Pathophysiology

Front 1

What is Pathophysiology?

Back 1

Changes at various levels (cellular to organ) that occur and *the effects these changes have on TOTAL BODY FUNCTION)

Pathology- just deals with the structural/functional changes that are related to disease

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What is Cellular Adaptation? What are the 5 types of Cellular Adaptations?

Back 2

Cells can adapt to stress to prevent injury.

*IMPORTANT* with adaptations there is NO LOSS OF FUNCTION at the cellular keel. So the adaptations are REVERSIBLE. This means that when the stress is removed, the cells can go back to normal.

Hint 2

1. Atrophy (become smaller or lose # of cells)
2. Hypertrophy (grow bigger [muscle, adaptive in heart, compensatory in kidney])
3. Hyperplasia (get more # of cells- but only in MITOTIC cells!)
4. Metaplasia (replace with new cells better adapted for stress, must come from same family!)
5. Dysplasia (increase # of cells with sequential mutations, atypical hyperplasia, NOT CANCER)

Front 3

What is Atrophy?
What are the causes and sites?

Back 3

*Decrease in size AND/OR number of cells.* resulting in a decrease in tissue organ size.

Principle of Supply vs Demand
-if the demand is low, then there is a lower need for supply and cells with atrophy to match the demand

Hint 3

Causes include disuse (laying in bed for a long time), pathology (decreased blood supply, insufficient nutrition, persistent cell injury, insufficient hormonal stimulation), and normal physiology (think thymus gland atrophy during childhood).

Common Sites:
-Skeletal Muscle
-Heart
-Secondary Sex Organs
-Brain

Front 4

What is Hypertrophy?
What are some physiologic and pathologic causes?

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*Increase in Cell Size*
(which results in increased functional tissue mass)

Note that the increased size is associated with increased protein accumulation in cellular components and NOT an increase in cellular fluid.

Hint 4

Cause can be:
-Physiologic (uterine response to pregnancy/skeletal muscle response to work
-Pathologic (heart responds to hypertension or bad valves

Front 5

What are 2 tissues that are particularly responsive to hypertrophy?
What are the 2 types of hypertrophic responses?

Back 5

Heart and Kidney.

ADAPTIVE Hypertrophy- describes the hypertrophic response of the heart to an increased after load.

COMPENSATORY Hypertrophy- describes the response of a kidney to nephron loss where surviving nephrons would hypertrophy to compensate for loss of renal function

Hint 5

Front 6

What is Hyperplasia? What is unique about it?

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*Increase in NUMBER of cells* due to an increased Mitotic Division

It often happens in conjunction with hypertrophy (like uterine/breast tissue during pregnancy) but since it can only happen in tissues capable of mitotic division, you won't see hyperplasia in places like skeletal muscle.

Remember, its a cellular adaptation so it is still WELL CONTROLLED and goes away when the stress is removed

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What is Metaplasia?

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*Normal Cell Type Replaced by Another Cell Type* that is more suitable for the stressful environment.

Remember, the change is still reversible!

Because the new cells are often thought to be a result of reprogramming of undifferentiated stem cells that are present in the tissue, *the new cell will ALWAYS be from WITHIN the overarching cell type FAMILY*
- so epithelial cells will only be replaced by epithelial cells

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What are 2 examples of Metaplasia?

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1. Barrett's Esophagus
-where your normal squamous cells get owned by acid due to GERD and are replaced by secretory columnar cells that can survive better in the acid environment

Hint 8

2. Smoking
-your normal ciliated columnar cells of your airway become replaced by unciliated stratified squamous epithelial cells in response to stressors like smoking.
-although your airway can now survive the environment induced by smoking, they lose the functional protective mechanism of the cilia

Front 9

What is Dysplasia?
What are some common sites?

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Deranged cell growth of a specific tissue that changes the size, shape, and organization of mature cells.

The variation in size, shape, and appearance is due to sequential mutations in proliferating cell populations. Therefore, as cell number increases, there is more variation.

Dysplasia is NOT cancer, but may progress to it.

It is still reversible if the stimulus for dysplasia is removed.

Hint 9

Common sites of dysplasia are the metaplastic squamous epithelium of the respiratory tract and cervix.

*What is important to remember is that dysplasia is an ATYPICAL HYPERPLASIA since you are often increasing the number of cells rather than replacing cell types.

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What is cell injury? What things cause it?

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The response she a cell can no longer adapt to the amount of stress it is receiving.

Cell injury is characterized by *loss of function*

There is a point before, which is *reversible*, BUT after enough stress you reach a "Point of no return" after which the injury is *irreversible* and will lead to cell death.

Hint 10

Causes:
-Mechanical Forces
-Electrical Injuries
-Nutritional Imbalances
-Biological Agents
-Poisons

Hypoxia→ pH problems and depolarized membranes → lysis

Heat→ enzyme problems, protein denaturation, increased nutrient demand

Cold→blood stasis→clots and gangrene

Lead→replaces calcium binding sites→passes thru BBB→ retardation

Front 11

What role does extreme heat play in cell injury?

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If proper nutrition isn't maintained for this higher cellular metabolism (heat causes its acceleration), tissue will suffer from ischemia (aka injury).

Heat can inappropriately activate (heat shock proteins) or deactivate (denature) temperature sensitive enzymes.
-having tons of denatured proteins not only wastes space, but they can also coagulate and clog up blood vessels!
-denatured proteins can make holes in the plasma membrane and the heat can make homeostasis even more difficult by "Over-fluidizing" the membrane and even making it more permeable!

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What role does extreme cold play in cell injury?

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Cold increases blood viscosity and activates sympathetics to induce vasoconstriction.

Overactive sympathetics in extremities can lead to frostbite!

Both of these effects due to cold temp can also lead to blood stasis.
-this sucks because bacteria can proliferate (gangrene) or clots can form (thrombosis)

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How does lead play a role in cell injury? What mechanism does it work by?

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Chemical Agent.

Even low exposure is unsafe!

Causes growth problems bc if lead hogs all of the calcium binding spots on your growing bones, the Ca can't bind to facilitate growth!

Hint 13

Lead exposure causes some competitive inhibition because it looks like calcium to the cell.

Lead can bind calcium-binding proteins and use calcium transporters but obvi can't function like Ca so the effects of Ca are blocked.

This is super problematic for the CNS, where lead causes some serious retardation. Lead uses Ca-channels to pass thru the blood brain barrier and hogs all of the calcium-binding enzymes. This screws with your neurons! uh oh!

Front 14

Mechanism of Cell Injury:
-what 2 categories can they fall into?
-what are the main 3 mechanisms?

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Can be Direct or Indirect

Main mechanisms?
1. Depletion of ATP
2. ROS Formation
3. Fuckked Up Calcium Homeostasis

Hint 14

ATP Depletion→pH problems/depolarized membranes→lysis

Calcium Homeostasis→from ATP depletion or Lead replacing Ca bind sites

ROS→react with everything, even your DNA

Ischemia-Reperfusion Injury→ lots of extra ROS, prime example of over active immune response

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How does ATP Depletion lead to cell injury?

Back 15

Increased ANAEROBIC respiration causes accumulation of lactic acid which *decreases pH!*
-at low pH, lysosomes lyse and release digestive enzymes which chew up the cell until it lyses

ATP depletion also leads to lack of ATP to power the Na/K Pump, which maintains cell polarity!
-a *depolarized membrane* causes opening of voltage gated channels and tons of intracellular Calcium rushes in.
-since NORMAL intracellular Ca levels are super low, an increase in intracellular [Ca] causes fluid to come rushing into the cell! This increases cell pressure and eventual leads to lyses.

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Front 16

Ischemia-Reperfusion Injury:
-What is it?
-Why does it suck?

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Often seen after strokes and cardiac infarctions.

We get damage due to an overactive immune response (underlying mechanism for almost all disease states)

Cells injured due to ischemia put out adhesion molecules and cytokines to try and attract immune cells. Reperfusion brings in immune cells which will respond by releasing ROS and inflammatory factors.
-These will cause more damage to more cells and activate even more immune cells.

Eventually you can actually cause a slugging of the blood due to all the cells adhering and cause ischemia again.

Reperfusion injury is worse than a normal immune response because there is all this extra ROS in addition to those released by immune cells that is causing nonspecific cell damage.

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How do free radicals lead to cell injury? When do ROS levels become a problem?

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The immune system uses free radicals during phagocytosis to destroy things

ROS are HIGHLY reactive!

They are predators in that they look for molecules that can't move or are large.
-these include *DNA*, large proteins, and the cellular membrane.

The effects of these free radicals, therefore, are mutation, oxidative modification of proteins, and lipid peroxidation respectively.

Hint 17

Normal free radicals are fine. But problems come up when we get more ROS formation due to non physiological forces like processed food, air pollution, smoking, and UV radiation.

DNA is a common target of ROS which means that these triggers can all contribute to cancer!

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Whats the difference between Apoptosis and Necrosis?

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APOPTOSIS
-"programmed cell death"
-highly regulated and does NOT illicit an inflammatory response
-normal cellular response (commonly found in aging/damaged cells)
-causes the cell membrane to break down into smaller bits that contain various pieces of cellular organelles, machinery, and other internal contents. These pieces then give off specific chemokines that attract phagocytes that can specifically remove the apoptotic bodies and clear out the area.

**apoptosis leads the way for renewed cell regrowth- remember that apoptosis is part of the normal cell cycle!

Hint 18

NECROSIS
-UNprogrammed cellular destruction
-cell membrane will lyse, depositing contents from inside the cell into the inter membrane space. Super Bad!
-the lysosomes and other degradative components can then go attack neighboring cells
-end result is an Immune Response (opposite of well-behaved apoptosis!)

**necrosis, unlike apoptosis, gets in the way of cellular development, inhibiting further cell growth!

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Characteristics of Apoptosis? Intrinsic vs Extrinsic Pathway?

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Propagated by a family of proteases called CASPASES

Remember that Apoptosis is a normal part of physiology! It is involved in the removal of proliferating cell populations (like GI cell turnover every 5 days), death of cells that served their purpose, embryogenesis (webbing in the toes, a tail), controlling immune cell numbers, and the involution of endometrial cells in menstruation.

Hint 19

Intrinsic Pathway: occurs within the cell when it knows something is wrong (this can be from stress, errant replication, etc.)

Extrinsic Pathway: Occurs when the cells around it tell it that it needs to die (usually because of overcrowding or from general disease conditions in the area)

Front 20

What role does apoptosis play in pathologies?

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Apoptosis becomes unregulated, which normally results in a loss of function. So you'll see pathologies like cancer growth (nothing dying), viral replications, and neurodegenerative disorders (the wrong things dying)

Front 21

Characteristics of Necrosis? What role does it play in the inflammatory response?

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Unregulated enzymatic destruction!

