thresholds than normal cells. Increased genetic mutations signals cancerous cells to undergo apoptosis.

What is a carcinoma? and a Sarcoma?

Carcinoma - Cancer of the epithelium Sarcoma - Cancer of the messenchyme. (connective or non-epithelial tissue)

What are the most common classification of cancers in humans?

Carcinomas

Differentiate the pathophysiology of common causes of shock: cardiogenic, hypovolemic, septic

Cardiogenic • myocardial damage • extrinsic compression • outflow obstruction Hypovolemic • Severe dehydration (vomiting, diarrhea) • Hemorrhage • Burns Septic • microbial infection

What are cardiogenic, septic, and hypovolemic shock?

Cardiogenic - Heart not pumping enough blood Hypovolemic - Blood volume too low to perfuse tissues Septic - infection causes widespread inflammation (vasodilation, vascular leakage, venous pooling -> lowered BP and poor tissue perfusion)

Pyrexia: Blocking cyclooxyrgenase activity causes what?

Causes production of NO prostaglandins and therefore no stimulation to increase body temperature. This is how NSAIDS work.

Does the usage of Celebrex increase or decrease clotting risk? Does acetaminophen?

Celebrex = Celecoxib. Increase clotting risk. Is a COX 2 inhibitor in periphery. Blocks prostacyclin in periphery. Acetaminophen - Does not affect it. Not a COX 2 inhibitor in the periphery.

Identify the major alterations in the cell membrane, mitochondrion and nucleus that occur during reversible cell injury

Cell membrane - blebbing, blunting, distortion of microvilli Mito - Swelling Nucleus - condensing, clumping chromatin.

What is caseous necrosis?

Cells lysed and fragmented due to infectious agents. Seen in tuberculosis infection. The central portion of the infected tissue is necrotic (attributed to toxic effects of mycobacteria) with fragmented cells and amorphous debris surrounded by granulomatous inflammation. On gross examination the necrosis has a chalky white appearance, not unlike the milk protein casein.

What are the morphological changes associated with reversible cell injury? What causes each?

Cellular swelling - Failure of ATP-dependent pumps, loss of osmotic balance Fatty Change - Accumulation of fats due to loss of metabolism of such

Describe the term "left shift" and what it indicates.

Changes in WBC differential towards more immature precursors (Segs, Bands).

What are the structural characteristics of glucocorticoids? What structural feature differentiates an active GC from an inactive GC? How dose this relate to topical effectivity?

Cholesterol backbone Hydroxyl group at the 11 position. - Active Ketone group at 11 position - Inactive Keytone group signifies NOT topically active. OH group IS topically active.

During which stage of inflammation does tissue repair occur?

Chronic inflammation.

What are Hassall's corpuscles?

Circular elements in Thymus morphology located in the medulla. They are the hallmark of the Thymus.

Describe the mechanism of action, major toxicities, and resistance mechanisms for Cisplatin and analogues (platinum compounds)?

Cisplatin - DNA Damage -> Apoptosis. Cross link DNA Toxicity - Kidneys, damage to inner ear, nausea, myelosuppression. Resistance mechanisms - Inactivation via glutathione,

What is the source for Arachidonic Acid (AA)? What enzyme is involved in its production?

Cleaved from membrane phospholipids from cellular debris via enzymes in white blood cells. Phospholipase A2

Relative to ibuprofen (Advil), agents that preferentially inhibit COX-2 over COX-1 will cause a higher incidence of: Bleeding side effects Gastric irritation Clotting-related disorders Kidney dysfunction Inhibition of labor contractions

Clotting-related disorders (most important) Inhibition of labor contractions

How do tumor cells survive the sheer stress and loss of adhesion related apoptosis once in the circulation?

Clumping together. Also they can activate clotting factors that help them clump together, causing emboli.

Describe the role of Hageman factor in the coagulation system, complement system, fibrinolytic system and the kinin system and their respective contributions to inflammation

Coagulation - Activation of thrombin and factor Xa Complement - Cleavage and activation of C5 -> C5a and C3-> C3a Fibrinolytic - Clevage of C3 -> C3a Kinin - Activates Kinin cascade yielding bradykinin Inflammation: Coagulation - Increased vascular permeability, leukocyte migration, fibrin clots Complement - C3a and C5a Fibrinolytic - Vasodilaiton and inc vasc permeability via C3a Kinin - increased vascular permeability, arteriolar dilation, and bronchial smooth muscle contraction

What are the four major types of necrosis seen in human disease.

Coagulative Liquefactive Caseous Fat

What are the most commonly observed pathologies associated with the 4 forms of necrosis?

Coagulative - Myocardial infarction Liquefactive - Acute bacterial or fungal infection Caseous - Tuberculosis Fat - Pancreatic lipase release (pancreatitis)

What type of collagen is largely present in the basement membrane?

Collagen type IV

What enzyme must leukocytes secrete to perform diapedesis?

Collagenases - to eat away at the basement membrane material of the venules through which they are passing

Discuss the composition of a typical conjugate vaccine, and describe its mode of action.

Conjugate Vaccine - attachment of a poor polysaccharide immunogen to a carrier protein -> class switching of B-cells to IgG. The polysaccharide IS the immunogen. B-cells bind this and activate T-cell independent antibody response. But polysaccharide antibody response is 100% IgM as the B-cell, without the help of the Tfh cell, can not class switch its antibodies to IgG. IgM does not penetrate well into tissues and on its own does not provide good enough immune response to actual infection. B-cells must switch to IgG to have effective and lasting immune response. Binding the polysaccharide to a carrier protein that ITSELF activates Tfh cells causes the B-cells to have an immune response (polysaccharide) AND class which to IgG (carrier protein)

Which of the following corticosteroids can be used for dermatological applications? Cortisol Cortisone Prednisone Methylprednisolone Dexamethasone Triamcinolone

Cortisol Methylprednisolone Dexamethasone Triamcinolone All but the two with no topical value (they have to go through the liver)

What is the phenomena called by which dendritic cells present foreign antigen on both MHC 1 and 2?

Cross-presentation.

COX 1 and COX 2 convert AA into an extremely unstable intermediate. What is that intermediate called and what does it become?

Cyclic endoperoxide, PGH2 Becomes all other prostaglandins, prostacyclin, and Thrombxane made via the COX pathway (PGD2, PGE2, PGF2, PGI2 (prostacyclin), or TXA2)

List the two major pathways of arachidonic acid metabolism.

Cyclooxygenase and Lipoxygenase pathways. 1) Cyclooxygenase pathway results in prostaglandins and thromboxanes 2) Lipoxygenase, which results in leukotrienes and lipoxins

Describe the mechanism of action, major toxicities, and resistance mechanisms for Alkylating agents? Give an example of one

Cyclophosphamide - DNA damage -> Apoptosis. Forms adducts and cross-links between DNA strands Toxicity - Hematopoietic, GI, Gonadal, Alopecia, inc Leukemia and solid tumors (due to mutations?) Resistance mechanisms - DNA repair. NER, removal of crosslinks.

What induces COX 2 expression?

Cytokines: IL-1, IL-2, IFN-g, LPS

What are the morphological changes associated with irreversible cellular injury? What causes each?

Cytoplasmic changes - increased binding of eosin by denatured proteins. Nucleus - breakdown of DNA and chromatin. Pyknosis, Karryhorhexis, Karyolysis

With are the effects of prostaglandins on the GI?

Cytoprotective effects So: • Decrease acid and pepsin production • Inc mucous • Inc bicarb production

What are the general classes of anti-tumor agents?

DNA damaging agents Topoisomerase interacting agents Antimetabolites Microtubule interacting agents Hormonal agents Antibodies Kinase inhibitors Immune Checkpoint inhibitors

Overview of cancer drugs

DNA damaging agents, toposiomerase interacting agents, microtubule interacting agents, hormonal agents, antibodies, kinase inhibitors. Some resistance mechanisms generally applicable- e.g. drug efflux through transporters, resistance to apoptosis. Some resistance mechanisms specific to agent- e.g. mutations in drug target, activation of repair mechanisms, other ways to activate steroid receptors. Many drugs have similar toxicities- usually associated with damage to fast growing cells- GI toxicity, myelosuppression. Specific toxicities depend upon mechanism of action- e.g. neurotoxicity associated with microtubule-interacting agents.

What is the most common site of embolus? What type of embolus? What is the most common cause?

DVT, venous thrombosis, legs, stasis is most common cause.

What is coagulative necrosis?

Damage from ischemia. Cells die but infrastructure remains intact, cells are present but ghost-like pale remnants. Mode of damage in myocardial infarction.

What is liquefactive necrosis?

Damage that results in the liqueficaiton of cells due to digestion by leukocyte enzymes. Usually associated with focal bacterial or fungal infection.

What does the imflammasome generally respond to? What does it activate?

Dead or damaged cells. Activates caspase-1

How long can active tuberculosis remain dormant in the lungs? Is it still harmful? What is the mechanism?

Decades. Stays in walled off compartments produced by the immune system. Later in life an event (or just immune decline) can cause the TB to become active and harmful.

Define neutropenia and describe the clinical consequences of neutropenia.

Decrease in absolute neutrophil count in peripheral blood. Decreased neutrophil counts in periphery can signify myeloid issues in marrow. Consequences - delivery of neutrophils to infected tissues can be so diminished that balance of power shifts to the microbes.

Define: Atrophy

Decrease/shrinkage in the size and functional capacity of the cell

What are the two general classes of neutropenia?

Decreased production/marrow (diminished reserve) - Primary or secondary causes Increased turnover (normal reserve) - Usually secondary causes (Also idiopathic)

Characterize the types of infections you might expect to see with defects of phagocyte function or complement.

Deficient phagocytosis - bacterial and fungal. Infections due to unusual organisms. Infections of exceptional severity. Deficient complement - Bacteria that would be seen with Ab deficiency. (flu, pneumonia, fever related..). Nisseria.

What is the general purpose of BH3 profiling of cancer cells?

Determines the cancer cell's proximity to their own death/apoptotic threshold. Used prior to chemo to assay its potential efficacy.

What GC is the greatest suppressor of the ACTH secretion from the ant pituitary

Dexamethasone.

What is the name for the process of leukocyte transmigration across epithelial layer?

Diapedesis

Discuss the role of metastasis in death by cancer: what are the ultimate effects of metastasis?

Direct effect - masses interfere with normal organ/tissue function Indirect Effect - 'Paraneoplastic Syndromes' (Pic)

What are the hallmarks of neoplasia?

Disruption of normal homeostatic mechanisms Altered cell-autonomous mechanisms • Activation of oncogenes • Inactivation of tumor suppressors Cell-nonautonomous mechanisms • Altered microenvironment: surrounding tissue, including stroma, blood vessels, immune cells • Altered macroenvironment: Circulating cells (eg: immune cells) and factors (eg: hormones, cytokines)

Describe the mechanism of action, and major toxicities for Topoisomerase interacting agents? Give an example of one

Doxorubicin, Etoposide - Blocks topoisomerase, block re-ligation after DNA cleavage by topoisomerase -> Apoptosis. Toxicity - Myelosupression, Cardiotoxicitiy

What is primary chemotherapy?

Drug treatment, no surgery or radiation.

Which primary cadherins are up and down regulated in the EMT?

E-cadherin down N-cadherin up

What adhesion factor is down regulated in cancer cell invasion?

E-cadherin. Epithelial cells are held together by E-cadherin. Intracellularly, E-cadherins are connected to β-catenin and the actin cytoskeleton. In epithelial tumors, such as adenocarcinomas E-cadherin is often down-regulated, reducing the ability of cells to adhere to each other and facilitating detachment from the primary tumor and invasion into the surrounding tissues.

What are MC related side effects in steroidal treatment?

Edema Hypertension Hypokalemia Metabolic Acidosis.

What is the difference between edema and effusion?

Edema - Extravasation of fluid into TISSUES Effusion - Extravasation of fluid into SPACES

What is the difference between edema and inflammation?

Edema - fluid into tissues with NO coupled immune response (no repair, anti-infection, ....) Inflammation - Fluid into tissues WITH coupled immune activity. (Response to a biological or physical insult, resulting in redness and usually, swelling)

Which cells in the body are involved in neovascularization in tissue repair?

Endothelial.

Define eosinophilia, basophilia, and monocytosis, and point out major causes for each.