Propagated by the action of CATHEPSIN- a protease that is normally inactivated and digests everything it can get its teeth on. Because it will also attack the cell membrane, it will lead to cell lysis, spewing the digested cellular contents (and the digestive enzymes) into the intercellular space.

Hint 21

Necrosis is dangerous because it initiates an inflammatory response- as one cell dies, it affects and subsequently kills the other cells around it.

Even while the immune system is revved up and trying to clean up the mess, necrotic tissue is tricky and forms a shell that sequesters the necrosing material inside to stop the inflammatory cells from getting in!

Front 22

What is Gangrene an example of? What is the difference between DRY and WET gangrene?

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Gangrene is a great example of significant necrotic tissue that is unable to be cleared.

DRY
-problem with the *arterial* blood supply (so its likely to affect the extremities)
-the ischemic tissue, as it dies, will build up and lead to a dead zone with blood stasis (which is basically like a playground for bacterial proliferation)
-tissues can turn black because the bacteria oxidize Hemoglobin into FeS, which is black

Hint 22

WET
-an interference with the *venous* blood supply
-instead of the extremities, this first affects the mucous membranes (a cause of bedsores)
-unlike dry gangrene, this lack of blood return leads to swelling and a pooling of blood in the tissue
-this blood stasis leads to bacterial proliferation
-you will see some degree of black, but the main difference one can discern is that wet gangrenous tissue is edemas, cold, and clammy!

Front 23

Hepatitis B
-Transmission
-Mechanism

Back 23

Transmitted through blood or sexual contact. People like doctors are at high risk due to our direct exposure to blood.

Half of all patients with acute HepB have been incarcerated or treated for an STD.

Hint 23

HBV can act thru direct cellular injury (viral lysis of new visions) or through the induction of the immune response.

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HBV Pathway

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What signs should we look for when diagnosing liver inflammation?

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Bilirubin Synthesis and Excretion

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Note that Globin is broken down by macrophages into amino acids that can be dealt with, while Heme needs 2 specific enzymes (Heme Oxidase and Biliverdin Reductase) to be effectively cleared.

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3 Possible Immune Outcomes in HBV

Back 27

They are based on the initial immune response.

1. if you can mount a really big, robust immune response upon infection (aka you get really sick in the acute phase) it is possible to completely clear the HBsAg and develop immunity!

2. If you have a light response and don't fully clear the initial infection you can enter an INACTIVE CARRIER STAGE (acute flares because the hepatocytes contain the DNA virus) or…

3. CHRONIC STAGE (virus isn't cleared and replication continues for more than 6 months.)

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Chronic Hepatitis

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Liver Failure

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Once injury has occurred, the immediate response of the immune system foes in one of two directions- vascular and cellular...

What is the Vascular Reaction?
What is the Cellular Reaction?

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What is Chronic inflammation?

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Involves the continuous activation of T cells, which increases the macrophage response and can lead to the release of non-specific inflammatory chemicals.

One that you will see a lot is TNFalpha- which causes fibroblast proliferation!

A major problem is fibrosis of the tissue- scar formation!

This proliferation is a danger sign! Whenever the STRUCTURE of the tissues is altered, the FUNCTION of the tissue will also change! This change in architecture is a huge precursor to disease!

Front 32

Diabetic Nephropathy

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Looks at the state of the kidney in diabetes.

Distinct gener differences! Staining for both MCP-1 and CD68 (which recruit macrophages over to the tissue), males have a much higher accumulation!
-this implies that diabetes appears to be more immune response driven in males than in females!

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What is Cancer? Neoplasia?

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A neoplasia is a tumor- an abnormal growth of tissue that has escaped from growth regulation. These neoplasias may be benign, in which case they only grow locally without affecting adjacent tissues.

Benign tumors are no completely harmless- growth can cause them to physically press on vital organs, or to secrete high levels of hormones (i.e. thyroid adenoma)

Cancer is a malignant neoplasia- it will spawn metastases and invade neighboring tissues.

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Cancer Nomenclature: Carcinoma

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cancer of epithelial origin (e.g. skin, lung, breast, colon, bladder)

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Cancer Nomenclature: Leukemia

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cancer of the bloodstream

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Cancer Nomenclature: Lymphoma

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cancer of lymphatics

(Note: both leukemia and lymphoma can involve lymphocytes. I.e. acute lymphocytic leukemia that arise from B and T-cells; the difference is circulating vs. solid tumors.)

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Cancer Nomenclature: Sarcoma

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Cancer of mesenchymal origin (i.e. adipocytes, osteoblasts/bone, myocytes/muscle)

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Cancer Nomenclature Prefixes:
adeno-

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Cancer Nomenclature Prefixes:
chondro-

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Cancer Nomenclature Prefixes:
erythro-

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Cancer Nomenclature Prefixes:
hemangio-

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Cancer Nomenclature Prefixes:
hepato-

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Cancer Nomenclature Prefixes:
melano

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Cancer Nomenclature Prefixes:
myelo-

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Stages of Abnormal Growth:
Normal
Hyperplasia
Dysplasia
Anaplasia

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Benign vs Malignant Tumors

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BENIGN tumors are essentially dysplasias. Cell function is preserved (e.g. hormone secretion). No local invasion or metastasis.

MALIGNANT tumors are anaplasias. Cells are dedifferentiated, locally invasive, and can form distant growths. One diagnostic measure is the maintenance of cell function. If the tumor is secreting high levels of hormone, it will be benign and not yet malignant (though still dangerous).

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Normal cells grow, but their growth is subject to outside signals that stimulate growth, e.g. injury in wound-healing.

Once the signal ends the growth must also stop. If this process is disrupted, the cell is induced to kill itself- apoptosis.

In tumors, this growth is not controlled.

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7 features of cancer cells

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In normal growth, GF's stimulate target cells. There must also be corresponding receptors on target cells.

Recepto binding will activate a phosphorylation cascade (thru signal transducing proteins) and until the signal is amplified and transmitted to the nucleus.

This is the most common pathway of growth activation. In the nucleus, TF's are activated (e.g. MYC/JUN/FOS), these will activate transcription of genes, and induce cell cycle progression.

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What are Proto-Oncogenes?

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They are normal genes; we all have them! They will normally stimulate cell proliferation.

If proto-oncogenes are altered via GAIN-OF-FUNCTION, then they are called "oncogenes" (a loss-of-function mutation in a proto-oncogene will not cause cancer; it'll just impede cell growth or cause cell arrest/death)

Hint 50

Since we normally express TWO alleles of each proto-oncogene, a gain-of-function mutation suggests that we will now be expressing MORE than previously.

Therefore, only one mutation is sufficient to cause tumor growth, and these are termed DOMINANT mutations.
-these mutations include point muttons, chromosomal rearrangements, and gene amplification.

It is also useful to note that oncogenes arise in SOMATIC cells, not germ line cells.
-it is unlikely that an embryo with a germ line dominant mutation in growth regulation could survive

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What are the mechanisms of oncogene activation?

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Amplification vs. Overexpression → Oncogenes

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Amplification involves multiple copies of the gene being expressed.

Over expression involves the PROMOTER being overstimulated so that more of the single copy is over expressed. This could happen because the gene is translocated behind a new, more powerful promoter (i.e. myc → c-myc oncogene).

Translocation can also create a novel chimeric or fusion protein that is oncogenic (i.e. BCR-ABL oncoprotein)

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Front 53

Growth Factors as Protooncogenes

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Over expression of AUTOCRINE growth factors can lead to tumor growth. Recall that not only is over expression bad, cells should not be able to self-stimulate growth either; they should not have both the ability to produce grout factor AND the receptors for that growth actor.

Examples of this are platelet-derived growth factor (PDGF) in glioblastomas and transforming growth factor (TGF-α) in sarcomas.

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Growth Factor Receptors as Protooncogenes

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Over expression or mutation in receptors can cause tumor growth. If a membrane receptor's extracellular domain becomes cleaved, in some cases the cytoplasmic signaling domain could become constitutively (always) active.

Hint 54

Another example is HER-2 receptor over expression in some breast cancers.

Testing is available to detect if HER-2 receptor is over expressed, and if so, targeted therapy against this receptor can be initiated.

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Signal Transduction Proteins as Protooncogenes: Ras

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Ras is a G-protein that stands in the middle of a complex signaling cascade. Ligand-activated GF receptors will activate Ras, causing it to release GDP (inactive Ras) and bind GTP (active Ras).

This active form of Ras-GTP will be able to activate a cohort of name-brand Ras effectors that lead to cell growth and cell proliferation (PI3K and Akt pathway), protein synthesis and transcription (MAP Kinase pathway).

Once the job is done, Ras will hydrolyze the GTP and return to the inactive Ras-GDP. Point mutations tat change the pocket-binding or GTP-hydroluzing regions in Ras will lead to constitutive Ras activation.

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Front 56

Signal Transduction Proteins as Protooncogenes: ABL

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ABL is a tyrosine kinase that will promote apoptosis.

Why is it a protooncogene?
-because a chromosomal translocation can cause it to fuse with the BCR gene.

Recall that kinases phosphorylate other proteins. Binding to BCR will allow the BCR-ABL fusion protein to be retained in the cytoplasm and activate other pathways, including Ras-Raf (MAP kinase).

This aberrant chromosomal translocation results in the distinctive "chromosome Philadelphia"

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Front 57

Nuclear Transcription Factors as Protooncogenes: Myc

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Translocation to a more powerful/active promotor.

In Burkitt's lymphoma, c-myc is transferred from chromosome 8 to chromosome 14, where IgH gene is located. The enhancer sequences that cause constitutive IgH production will also cause structurally normal MYC to be produced at high levels.

Hint 57

Myc translocation can also cause neuroblastoma- a pediatric cancer. The aggressive form of neuroblastoma is created through amplification. The chromosomal region containing N-myc can break away and be seen as small, independently replicating, extrachromosomal particles called "double minutes".

The blue-blob pictures show a normal-staining cell with only 2 copies of the N-myc gene (either in its normal location, or translocated), and an abnormal-staining cell ail many copies of the N-myc gene, widely dispersed.

Front 58

Cell Cycle Regulation

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A layer of regulation after growth factors/signals.

The cell cycle is driven by cyclins and CDKs, and inhibited by CDK inhibitors.

The transition from G1 to S phase is a particularly important checkpoint.

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Front 60

Mechanisms of Tumor Suppressor gene inactivation?

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Importantly- remember that in epigenetic modifications, the TS gene is still normal and unchanged. However, the promotor has been methylated which inactivates the TS gene by preventing TF's from accessing the promotor. Epigenetic modifications are interesting and the current focus of a lot of cancer research because they can be influenced by environmental factors.

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Tumor Suppressor Genes: Retinoblastoma Gene (RB)

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The RB gene is universal and present in all cel types.

It codes for proteins that are responsible for inhibiting the cell cycle and is the checkpoint for progression from the G1 to S phase.

Hint 61

When a cell is not supposed to proliferate, the RB proteins are hyperphosphorylized and prevent activation of S-phase genes.

When appropriate signals for proliferation occur, RB proteins are phosphorylated and the cell cycle progresses.

Mutations in the RB gene are found in the majority of cancers.

The interesting thing about the RB gene is that the mutation in such a universal gene causes only one specific type of tumor. In most cells, the presence of mutations in both copies will lead to cell death. However, in the retina, for some reason, these cells don't die off and tumors form.

Front 62

Knudson Two-Hit Hypothesis: Familial vs Sporadic form of Retinoblastoma

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Tumor Suppressor Gene: APC Gene

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Hint 63

Even if you remove the entire colon, polyps will still form in the remaining scar tissue.

The formation of multiple benign polyps is oftentimes the warning sign for future formation of colon cancer.

So how the APC gene works in suppressing tumor formation is by encoding proteins that inhibit β-catenin. When the cell is supposed to undergo proliferation, the WNT pathway is activated and the β-catenin is unbound from APC protein. Free β-catenin can then bind to nuclear DNA and promote the cell cycle.

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considered the "guardian of the genome"

any damage to the cell due to abnormal conditions (i.e. hypoxia, DNA damage, over expression of mitogenic factors) will activate p53.

1st, activate p53 arrests the cell cycle via transcription of p21 (a CDK inhibitor).

2nd, it stimulates DNA repair mechanisms.

If repair is successful, then the cell cycle continues. If not, then the cell undergoes apoptosis.

Hint 64

The important thing to remember is that mutation of an oncogene alone is not enough for tumor formation!

If you have a functioning p53 and other tumor suppressor pathways, cells containing mutations in oncogenes will be killed off before they have the change to over proliferate.
**Thus, inactivation of TS genes is the first step for tumor formation, not oncogene over expression**

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What is Li-Fraumeni Syndrome (LFS) caused by?

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Germline mutations in the p53 gene. Associated with highly elevated risk of the development of a number of types of cancer (i.e. breast cancer, osteosarcomas, soft tissue sarcomas, brain tumors, leukemias) at a very young age.

Keep in mind that p53 mutation alone isn't the single causative factor for LFS. Other factors such as mutations of the CHK2 gene and polymorphisms in the normal form of the p53 gene can also contribute.

Hint 65

This shows the 3 types of p53 mutations that can lead to LFS.

With loss of function mutation, the mutant form is nonfunctional but it does not interfere with the function of the normal allele. With a loss of function mutation, you also need another germ line mutation that causes a loss of heterozygosity ("LOH") to see any symptoms.

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What are the consequences of a p53 mutation? (loss of function mutation, dominant negative mutant, fain of function mutation)

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BRCA1 and BRCA2

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Get activated in response to DNA damage and encode proteins that are involved in DNA repair.

Keep in mind that these genes are different from RB, APC, and p53 genes in that they are not directly involved in regulating the cell cycle.

However, DNA repair is a very important mechanism considering that any DNA damage can lead to cell instability, mutations, etc.

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HNPCC and XP are other cancers that are associated with faulty DNA repair mechanisms

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Anaplastic Lymphoma Kinase (ALK): Why is this an exception to the general rule that mutations in oncogenes typically do not contribute to familial tumors?

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ALK is a receptor tyrosine kinase that is expressed preferentially in the CNS and PNS.

It is inherited in an *AUTOSOMAL DOMINANT fashion with LIMITED PENETRANCE* and causes familial neuroblastoma.

Keep in mind that ALK is not a universal oncogene.

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MicroRNAs in Cancer

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How can the apoptosis pathway be disrupted in cancer cells?

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How are cancer cells capable of limitless replicative potential?

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What is Angiogenesis?
How is this relevant to tumor cells?

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What are the steps of Angiogenesis?

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What factors control Angiogenesis?

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What is an Angiogenic-Switch?

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How do cancer cells invade and metastasize?

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Note 1: Begins with local invasion. Needs to break into the basement membrane and get into the vessel ("Intravasation")
There are a lot of limiting steps in this process:
-not every cell has ability invade endothelium
-not all cells can survive the evasion
-if not attached to anything, they will die! (that is the signal for them to die!); so even if the cells can get to the blood, if they cant attach to anything, then they will die!

Note 2:
Can also use lymphatics!

Localization depends on where it begins AND the type of chemokine receptors that it expresses on its surface.

Note 3: "Sit and Soil"
Tumor cells have cytokine receptors and if certain organs have the specific chemokines, then they will attract the tumor cell to the organ for invasion.

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How do cancer cells evade the host immune response?

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What causes cancer?

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What are some chemical carcinogens?

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How can viruses contribute to cancer development?

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Genomic Instability as a model of tumor progression

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No longer protected from DNA damage, so the cells can start to proliferate uncontrollably.

Hint 82

Multiple translocations between chromosomes that caused massive changes. Under normal conditions this cell wouldn't survive- but when we lose the protective mechanisms, it WILL survive.

It becomes more and more disorganized with each round of replication- this is called genomic instability.

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How does tumor progression occur?

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First step is us losing our tumor suppressor genes.

Then we get more and more changes with time.

Hint 83

It takes years to develop cancer.

In many tumors, the changes are very disorganized.

This is the CLASSICAL method, but tumor progression doesn't always follow this model. For example, cancer in children doesn't follow this- they don't have YEARS to develop the cancer.

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What is the Clonal Evolution model of tumor progression?

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Starts in One cell that goes under a change. These changes are very RANDOM- its not like the tumor has a path- its all very very random and completely disorganized! So the tumor changes in very random ways.

Some of the cells will die, and some of them will gain new features, allowing them to proliferate.

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How are cancer stem cells involved in tumor progression?

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What are some symptoms of cancer?

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Why do we die of cancer?

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How is imagine used in diagnosing cancer?

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How are biopsies and immmunocytochemistry used in cancer diagnosis?

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What is the Molecular Diagnosis for detecting cancer?

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How is Flow Cytometry used in cancer diagnosis?

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Biomarkers (like PSA) in cancer diagnosis

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Molecular Profiling in Cancer diagnosis

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Conventional Cancer Therapy

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Why is cancer so difficult to treat?

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Hormone Therapy in Cancer

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Cancer Stem Cell Targeting Therapies

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Tyrosine Kinase Inhibitors and Cancer Therapy

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Cancer Therapies Targeting Tumor-Specific Proteins

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Immune Therapy for Cancer Treatment

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Gene Therapy for Cancer Treatment

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Epigenetic Therapy for Cancer Treatment

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DESCRIBE the mechanisms that contribute to edema.

Back 104

Edema can be defined as increased fluid in the interstitial spaces. Under normal
conditions, fluid enters in arterial end of the microcirculation and should be
balanced by inflow into the venular end with excess drained by lymphatics, which
then returns to bloodstream via
thoracic duct.
Disturbances in fluid
homeostasis can result the
development of major
disorders.
Increased Hydrostatic Pressure:
impaired venous drainage, CHF
Decreased Oncotic Pressure:
reduced albumin (nephrotic
syndrome, cirrhosis, protein
malnutrition)

Hint 104

Common presentations include lymphedema (obstruction), which is normally
localized. In contrast, anasarca has a severely generalized distribution.
Subcutaneous edema can be distinguished regional insults, such as with the
heart, while systemic disturbances are commonly related to the kidneys. Other
common forms include
pulmonary edema as a result of left ventricular failure and ARDS. Brain edema
can also occur with focal injury, as is the case with abscesses and neoplasms, or in
a generalized form due to trauma.
Clinical Relevance: Edema points to underlying disease, and is commonly
associated with diminished inflammatory processes, e.g., impaired wound
healing and ability to fight infection.

Front 105

DESCRIBE hemostasis as it relates to hemorrhage

Back 105

generally represents an extravasation of blood due to a rupture in the vessel wall. When blood accumulates within a tissue, it is generally referred to as a hematoma. Characterized by their trlative size, hemorrhages can be classified as:
petechiae (1-2mm) - minute, into skin, mucus or serosal m
purporas (3-5mm)
bruises (ecchymoses) (1-2cm) – subcutaneous hematomas with RBC deposition, which are then phagocytosed by macrophages. The Hb released (R-B) is metabolized into bilirubin (B-G), which is then converted to hemosiderin (golden brown).

Front 106

DESCRIBE hemostasis as it relates to thrombosis.

Back 106

Following thrombus formation, beyond and related vascular obstruction, the following processes may occur:
*propagation* due to the accumulation of platelets and fibrin
*embolization* resulting from a dislodged clot
*dissolution* can occur with adequate fibrinolytic activity
*organization* due to inflammation, fibrosis, and EC and SMC ingrowth, and incorporation into the thickened vascular wall, followed by recanalization and subsequently re-establishing blood flow.
Cardiac dysfunction is often the origin of arterial thrombi. Thrombus formation will begin at the site of injury (plaque) or turbulence (bifurcation), and is associated with retrograde growth. Examples include:
• MI (dyskinetic contraction of myocardium and damage to endocardium)
to mural thrombus
• Rheumatic heart disease resulting in mitral valve stenosis, followed by left
atrial dilation with atrial fibrillation, which then augments any existing
atrial blood stasis, resulting in a mural thrombus
• Atherosclerosis (EC injury, abnormal BF)

Hint 106

Venous thrombi, on the other hand, commonly occur at sites of stasis, and extend
in the direction of growth. Here, the propagating tail may not be well attached
and is therefore prone to embolus, cast formation. Examples include:
superficial (varicosities) or deep veins of the leg
1) local congestion, pain, swelling, tenderness, rarely embolize
HOWEVER, edema and impaired venous drainage predispose skin to infection
from slight trauma, and can develop into varicose ulcers
2) deep thrombi (larger leg veins above knee) embolize, and are asymptomatic,
realized in retrospect.
a. stasis, hypercoagulability --> cardiac failure, pro-coagulation factors
3) bypass channels commonly open to facilitate proper venous drainage.

Clinical Relevance: commonly found at area of attachment, can be occlusive, are common sources of emboli (lungs).

Front 107

DESCRIBE hemostasis as it relates to pulmonary and systemic embolism

Back 107

Pulmonary Thromboembolism commonly results from a thrombus originating
from a deep vein in the leg. Commonly, individuals with one are predisposed to
have multiple. Most pulmonary emboli most are clinically silent. However, if
>60% of pulmonary circulation is obstructed, the outcome can be as severe as
sudden death, cor pulmonae, or cardiovascular collapse. Clinical presentation is
associated with the relative of the pulmonary vasculature obstructed:
• medium-sized commonly have sufficient collateral flow, and
therefore do not usually infarct, but can be problematic w left
ventricular failure
• smaller - associated w infarct
• multiple --> pulmonary hypertension with right ventricular failure

Hint 107

Systemic Thromboembolism describes emboli migrating through the arterial
circulation. Examples of this form include:
Intracardiac thrombi (LV wall infarcts, dilated LA)
Ulcerated athersclerotic plaques
Aortic aneurysms
These emboli can also cause complications within the lower extremities, brain,
intestines, kidneys and spleen dependent on point of origin and relative blood
flow. As mentioned above, consequences of a systemic thromboembolism are on
dependent the collateral supply and caliber of the vessel occluded.