Eosinophilia - inc Eosinophils. Allergic disorders, parasitic infections, drug reactions Basophilia - Inc in Basophils. Food hypersensitivity, urticaria (hives), infection/inflammation, CML. Monocytosis - inc Monocytes. Hematologic malignancies, collagen vascular disease, granulomatous disease, infections, carcinoma.

What is the main chemokine for eosinophils?

Eotaxin.

What is the cellular origin of pancreatic cancer?

Epithelial cells within pancreatic ducts and ductules.

The loss of e-cadherin is a part of what cell transition?

Epithelial-to mesenchymal transition (EMT)

What cell type in the body is mosts commonly injured leading to disease?

Epithelium.

What does reaction with certain chemicals and CYP450 generate?

Epoxides. Highly reactive.

What is a test you can perform on RBCs to assay for the presence of inflammation?

Erythrocyte sedimentation rate (ESR) - a long-used test for the presence of inflammation. Tests for Rouleaux of RBC caused by up regulation of fibrinogen.

What does Barrett esophagus increase the risk of?

Esophageal neoplasia.

Give examples of metaplasia. What is Barrett esophagus?

Examples: 1) replacement of the ciliated columnar epithelium of the bronchus by squamous epithelium in response to injury from noxious chemicals in cigarette smoke; 2) replacement of the squamous epithelium in the distal esophagus by columnar intestinal epithelium in chronic reflux esophagitis (Barrett esophagus). Barrett Esophagus: Chronic acid reflux alters the cell type within the lining of the distal esophagus (right next to the stomach) (metaplasia: Stratified squamous -> simple columnar)

What are exudates and transudates? What causes each?

Exudate: a mass of cells, protein and fluid that has seeped out of blood vessels or an organ. Caused by permeability increase in vessel. Transudate: Filtered exudate (no cells or large proteins) usually resulting from increased intravascular pressure.

True or False CD4 and CD8 can bind MHCs without prior TCR binding.

FALSE

True or False Chronic inflammation must always be preceded by acute inflammation

FALSE

True or False Septic Shock is consistently responsive to IV fluids

FALSE

True or False There is no correlation between tumor size and likelihood of metastasis

FALSE

True or False Tissue regeneration can occur without an ECM

FALSE

True or False Increased blood flow to a tissue will always lead to an increase in edema or effusion

FALSE

True or False The alpha and beta chains of TCR have V, D and J regions

FALSE Alpha - V, J Beta - V, D, J

True or False Renal blood flow is only regulated by COX 1

FALSE COX 2 also regulates renal blood flow.

True or False Pregnant women near the time of delivery should be on a steady regimen of COX 2 inhibiting NSAID

FALSE COX 2 induction causes and induction in uterine smooth muscle activity (contractions). Blocking COX 2 blocks contractions.

True or False Exposing someone to a tumor promoter, halting administration, and then exposing them to a weak carcinogen generally results in tumors.

FALSE Carcinogen must come first. Tumor promoters only proliferate cells, carcinogens must first mutate them in order for them to be cancerous.

True or False Celecoxib can not cause GI issues

FALSE Celecoxib is 5-7 fold more selective for COX 2, but can still inhibit COX 1. High doses of Celecoxib impair GI function.

True or False The fluid in effusions is always Exudate and the fluid in Edema is always Transudate

FALSE Edema and effusion can be either transudate or exudate. They are different classifications.

True or False Pyrogens always act directly on the hypothalamus to induce pyrexia during the acute phase reaction

FALSE Exogenous pyrogens are known to act on endogenous-producing cells to stimulate their activity rather than acting on the hypothalamus themselves

True or False IL1, IL-2, and IL-17 are all lymphokines

FALSE IL-1 is secreted by M1 macrophages, NOT the lymphocyte.

True or False Recipients of organ transplants are normally started out on heavy immunosuppressants but those dosages are tapered to a halt over time.

FALSE Immunorejection is pretty much 'for life'. Tapering off suppressants results in rejection of the transplant.

True or False T-Cell receptor binds both the antigen and the plasma membrane of the antigen presenting cell in order to become active.

FALSE It binds (associates with) the antigen and the cell surface MCH molecule. T-cell does not activate unless antigen and MCH are present.

True or False Acetaminophen has anti-inflammatory therapeutic effects

FALSE It has no anti-inflammatory activity

True or False Epithelial to Mesenchymal transition (EMT) is only seen in cancer

FALSE It is a normal physiological process that is coopted by cancer cells.

True or False Metastatic cancer cells are highly efficient in colonizing distant tissues.

FALSE Millions of tumors cells shed daily from even small tumors and can be detected in the bloodstream and in small foci in the bone marrow, even in patients that never develop gross metastatic lesions.

True or False It is more important to get MHC I matched between donors (CTL activating) than MHC II matched (Th activation)

FALSE More important to get MHC II matched. If the donor and recipient are different at Class I but identical at Class II, there will be NO Th1 activated, no IL-2 will be generated, and so few CTL will be activated. In addition as MHC IIs are matched there will also be no Th/M1/inflammatory response.

True or False If a tumor is observed to be malignant, surgery is never attempted

FALSE Mostly yes (metastasis), but in cases where the malignant tumor is in situ, surgical resection can halt/slow progression.

True or False Macrophages and lymphocytes are the primary cellular infiltrate from the blood stream into the inflamed area in acute inflammation

FALSE NEUTROPHILS are the primary cellular infiltrate in ACUTE inflammation. Macrophages and lymphocytes are the primary infiltrate in CHRONIC inflammation.

True or False B and T cells must be present at the site of infection in order to have effect

FALSE Only T cells do.

True or False Benign neoplasms are also typically referred to as 'cancer'

FALSE Only malignant neoplasms are called 'cancer'. Benign are commonly called tumors ('swellings')

True or False Prostatic carcinomas usually cause problems voiding the bladder.

FALSE Prostatic carcinomas usually form on the periphery of the prostate and therefore do not affect the prostatic urethra. HOWEVER, benign prostatic hypertrophy (BPH) tends to enlarge the central, peri-urethral region of the gland, and often produces problems with voiding

True or False Upon antigen binding by TCR, signal is sent into the cell via TCR dimerization of the alpha and beta transmembrane domains.

FALSE Signal is not sent into the cell by TCR at all. It is sent into the cell by its associated CD3 proteins.

True or False B cells MUST interact with T cells to mount an Ab response

FALSE T-independent mechanisms allow B cells to mount Ab response without Tfh involvement.

True or False IL-2, INF-g and TNFa are all lymphokines

FALSE TNFa is secreted by the M1 macrophage (not a lymphocyte) so it is a cytokine. Lymphokines are a subclass of cytokines.

True or False The epitope that the B cell binds is always the same one that it shows to its specifically associated Tfh cell

FALSE They MUST be on the same antigen, but they are almost never the same epitope.

True or False Once cancerous, cancer cells stop changing and mutating.

FALSE They are always undergoing change. This is why they are difficult for targeted therapy.

True or False Patients with defective Th-1 cells bear macrophages (M1 Macrophages) incapable of phagocytosis of pathogens.

FALSE They are capable of phagocytosis, but they are not activated by the Th-1 cells and therefore do not KILL the foreign elements. This allows pathogens to remain entirely infectious and harmful.

True or False Complement proteins are produced largely in the liver and are all active upon release into the blood stream

FALSE They circulate as inactive precursors and are activated by proteases.

True or False The granules in neutrophils have uniform contents.

FALSE They have different constituents and function differently which includes tendency for extra- versus intra- cellular activity.

True or False Both Opioids and Acetaminophen develop tolerance in the patent requiring gradually increasing doses to achieve the same therapeutic effects

FALSE This is true for opioids, but not for acetaminophen. NO tolerance is built against Acetaminophen.

True or False Traditional NSAIDs, via their COX 1 inhibition, are anti platelet.

FALSE To be anti platelet, inhibition of COX 1 must be irreversible. ONLY aspirin is COX 1 irreversible inhibitor. (that we discussed).

True or False Chemotherapy is usually the administration of a single drug so that negative collective effects can be avoided. Explain why this is True or False

FALSE Usually 3+ drugs administered at the same time. Many tumor cells will acquire resistance to certain drugs. Administration of a single drug increases the chance that you will simply select (darwinian) for that resistant cell and proliferate it. Multiple drugs target heterogenous cancer cells simultaneously.

True or False Much is known about benign neoplasms.

FALSE We pretty much don't know @#$%.

True or False You can obtain the anti-inflammatory effects of GCs without getting the immune suppressive effects.

FALSE You can not separate AI effects from IS activity in GCs

True or False No cell can activate and load BOTH MHC 1 and MHC 2 receptors.

FALSE The dendritic cell can 'leak' some of the digested antigen (on its way to MHC2/surface via extrinsic pathway) to the ER where it is packaged and loaded onto MHC 1.

Identify the distinguishing features of and the clinical etiologies associated with granulomatous inflammation.

Features: large aggregates of macrophages around infectious agents, walling them off. Can lead to subsequent fibrosis if agent to hard to kill. Etiologies: 1) Persistent T cell response with subsequent activation signaling to macrophages. 2) Immune-mediated: Chrons. 3) Foreign material: sutures, etc... 4) Sarcoidosis: granulomas all over, mainly in lungs and associated lymph nodes.

What is pyrexia?

Fever. Raised body temperature.

What binds to erythrocytes and causes them to form stacks? What are these stacks called?

Fibrinogen Rouleaux

Which cells are responsible for Collagen deposition and Collagen remodeling / retraction?

Fibroblasts, Myofibroblasts (just in collagen deposition)

What is the process called by which connective tissue in scarring fills in an area of damaged or non-regenerative tissue?

Fibrosis.

What are the general components of the ECM?

Fibrous structural proteins (collagens, elastins) - tensile strength and recoil Water-hydrated gels (proteoglycans and hyaluronan) -resilience and lubrication Adhesive glycoproteins - connect the matrix elements to one another and to cells

A patient with Addison's disease is being treated with hydrocortisone (cortisol) but is still having problems with dehydration and hyponatremia. Which of the following drugs would be best to add to the patient's therapy? Dexamethasone Prednisone Prednisolone Fludrocortisone Triamcinolone Prior to receiving the new drug, what would be the status of the patient's blood potassium levels?

Fludrocortisone Because of higher salt retention factor (MC) Prior to receiving the new drug, what would be the status of the patient's blood potassium levels? Hyperkalemic - because Aldosterone (MC) basically trades K+ (out) for Na+ (in) a the collecting duct. Addisons -> MC is low -> K+ is high.

Adverse effects of pharmacologic doses unlikely to be seen with dexamethasone but possible with prednisone include: Secondary adrenal insufficiency resulting from block of pituitary ACTH release Hyperglycemia Fluid retention Osteoporosis with extended duration of use Hypokalemia Centripetal obesity Muscle wasting

Fluid retention - MC Hypokalemia - MC Due to prednisone's small amount of MC activity and dexamethasone's 0 MC activity. All other effects you would see with both.

Which T cells migrate into the cortex of the lymph node shortly following arrival of the antigen-presenting dendritic cells?

Follicular helper T cells (going into the follicle of the lymph node)

Describe the way in which memory cells develop and function to enact more rapid immune response to subsequent infection.

Following rapid antigen-triggered expansion of T cell populations the target T-cell population declines back to 5% of max value achieved. These are memory cells, which have some of the attributes of stem cells, in that they replace themselves, as well as rapidly differentiating into effector (helper, killer) cells when re-exposed to low antigen concentrations.

What factors are produced by Treg cells? Which of these are lymphokines and/or transcription factors?

Foxp3 - transcription factor TGFb - lymphokine IL-10 - lymphokine

What are the functions of NO in the body?

Free Radical Kill Microbes Vasodilation Anti platelet-activation (anti adhesion) Anti Leukocyte adhesion

How do you differentiate between G6PD and HS based using genetics?

G6PD is X-linked. You should only (mainly) see this in boys. HS should have a family history. (Splenectomies)

What effect can chronic administration of exogenous glucocorticoids have on adrenal function? How can this be a problem?

GC will indeed treat the inflammation but GC will also suppress ACTH release from the ant pituitary which leads to atrophy of adrenal gland and less cortisol production. Adrenal Crisis - Atrophied adrenal glands not strong enough to spike production of cortisol in times of stress. Shortfall.

For glucocorticoid agents used as anti-inflammatory and immunosuppressive drugs, compare and contrast their relative salt-retaining vs. anti-inflammatory activities vs. ACTH suppression and their routes of administration.