Front 108

EXPLAIN Virchow’s Triad

Back 108

Virchow triad:
1) EC injury describes the
perturbation of balance via
hypertension, shear stress,
turbulent flow, and bacterial
infection.
2) Alterations in blood flow relate
to hemodynamic properties of
turbulence and stasis. A
disruption in laminar flow or
contact of activated platelets with
EC, which normally prevent
dilution of clotting factors, retard
inflow, can commonly occur with atherosclerotic plaques, aneurysms, MI, and
mitral valve stenosis.
3) Hypercoagulability contributes less frequently, yet is an important aspect
comprised of genetic (V and prothrombin gene) and acquired (1 and 2)
components.

Front 109

COMPARE arterial and venous thrombi.

Back 109

Following thrombus formation, beyond and related vascular obstruction, the following processes may occur:
*propagation* due to the accumulation of platelets and fibrin
*embolization* resulting from a dislodged clot
*dissolution* can occur with adequate fibrinolytic activity
*organization* due to inflammation, fibrosis, and EC and SMC ingrowth, and incorporation into the thickened vascular wall, followed by recanalization and subsequently re-establishing blood flow.
Cardiac dysfunction is often the origin of arterial thrombi. Thrombus formation will begin at the site of injury (plaque) or turbulence (bifurcation), and is associated with retrograde growth. Examples include:
• MI (dyskinetic contraction of myocardium and damage to endocardium)
to mural thrombus
• Rheumatic heart disease resulting in mitral valve stenosis, followed by left
atrial dilation with atrial fibrillation, which then augments any existing
atrial blood stasis, resulting in a mural thrombus
• Atherosclerosis (EC injury, abnormal BF)

Hint 109

Venous thrombi, on the other hand, commonly occur at sites of stasis, and extend
in the direction of growth. Here, the propagating tail may not be well attached
and is therefore prone to embolus, cast formation. Examples include:
superficial (varicosities) or deep veins of the leg
1) local congestion, pain, swelling, tenderness, rarely embolize
HOWEVER, edema and impaired venous drainage predispose skin to infection
from slight trauma, and can develop into varicose ulcers
2) deep thrombi (larger leg veins above knee) embolize, and are asymptomatic,
realized in retrospect.
a. stasis, hypercoagulability --> cardiac failure, pro-coagulation factors
3) bypass channels commonly open to facilitate proper venous drainage.

Clinical Relevance: commonly found at area of attachment, can be occlusive, are common sources of emboli (lungs).

Front 110

DESCRIBE disseminated intravascular coagulation as a complication for major disorders.

Back 110

Though it is not a primary disease, DIC is a potential complication associated with WIDESPREAD ACTIVATION OF THROMBIN WITHIN THE MICROCIRCULATION. It is capable of causing diffuse circulatory insufficiency (brain, heart, lung, kidneys) to the extent of ischemia/microinfarcts and hemolysis.

In the setting of multiple thrombi, the rapid concurrent CONSUMPTION of platelets and coagulation proteins provide an understanding of this complication as a "consumptive coagulopathy".

Hint 110

Highlights associated with this condition include:

1. Release of TF or thromboplastic agents (placenta- obstetric complications, cytoplasmic granules of leukemic cells, carcinomas and procoags, bacterial sepsis induced monocle release of TF).

2. Widespread injury to ECs.

Front 111

Pathophysiology of Disseminated Intravascular Coagulation (DIC)

Back 111

In an acute setting the concern is primarily related to bleeding diathesis, while in contrast, chronic complications relate to thrombotic activation. On top of severe pathophysiological states, DIC will result in an increase in fibrin degradation products (e.g. D-dimer), as well as a severe drop in blood pressure (hypotension), and ultimately, shock.

Hint 111

Front 112

Describe the importance of the endothelium in regards to cardiovascular pathology

Back 112

The vessel wall is made of three layers. The tunica intima is made up of the endothelium and basement membrane, a monolayer, and this serves as a barrier between the intravascular space and anything behind it (media layer, adventitia, extravascular space). The middle later is the tunica media, and it is a thick stack of vascular smooth muscle cells – these are responsible for vessel activity and respond to signals from vasoconstrictors/vasodilators. The adventitia is the most distal from the lumen. The Take Home Message from this slide is that the structure of the wall varies greatly between different types and sizes of vessels. The endothelium can inhibit or promote smooth muscle activity and the coagulability of the blood, platelet interactions – Dr. Tilan said that the endothelium controls everything within the vasculature.

Front 113

What is Infarction? How does it develop?

Back 113

Infarction is defined as an area of ischemic necrosis due to occlusion of arterial supply or venous drainage.

This primarily occurs from thrombotic/embolic events leading to arterial occlusion. Other initiating factors include local vasospasm, swelling of atheroma (hemorrhage within a plaque), and compression of a vessel (tumor). Classification of infarcts are based on their color (hemorrhage)- red/white; and the presence of microbial infection infection- septic/bland.

Hint 113

The development of an infarct and subsequent complications are wide ranging. Factors that contribute are the:

1. Nature of vascular supply- alternative blood supply.
2. Rate of development of occlusion- slow is less likely due to development of alternative flow (pre-existing collaterals).
3. Vulnerability to hypoxia- neurons, myocardial cells, fibroblasts within myocardium.
4. O2 content of blood- anemia, cya tonic patient, CHF.

Front 114

What is Cardiogenic Shock?

Back 114

Shock, or "CV collapse," is a final common final pathway for many severe events
(hemorrhage, trauma, burns, MIs, PEs, sepsis). In all cases, there is systemic
hypoperfusion due to reduced CO or circulating BV --> hypotension, impaired
tissue perfusion --> cellular hypoxia (initially reversible, if sustained -->
irreversible tissue injury --> death.


cardiogenic: pump failure (intrinsic myocardial damage, ventricular arrhythmias, outflow obstruction)

Front 115

What is Hypovolemic Shock?

Back 115

Hypovolemic: loss of blood or plasma (hemorrhage, sever burns, trauma).

Front 116

What is Septic Shock?

Back 116

Septic: systemic microbial infection (gram negative endotoxins, also gram positive and fungal).

This form is first among deaths in ICUs, resulting from the spread of localized infection into the blood stream. This mostly occurs with gram negative endotoxins, though analogous molecules can be found on gram positive bacteria and fungi.

When the bacterial wall LPS is released following cell walls degradation, the toxic FA core and polysaccharide coat unique to species induce an inflammatory response. This could lead to systemic vasodilation (hypo perfusion), pump failure, and even DIC (EC injury, activation of coagulation factors).

Septic shock has a 25-50% mortality rate and is associated with multi-organ system failure (liver, kidneys, CNS).

Hint 116

Front 117

What is Neurogenic Shock?

Back 117

Neurogenic: anesthetic/spinal cord injury- lose vascular tone, peripheral pooling of blood.

Front 118

What is Anaphylactic Shock?

Back 118

Anaphylactic Shock is a specific form associated with generalized IgE hypersensitivity, which results in systemic vasodilation and increased vascular permeability. Ultimately, this widespread vasodilation increases capacity of vascular bed and brings about hypo perfusion and cellular hypoxia to other tissues.

Front 119

DESCRIBE Shock as a Progressive Disorder

Back 119

If left unattended, shock can result in death because it is a progressive disorder that develops through stages.

Nonprogressive Stage: compensatory mechanisms activated, perfusion maintained, primarily affecting cardiac, cerebral, pulmonary systems.

Progressive Stage: tissue hypoperfusion (hypoxia) and onset of worsening of circulatory and metabolic imbalances, frequently with the patient in a confused state and decreased urine output, reflecting renal damage.

Irreversible Stage: tissue/cellular injury too severe, possibly with ischemic bowel allowing flora into circulation (superimposed endotoxic shock), renal shutdown due to acute tubular necrosis compounding in a state that cannot be corrected by hemodynamics.

Front 120

EXPLAIN how factors that influence cardiac output and peripheral resistance ultimately affect blood pressure.

Back 120

Hint 120

Front 121

DISTINGUISH True from False Aneurysms.

Back 121

Aneurysms are localized abnormal dilations on the vessel or heart, primarily due to a weakened wall.

TRUE Aneurysms are bound by the vascular wall, e.g., athersclerotic, congenital vascular aneurysms, and left ventricular after a myocardial infarction.

FALSE Aneurysms occur with a break in the wall, leading to an extravascular hematoma that communicates with the intravascular space.

Hint 121

The most common cause is atherosclerosis via medial destruction secondary to plaque formation in the intima, primarily and abdominal aortic aneurysm.

The clinical course is dependent on size, location, and can lead to rupture, obstruction, embolism, impingement, and formation of a mass.

Due to the systemic nature of atherosclerosis, individuals with abdominal aortic aneurysms are at an increased risk for ischemic heart disease and stroke.

Front 122

EXPLAIN Congestive Heart Failure as a common endpoint of heart disease.

Back 122

Heart is no longer able to pump blood.

Adaptive mechanisms include neurohumoral responses, hypertrophy (primarily because cardia muscle fibers do not proliferate), and dilation (think preload!).

In the presence of a pressure load, an increase in the thickness of muscle fibers that constitute the wall without an increase in the chamber will develop- "concentric hypertrophy".

With a volume load, however, the length of cardiac muscle fibers will increase along with diameter. This increase in size and thickness is characterized as eccentric hypertrophy.

Hint 122

In general, hypertrophy has benefits in the short term, but over time, the increased O₂ requirements predispose the heart to ischemic injury.

When sympathetics and myocyte hypertrophy are insufficient, dilation (chamber enlargement) occurs in order to increase preload.

In a state by which cardiac output meets the oxygen demands, and individual has achieved compensated heart failure. BUT, with increases in wall tension over time, and an underlying oxygen demand, an individual will reach a phase of decompensated heart failure. Here, the myocardium is unable to meet the demands of the body. Insufficient oxygen supply is not the only effect on tissues. In particular, backward

Front 123

COMPARE the different clinical course outcomes of ischemic heart disease.

Back 123

Ischemic Heart Disease is an imbalance in myocardial O₂ demand and supply. It is commonly caused by a narrowing lumen of coronary arteries associated with atherosclerosis, termed "Coronary Heart Disease".

Hint 123

Depending on the severity of the narrowed lumen, as well as cardiac compensation, any one of four syndromes can develop.