GC:MC ratios Cortisol - 1:1 Prednisone - 4:.3 Dexamethasone - 30:0 (Only GC activity) Aldosterone - .3:3000 (Almost all MC) Fludrocortisone - 10:250 (Has good GC with High salt retention)

What are COX 1 product's activities in: The GI Platelets Kidneys Vascular Smooth Muscle

GI: cytoprotective Platelets: Pro-platelet aggregatory effect Kidneys: Inc renal blood flow Vascular: Vasodilation (prostaglandins and prostacyclin), Vasoconstriction (Thromboxanes)

What is meant by 'grade' and 'stage' of cancer? What aspects are 'rated' in each?

GRADE: Degree of differentiation based on morphological appearance. - Low grade = highly differentiated, like original tissue - High grade = little differentiation, not like original tissue STAGE: extent of the tumor (T), lymph node involvement (N), and spread of the disease (M). (stage is 1-4 but has many factors involved in its number)

What is the major endogenous glucocorticoid? What is the major endogenous mineralocorticoid? What mineral does the mineralocorticoid control?

Glucocorticoid: Cortisol - a stress hormone Mineralocorticoid: Aldosterone ,Na+

What are the most powerful class of anti-inflammatory drugs that you can prescribe?

Glucocorticoids.

What are GC related side effects in steroidal treatment?

Glucose intolerance in diabetics Mood changes Insomnia GI upset.

What enzyme turns hydroxy radical into water?

Glutathione peroxidase.

Discuss the principles of Gleason grading of prostate cancer

Grade 1 is very well differentiated (lowest grade), and the neoplastic glands appear nice and round/uniform. Grade 5 indicates no gland formation (highest grade), and the tumor cells infiltrate as sheets and cords. In Gleason grading, the Gleason grade of the predominant pattern and the Gleason grade of the subordinate pattern are added together. Values of 8 to 10 indicate aggressive behavior.

A boy experiences a moderately severe reaction to a wasp sting. Which method of corticosteroid administration is appropriate for this patient? Continuous high dose therapy for several weeks Continuous low dose therapy for several weeks Gradually increasing doses over several days Gradually decreasing doses over several days Intermittent every-other-day therapy until symptoms resolve

Gradually decreasing doses over several days

Define and give a specific example of "granulation tissue" and its components.

Granulation tissue - The 'granular' looking tissue that forms under a scar. Comprised of fibroblasts, new capillaries (angiogenesis), loose extracellular matrix, and inflammatory cells (predominantly macrophages)

Tuberculosis causes which type of inflammation? And which type of necrosis?

Granulomatous Inflammation Caseous necrosis

What is dysplasia? What are low grade and high grade dysplasia?

Growth becomes disordered. (is not metaplasia. Dysplastic cells do not change their cell type) Dysplasia is a hallmark of early pre-malignant changes. (pic for grades)

What are HLA?

HLA -Human leukocyte Antigens. These are the genes (having various alleles) that code for the MHC I and MHC II receptors in cells.

What are the main HLA alleles/loci that you want to know about in transplantation?

HLA-A HLA-B HLA-DR

Between HLA-A and HLA-B and the HLA-D group: which associate with foreign antigens for recognition by helper T cells; which, in association with foreign antigens, are the targets for killer T cells

HLA-A and HLA-B make up MHC I receptors: These are on all nucleated cells and, when associated with foreign antigen are the target for Killer T-Cells HLA-D make up MHC II Receptors: These are on antigen presenting cells (Dendritic, B-Cells, Macrophages) and, when associated with foreign antigen, are the target for Th cells. So. A/B -> 1 -> Killer D -> 2 -> Helper

What is Addison's disease?

HYPOcorticolism - low glucocorticoid and mineralocorticoid production.

What is another name for factor XII?

Hageman factor

What is a double positive T-cell and why are there high concentrations of them in the thymus? What is their fate in the thymus?

Having BOTH CD4 and CD8. (CD4+/CD8+). This is an immature T-cell as it has not selected for one or the other yet. They will die in the thymus if they remain double positive.

What three organs are the primary culprits involved in fluid issues (edema, effusion)?

Heart, Kidney, Liver

Fluid from a pleural effusion is suspected to be an exudate. Which laboratory result would support this supposition? High fluid/serum protein ratio Low absolute protein Low fluid/serum LDH ratio Very few white blood cells

High fluid/serum protein ratio Its and EXUDATE.

What are the key mediators in vasodilation?

Histamine Bradykinin Prostaglandins Nitric Oxide

What factors induce E and P selectin on the apical side of endothelial cells? Which induces which?

Histamine -> P-Selectin IL-1 -> E-Selectin

What are two vasoactive amines we discussed involved in vasoregulation during inflammation? What are their source and function?

Histamine and Serotonin. HISTAMINE: Source: basophils, eosinophils, mast cells, and platelets. Granules loaded for quick release. Function: - Histamine: Arterial dilation and endothelial contraction (tumor) SEROTONIN Produced by platelets Function: - Serotonin: Vasoconstriction, assists in clotting

Describe the mechanism of hormonal agents. Give four examples of these.

Hormonal agents - treat hormonally responsive cancers (breast, prostate, endometrial) 1) Tamoxifen - Estrogen receptor inhibitor 2) Antiandrogen - Androgen receptor inhibitor 3) Aromatase inhibitors (letrozole) - Blocks aromatase which catalyzes synthesis of estrogen 4) Gonadotropin releasing hormone analogues (Leuprolide) - Inhibit testosterone production.

Give an example of a human and an animal antitoxin; a toxoid; a killed virus vaccine; and a live virus vaccine. Identify the one which produces the longest-lasting immunity. Discuss possible hazards of each type of preparation.

Human Antitoxin - Human tetanus immune globulin Animal Antitoxin - Animal derived tetanus antitoxin (issues with serum sickness if not from the same species) Toxoid - Tetanus toxoid, Diptheria Killed Virus Vaccine - Polio (Salk), Hep A Live Virus Vaccine - MMR, Varicella, RotaVirus, Polio (Sabin) Longest lasting immunity - Natural, active. Live preparations. Encountering the live antigen.

Compare the roles of cell-mediated and humoral immunity in virus infections with regards to: preventing the infection; controlling spread of viruses in the body; which is responsible for recovery from disease.

Humoral - Antibody (IgA) can be secreted on surface of mucous membranes. Can prevent initial colonization by the virus. If virus gets past this, circulating antibody (IgG) can stop the virus in circulation. Cell mediated - if there is no Ab present, T-cells (using their TLR receptors) can recognize viral RNA -> produce cytokines/chemokines that activate dendritic cells -> DC process free virus into peptides -> present on MHC II AND MHC I -> CTL cells activated to recognize these viral products showcased on the surface of all cells -> signal apoptosis in infected cells. Cell mediated is responsible for recovery from disease. Humoral is responsible for preventing infection in the first place.

What does O2- become via SOD reaction? What can that product become?

Hydrogen peroxide - H2O2 Can become hydroxyl radical (OH•) or hypochlorous radical (HOCl•).

What is Cushing's Disease? When is it Iatrogenic?

Hypercortisolism. Causes diabetes like state where muscles are wasting away. Extremities thin with fat abdomen and fat bump (buffalo hump) between shoulder blades. Iatrogenic when excess treatment with GCs causes symptoms.

Define and describe hyperemia and congestion

Hyperimia - Normal physiologic increase in blood flow due to arteriolar dilation. Congestion - pathologic accumulation of blood due to impaired outflow of venous blood.

A 16-year-old girl comes to the emergency department suffering from the effects of an aspirin overdose. Which of the following syndromes is this patent most likely to exhibit as a result of this drug overdose? Bone marrow suppression and possibly aplastic anemia Fever, hepatic dysfunction, and encephalopathy Hyperthermia, metabolic acidosis, and coma Rapid, fulminant hepatic failure Rash, interstitial nephritis, and renal failure

Hyperthermia, metabolic acidosis, and coma

What is the difference between a Hypertrophic scar and a Keloid scar?

Hypertrophic scar (regresses) Keloid (does not regress)

What are the 4 classic types of cellular adaptation to stress/injury/disease

Hypertrophy Hyperplasia Atrophy Metaplasia

Describe the regulation of glucocorticoid secretion by the hypothalamic-pituitary-adrenal gland axis.

Hypothalamus secretes corticotropin releasing factor (CRF) which signals anterior pituitary to release ACTH which signals adrenal gland to synthesize and release glucocorticoids (which can then negative feedback (when levels are sufficient) to hypothalamus and anterior pituitary signaling to halt CRF and ACTH production)

What type of shock is associated with a massive laceration causing blood loss.

Hypovolemic

What are the Important chronic inflammatory cytokines and their functions?

IFN-γ: Stimulates classical macrophage activation IL-12: Stimulate the growth and function of T cells

What cells in the body express MCH I and II?

II: Macrophages, Dendritic cells, B-cells I: All cells with a nucleus.

What factor is the cause of fever that accompanies inflammation? What secretes this factor? What is the mechanism of this factor's action to raise body temp?

IL-1 M1 macrophages. Stimulates formation of PGE2, which slows the firing rate of certain temperature-control neurons to what they would normally do at, say 35°C. This activates the heat generation response (e.g., shivering,) producing fever.

What factors induce NOS/NO production.

IL-1 TNF IFN-γ Bacterial endotoxins

What is the function of IL-10?

IL-10 - anti inflammatory cytokine. Secreted by Treg, so it opposes actions of other T helper cells (inflammation)

What primary lymphokine is secreted by Th17 and what is its function?

IL-17 - Pro-inflammatory response - Allergic reaction response - Induce production of many other cytokines.

Th1 cells also release another factor that influences other T-cells. What is it and what does it do?

IL-2. Assists in full activation of CTL (killer T) after they recognize antigen.

What lymphokines do Th2 cells make and what is their function?

IL-4, IL-5, and IL-13 They attract (chemotactic) and activate M2 macrophages. IL-4 is also chemotactic for eosinophils, which destroy parasites.

How can macrophages call in more neutrophils once they arrive on the scene of inflammation? (what factor)

IL-8

What is the safest NSAID for someone with GI problems? Why?

Ibuprofen (celecoxib is an option, naproxen is dangerous) Might want to use a PPI with this. Ibuprofen blocks COX 2 more than COX 1

What is a Reversible inhibitor of COX (cyclooxygenase) 1 and 2 1) Aspirin 2) Ibuprofen (Motrin, Advil) / Naproxen (Naprosyn, Aleve) 3) Celecoxib (Celebrex) 4) Acetaminophen (Tylenol)

Ibuprofen/Naproxen

What antibody is found in breast milk

IgA

Which antibody class is most effective at halting infection at the mucous membrane?

IgA, secreted there.

Which antibody class, activated via the Tfh pathway, activates Mast cells and is important in worm defense?

IgE Class switching of B cells to IgE aids in worm defense mounted by Th2 cells.

Allergic reactions involve which immunoglobin and which leukocyte?

IgE Eosinophils. Think AlergEEEEEE (Es) Some sources say basophils also involved.

What are the key opsonizing factors we discussed that when expressed on the surface of a cell signal it to be phagocytosed

IgG C3b

Discuss the use of IgG and IgM antibody titers in the diagnosis of intrauterine and neonatal infections.

IgG in an intrauterine baby is maternal. IgM in an intrauterine baby is fetal.

What is the characteristic Ab (class) response by a B cell to a carbohydrate? Why?

IgM B cell does not class switch its Ab. Owing to the binding nature of carbohydrates (binds many surface antibodies) it is not ingested, digested and presented to a T helper cell which is required for class switching.

Describe the mechanism of the extrinsic pathway utilized by antigen presenting cells

Immune cell ingests foreign entity -> Breaks it apart in lysosomes/endosomes -> pieces loaded onto membrane bound MHC proteins present in endosomes -> Taken to surface.

Define "local immunity" and give an example.

Immunologic response located to a certain area in the body. EX: oral polio vaccine causes strong immune reponse, so strong that people secrete IgA antibody to polio on their mucous membranes (the most common entry point for virus' into the human body). IgA acts locally at the mucous membranes to kill Polio virus before it can enter the body.

Where are the 'T0' or undecided T cells located?

In the paracortex of lymph nodes or other secondary lymphoid tissues.

What are some theories regarding why and how metastasis occurs? What "motivates" cancer cells in a primary tumor to metastasize?

In the primary tumor it becomes advantageous to move beyond basement membrane when conditions get crowded & harsh (hypoxia caused by limited blood supply and lack of nutrients). Then there is selective pressure to "move out" or metastasize (get away from the primary tumor site) Hypoxia/lack of nutrients seems to be primary cause.