1. Angina Pectoris: qualifies as a 75% reduction in the lumen leading to intermittent chest pain due to transient reversible myocardial ischemia; forms include Stable (exertion), Variant (rest or in sleep), and Unstable (increased frequency of pain)- platelet aggregation, vasoconstriction, and formation of mural thrombus → reduce O2.

2. Acute MI ("heart attack"): under complete occlusion.

3. Sudden Cardiac Death: is associated with pulmonary embolism, ruptured aortic aneurysm, and infections, The myocardium is predisposed to such an event due to chronic ischemia, which can lead to ventricular arrhythmias, in particular ventricular fibrillation, the most common cause of death.

4. Chronic Ischemic Heart Disease with Congestive Heart Failure ("Ischemic Cardiomyopathy"): is a progressive form associated with the degeneration of the myocardium with angina or myocardial infarction.

Front 124

EXPLAIN the therapeutic potential of Angiogenesis in relation to Cardiovascular Disease.

Back 124

Hint 124

Insufficient vascularization is relevant to our discussion of ischemic heart disease/ cardiac failure, specifically an imbalance in capitulary-to-cardiomyocyte fiber ration, primarily due to reduced VEGF levels.

Physiological angiogenesis is a tightly regulated process, activated in certain physiological processes and during tissue regeneration.

Deregulation of the angiogenic processes has been implicated in a growing number of diseases.

Front 125

What is Intimal Thickening?

Back 125

A healing response to vascular injury. A process where SMCs will migrate, proliferate, and synthesize and deposit ECM, ultimately forming a neointimal.

In this new layer of the vessel wall, SMC essentially undergo dedifferentiation, losing the ability to contract.

However, these cells can return to a quiescent state with overlying EC layer development. An exaggerated healing process can lead to intimal thickening → stenosis or occlusion.

Front 126

What is Atherosclerosis?

Back 126

Atherosclerosis involves the accumulation of fatty streaks. These are made up of foam cells and are not raised, and therefore do not disturb flow.

This can progress with intimal thickening and lipid accumulation to form an atheroma (intimal lesion from fatty streak): lipid core covered by fibrous cap.

Hint 126

Front 127

Atheroma vs. Plaque

Back 127

Atheroma: intimal lesion from a fatty streak with a lipid core covered by a fibrous cap.

Plaque: comprised of cells, ECM, and Intra- and Extra-cellular lipid.

In general, plaques are more prevalent in the abdominal aorta more so than in the thoracic aorta

Front 128

What is this showing?

Back 128

Front 129

What is this showing?

Back 129

Front 130

Explain the vascular remodeling involved in Atherosclerosis

Back 130

Vascular remodeling is a common occurrence within many plaques undergoing calcification. Advanced lesions are of concern for rupture, ulceration or erosion of luminal surface (thrombogenic), hemorrhage into a plaque, or aneurysmal dilation due to pressure or ischemic atrophy of the underlying tissue.

Further, atherosclerosis is multifactorial, polygenic disease process.

Risk factors include hyperlipidemia (cholesterolemia)- LDL/HDL, diet, hypertension, diabetes, cigarette smoking, and endothelial dysfunction (duh).

Front 131

What factors influence the ability to regulate blood pressure/ develop hypertension?

Back 131

Regulation of blood pressure is a complex equilibrium maintained and influenced by several factors. Both genetic and environmental components contribute to hypertension.

Front 132

What is Myocardial Infarction?

Back 132

MI refers to an area of myocardial necrosis caused by local ischemia, which is often due to coronary artery thrombosis.

Necrosis of cardiomyocytes begins within 20-30 minutes after an occlusion, primarily affecting the subendocardial region of the heart.

A zone of necrosis then extends to the mid- and subepi- areas of myocardium over the next couple of hours.

Thrombolytic agents, however, can limit the size of infarct.

The location and severity of the infarct is determinedly location of the vascular occlusion along with the anatomy of the coronary vasculature.

Hint 132

Clinical presentation is associated with severe chest pain, which may radiate, and may last from several hours to days afterward.

Patients are often diaphoretic and can develop pulmonary edema/congestion. If >40% of the ventricle is involved, an individual may go into cardiogenic shock. However, up to ⅓ of patients can experience MI without chest pain. These silent infarcts are common in those with diabetes and hypertension, and in the elderly.

Surviving sudden cardiac death, a fraction of patients will experience no further complications, while the majority of patients develop cardiac arrhythmias, left ventricular failure, rupture of the wall, or thromboembolism.

Front 133

What is Dilated Cardiomyopathy?

Back 133

Progressive form of cardiac hypertrophy associated with dilation and cardiac systolic dysfunction.

Several environmental factors can abuse this "congestive cardiomyopathy", including viruses, alcohol abuse, and chemotherapeutic agents.

Also present is a genetic component, most commonly associated with cytoskeletal proteins such as dystrophin.

These factors contribute to a diseased state of ineffective contraction, which is quantified as an ejection fraction of 25% or less, and tends to affect all chambers of the heart.

Hint 133

Front 134

What is Hypertrophic Cardiomyopathy?

Back 134

This form of cardiomyopathy is commonly referred to as asymmetric septal hypertrophy or idiopathic hypertrophic sub aortic stenosis.

Classic features include myocardial hypertrophy, abnormal diastolic filling, and (in many cases) intermittent ventricular outflow obstruction or the inability to fill a hypertrophic left ventricle during diastole.

Hint 134

In contrast to the weak contraction in dilated cardiomyopathy, here, powerful hyperkinetic contractions rapidly expel blood from ventricular cavities. However, the stiff, thick-walled ventricle causes impaired diastolic filling.

There is also a hereditary component related to the various sarcomeric contractile proteins. Therefore, given this variability in affected proteins, there is a heterogeneity with respect to a locus or allele, which affects risk for mortality. With impaired filling during diastole, individuals are predisposed to ventricular arrhythmias and sudden death.

Front 135

What is Restrictive Cardiomyopathy?

Back 135

This form of cardiomyopathy is primarily associated with a decrease in ventricular compliance, which results in impaired ventricular filling during diastole without a forceful systole.

A common cause of this form is endomyocardial fibrosis.

It is the rarest of the 3, and is characterized by a stiff and inelastic ventricle that fills only with great effort. Thus, over time, myocardial contractility declines.

Front 136

Define:
1. Thrombus
2. Thrombosis
3. Embolism
4. Coagulation
5. Hemostasis
6. Primary Hemostasis
7. Coagulation Cascade
8. Fibrinolysis

Back 136

Hint 136

Front 137

How are Platelets activated?

Back 137

The granules are released upon activation, and their contents are important in the clotting process.

They synthesize Thromboxane A2 which is an very powerful vasoconstrictor and platelet aggregating substance.

Front 138

Step 1 in Platelet Activation: Adhesion

Back 138

Dysfunctional endothelium expresses different factors that attract platelets, bind to glycoproteins on the platelet surface, and allow them to stick.

One of these is Collagen, which lies under the endothelium (as part of the sub endothelial tissues) and is exposed upon injury.

Another key substance is vWF, which binds to both collagen and the platelets and helps the platelet to adhere. vWF binds GP-Iba on the platelet's surface. vWF is especially useful in helping with platelet adhesion under conditions of high shear stress on the endothelium, which occurs due to fast moving blood flow.

It is important to remember that adhesions is PASSIVE and REVERSIBLE. It requires no expenditure of energy, and adhered platelets can still unstick and return to the bloodstream unaffected.

Hint 138

Front 139

Step 2 in Platelet Activation: Activation

Back 139

Can be activated by both external and internal factors.

External: binding of adhesion factors like collagen or vWF results in signal transduction within the platelet.

Internal: further stimulating receptors after their release (i.e. ADP or thromboxane)

Hint 139

Platelet activation results in an increase in cytosolic calcium concentration, which causes a shape change (more spherical, pseudopods).

Activated platelets also express new substances on their outer membrane making it easy for them to interact with their environment in different ways.

Activated platelets also secrete substances to help further the process of thrombosis. The secretion of ADP helps to accelerate the activation process. The platelets also produce and secrete thromboxane A2, which also helps to speed the activation process and activate and recruit more platelets. Once a platelet is activated, it cannot be un-activated and return to the bloodstream. For a platelet, activation is the point of no return.

Front 140

Step 3 in Platelet Activation: Aggregation

Back 140

The final step in platelet activation.

IRREVERSIBLE

The key to aggregation is the glycoprotein from the activation step, GPIIb/IIIa. This glycoprotein, newly expressed on the outside of the platelet, recognizes and binds to fibrinogen.

This causes cross linking with the fibrinogen and the platelets, and also helps to recruit more platelets to come be part of the clot.

As contractile elements of the platelets are activated, the clot will retract back towards to injured vessel.

Front 141

Name the 3 Stages of Hemostasis

Back 141

Front 142

Stage 1 of Hemostasis: Primary Hemostasis/Platelet Plug Formation

Back 142

Front 143

Stage 2 of Hemostasis: Blood Clotting/Coagulation

Back 143

A clot is simply a mesh of fibrin proteins in the blood that trap the formed elements of blood (i.e. RBCs). Formation of this clot is dependent on the cleavage of fibrinogen to fibrin, and this involves the coagulation cascade.

Hint 143

Note that many of the steps in the coagulation cascade require Ca+ and platelet phospholipids to aid in the enzymatic conversions.

These platelet phospholipids include the phosphatidyl serine, which moves to the outer leaflet of the membrane and is a docking site for coagulation factors.

Vitamin K is also a crucial part of the coagulation cascade, and it is required by the liver to synthesize 4 of the 30 factors involved in the coagulation cascade.

Front 144

Fibrinolysis

Back 144

Important to realize that vascular injuries are local events, so the majority of a vessel is still healthy and producing anti-thrombogenic factors (antithrombin, NO, prostaglandins, and heparin).

Blood flow past the affected area brings these anti-thrombogenic factors in contact with the clot. This anti-caogulatory effect of blood flow is the reason that stasis contributes to clotting disorders.

The clot is also self-limiting, as thrombin can get caught in the fibrin mesh and be unable to activate more fibrinogen.

Hint 144

The actual breakdown of the clot is the result of an enzyme called plasmin. Plasmin dissolves fibrin.

Plasmin is the activated form of plasminogen, and is formed through the action of several enzymes including thrombin, factor XII, and tPA.

tPA is released endogenously by the endothelial cells within 2 days of injury, and it contributes to plasmin formation and clot breakdown. Clot breakdown normally takes a couple of days.

Actual repair of the vascular injury is again due to the platelets. When activated, they release PDGF, which stimulates the growth of fibroblasts, endothelial cells, and smooth muscle cells.

Front 145

Thromboembolic Disorders

Back 145

Disorders with too much clotting.

Blocking blood flow to an organ results in that organ becoming ischemic and dying.

Treatment is aimed at disrupting the clot: exogenous tPA, warfarin, streptokinase, heparin, aspirin.
-Aspirin inhibits the formation of thromboxane A2, and thus partially turns off platelets without seriously endangering the entire hemostatic response.

Front 146

Thrombocytopenia

Back 146

A bleeding disorder related to a decrease in the number of platelets.

Front 147

Hemophilia

Back 147

Recessive pattern of inheritance.

The most common form of hemophilia is hemophilia A, which is due to a lack of Factor VIII.

Hemophilia A is treated with synthetic or recombinant factor VIII.

Front 148

Von Willebrand's disease

Back 148

Bleeding disorder caused by a lack of vWF.

Hemostasis is more difficult without vWF, but it is not impossible.

Front 149

Idiopathic Thrombocytopenia Purpura (ITP)

Back 149

Bleeding disorder.

Autoimmune disease that results in a platelet deficiency.

Front 150

Disseminated Intravascular Coagulation (DIC)

Back 150

Bleeding disorder.

The activation of many inflammatory pathways in the body that results in the coagulation cascade being turned on in a disseminated way throughout the body.

DIC is common in shock, and results in bleeding because the body is less able to respond to actual injury if all of the coagulation cascades have already been turned on.

Front 151

Atherosclerosis and Thrombosis

Back 151

Hint 151

Maximal coronary blood flow is affected with only a 40-50% occlusion, which is why exercise-induced angina is common.

The body can also compensate for occlusions by dilating vessels downstream. Remember, the most resistance is found in arterioles!

Front 152

Pathophysiology of Shock

Back 152

In shock, the organs do not receive sufficient oxygen, and therefore build up metabolites and affect acid/base balance.

In addition, the imbalance of oxygen supple and demand leads to both appropriate and inappropriate metabolic changes (compensation for lack of oxygen actually leads to further problems).

The lack of oxygen leads to the conversion from aerobic to anaerobic metabolism and has cellular effects: ion pump dysfunction, leakage of intracellular contents, intracellular pH dysfunction.

All of these problems ultimately lead to cell death and end organ dysfunction. When all organ systems begin failing, the patient is in Multiple System Organ Failure (MSOF), and can die.

Hint 152

Front 153

3 Stages of Shock

Back 153

Hint 153

1. Compensated- the body will work to maintain BP and restore BF.
- if due to low preload (hypovolemia), compensation includes tachycardia and vasoconstriction in an effort to bring up the mildly decreased BP back to normal.
-if due to low after load, that means that there are distributive problems (low peripheral resistance), and compensation will involve peripheral vasodilation and hyper dynamic state in an effort to perfuse the vital tissues.

2. Progressive- when compensation fails, your body gets worse and ends up in this decompensated stage. This is when inadequate BF and the switch to anaerobic metabolism occur. You also begin to see the common signs of multiple end organ dysfunction.

3. Irreversible- in the long term, progressive end organ dysfunction leads to anuria, brain dysfunction due to progressive acidosis and decreased CO, resulting in agitation, obtundation (non-responsiveness), coma, and death. There is nothing that can be done to save the patient.

Front 154

Hypovolemic Shock

Back 154

This low volume decreases preload on the heart, which decreases cardiac output and results in shock.

Hint 154

Once the body detects a sudden decrease in blood volume (and blood pressure), it will try to compensate to bring BP back to normal.

The baroreceptor reflex and autonomic nervous system (renin, ADH, aldosterone) will kick in and produce increased TPR via vasoconstriction, elevation of HR, decrease in SV, and restriction of flow to places where blood is not as acutely needed. In the short term, this compensation delivers enough CO to the vital organs. In the long term, however, the body will need to restore BV to its normal state.

Front 155

Cardiogenic Shock

Back 155

Results from pump failure due to anything affecting the heart's ability to fill, contract or pump blood. Thus, there is inadequate CO.

Hint 155

Once the body detects a decrease in CO, it activates SNS to retain fluids. However, unlike in hypovolemic shock, this compensatory mechanism is both good and bad.

It is good because it helps increase CO, but at the same time you are making your already problematic heart work harder to pump harder when you retain fluids (and can cause pulmonary edema!).

Ultimately, by trying to help the heart, you can often times make it worse, which is why heart failure and cardiogenic shock is considered to be progressive.

Front 156

Obstructive Shock and Sever Pulmonary Embolism

Back 156

Results from an obstruction, such as a pulmonary embolus, which prevents blood from entering the left heart.

If there is pooling of blood, platelets can aggregate and bind fibrin to form the venous thrombus. This thrombus may dislodge and travel through the right heart to the lungs, where it can obstruct the pulmonary artery and lead to a pulmonary embolism.

Hint 156

Note: obstructive shock is particularly common with diabetics, those who travel on international flights, and pregnant women because they are more likely to have less blood moving in their legs and can end up more easily with deep vein thrombosis (DVT).

Front 157

Distributive Shock

Back 157

Results from a severe decrease in systemic vascular resistance/total peripheral resistance. This is usually caused by anaphylaxis, which causes vasodilation through the release of cytokines and inflammatory mediators.

Distributive shock may also be associated with increased CO but this *blood does not perfuse the necessary organs because of these cytokines and mediators*

Hint 157

Front 158

Anaphylactic Shock

Back 158

A type of distributive shock caused by a *hypersensitivity reaction* to an allergen in a previously sensitized patient.

Angioedema- puffy face caused by edema in the dermal subcutaneous tissue.

Effects lead to increased vascular permeability, relative hypovolemia (lose control of fluids and lose it out of vascular space), decreased CO, decreased tissue perfusion, impaired cellular metabolism and organ dysfunction.

Hint 158

Shock Treatment: Epinephrine to ensure airway latency; oxygen, IV fluids, antihistamines, bronchodilators, steroids

Front 159

Septic Shock

Back 159

Image shows the progression of the inflammatory response, which leads to increasingly critical levels of sepsis (infection).

There is a SIGNIFICANT MORTALITY associated with septic shock: half of in-hospital deaths are associated with sepsis! This sepsis is not just a consequence of the underlying disease state but of being exposed to invasive procedures and other sick people. Furthermore, many hospitalized patients have reduced immunocompetence, which further increases the chance of septic shock.

Hint 159

Front 160

Shock: Clinical Presentation

Back 160

Hint 160

In general, if the shock is associated with TRAUMA, the cause is most likely Hypovolemic (hemorrhagic) or Distributive (neural damage).

If the shock develops POST-OPERATIVELY, the cause is most likely Hypovolemic (hemorrhagic/third-spacing).

If the shock develops in DEBILITATED HOSPITALIZED PATIENTS, the cause is most likely Septic.

Furthermore, it is necessary to evaluate all patients for risk factors for MI and consider Cardiogenic cause, because this can further exacerbate any organ dysfunctions or complications due to shock.

Front 161

Treatment of Shock

Back 161

Keep in mind, however, that there is a cost to compensation and restoration of blood pressure. We discussed this with cardiogenic shock earlier: giving fluids to improve blood pressure also makes the heart work harder, so cardiogenic shock is difficult to manage.

Similarly, fluid resuscitation does not always work in distributive shock- you need to manage HOW this fluid is distributed because you need it to go to the organs that are the least perfused!

Front 162

Compensatory Response to Sudden Changes in Blood Pressure

Back 162

The fastest response to this sudden pressure change is by baroreceptors. Chemoreceptors are slower to respond because it takes longer to affect the chemistry of the blood (takes longer for oxygen to decrease, CO2 to increase, and for pH to decrease).

The CNS ischemic response takes even longer since it takes a while for the brain to become ischemic. However, when this response happens, it's very powerful- we need our brain to survive!

These compensatory mechanisms help our bodies maintain blood pressure in the short term, but ultimately, the renal-blood volume pressure control has the greatest gain and responsiveness because in the long term, the real solution is restoring blood volume.

Hint 162

Front 163

Mechanisms for Hormon Signaling: Steroid vs Peptide

Back 163

Hint 163

Front 164

Anterior Pituitary

Back 164

"Pars Distalis"/ "Adenohypophysis"

neuronal cell bodes make PEPTIDES in the HT. When an ap travels down the axon, the terminal buttons release their vesicles into primary capillary plexus. The neuro-hormones (TRH or GnRH) drift down into the secondary capillary plexus where they bind to specific cells in the AP, signaling them to produce their hormone.

-Only AP cells that make a certain hormone have receptors for the HT releasing hormone- so only TSH producing cells have receptors for and respond to TRH

Adeno= gland (the cells in the AP are glandular and not neural)

Hint 164

Front 165

Posterior Pituitary

Back 165

"Pars Nervosa"/ "Neurohypophysis"

cell bodies that make ADH and OT- produced in neuronal cell bodies and stored in axon termini until we need them.

Action potential fuses vesicles to membrane and releases them into the systemic blood supply so they can go ANYWHERE
-the PP does not have a local portal system like its friend, the pars distalis (since neural tissue is producing these hormones, we call it the neurohypophysis)

because PP hormones are released into the systemic circulation, serum concentration in the PP would be the same as in some random vein

Front 166

HPA Feedback Loops

Back 166

The endocrine system achieves balance through negative feedback.

Front 167

Hyperpituitarism

Back 167

Generally the result of pituitary adenomas. Pituitary adenomas are problematic because the gland is encased by the rigid sphenoid bone.

Tumors are basically many copies of a single crazy cell. So tumors in the pituitary can take on the cell type of hormone-producing cells of the pituitary- so we see prolactinomas, GH-omas, ACTH-omas, LH?FSH-omas, etc

Hint 167

GENERAL RULE- usually only one hormone is being overproduced- although there are special cases of tumors that produce multiple hormone types. So whatever adenoma you have, expect to see MORE of this cell's hormone product and LESS of every other hormone type produced in that region (because the tumor invades the space taken up by those other hormone-producing cells)

A major concern with adenoma is brain volume and hormone imbalance- its a benign tumor so we aren't concerned about invasion or metastasis!

Front 168

Hypopituitarism
-Null Cell Adenoma
-Ischemic Necrosis
-Ablation

Back 168

Hint 168

Null Cell Adenoma: so half of the cells in the AP are not producing any hormone, just kinda chill in in case we need to recruit them to make more of a certain cell type- so therefore such Null Cells have a 50% chance of being responsible for the adenoma
-NO hormone overproduced
-EXPECT TO SEE LESS OF EVERY HORMONE PRODUCED IN THE AP

Ischemic Necrosis: decreased blood flow to gland causing death of tissue- AP is uniquely at risk of this due to the low-pressure portal system that feeds it. This is venous blood so it has already been used once. The portal system feeding AP cannot auto regulate the way normal vasculature can. So death of tissue= can't produce the hormones.