What does an increase in Hepcidin implicate?

Inability to transfer iron across basolateral membrane of endothelium and also does not allow macrophages to export the iron it takes on during macrophage-mediated RBC destruction. Shuts down recycling. Iron largely held in stores (Ferritin up, TIBC down, Serum Fe down)

What are aldosterone's effects on the kidney? What happens when this is in excess?

Increase Na reabsorption in the collecting tubules -> inc blood volume -> Inc BP Excess: HTN, Hypo-K, Metabolic alkalosis.

Define: Hyperplasia

Increase in NUMBER of cells

Define: Hypertrophy

Increase in cell SIZE. Increases size of organ.

What are the effects of bradykinin?

Increased vascular permeability Vasodilation Pain

Why, aside from adhesion/rolling, do leukocytes slow down in the blood stream near areas of active inflammation?

Increased vessel permeability in areas of inflammation causes blood volume and speed of flow to decrease (stasis). This slows the leukocyte's movement.

What is the primary function of Th1 cells? And of Th17 cells?

Induce inflammation.

What is the most common cause of neutropenia? What are its mechanisms?

Infection. Usually acute, resolves in days or months. Multiple mechanisms (one or more) 1. Increased utilization 2. Complement mediated margination 3. Marrow suppression/failure, direct effect 4. Cytokine/chemokine induced margination 5. Antibody production

Identify the major stimuli for ACUTE inflammation.

Infections Bacteria, virus, fungus, parasites Also toxins from infectious organisms Inflam type/severity depends on organism Trauma Mechanical, thermal, chemical, nuclear Direct physical/chemical damages to cells In fact any thing that causes necrosis Foreign material Substance may directly stimulate inflam Associated stuff: microbes trauma, etc. Immune Reactions Host/environmental antigens cause inflam

What is steatosis?

Infiltration of liver cells with fat. Fat accumulation.

How does Acetaminophen compare to Ibuprofen in regards to Inflammation Analgesia Pyrexia

Inflammation - Acetaminophen is not anti-inflammatory Analgesia - Both work, Ibuprofen is bettter. Pyrexia - Same relative effect.

Which of the following actions of prostaglandins is INCORRECTLY matched with the form of the cyclooxygenase enzyme (COX-1 or COX-2) that synthesizes the particular prostaglandin? Fever : COX-2 Inflammation : COX-1 Protection of GI cells : COX-1 Vasodilation in the kidney : COX-2 Activation of platelet aggregation : COX-1 Contraction of uterine smooth muscle : COX-2 Opening of ductus arteriosus : COX-1

Inflammation : COX-1 Opening of ductus arteriosus : COX-1

What are some factors that cause COX 2 induction?

Inflammation, trauma

What are the functions of macrophages?

Ingest microbes and necrotic cellular debris (main phagocytes of adaptive immune system) Initiate tissue repair, often results in fibrosis (scar) Secrete inflammatory mediators (cytokines, eicosanoids) that promote inflammation

What is the specific function of Lipoxins?

Inhibit neutrophil chemotaxis and endothelial adhesion.

Which of the following is a pharmacologic effect of exogenous glucocorticoids? Increased muscle mass Hypoglycemia Inhibition of leukotriene synthesis Improved wound healing Increased excretion of salt and water

Inhibition of leukotriene synthesis

Recap: What is the function of Alpha 1-antitrypsin

Inhibits elastase, mainly active in the lungs. Deficiency in this causes emphysema.

What effect do glucocorticoids have on collagen synthesis/fibrosis?

Inhibits synthesis (via inhibiting TGF-b production)

What is the basic sequence of repair starting with injury and ending with either regeneration or scarring?

Injury -> Inc vascular dilation/permeability -> Acute Inflammation -> Chronic inflammation -> repair or fibrosis.

Name the key factors (Virchow's Triad) that are involved in thrombosis.

Injury to the endothelium Abnormal Blood flow Hypercoagulability

How are interns involved in invasion?

Integrins on BL side of epithelial cells attached to collagen. As that collagen is degraded (tumor proteases) epithelial cell loses integrin connection to collagen. Disconnected epithelial cells commit apoptosis.

Which factor activates M1 macrophages?

Interferon Gamma. (INFg)

What lymphokine is secreted by Th1 that causes an inflammatory response? What else does that lymphokine do?

Interferon-Gamma (INF-g) - (Causes inflammatory response) - Chemotactic to blood monocytes - Induces macrophages to become M1 'angry' macrophages

Which vessels are the blood supply for the thymus?

Internal thoracic and inferior thyroid

What are the two basic forms of ECM and what synthesizes each?

Interstitial matrix - Synthesized by mesenchymal cells Basement membrane - Synthesized by overlying epithelium and underlying mesenchyme

What is the process by which metastatic cells gain access to the circulation by penetrating the vascular basement membrane?

Intravasation

What is the difference between intrinsic and extrinsic pathway for antigen presentation by an APC? Which class of MCH does each use?

Intrinsic - the cell made the peptide itself. MCH 1. Extrinsic - the cell took in the peptide from external environment. MCH 2. Both pathways present antigen/peptide on surface.

What is the difference between invasion and metastasis?

Invasion - Malignant cells PUSHING into new territory Metastasis - the TRANSFER of malignant cells from the primary site to a non-connected (secondary) site.

What are the 4 main steps of the metastatic cascade? What factors (primary discussed) are associated with each?

Invasion -> E-cadherin, MMP, cytokines, Integrins Intravasation -> Extravasation -> CD44, chemokines Colonization

What is an in situ cancer?

Is malignant, but has not yet invaded other tissues (broken through basement membranes)

Define isografts, allografts, xenografts and autografts.

Isograft - Grafts between genetically identical individuals Allograft - Grafts between non identical members of the same species. Xenograft - Grafts between members of different species Autograft - graft from an individual back to the same individual (e.g. hair transplants, Skin relocation in burn victims)

What is the function of prostaglandins and thromboxanes?

It depends on the tissues from which they originate. Most prostaglandins are vasodilators. Prostaglandins also contribute to the pain and fever that accompany inflammation ThromboxaneA2 is a vaso constrictor.

Describe why Acetaminophen is not anti-inflammatory in the periphery but is an analgesic and antipyretic in the periphery.

It is not a COX 2 inhibitor in the periphery, only in the CNS. Therefore it does not block COX 2 action in the periphery (inflammation, pain, etc..). The analgesic and antipyretic effects are coming from its activity on blocking COX 2 in the CNS/hypothalamus. Analgesia here causes central desensitization of nervous system to pain. Pyrexic induction in CNS is systemic.

What is the Intermediate product of the kinin cascade that is chemotatic and activates Factor XII

Kallikrein

What NSAID, available only in Rx - IV/IM form, is especially hard on the GI? What is it used for?

Ketorolac - post operative pain.

The liver activates ketone bearing GC precursors into active factors. Which organ can inactive cortisol back to a ketone-bearing form? What are the names for active and inactive cortisol?

Kidneys. Active : cortisol Inactive: cortisone

What are the two possible fates for a Pre-T cell who which factors in the thymus bind very tightly (all CDRs bound tightly)

Kill its self Become T regulatory cell.

Describe the mechanism of anti cancer kinase inhibitors. Give examples of these.

Kinase inhibitors - block kinases that act in oncogenic, or anti-tumor suppressor pathways. (EX; CML due to Bcr-Abl active kinase) Imatinib (Gleevec) - blocks active site of Bcr-Abl Dasatinib - When gleevec fails (mutated Bcr-Abl active site) this works

Explain how neutrophil function is affected in the following disorders: leukocyte adhesion deficiency (LAD) I and II, actin dysfunction, specific granule deficiency, myeloperoxidase deficiency, Chediak-Higashi syndrome, and chronic granulomatous disease (CGD).

LAD I - Decreased adherence LAD II - Decreased rolling Actin dysfunction - Decreased chemotaxis, ingestion Granule deficiency - Decreased chemotaxis, microbicidal capacity Myeloperoxidase deficiency - Decreased ability to kill Candida, bacteria Chediak-Higashi syndrome - Giant granules, poor movement, microbicidal activity CGD - no ROS

What are the functions of the individual leukotrienes?

LTB4 is a chemotatic agent for neutrophils LTC4, LTD4, LTE4 cause vascular permeability and vasoconstriction

What are the three proliferative capacities of tissues? Define each

Labile - Continuous turnover from stem cells. Stable - Minimal replicative activity, but capable of proliferating in response to injury or loss of tissue mass Permanent - Terminally differentiated and nonproliferative

Give examples of labile, stable, and permanent tissue.

Labile - GI, Skin, Marrow, mucosa Stable - liver, kidney, pancreas; also endothelial cells, fibroblasts, smooth muscle cells Permanent - Neurons and Cardiac tissues

Describe the pathologic features of lung Large Cell Carcinoma

Large Cell - anaplastic appearing cells. Usually no keratin or mucin. High grade

Describe the aberrant hemodynamics involved in LEFT sided heart failure and relate them to edema of the lower extremities. Mechanism, areas of edema/effusion, organs involved.

Left heart not pumping well (injury, infarction, hyperplasia...) -> left ventricle not ejecting enough blood -> blood backs up in lungs (higher pulmonary BP) -> pulmonary edema and pleural effusions -> Low BP in aorta/periphery -> Kidney senses low BP, triggers uptake of Na+ (and therefore H2O) to increase blood volume -> Drop in osmotic pressure of blood -> Fluid leaves vessels as edema -> Starts at ankles and works its way up.

Describe leukocyte adhesion. Complete mechanism.

Leukocytes roll slowly along the vessel walls in areas of active inflammation. There they can become activated by chemokines. Once activated leukocyte Integrins are engaged and cluster together on the surface of the leukocyte. The integrins firmly bind ligands (which have also been increased in number) on the surface of the endothelial cells.

What are the sources for AA in the body?

Leukocytes, mast cells, endothelial cells, and platelets

Define leukocytosis and provide reasons for a high white blood cell count.

Leukocytosis - inc number of WBC over normal values. Reasons: infection, inflammation, non-specific physiologic stress, malignancy (leukemia)

What are the general functions of leukotrienes and lipoxins.

Leukotrienes - Mediate processes in inflammation Lipoxins - Antagonize Leukotrienes.

What cancer is prevalent in Africa that is relatively not prevalent in USA?

Liver cancer

Where does pancreatic cancer often metastasize to?

Liver.

What are specialized macrophages called that are: In the liver On the surface of bone In lymph Nodes In/on skin and mucosa In the CNS

Liver: Kupffer Cells Surface of Bone: Osteoclasts Lymph Nodes: Sinus Histiocytes In/on skin mucosa: Langerhan's Cell CNS: Microglia

List local factors and systemic factors that might adversely influence the repair/regeneration process.

Local: • Infection, persistence of insult, trauma (early movement prior to completion of repair), trauma (foreign material) Systemic: • Nutritional (impaired collagen synthesis): protein deficiency, vitamin C deficiency • Metabolic (delayed repair): diabetes, glucocorticoids (inhibit collagen synthesis) • Vascular, Ischemia: Thrombosis, Arteriosclerosis and atherosclerosis/diabetic change

What causes fat/marrow emboli?

Long bone fractures, most common cause.

What are the steps of invasion of the ECM by cancer cells? What is the primary factor involved in each step?

Loosening up of tumor cell-cell interactions - E-cadherin Degradation of ECM - Matrix Metal-proteases Attachment to ECM components - Integrin Migration of tumor cells (locomotion) - Cytokines, auto-endocrine mobility factors.

Why is low dose aspirin always prescribed to protect against secondary heart attacks and not always prescribed to prevent a first heart attack?

Low dose Aspirin is COX 1 selective. Aspirin causes increased GI bleeds due to blockage of COX 1 activity (loss of cytoprotectivity). In primary (precautionary) cases the benefits don't necessarily outweigh the risk. In secondary they are at a very high risk for another MI so the anti-platelet therapeutic effect of aspirin or coronary health outweighs the GI bleed risk.

The primary reason for developing drugs that selectively inhibit the COX-2 enzyme (e.g., celecoxib [Celebrex]) is to: 1) Decrease the risk of myocardial infarction 2) Improve anti-inflammatory effectiveness 3) Lower the risk of gastrointestinal toxicity associated with existing anti-inflammatory agents 4) Reduce the cost of treatment of rheumatoid arthritis 5) Selectively decrease levels of thromboxane A2

Lower the risk of gastrointestinal toxicity associated with existing anti-inflammatory agents

What are the 5+ year survival rates for the four main carcinomas?

Lung: 16% 5 yr survival Pancreas: < 5% 5 yr survival Colorectal: 65% 5 yr survival Prostate: 99% 5 yr survival

What are the differences in the blood flow between the thymus, lymph node and spleen?

Lymph node/thymus - RBCs to not leave the arterial or venous supply. In thymus is a barrier. high endothelial venule allows lymphocyte exchange. Spleen - RBC are able to leave the arteries within the spleen, leaving RBC in a 'free for all' zone full of macrpophages (RBC digestion)

TNM Scale: What does M0 mean? and M1?

M0 = no distant metastasis M1 = yes distant metastasis.

What TNM feature of stage IV cancer is found in no other stage?

M1 - distant metastases.

How do you avoid GC or MC side effects?

MC - Use specific drug with no MC GC - These side effects are unaviodable as all steroid inflammatory drugs have GC activity. Must manage this with dosing.

Via which pathway are antigens presented that are bound to MHC I? And for MHC II?

MHC 2 - Extrinsic, so only antigens that are ingested. MHC 1 - Intrinsic, so ALL peptides made by cell.

Which cells have MHC I? And MHC II?

MHC I - all cells with a nucleus MHC II - Antigen presenting cells (Dendritic cells, macrophages, B cells (and some others))

What are CTL programmed to see, antigen-MHC I or antigen-MHC II? And via which pathway (intrinsic/extrinsic) did this antigen come to be presented?

MHC I presented via intrinsic pathway.

A person with a virus activates an immune response that targets certain cells int he body. A different person's cells, infected withe the SAME virus are infected into the first person, those cells are not targeted by the immune system. What is this an example of? What is its mechanism?

MHC restriction. T cells do not see antigen alone. Only antigen presented in an MHC (which are specific per person). This means that the T-cell is tailored to the MHC/Antigen combo and any deviation from that combo elicits no T-cell response.

What are the three most common types of cancer (other than skin cancer) among men and women (incidence), and the three leading types responsible for cancer mortality for men and women (mortality) in the United States.

MOST COMMON Men: 1) Prostate (Number 2 in mortality) 2) Lung/bronchus (Number 1 in mortality) 3) Colon/rectum (number 3 in both incidence/mortality) Women 1) Breast (Number 2 in mortality) 2) Lung/Bronchus (number 1 in mortality) 3) Colon/Rectum (number 3 in both incidence/mortality) Basically (regardless of sex) number 1 in mortality is lung number 3 is colon And number 2 is related to sex organs (prostate, breast)

Which class of NSAID has the most widespread side effects? Which has the least? Why?

MOST: Aspirin and tNSAIDs. Block COX 1 AND 2. LEAST: Acetaminophen. Only blocks COX 2 in CNS.

What makes NO? From what?

Made by the enzyme nitric oxide synthase (NOS) from L-arginine

What are three proteins that can be measured clinically that are used to detect and monitor the presence of inflammation? Where are they made? What stimulates their production?

Made in the Liver: Liver stimulated by the cytokine IL-6 to make... C-reactive protein (CRP) Fibrinogen Serum amyloid A (SAA) Protein

Discuss TNM relationship to clinical outcome.

Main features (survival at 5 years): Stage I = 93% survival Stage III = Varied based on T and N value. N2 = very bad. Stage IV = 5% survival.

Which cells secrete growth factors in tissue repair?

Mainly macrophages but also Lymphocytes and stream cells

Diagram the major causes and differentiate the major acquired or congenital/genetic disorders of neutropenia.

Major Acquired Causes: - Infection - Viral - Drug-induced - Chemotherapy - Nutritional deficiency - Folate, B12, Copper, protein/calorie malnutrition. Congenital - Kostmann Syndrome - Decreased myeloid production - Schwann-Diamond Syndrome - apoptosis of precursors and defects in 'nurse' cells helping myeloid development.

What is the cellular origin of a carcinoma?

Malignant stem cell - acquires oncogenes, loses tumor suppressor genes, develops genome instability, and/or loses the ability to undergo apoptosis

What are the four main phases of leukocyte recruitment in inflammation?

Margination/rolling Adhesion Transmigration Chemotaxis

What family of enzymes is responsible for the degradation of collagens and other ECM components?

Matrix Metalloproteinases (MMPs)

What other type of cell can CTL become? What factor signals this change?

Memory cells IL-21

What gets damaged by reactive oxygen species?

Microbes and host tissues

What are M cells? What is their function?

Microfold Cells - found in association with Peyer's Patches (MALT). They transport organisms and particles from the gut lumen to immune cells across the epithelial barrier.

Which of the following is the primary clinical advantage of the alternate day glucocorticoid regimen? 1) Can be used to directly stimulate growth if used in children 2) Can be used to treat patients who require elevated and sustained immunosuppression 3) Can be used to withdraw patients from chronic glucocorticoid treatment by systematically lowering dosage 4) Minimizes glucocorticoid block of ACTH release which can significantly reduce adrenal atrophy 5) Allows satisfactory replacement of cortisol in the treatment of Addison's disease

Minimizes glucocorticoid block of ACTH release which can significantly reduce adrenal atrophy

Describe the one-way mixed leukocyte reaction (MLR) and discuss its use.

Mixed Leukocyte Reaction - A way to test potential for transplant before doing it. Take WBC from donor and recipient. Mix together. Th of one person (looking for class II) will see class II on monocyte of other person and activate/proliferate -> release cytokines. The question is "how strongly will the recipient's Th cells recognize the donor's MHC II". We dont care about the donor's reaction to the recipient. This is the 'one way' part. We only care about the recipient's reaction. You may line up 50 one way MLRs and you are of course looking for the LEAST amount of lymphocyte activation/reaction to donor WBC/tissue. MLR that has little to no lymphocyte activation is best bet for donor.

What circulating cell gives rise to macrophages?

Monocytes. Give rise to macrophages in tissues.

Basophils: Morphological features Production Distribution Turnover Primary roles

Morphological features - bilobed nucleus, but very dark granules, shroud nucleus Production - in marrow, under influence of IL-3 Distribution - Turnover - Primary roles - hypersensitivity reactions. Allergies.

Eosinophils: Morphological features Production Distribution Turnover Primary roles

Morphological features - bilobed nucleus, darker granules Production - in marrow under influence of IL-5 Distribution - peripheral blood -> external surfaces . Turnover - survive for weeks. Primary roles - allergies, parasites

Neutrophils: Morphological features Production Distribution Turnover Primary role

Morphological features - multi lobed nucleus, pale granules. Production - in marrow, storage pool for host defense Distribution - tissues, non-specific defense against microbes. Turnover - 1-2 days. Primary role - non-specific defense

What are some of the ultimate causes of mortality due to cancer?

Mostly infection.

We eat about 1g of mutagens a day. What is the difference between a mutagen and a carcinogen?

Mutagen - any substance that mutates genetic material Carcinogen - Mutagens that cause cancer.

What is used to treat acetaminophen hepatotoxicity? What is its mechanism?

N-Acetylcystiene Pic for mechanism

TNM Scale: What does N1 mean? and N2?

N0 = no regional lymph node metastasis. N1 = Metastasis into 1-3 regional lymph nodes N2 = Metastasis into 4+ regional lymph nodes.

Why do NSAIDS cause GI issues?

NSAIDS block COX 1 which is cytoprotective of the GI tract. Cytoprotective: making bicarbonate and mucous while decreasing pepsin and acid production.

Explain the total effects of NSAIDs on the kidneys and the systemic effects that can result.

NSAIDs block COX 1 and 2 (inc vasodilation and diuresis in kidneys) which causes fluid retention in the body leading to: • Inc BP • Exacerbation of heart failure • Interfere with cardioprotective effect of aspirin.

What are non-narcotic (non-opiate) analgesics?

NSAIDs. Just another name.

What enzyme in the AA metabolic pathway is blocked by NSAIDS? And what enzyme is blocked by Glucocorticoids? What results?

NSAIDs: Block cyclooxyrgenase. Yields no Prostaglandins or Thromboxanes Glucocorticoids: Block PhospholipaseA2, which shuts down all AA metabolism.

What is the safest NSAID for someone with cardiovascular problems? Why?

Naproxen (high IB or Celecoxib are dangerous) Naproxen inhibits COX 1 more than COX 2

A 64-year-old male presents with mild to moderate musculoskeletal back pain after playing golf. He states he has tried acetaminophen and that it did not help. His past medical history includes diabetes, hypertension, hyperlipidemia, gastric ulcer (resolved), coronary artery disease. Which of the following is the most appropriate NSAID regimen to treat this patient's pain? Celecoxib Ketorolac and omeprazole Naproxen and omeprazole Naproxen Ibuprofen

Naproxen and omeprazole CV concerns outweighing GI concerns as those can be treated with a PPI. Choosing between ketorolac and naproxen, go with one having less detriment to GI as he has history of PUD. Ketorolac is the WORST for GI.

What are natural active, natural passive, artificial active, artificial passive immunity? Give examples of each

Natural active - Real life exposure to antigen, make your own immune response. long-lasting Natural Passive - Someone else made immune response. EX: Fetus gets IgG immunity from mom. Nursing gives kids IgA Artificial Active - Intentional immunization with vaccines, toxoids, antigenic preparations. Triggers immune response by host. EX: Live attenuated viral vaccines Artificial Passive - Direct administration of immune serum or purified antibodies. Bypasses activation of host immune system. EX: rattlesnake antivenom.

What are the irreversible forms of cellular injury?

Necrosis and Apoptosis.

Describe negative repertoire selection in the thymus

Negative: TCR that binds very tightly to self antigen and self MHC (strong enough to engage ALL CDRs and activate cell) -> either apoptosis or become Treg due to their ability to recognize self.

What is the difference between neovascularization and angiogenesis?

Neo - new vessels de novo (from nothing) Angiogenesis - New vessels sprouted off of previously formed ones.

As a general rule, what type of infection do increases in the following leukocytes implicate? Neutrophils Lymphocytes Eosinophils

Neutrophils - bacterial infection Lymphocytes - Viral infection Eosinophils - parasitic infection (Or Asthma/allergen)

What cell types are primary producers of reactive oxygen species?

Neutrophils and Macrophages.

Terminal complement deficiencies (C5-C9) have problems killing what specific class of organisms?

Nisseria. (meningitis and gonorrhea causing bacteria)

What are the main processes of chronic inflammation and in what order do they occur?

No specific order. Unlike acute inf, Chronic inf events can happen simultaneously. Influx of mononuclear cells - (lymphocytes, plasma cells, monocytes/macrophages) Tissue destruction Repair - includes neovascuslarization and fibrois

Describe non-selection repertoire selection in the thymus

Non-selection: TCR generation is random. So most TCR will not bind most MHCs and will not become activated to proceed to maturity.

What is the relationship of fat to normal and excess levels of cortisol? Why is fat shifted from periphery to trunk when cortisol in excess?

Normal cortisol: Fat breakdown to use for energy (mainly peripheral fat) Excess cortisol: Causes glucose to go up which causes insulin to go up. Insulin shuts down lipolysis so high insulin shuts down the breakdown of fat and up regulates the storage of glucose into fat tissue (causing the fatty tissue to grow) Fat Trunk: Cortisol and Insulin are directly opposing mechanisms on fat. In periphery Cortisol wins and in trunk area insulin wins.

Define and describe normal scar formation and pathologic scar formation:

Normal scar: angiogenesis -> granulation tissue -> maturation and reorganization of fibrous tissue (remodeling) -> stable fibrous scar - Initial Scar: Collagen type III - Scar remodeling: Collagen type I Pathologic Scar: accumulation of excessive amounts of collagen - Hypertrophic scar: outside boundaries of injury. Regresses - Keloid: outside boundaries of injury. Persists

When are leukocytes 'active'?

Not until they encounter certain (usually pathological) substances (microbial products, cellular debris, chemical signals...)

When does scarring occur? What general process occurs?

Occurs when repair can not be accomplished by regeneration alone. Occurs via replacement of non-regenerated cells with connective tissue leading to formation of scar, or by combination of regeneration of some cells and scar formation

Describe the functional interaction of prostacyclin and thromboxane A2 with relation to physiologic effects on vascular smooth muscle and platelets.

Opposing actions. Prostacyclin -> dec platelet clotting, vasodilation Thrombaxane A2 -> inc platelet clotting, Vaso constriction.