Ablation: cutting out adenoma- taking part or all of the other pituitary tissue with it. You are going to get lower levels of hormones as a result

Front 169

Posterior Pituitary Syndromes

Back 169

we don't see adenomas here because the PP is neural tissue and neurons typically don't develop tumors because they are post-mitotic

examples:
-central DI (too little ADH)
-SIADH (too much ADH)
-OT deficiency

Front 170

Hypopituitarism
vs.
Panhypopitutarism
vs.
Hyperpituitarism

Back 170

Hypopituitarism: results from infarction
-affect blood flow to AP (can be Sheehan's, or just a general hemorrhagic shock causing tissue death)

Panhypopituitarism: generally results from trauma to the pituitary stalk
-you are going to absent in all of FLATPiG

Hyperpituitarism: generally a result of the benign, slow growing adenoma that we have been discussing

Front 171

Pituitary Adenoma
-What do patients present with?

Back 171

Present with:
1. Headache
2. Visual Changes
3. Hyposecretion of Neighboring AP hormones
-will notice and present with headache LONG before the endocrine changes become apparent

Hint 171

The normal gland is populated by different cell types producing hormones with different staining patterns, some dark and some light.

In a section of pituitary adenoma, there is a population of only one cell type and the preparation looks mch more homogenous

Front 172

Bilateral Hemianopsia

Back 172

Result of pituitary adenoma

The idea is that the tumor is pressing on a nerve and preventing signals from running through it

The visual field coming from the right lateral field lands on the medial side of the right retina and lateral side of left retina
-this allows the two eyes to work together to form an image

Tumor in the right side of the visual field causes loss of the medial part of the retina, which corresponds to the lateral visual field, and this is the vision you lose as a result of pituitary adenoma

BASICALLY, you lose peripheral vision

Hint 172

Bilateral Hemiansopsia is PATHOGNOMONIC for pituitary adenoma- meaning that when you see this presentation, you can be sure that it is caused by a pituitary adenoma

Front 173

Hypo-Growth Hormone
vs.
Hyper-Growth Hormone

Back 173

Hyposecretion of GH causes *pituitary dwarfism*
-GH causes skeletal tissue growth in children and so these people end up very short- but still appear proportional

Hint 173

Hypersecretion of GH
- in children, these people grow to be big- this is called *gigantism* when occurring in children (still appear proportional)
-in adults, don't get any taller but bones still get wider by apposition- *acromegaly* is the description of the enlargement of the flat bones of the face when GH is over-secreted in adulthood

Front 174

Acromegaly

Back 174

excess growth in chin, forehead, zygomatic process
-the face continues to grow normally through life but NOT to this extent

Hint 174

Fingers widen but don't elongate, giving them the stubby appearance seen here

Front 175

Prolactinomas

Back 175

The most common hormone secreting adenoma.

Hypersecretion of prolactin results in milk production, or galactorrhea, in women but not men due to a lack of milk producing tissue

Other side effects in women are amenhorrea (no menstruation), hirsutism (excess hair), and osteopenia resulting from bone breakdown to release calcium for milk production

Front 176

Posterior Pituitary Hormones

Back 176

Both of these hormones are short peptide hormones.

Keep in mind that if there is no receptor, a hormone cannot have its effect. Soooo, relating the receptor controls the ffect of the hormone.

Hint 176

Front 177

SIADH (Syndrom of Inappropriate ADH)

Back 177

Here, ADH levels are too high. This causes water retention, resulting in low blood osmolality and hyponatremia.
Urine will appear concentrated.

Causes for SIADH include an ADH secreting tumor which will slowly dilute the blood and gradually lower sodium concentrations.

Front 178

Diabetes Insipidus

Back 178

DI is either a central inability to produce adequate ADH (neurogenic) or ADH insensitivity at the kidneys (nephrogenic) resulting in large amounts of very dilute urine.

ADH has a very short half life, making it difficult to treat patients. It is a peptide hormone, and can't be ingested, and since it has such a short half life it would have to be injected ver often.

Synthetic ADH will not help patients with nephrogenic DI!

Front 179

Describe the Thyroid Gland

Back 179

The thyroid gland is a bilobed structure with each lobe resting lateral to the trachea and connected by an isthmus of tissue.

It contains many follicles that surround colloid which contains thyroid hormone precursors. These are the areas that thyroid hormone is produced

Hint 179

Parafollicular cells secrete calcitonin

TRH release from the HT stimulates release of TSH from the AP which stimulates the release of T3/T4 from the gyroid gland.

Thyroid hormone inhibits TRH and TSH secretion.

Front 180

Thyroid Hormone

Back 180

Is lipophilic and therefore requires a carrier protein to travel around the body in the blood, namely thyroxine-binding globulin, thyroxine-binding prealbumin, or albumin.

Thyroid hormone controls cell metabolism, affects heat control, oxygen consumption, and growth and function.

Front 181

Back 181

Front 182

Hyper-Thyroidism

Back 182

Graves Disease: involves an antibody (IgG) binding to the TSH receptor causing lots of production and secretion of thyroid hormone. Overstimulation also causes enlargement of the thyroid.

Toxic Goiter: an adenoma that constantly secretes thyroid hormone.

TSH Secreting Adenoma: in the pituitary, would result in hyperthyroidism.

Hint 182

Excess TH upregulates catecholamine receptors. Those with hypothyroidism can be expected to exhibit symptoms of anxiety, irritability, difficulty sleeping, sweating, fast irregular heartbeat, and other symptoms of overactivity.

Treatments include beta blockers, anti-thyroid meds, radioactive iodine treatments, and surgery.

Front 183

Hypo-Thyroidism

Back 183

Iodide is used in thyroid synthesis, so *iodine deficiency* should cause hypothyroidism

Hypothyroid patients will show signs of increased sensitivity to cold, depression, muscle weakness, mental retardation in utero and children.

Hint 183

Hashimotos: autoimmune destruction of the thyroid. Follicle centers get destroyed, hindering thyroid hormone synthesis and release.

Front 184

Parathyroid Glands

Back 184

4 small glands located SUPERIORLY and INFERIORLY posterior to the 2 lobes of the thyroid.

They produce PTH, which is involved in maintaining serum calcium levels and phosphate excretion.

PTH is released in response to low serum calcium levels and stimulates bone breakdown to release stored calcium.

As a safeguard against depleting our calcium stores and losing too much bone density, PTH also acts at the kidney to stimulate calcium reabsorption and incite activation of vitamin D which increases calcium absorption in the gut

Hint 184

Front 185

Hyperparathyroidism
vs.
Hypoparathyroidism

Back 185

Front 186

Back 186

Front 187

Adrenal Cortex
vs.
Adrenal Medulla

Back 187

Cortex: outer, steroid-producing (lipophilic)

Medulla: inner, produces hydrophilic catecholamines that utilize adrenergic cell surface receptors.
-the adrenal medulla receives input from preganglionic sympathetic fibers, which stimulate catecholamine secretion directly into the blood for an immediate fight or flight response.
-The blood supply through the adrenal glands goes from the external capsule, through the three cortical zones to reach the medulla, and ultimately drain into a central vein.

Front 188

Feedback Control of Glucocorticoid Synthesis and Secretion

Back 188

Hint 188

Front 189

Back 189

Front 190

Back 190

Front 191

Back 191

Front 192

Back 192

Hint 192

Front 193

Back 193

Front 194

Back 194

Hint 194

Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones (chemicals produced by the body that regulate organ function), primarily cortisol; but may also include impaired production of aldosterone (a mineralocorticoid), which regulates sodium conservation, potassium secretion, and water retention.[1][2] Craving for salt or salty foods due to the urinary losses of sodium is common.[3]
Addison's disease and congenital adrenal hyperplasia can manifest as adrenal insufficiency. If not treated, adrenal insufficiency may result in severe abdominal pains, vomiting, profound muscle weakness and fatigue, depression, extremely low blood pressure (hypotension), weight loss, kidney failure, changes in mood and personality, and shock (adrenal crisis).[4]

Front 195

Back 195

Hint 195

Front 196

Structure and Function of Adrenal Cortex

Back 196

Hint 196

Front 197

Cushing Syndrome

Back 197

Hint 197

Front 198

Conn's Syndrome

Back 198

Aldosterone enhances exchange of sodium for potassium in the kidney, so increased aldosteronism will lead to hypernatremia (elevated sodium level) and hypokalemia (low blood potassium). Once the potassium has been significantly reduced by aldosterone, a sodium/hydrogen pump in the nephron becomes more active, leading to increased excretion of hydrogen ions and further exacerbating the elevated sodium level resulting in a further increase in hypernatremia. The hydrogen ions exchanged for sodium are generated by carbonic anhydrase in the renal tubule epithelium, causing increased production of bicarbonate. The increased bicarbonate and the excreted hydrogen combine to generate a metabolic alkalosis.
The high pH of the blood makes calcium less available to the tissues and causes symptoms of hypocalcemia (low calcium levels).
The sodium retention leads to plasma volume expansion and elevated blood pressure. The increased blood pressure will lead to an increased glomerular filtration rate and cause a decrease in renin release from the granular cells of the juxtaglomerular apparatus in the kidney. If a patient is thought to suffer from primary hyperaldosteronism, the aldosterone:renin activity ratio is used to assess this. The decreased renin levels and in turn the reactive down-regulation of angiotensin II are thought to be unable to down-regulate the constitutively formed aldosterone, thus leading to an elevated [plasma aldosterone:plasma renin activity] ratio (lending the assay to be a clinical tool for diagnostic purposes).

Front 199

Congenital Adrenal Hyperplasia

Back 199

Hint 199

Front 200

Insulin action on cells
-effects of excess insulin
-effects of lack of insulin

Back 200

Insulin is the signal to your body that you are in a "well-fed" state; thus, its actions are a response to that signal. After insulin binds its receptor on the surface of a target cell (typically myocytes or adipocytes), that receptor initiates a signal transduction cascade, which results in 3 key processes:

1. ATP Production:
-GLUT4 is recruited and inserted into the cell membrane. Glucose enters passively thru it and is immediately phosphorylated to Glc-6P. This ensures that the chemical gradient driving Glc into the cell is maintained for continued influx. This allows for Glc-transport to only be limited by the number of GLUT4's in the membrane. Glc-6-P is stored as either glycogen in the liver or fat in adipocytes (if ATP is in excess) or its converted to ATP (if ATP is lacking).

2. Protein Synthesis/Repair:
- insulin receptors signal AA to be taken up by cells

3. K+ Influx:
-ATP generation drives Na-K ATPase pumps, which drive K+ into cells

Hint 200

Front 201

How is blood glucose controlled?

Back 201

Blood glucose is controlled by the balance between insulin and glucagon in the blood- which are peptide hormones secreted from β and α cells, respectively, within pancreatic Islets of Langerhans.If you just ate a big meal and BG is high, β-cells will increase insulin secretion into the blood, causing increased glucose uptake into cells & tissues.