Which of these are benign or malignant: Osteoadenoma Firbocarcinoma Leiomyoma Fibroadenoma Leiomyosarcoma Fibroadenoma Lymphoma Leukemia

Osteoadenoma - benign Firbocarcinoma - malignant Leiomyoma - benign Fibroadenocarcinoma - malignant Leiomyosarcoma - malignant Fibroadenoma - benign Lymphoma - Malignant Leukemia - Malignant Again, looking for -sarcoma, -carcinoma in most cases.

What is the primary prostaglandin involved in pyrexia during the acute-phase reaction? What does it do?

PGE2 Stimulates the production of neurotransmitters that act on the hypothalamus to reset the body set-temp.

What mitogen binds CD3 and causes all T cells to divide? What is its clinical usefulness?

PHA - phytohemagglutinin Can be good to induce mitosis for karyotyping WBC.

What overall physiological mechanisms are regulated by either by COX1 and COX 2

PIC COX 1 - considered all 'good' things COX 2 - has some bad things, fever, pain, inflammation. COX 2 is the target of NSAIDS.

What are COX 2 product's activities in: (When COX2 is activated) Endothelial Cells Uterine Smooth Muscle Kidneys Ductus Arteriosus What causes each of these COX 2 activations?

PIC Kidney - always unregulated Endothelial Cells - Upregulated by shear stress Uterine Smooth Muscle - Induced when in labor Ductus Arteriosus - Induced when fetus needs ductus arteriosus.

What are parenchymal and stromal cells?

Parenchymal cells are the FUNCTIONAL cells in an organ/tissue and stromal cells are the STRUCTURAL cells (mainly connective tissue)

Describe the pathologic and clinical features of colorectal carcinoma and the germline mutations and other disease states that increase the risk for colorectal carcinoma.

Pathologic features - Nearly all arise in pre-existing adenomatous polyps. Clinical features - constipation, abdominal pain, blood/mucous in stool, anemia. Risks - polyp >3cm, ulcerative colitis, alcohol consumption, diet rich in animal meat and fat, obesity.

Describe the pathologic features of pancreatic carcinoma, risk factors, prognosis, and treatment options

Pathologic features - back pain, jaundice, cachexia, migratory thrombophlebitis Risk Factors - age, smoking, chronic pancreatitis (EtOH), Diabetes, family history Prognosis - horrible, <5% live 5yrs after diagnosis. Treatment - Whipple procedure

What is Acetaminophen's niche?

People that respond very poorly to other NSAIDs (too many side effects), Wanting to control fever and mild to moderate pain, with no inflammatory problem.

What is a neuropeptide? What is their function in inflammation?

Peptides used by neurons to communicate with each other. • Can initiate inflammation • Particularly active in vascular tone and permeability • These are particularly active in Lung and GI

Acetaminophen is an efficacious analgesic and antipyretic agent, but differs from NSAIDs in that it has no anti-inflammatory action. Which of the following reasons explains this unique aspect of acetaminophen? The distribution of acetaminophen does not reach peripheral sites of inflammation Acetaminophen is not an inhibitor of the COX enzyme Peroxide formation at sites of inflammation inhibits the activity of acetaminophen Anti-inflammatory doses of acetaminophen are too high and toxic Acetaminophen undergoes significant first-pass metabolism

Peroxide formation at sites of inflammation inhibits the activity of acetaminophen In the CNS there is not this peroxide formation formed in inflammation such as in the periphery

What settings induce chronic inflammation?

Persistent infections Immune-mediated disease (auto immune or allergic) Prolonged exposure to toxins.

What do activated leukocytes do?

Phagocytize materials Kill/degrade engulfed material Secrete material to kill/degrade Produce inflammatory mediators (amplifies inflammatory process)

What enzyme is directly inhibited by GCs?

Phospholipase A2

Name stimuli that cause mast cells to release histamine.

Physical features - Mechanical, temperature Immune - Binding of IgE (allergic response) Compliment (C3a, C5a) Histamine releasing proteins (from leukocytes) Neuropeptides Cytokines (IL-1, IL-8)

What is the principle of margination with larger cells in vessels?

Physics. In laminar flow larger, slower moving cells are pushed to the walls of the vessel by smaller faster moving cells more towards center of vessel.

Define and give examples of pathologic and physiologic hypertrophy

Physiologic hypertrophy = normal increase in cell size. Uterus during pregnancy Pathologic hypertrophy = abnormal or disease related increase in cell size. left ventricular hypertrophy due to hypertension

Give examples of pathologic and physiologic atrophy

Physiologic: loss of hormone stimulation in menopause Pathologic: Denervation (Alzheimer) or diminished blood supply

Give examples of pathologic and physiologic hyperplasia

Physiologic: proliferation of glandular epithelium of female breast during puberty or pregnancy Pathologic: Endometrial hyperplasia in abnormal menstrual bleeding

What organ/tissue protects the fetus from GC if the mother is to be treated with GC? How?

Placenta Contains the same enzyme as the kidneys (11b-HSD2) in an adult that turns active GC back into inactive GC.

What are cytokines?

Polypeptides that function as mediators in both innate and adaptive immune system

Describe positive repertoire selection in the thymus

Positive: TCR's (t-cells) selected to bind self-MHC strongly but self peptide not at all. This way in periphery they will bind with high affinity for self-MHC + some foreign peptide. Tailored to bind self-MHC strongly.

Recognize the features of disseminated intravascular coagulation (DIC)

Presentation - Affects many organs. Can cause clotting and bleeding anywhere (petechiae, purpura)

What are the clinical presentation, and the screening methods to detect prostate cancer?

Presentation - trouble getting erection, problems urinating, blood in urine. Detection/diagnosis - • Serum prostate specific antigen (PSA) (>4ng/ml) - though not used much anymore as high PSA does not necessarily mean prostate cancer. • Digital rectal exam - Ultrasound, digital guided biopsies.

What are the primary and secondary lymph organs/tissues?

Primary - Marrow and thymus Secondary - lymph nodes, tonsils, spleen, Peyer's patches and mucosa associated lymphoid tissue (MALT)

Contrast and compare differences and purposes of different kinds of chemotherapy - adjuvant, neoadjuvant, and primary chemotherapy.

Primary - May be curative. Also used for advanced cases with no alternative treatment. Goal is to palliate symptoms, improve length of survival Neoadjuvant - Used prior to surgery or radiation, goal is to increase surgery/radiation efficacy. Adjuvant - Used after surgery/radiation, Goal is to limit local/systemic recurrence.

The balance between which two COX 1/2 products mediates platelet aggregation (clotting)?

Prostacyclin (PGI2) and Thromboxane (TXA2) PGI2 - Anti-aggregatory (endothelial cells) TXA2 - Pro-aggregatory (platelets themselves)

What is produced in endothelial cells via COX 2 activity? What are its effects? What NSAID blocks this specific pathway? What its this NSAIDs mechanism?

Prostacyclin PGI2 • Vasodilation • Anti-aggretory platelet effects. Celecoxib blocks COX 2 activity thereby halting PGI2 production in endothelial cells causing clotting disorders.

What metabolites arise from AA metabolism?

Prostaglandins Thromboxanes Leukotrtienes Lipoxins

How does the body protect against endogenous proteases?

Protease inhibitors - Alpha-1-antitrypsin: neutrophil elastase inhibitor - Alpha-2-Macroglobulin: inhibits a large variety of proteinases (e.g. collagenase)

Which nutritional deficiencies can impair collagen synthesis?

Protein deficiency Vitamin C deficiency (Scurvy) (required to make hydroxyproline, a vital component of collagen)

What are growth factors?

Proteins that stimulate the survival and proliferation of particular cells, and may also promote migration, differentiation, and other cellular responses

What are pyknosis, karyorrhexis, and karyolysis?

Pyknosis - chromatin shrinkage, condensation Karyorrhexis - chromatin fragments Karyolysis - dissolution of nucleus, break down of chromatin.

What are the nuclear changes associated with irreversible injury and in what sequence do they occur?

Pyknosis -> Karryhorhexis -> Karyolysis See pic

What causes pyrexia in the acute phase reaction?

Pyrogens (endogenous or exogenous) act on cells in hypothalamus vasculature, inducing them to make prostaglandins which stimulate production of neurotransmitters that act to reset the 'temperature set point' to a higher level.

Describe the process of repair with respect to the epithelium (i.e., re-epithelialization) and organs such as the liver (i.e., regeneration).

Re-epithelialization - Cells rapidly replaced by proliferation of residual cells (provided that the underlying basement membrane is intact) Regeneration - Organ systems: Liver: Triggered by cytokines and growth factors in response to loss of liver mass and/or inflammation. May occur by proliferation of surviving hepatocytes and/or repopulation from progenitor cells.

Define and describe hyperacute graft rejection.

Recipient has PREEXISTING anti-body (IgG, IgM) Against donor tissue (either Ab against tissue due to prior graft/transfusion, or due to ABO blood group mismatch) . Ab immediately binds to endothelial cells of organ blood vessels -> complement activated -> vasospasm results -> organ may never even receive blood ('white graft')

Contrast the gross morphology and pathophysiologic differences of red and white infarcts.

Red - Venous occlusion in loose tissues. Occurs in organs receiving dual blood flow. Hemorrhagic damage. White - Arterial blockage in dense tissues. Occurs in organs having singular blood source. anemic/hypoxic damage.

What is the role of the ECM in tissue repair?

Regulates proliferation, movement and differentiation of cells Provides substrate/scaffolding for cell adhesion and migration (stromal scaffolding) Serves as reservoir for growth factors

What triggers more leukocyte release from the marrow in acute-response leukocytosis? What triggers more production?

Release: TNF and IL-1 Production: Colony stimulating factors (CSF)

Which GCs would you want to use for: Replacement therapy Steroid burst therapy Minimal MC activity Most potent anti-inflammatory Good topical -> systemic

Replacement therapy - cortisol (hydrocortisone) Steroid burst therapy - Prednisone Minimal MC activity - Methylprednisolone (methyl group added to active prednisone to eliminate MC activity) Most potent anti-inflammatory - Dexamethasone (only serious and short term uses) Good topical -> Systemic - Triamcinolone

Define: Metaplasia

Reversible change in which one adult cell type is replaced by another.

Describe the aberrant hemodynamics involved in RIGHT sided heart failure and relate them to edema of the lower extremities. Mechanism, areas of edema/effusion, organs involved.

Right heart not pumping well -> Venous system backs up -> Liver congestion -> spleen congestion -> Back up of blood into all abdominal organs -> effusion of fluid into peritoneal cavity -> Acites

Describe the normal functions of neutrophils, including adherence, chemotaxis, ingestion, and degranulation/microbicidal activity.

Rolling -> Adhesion -> Diapedesis -> Chemotaxis -> engage invader -> pseudopods extend, fuse -> Phagosome formed -> intracellular granules fuse with phagosome (ROS, Proteases, lysozyme, etc..) -> forms phagolysosome -> death and dissolution of encapsulated microbe. HELPFUL: Passing through the junctions between endothelial cells (diapedesis), the cells move towards the offending organisms (chemotaxis), following the trail of chemoattractants (bacterial products, complement products such as C5a, cytokines and chemokines) up the concentration gradients to engage the microbial invader

What are the three anti oxidative enzymes we discussed? What are their respective targets? What are their final reaction products?

SOD: superoxide Catalase: Hydrogen peroxide Glutathione peroxidase: Hydroxyl radical Superoxide dismutase: O2- => into either O2 or into H2O2 Catalase: H2O2 => O2 + H2O Glutathione Peroxidase: 2 OH(radical) + 2GSH => 2H2O + GssG

Identify the oral and parenteral polio vaccines by the names of their developers and discuss their relative advantages and disadvantages, and note which is currently used in the USA.

Sabin vaccine - Causes IgA response on surface of mucous membranes. Attenuated live. ORAL Salk vaccine - Causes IgG response in circulation. Currently used in the USA. Killed. PARENTERAL

Describe the Ames test and its significance

Salmonella bacteria (with a mutated gene involved Histidine synthesis (they need His to survive)) are placed on an agar plate bearing: 1) media lacking histidine 2) approximately 10^8 His- bacteria 3) a crude fraction of liver microsomal enzymes. Then exposed to the chemical to be tested.... If a chemical is mutagenic then large numbers of His+ revertants arise around the central disc. (their genome is mutated and the gene mutated to be HIs- is now His+). The more bacteria that proliferate, the more carcinogenic the tested substance is.

What is anaphylactic shock?

Schock due to an allergic response. Still technically a SIRS. Mast cells release massive amounts of histamine, inc post cap venule permeability and arteriolar vasodilation

Discuss TWO major theories to explain the bias of metastasis of certain types of cancer towards certain organs. Which has proven to be true?

Seed and Soil - target of metastatic cell is tissue that meets its needs. Mechanical Arrest - cells mechanically arrest in the first capillary bed encountered. They are both true and work in concert to describe observed patterns of metastasis.

Describe the mechanism and cause of leukocyte rolling.

Selectins (E and P) expressed by ACTIVATED endothelial cells reversibly bind the sugars on leukocyte surfaces. Causes intermittent binding leading to a 'sticky' surface and rolling of the leukocyte

What two properties are characteristic of stem cells (in regards to tissue repair)?

Self-renewal Asymmetric replication

What is sepsis? What is SIRS?

Sepsis - whole body inflammatory response to infection. (bacteria, fungi) Systemic Inflammatory Response Syndrome Causes septic shock.

What is cyclic neutropenia?

Severe peripheral neutropenia for 5-7 days with specific periodicity (15-25 day cycles).

What is the basic mechanism of hypohidrosis? Why does the body induce hypohdrosis during pyrexia?

Shunt blood from capillaries and surface vasculature to deeper vasculature thereby limiting fluids to the surface available for sweating. Body trying to raise core temp. Shunt blood to deeper layers. Minimize heat loss though the skin.

Which is a better organ donor, your parent or your sibling? Why?

Sibling Because their allelic haplotypes for HLA are more similar to your own. Parents will always have 50% of their HLA loci that are different from your own. Some siblings may have the same basic haplotypes as you.

What tissue appears to be an example of 'unfavorable soil'?

Skeletal muscle. Though well vascularized are hardly ever a target.

Describe the pathologic features of lung Small Cell Carcinoma

Small Cell - Cells small and dark staining, form clusters, high grade, metastasis to the brain, horrible prognosis. paraneoplastic characteristics.

Recognize the risk factors for major types of lung cancer.

Smoking. It all goes back to smoking.

Explain how environmental chemicals cause cancer and the importance of "activation" by microsomal enzymes.

Some common carcinogenic chemicals are not carcinogenic until acted upon by endogenous enzymes. 1) Chemical carcinogens are usually metabolized by microsomal enzymes into chemically active forms. 2) The active metabolite is a strong electrophile. 3) These electrophyllic species can chemically modify proteins, RNA, and DNA. Some chemicals (Alkylating, Acylating) do not require activation to be carcinogenic.

What is the most common cause of DIC?

Some free floating element(s) in circulation causing damage to endothelium all over the place.

How does specific gravity apply to transudate/exudate?

Specific gravity of water is 1. So anything closer to 1 is more like water (transudate, filtered) and anything with a higher SG has more substance than just water (exudate)

What are the four major types of lung carcinoma?

Squamous Cell Carcinoma Adenocarcinoma Large Cell Carcinoma Small Cell Carcinoma

Describe the pathologic features of lung squamous cell carcinoma along with associated mutations.

Squamous Cell Carcinoma - metaplasia (columnar -> squamous), necrotic and hemorrhagic near center, formation of keratin and keratin pearls. Larger overall (>3cm). p53 and Rb mutations.

Pic of four types of lung carcinoma

Squamous Cell Carcinoma - top left (keratin pearl) Adenocarcinoma - glandular tissue, mucin Large Cell Carcinoma - Bottom right, anaplastic (chaos) Small Cell Carcinoma - Bottom left, dark staining clumped cells

Which two types of lung carcinomas are treated surgically?

Squamous and adenocarcinoma.

Describe the two-step model of carcinogenesis and the difference between carcinogen and tumor promoter.

Stage 1 - Initiation: caused by mutagen, irreversible CARCINOGEN Stage 2 - Promotion: caused by NON-mutagen. Often irritants that cause inflammation -> cell proliferation. TUMOR PROMOTER

Cancer cells generally upregulate VEGF. What does this do?

Stimulates angiogenesis. Increases blood supply to the cancerous tissue.

What is an example of an inflammatory neuropeptide? What produces it? What is its function?

Substance P • Secreted by nerves and inflammatory cells (macrophages, eosinophils, lymphocytes, dendritic cells) • Binds the neurokinin-1 receptor • Generates proinflammatory effects in immune and epithelial cells

What exact chemicals are produced by the lysosome in phagocytitic digestion of foreign materials?

Superoxide: O2- Hydrogen Peroxide: H2O2 Hyperchlorus Radical: From H2O2 via Myeloperoxidase Nitrogen radicals: NO Lysosomal Enzymes: Elastase, Lysozyme

What is the Whipple procedure?

Surgical removal of a large part of the pancreas, along with the common bile duct, gall bladder, and duodenum

What is the relative susceptibility of tissue types to ischemia injury? List the time ranges at which damage starts to occur.

Susceptibility Neurological (3-5min) > Cardiac, liver, renal (30-min-2hr) > soft tissue, skin, skeletal muscle (Many hours)

What is TNM classification in neoplasms?

T describes the size of the original (primary) tumor and whether it has invaded nearby tissue, N describes nearby (regional) lymph nodes that are involved M describes distant metastasis (spread of cancer from one part of the body to another).

TNM scale: What are T1, T2, T3 and T4?

T1 = Tumor invades submucosa T2 = Tumor invades into muscularis propria T3 = Tumor invades through muscularis propria T4 = Tumor invades adjacent organs or visceral periosteum.

What is the antigen binding receptor called in T cells?

TCR - T cell receptor

Recap: Types of CD4+ T cells, their secreted factors, and those factor's basis effects.

TH1 CD4+ T lymphocytes secrete IFN-ɣ: activates classical pathway macrophages. AND IL-2: activates CTLs TH2 CD4+ T lymphocytes secrete IL-4, IL-5, IL-13: activates alternative pathway macrophages; also activates eosinophils (IL-4 chemotactic) TH17 CD4+ T lymphocytes secrete IL-17: recruitment of neutrophils and monocytes

What are the most important cytokines involved in the acute-phase reaction? What produces these?

TNF, IL-1, IL-6 TNF - M1 macrophages IL-1 - M1 macrophages IL-6 - Macrophages, T-Cells, and Osteoblasts.

What are the Important acute inflammatory cytokines and their functions?

TNF, IL-1: Cause endothelial activation (leukocyte binding and recruitment (IL-1 -> E-selectin). Also induce systemic effects of inflammation: Fever, acute phase protein synthesis, etc. Chemokines: Chemotaxis and activation of leukocytes.

True or False Aspirin's irreversible binding and inhibition of COX 1 and 2 have largely ruled out this NSAID for general pain/inflammation/antipyretic use

TRUE

True or False IL-2, IFNγ, IL-4, IL-5, IL-10 are all lymphokines

TRUE

True or False In regards to increased blood volume, areas affected by hyperemia are more red and areas affected by congestion are more blueish

TRUE

True or False Macrophages are APCs

TRUE

True or False Once active, complement proteins can proteolyze and amplify complement activation

TRUE

True or False Proteins/peptides that are going to be presented via the intrinsic pathway pass though the endoplasmic reticulum

TRUE

True or False The innate immune response to inflammation can also damage regular tissue.

TRUE

True or False Treg cells suppress all nearby Th cells regardless of antigen binding.

TRUE

True or False Acetaminophen, in the periphery, inhibits neither COX 1 nor COX 2

TRUE

True or False As a neoplasm becomes more invasive its cellular makeup is less differentiated

TRUE

True or False B cells MUST interact with T cells in order to class switch

TRUE

True or False B-cells that bind antigenic carbohydrates can activate the production of antibodies without stimulation from T-cells.

TRUE

True or False Glucocorticoids bound to GC receptor shut down inflammation and are very effective

TRUE

True or False Ibuprofen is anti-pyritic

TRUE

True or False If you block the endocytotic capability of B cells it can not make antibody in an immune response.

TRUE

True or False Our CBC lecture was an hour of wasted life.

TRUE

True or False Tfh cells stimulate Ab class switching in B-cells via direct contact

TRUE

True or False The only immunoglobin produced via the T-independednt pathway is IgM

TRUE

True or False There is no afferent supply of lymph to the thymus

TRUE

True or False Tissue repair occurring without an ECM results solely in scarring

TRUE

True or False To achieve anti-inflammatory therapeutic effect, steroidal drugs must bind the glucocorticoid receptor

TRUE

True or False Unlike B-cells, T-cell epitopes are not intermittent AA chunks but rather a continuous peptide.

TRUE

True or False In general, if you up regulate prostaglandins you get fever

TRUE COX 2 pathway -> PGE2 -> Hypothalamus -> Fever

True or False In transplant situations, CTLs recognize foreign HLA-A and HLA-B at the SAME time that Th cells are recognizing foreign HLA-DR, but do not react.

TRUE CTLs will get the signal that these tissues are foreign and need to react, but will not do so until the Th cells have signaled them to do so via Th1 derived IL-2.

True or False Every single cytoplasmic protein in a body cell is also on the surface.

TRUE Held there by MCH 1 for exposure to the immune system for judgement.

True or False All chains of a TCR have transmembrane domains whereas all chains of Ab do not

TRUE L chains in Ab do not have transmembrane domains.

True or False Right heart failure affects the arterial system and left heart failure affects the venous system. (not considering pulmonary)

TRUE Right heart failure affects DOWNSTREAM arterial system Left heart failure affects UPSTREAM venous system

True or False Hyperplasia can give rise to neoplasia and is a concern in cancer

TRUE So is metaplasia.

True or False The donor and recipient have identical MHC I and different MHC II. Due to this the CTL will mount little to no response but the Th cells will.

TRUE There is no pathogenic/antigenic MHC I for them to see.

True or False Treg cells express CD4 on their surface

TRUE They are still a T helper cell so they have CD4 (in addition to CD25 which is ill-discussed)

True or False A chondrosarcoma is malignant by name.

TRUE having '-sarcoma' in the name means it is malignant.

True or False Particles perfusing in the blood will not collect in the thymus or lymph nodes but will collect in the spleen

TRUE the spleen is the only lymph organ that allows particles, RBC, and otherwise to perfuse into the organ lumen.

True or False Prostaglandin induced fever requires COX 2 induction

TRUE (as far as we know) COX 2 induced PGE2 is the pyrogen required ton induce pyrexia in the hypothalamus.

True or False A liver is transplanted. The first cells from the transplanted liver to be recognized, and reacted to, are macrophages, dendritic cells and B-cells.

TRUE, NOT the hepatic cells. T-helper cells recognize MCH II/HLA-DR which are expressed by APCs. T helper cells are activated first.

Describe major differences between "targeted therapies" and conventional cytotoxics

Targeted therapies - Therapies designed to act on a targeted aspect of cancer cell development. Tailored to the type of cancer cell hallmark present. Cytotoxics - Systemic toxins.

What are taxanes? What are their mechanism, toxicity, and resistance mechanisms?

Taxanes - MT stabilizers -> Block mitosis -> Apoptosis. Toxicity - myelosupression, alopecia, neuropathy. Resistance - mutations in tubulin preventing taxane binding, drug efflux

What is histocompatibility. What is the basis of immune response in organ transplant?

Term to describe the outcome of a living graft between two people. Histocompatible if graft accepted for a long time, otherwise are histoincompatible. Looking at the reaction to another person's MHC's, bound to the cells. Endogenous lymphocytes will normally only be reacting to ANTIGEN presented on MHC. But what if the MHC ITSELF is foreign? Still triggers an immune response as though IT was the pathogenic antigen. This is the basis of tissue transplant immune response.

Discuss tests which would characterize a phagocyte or complement problem. Differentiate between screening or confirmatory tests.

Testing phagocytes: Assay for typical capabilities of a phagocyte: Adhesion, chemoattractive capability, chemotaxis, ingestion, ROS production Testing complement: Screen for C3, Ig's, and lymphocyte numbers. Measure complement components.

List the six main types of T cells.

Th1 Th2 Th17 Tfh Treg CTL

Describe the cellular and molecular events which go on during graft rejection, including cytotoxic T cells, Th1 cells, and macrophages.

Th1 cells recognize foreign HLA-DR on graft cells -> react and release IL-2 (activates CTLs) and IFN-g (recruits endogenous M1, classical Macrophages) -> Inflammation response triggered and CTLs cytoxicity begin to kill foreign transplanted cells.

Which T cells are most active in the killing of infectious worms?

Th2 - Via their ability to stimulate M2 to wall off invader and via their ability (IL-4) to recruit Eosinophils to kill parasites.

What does 'left-shift' of leukocytes mean?

That the WBC released by the marrow are more immature. (left on the diagrams (always read to the right?) towards more immature pre-cursors released.

What is the basic quaternary structural difference between class I and class II MCH receptors.

The 'bowl' or cleft formed that holds the antigen ia made up of either two different proteins (Class 2) or 1 protein (Class 1). Just remember class 1 = 1 protein cleft Class 2 = 2 protein cleft.

Describe the characteristics of T-independent antigens

The antigens tend to be large molecules with same epitope repeated over and over (carbohydrates)

Why are there no foreign antigens in the thymus? What is the purpose of this?

The blood-thymus barrier. This allows only self peptides to be present here, and just as in B-cell maturation in the marrow, T cells will be selected for non-self then exported.

What receptor does the endogenous molecule, cortisol, react with?

The glucocortcoid receptor.

What is an example of a stable tissue with high regenerative capability?

The liver. It is known that as little as 25% of the original liver mass can regenerate back to its full size. 40-60% of liver can be removed in living transplant donation.

What is the overall function of NSAIDs? (therapeutic action, biochemical target to give this effect)

Therapeutic actions to reduce pain and inflammation via Inhibition of cyclooxygenase-1 and -2 (COX-1 and -2) which results in decrease in production of inflammatory prostaglandins and thromboxanes.

Distinguish between "HLA-D" and HLA-DR, -DP, -DQ.

There is no HLA-D itself. That is the category in which the -DR, -DQ, -DP HLA genes fit.

What are: Petechiae Purpura Ecchymoses Hematoma

These are different classes of hemorrhage based on size. Petechiae - pin point. 1-2mm Purpura - >3mm Ecchymoses - 1-2 cm, seen in bruising Hematoma - Large blood collection in tissue.

What are HLA?

They are MHC, but just specifically in humans.

What does 0 Topical value mean for a corticosteroid?

They are not effective in topical application because they are not active until it goes through the liver and is activated there.

Identify free radicals, how they arise, how they produce cell injury and how the body gets rid of them.

They arise via intrinsic oxidases (in ER or in PMNs) and via mitochondrial respiration. They chemically damage proteins, DNA, RNA, and trigger lipid peroxidation in cell membranes. The body gets rid of them by utilizing enzymes to convert the free radicals into harmless entities.

In terms of reversible or irreversible inhibition, which of these must a factor be to be either COX1 or COX2 'selective'?

They must bind irreversibly. This is why aspirin is COX 1 selective, its actions bind and inhibit COX 1 irreversibly.

What do COX 2 products do in the CNS in regards to pain?

They sensitize the CNS for increased pain perception. PGE2 and PGI2 (culprits)

What effect do glucocorticoids have on glucose?

They stimulate gluconeogenesis in the liver (generation of glucose from other carbohydrates, causes inc in blood sugar)

What is disseminated intravascular coagulation (DIC)?

Thrombosis and hemorrhage occurring simultaneously. Systemic activation of clotting factors that leads to widespread thrombosis and subsequent bleeding (all clotting factors consumed, bleeding risk increased)

What are the common causes of thrombosis in the arterial system?

Thrombosis in the arterial system most commonly occurs due to endothelial injury and turbulent blood flow, often associated with atherosclerosis.

Aspirin is often used in low doses to prevent platelet aggregation by inhibiting the synthesis of which substance? Leukotriene B4 Prostacyclin (PGI2) Thromboxane A2 Arachidonic acid Phospholipase A2

Thromboxane A2

What is produced by the COX 1 pathway in platelets? What is this factor's effect in platelets? What NSAID blocks this specific pathway? What its this NSAIDs mechanism?

Thromboxane. TXA2 TXA2 causes platelet aggregation. Aspirin. It is anti-platelet. Blocks COX 1 activity in platelets thereby blocking TXA2 production.

What is the difference between a thrombus and an embolus?

Thrombus form along vessel walls Emboli are free floating elements (usually released from a developing thrombus)

Antigen presenting cells arriving at a peripheral lymph node via the afferent ducts, must pass through what on their way to the T-cells where they present their antigens

Through the cortex (B-cells) on their way to the paracortex (T-cells)

Describe the blood flow through the thymus and discuss the differences between a lymph node, thymic lymphoid tissue, and that of the spleen.

Thymus blood flow comes in through trabeculae that sequester the blood from the thymus (this allows T-cells to remain unexposed to blood during their development).

Describe the basic steps in scar formation

Tissue injury -> Inflammation -> Formation of Granulation tissue -> Maturation and reorganization of the fibrous tissue to produce stable scar

What is the function of Tfh cells?

To help B-cells, that have recognized antigen, to become active and start secreting Ab (Plasma cells). They also stimulate Ab class switching in the activated B cells. (IgM -> IgG, IgA, or IgE)

Pic and histology of pulmonary edema

Top left - normal alveolar space with air between cells Boom left - alveolar spaces filled with fluid Bottom right - Pleural effusion image of someone laying on back (for CT), effusion collected along posterior area.

What is the most important cytokine involved in synthesis and deposition of CONNECTIVE tissue proteins?

Transforming growth factor-ß (TFG-ß)

Distinguish the features of exudate and transudate

Transudate • Epithelial wall intact • Ultra-filtrate • Low to no protein content • Causes: inc hydrostatic pressure, reduced oncotic pressure Exudate • Increased vascular permeability • Normally high levels of WBC • Causes: damage to vascular wall, inflammation mechanisms • Higher protein content

What is the basic mechanism of successful colonization?

Tumor cell makes its own home. tumor cells secrete cytokines, growth factors, and ECM molecules that act on stromal cells, which in turn make the metastatic site habitable

What do M1 macrophages release when they are activated by Th1? What do they do?

Tumor necrosis factor alpha IL-1 Both increase inflammation.

What is a metastasis in relation to the primary tumor?

Tumors discontinuous with the primary tumor (source).

Discuss the evidence that tumor promotion plays a role in the development of human cancers.

Tumors dont develop when tissue exposed to weak carcinogen, but WILL develop if exposed to weak carcinogen THEN tumor promoter, even if the gap between administrations is very long.

How EXACTLY does pyrexia help ward off infection?

Turns out that is largely unknown.

What protects host tissue from activated compliment?

Two factors: C1 inhibitor - inhibits C1 activation Decay-accelerating factor (DAF) and factor H - limit C3/C5 convertase formation

What is the difference between Type 2 and Type 3 nitric oxide synthase?

Type II: Inducible. Induces macrophages and endothelial cells to make NOS Type III: Constitutive. Endothelial cells always make it anyways.

What are the risks for prostate carcinoma in relation to age? What are the risks at certain age ranges?

Under 40 = RARE, 1:10000 By 80 = Extremely common, >1:12 Thought that all men by age 85 have it in some form.

What is adjuvant chemotherapy?

Use of chemotherapy in patients after local treatment modalities such as surgery/ radiation treatment "in addition to"

What is neoadjuvant chemotherapy?

Use of chemotherapy in patients who present with localized cancer for which useful local therapies (surgery/ radiation) exist but may not be completely effective.

Which products of the COX1/COX2 pathway cause vasodilation? And vasoconstriction?

Vasodilation: PGI2, PGE2 Vasoconstriction: TXA2

Compare the clinical outcomes for blockage of right/venous and left/arterial sided circulation.

Venous/right sided emboli - commonly lodge in the lungs. Arterial/left sided emboli - Can affect any organ, but most commonly travel to the legs or brain.

List defects that lead to hemorrhage.

Vessel damage. Impaired integrity of vessel walls Low level and/or function of platelets Low level and/or function of coagulation factors

Describe the mechanism of action, major toxicities and resistance mechanisms for Micro Tubule inhibiting agents? Give an example of one

Vinca Alkaloids - Binds to tubulin, causes depolymerization -> Apoptosis. Toxicity - Nerve damage Resistance - Increased efflux of drug.

What is the function of M2 macrophages?

Walling off pathogens (that M1 failed to kill) scarring healing debris removal, cleaning.

Describe how ischemia/hypoxia creates a setting where free radical damage becomes an important cause of cell injury.

When you treat the hypoxic tissues with O2 that influx generates a lot of oxygen free radical species, damaging the cells.

What is white pulp? And red pulp?

White - Lymphocytes (mainly T-cells) arranged around arteries in the spleen. Red - Areas (splenic sinusoids) between white pulp where macrophages are hanging on reticular fibers (RBC processing area)

Describe the major biologic activity, and major sources for platelet-activating factor

Wide variety of effects including platelet aggregation, vasodilation, vascular permeability and bronchoconstriction along with stimulation of platelets and cells to form other mediators. Its production is similar to AA: phospholipase A2 cleaves lipids from cell membranes

Quick break ->

Yay first and second year of medical education. yay.

All NSAIDs inhibit COX 2. Celecoxib and Acetaminophen ONLY inhibit COX 2. Are there any NSAIDs that only inhibit COX 1?

Yes (sort of). Low dose aspirin is considered an inhibitor of ONLY COX 1. At higher doses it inhibits both COX 1 and 2.

A vaccine containing IgG antibodies aggregates (IgG aggregates). You administer the vaccine IV route. What should you expect to happen?

You activate complement. Remember that close proximity Fc regions of Ab (IgM and IgG) Activate complement. Complement leads to anaphylactic activation.

What factor, when expressed, represses E-cadherin?

ZEB1

What is the main mechanism of injury caused by benign neoplasms?

by compression/ interference in function of adjacent structures

How does a patient with hypovolemic or cariogenic shock normally present? How does this compare to a patient presenting with septic shock?

cool skin (less perfusion) pallor (Less perfusion) tachycardia (heart trying to move more blood to tissues) dec urine output (Kidney trying to inc blood volume, hold on to fluid) Septic - Skin is WARM and FLUSHED (inflammation) Also with fever.

Again, what are the basic steps, in sequence ,of acute inflammation?

insulting agent recognized, chemical mediators cause vascular changes, plasma proteins/inflammatory cells delivered, agent elimination, resolution

What converts H2O2 to HOCl•? In what cell is this found?

myeloperoxidase in neutrophils

What is iatrogenic?

of or relating to illness caused by medical examination or treatment.

What class of cells are in the epithelium of the lung?

pseudostratifed ciliated columnar epithelial cells

Compare and contrast the general characteristics of acute vs chronic inflammation

see pic

What is an eicosanoid? What is an example of one?

signaling molecules made by oxidation of 20-carbon fatty acids. Arachidonic Acid

Define etiology

the cause, set of causes, or manner of causation of a disease or condition.

What are the specific therapeutic uses of NSAIDs?

• Analgesia [inhibition of inducible COX-2 at sites of tissue injury]: Relief of low-to-moderate intensity pain • Antipyretic effect [inhibition of inducible COX-2 in the hypothalamus]: Fever reduction • Anti-inflammatory effect [inhibition of inducible COX-2 at sites of inflammation]: Treatment of rheumatoid arthritis • Antithrombogenesis (anti-clotting) [inhibition of constitutive COX-1 in platelets]: Primary and secondary reduction of risk of myocardial infarction (only aspirin)

What are the main results of compliment activation.

• C3a, C5a increase vascular permeability & stim mast cells to release histamine • C5a activates the lipogenous pathway for AA metabolism • C5a, C4a, C3a activate leukocytes increasing their endothelial adhesion • Also chemotatic agents for neuts, eos, basophils and monocytes • C3b acts as opsonin for enhanced phagocytosis • The MAC: essentially multiple C9 proteins (formed by 5b-C9) • Creates pores that violate the membranes of some bacteria

What are the plasma protein derived mediators of inflammation?

• Compliment • Coagulation & Kinin

What are some of the factors that antagonize or diminish inflammation?

• Many of the mediators are destroyed by circulating enzymes and have short active periods • Lipoxins: antagonize leukotrienes • Compliment regulatory proteins (C1 inhibitor ) • IL-10 (secreted by macrophages) down regulates activated macrophages • TGF-beta (promotes fibrosis) is anti-inflammatory • Intracellular compounds also antagonize pro-inflammatory cell states

What are the cell derived mediators of inflammation

• Vasoactive Amines • Arachidonic Acid Metabolites • Platelet-activating Factor • Cytokines • Reactive Oxygen Species • Nitric Oxide • Lysosomal Enzymes • Neuropeptides