If you are starving and BG is low, β-cells stop insulin secretion, decreasing insulin in the blood, causing α-cells to secrete glucagon into the blood, stimulating the liver to convert glycogen into glucose & release it into the blood.

Hint 201

↑ BG > ↑ Insulin > Glucose uptake into tissues/cells

↓BG > ↓ Insulin > ↑Glucagon > Glucose released into blood

**Glucagon secretion is due to ↓ Insulin levels in blood!!! NOT due to ↓ BG!!!**

Front 202

Insulin Secretion

Back 202

Insulin is secreted from β-cells in a very specific way. Increased BG concentration results in passive glucose uptake through GLUT2 transporters, constitutively expressed and inserted into the β-cell membrane.

The glucose is used to make ATP, which binds and closes ATP-gated K-channels. Intracellular K+ concentrations build up, as it can no longer exit via the channels. This results in cellular depolarization, activating the V-gated Ca-channels. Ca+ flows into the cell, triggering insulin release into the blood.

Thus, the amount of Ca in the extracellular fluid affects insulin release, as it diffuses through open Ca-channels.

Hint 202

NB: a lot of INSULIN-RELEASING DRUGS given to diabetic patients act to close these ATP-gated K-channels

Front 203

Back 203

Front 204

Explain this Graph

Back 204

Front 205

Types of Diabetes

Back 205

Hint 205

Front 206

Diabetes Progression

Back 206

T1D:
-autoimmune disease; T cells attack and kill pancreatic β-cells-symptoms don't appear until long after the destruction begins because we actually have a surplus of pancreatic β-cells; but once enough are killed, glucose-telerance is lost, and the symptoms present

T2D:
-due to development of insulin resistance
-cells (myocytes & adipocytes) only want to take up glucose if they're not full of it already. As cells become full of glucose, they become insulin resistant. Cells that are insulin resistant require more insulin to stimulate glucose uptake. Eventually, they become non responsive to insulin, can't take up any more glucose, and BG rises.
-chronic hyperglycemia results in a large glucose influx into β-cells, leading to less insulin production. This is "Glucose Toxicity" that results in β-cell malfunction.

Front 207

Back 207

Front 208

Oral Glucose Tolerance Tests

Back 208

First, a patient is given sugar water (pure glucose ins ayer) to drink. Then the patients BG level is measured over time.

A NON-DIABETIC patient will show a BG spike (120 mg/dL), and then a rapid BG drop to their fasten level (<100 mg/dL) within 2 hours.

A patient can be diagnosed as DIABETIC if they present with a larger BG spike (>200 mg/dL) that remains high for more than 2 hours, and then it gradually drops to a higher than normal fasting level (> 126 mg/dL).


Note that either a higher spike that persists >2 hours OR a higher than normal fasting level are sufficient for diagnosis of DM

Front 209

What is pre-diabetes?

Back 209

Considered to have "impaired fasting glucose" (IFG) and/or "impaired glucose tolerance" (IGT).

A patient has IFG if their fasting BG level is 100-125 mg/dL after fasting overnight.

IGT is diagnosed when a patient's BG is 140-199 mg/dL 2-hours into an OGTT.

Both of these conditions do not fall into the "diabetic" ranges.

Front 210

Acute Complications of DM: Glucosuria & Polyuria

Back 210

Out kidney tubules have a Tmax for glucose, which limits the amount of glucose we cane absorb from the filtrate based on the number of glucose channels inserted into the tubules. That threshold is 300 mg/min.

Normally, we are able to absorb all the glucose from the filtrate, because our filtered load of glucose is less than this threshold.

Diabetics, however, have very high BG levels; thus, their filtered loads will exceed this threshold, and any glucose that can't be reabsorbed will be excreted in the urine. Glucose in urine acts as an osmotic diuretic, it binds water, and results in polyuria

Front 211

Acute Complications of DM: Hypoglycemia

Back 211

Most often occurs with T1 diabetics *take too much insulin without eating*.

A drop in BG is what makes people feel sick//ill.

Thus, T1 diabetics need to find a balance between aggressive insulin use and eating to balance their BG levels.

Front 212

Acute Complications of DM: Diabetic Ketoacidosis

Back 212

This occurs in *T1*diabetics when they take *too little insulin*.

Obviously the treatment for this is to give insulin. Without insulin, glucagon levels are very high, which leads to lots of lipolysis, resulting in an increase in ketone bodies, which will lead to metabolic ketoacidosis.

CNS depression as a result of the metabolic ketoacidosis and hypovolemia, due to polyuria, can result in *shock*!

Hint 212

Note, basically only diabetics can burn fat fast enough to end up in ketoacidosis.

Front 213

Acute Complications of DM: HHNKS or HONKS

Back 213

("Hyperosmolar Hyperglycemic Nonketotic Syndrome)

*T2* diabetics will get this because it is hyperglycemia without ketoacidosis.

This occurs when BG is SUPER high (>600 mg/dL), such that the blood becomes hyperosmolar, drawing water out of cells. When water leaves cells in the brain, the patient becomes unconscious and can die.

Death usually requires BG > 1000 mg/dL

RX= Insulin!

Front 214

Chronic Complications of DM

Back 214

Chronic hyperglycemia increases the rate of NON-ENZYMATIC glycosylation of protein. This results in large amounts of *Advanced Glycosylation End-Products (AGEs)*
-AGEs are cross-linked proteins that can no longer perform their normal function.

Hint 214

Glycosylated hemoglobin (HbA1c) is the easiest glycosylated protein to measure in the blood.

Thus, the HbA1c concentration will tell you the average blood glucose of a patient over the last week.

HbA1c is normally 4-5% and the goal for patients with DM is <7%.

This measure is considered important, because it has been shown that HbA1c is greatly correlated with chronic diabetic complications. BUT… the studies that show decreased HbA1c results in decreased diabetic complications ONLY used T1 diabetics.

Further studies that used T2 diabetics showed that lowering HbA1c and BG does NOT decrease diabetic complications or mortality.
-This indicates that the treatments for T1D and T2D must be different!!!!

Front 215

Chronic Complications of DM: Diabetic Retinopathy

Back 215

A microvascular disease (affects capillaries and small arterioles)

This is retinal damage that leads to blindness.

More common in T1D.

Front 216

Chronic Complications of DM: Diabetic Nephropathy

Back 216

microvascular disease

Characterized by narrowing of renal arterioles & glomerular capillaries

Hint 216

ACE inhibitors and ARB's are the most effective treatments
-these aren't cures, but they delay the onset of kidney failure

Front 217

Chronic Complications of DM: Diabetic Neuropathy and Cataracts

Back 217

Your Schwann cells become bloated, compressing the axons they myelin ate, and altering peripheral neural function.

Hint 217

Cataracts:
-cells lining the lens of the eye produce too much sorbitol, which acts as an osmotic diuretic, causing cellular swelling, which turns the lens opaque.

Front 218

What is COPD? What are the symptoms and characteristics?

Back 218

Asthma, Chronic Bronchitis, and Emphysema

Hint 218

Patient cannot fully exhale

Front 219

Lung Volume Comparison of a Normal Patient vs. COPD Patient

Back 219

COPD Differences:

1. Increased Functional Reserve Capacity and Residual Volume, even after maximum expiration.

2. Decreased Tidal Volume

Hint 219

The resulting trapped air inside the lungs increases normal inspiratory resistance and requires higher pressure. This is analogous to the increased effort needed to further expand an inflated balloon compared to expanding a deflated one.

Air trapping also manifests as a change in the inspiration/expiration ratio (IE ratio).
-In normal patients, the IE ratio is 2 seconds of inspiration for 4 seconds of expiration (1:2)
-a COPD patient can experience a 1:3 IE ratio because the trapped air has difficulty being exhaled

Front 220

Flow-Volume Loop for Normal vs. COPD Patients

Back 220

The obstructed patient will have:
1. Increased overall lung volume
2. Decrease inspiratory/expiratory flow

Front 221

What is the mechanism behind COPD air trapping?

Back 221

Physiological insults destroy bronchial *elastin protein fibers*.

These fibers are important in maintaining a patent airway by resisting the deformations induced by various pressure changes associated with inspiration and expiration as well as smooth muscle constriction.

With compromised elastin fibers, the airway *over expands upon inspiration* but *collapses upon expiration*, trapping air.

This elastin destruction is coupled with *mucous plugs* which exacerbate the obstruction.
-mucous production is increased upon epithelial irritation from pollutants or smoking.
-the consequence of air trapping is decreased gas exchange and thus retained CO2.
-Prolonged/excessive CO2 retention leads to metabolic acidosis, compensated by renal production of bicarbonate.

Front 222

Asthma

Back 222

Chronic Inflammatory Disorder

Hint 222

Front 223

Asthmatic Response

Back 223

Treatment is with β-agonists and anti-cholinergics, which *reduce the PNS outflow*

Hint 223

Front 224

Pathophysiology of Asthma
-Vasoactive and Chemotactic Mediators

Back 224

The initial irritant will cause a disproportionate mast cell degranulation via IgE. The contents of mast cell granules have 2 effects that contribute to asthmatic symptoms:
-Vasoactive and Chemotactic Mediators. (Both will eventually coalesce and lead to bronchial hyper-responsiveness and airway obstruction.

Vasoactive Mediators:
-cause increased vasodilation and capillary permeability. This is the fluid source of the mucous plug and airway obstruction.
-hypoxic pulmonary vasoconstriction (HPV) is an innate response to reduced alveolar ventilation caused by mucous or fluid infiltration.
-in order to maintain an adequate ventilation/perfusion ratio, pulmonary circulation is shunted to better ventilated alveoli. However, during bronchospasm and its accompanying airway obstruction, a significant portion of the lungs can become hypoxic while the remaining portion continues to be perfused at higher pressures. The combination of higher pressures and capillary permeability cause more fluid exudation, mucous production, and obstruction.

Hint 224

(occurring simultaneously)

Chemotactic Mediators:
-will induce cellular infiltration of immune cells through the new permeable capillaries.
-The positive feedback loop of the inflammatory immune response will disrupt the PNS/SNS homeostasis.
-The PNS will dominate and release toxic neuropeptides. This response can be moderated by β-agonists and anti-cholinergics.
-eventually the immune response will lead to the irreversible epithelial membrane destruction of late asthmatic response

Front 225

Membrane Destruction in the Late Asthmatic Response

Back 225

The membrane destruction comes in 3 forms:

1. Desquamation:
-the loss of epithelial cells, causing abnormal permeability and further exposure to irritants. The ciliated cells, which normally provide the upward movement of mucous to clear it out, are damaged and display reduced function.

2. Elastin Destruction:
-leads to air trapping and allows the bronchial smooth muscles to exhibit enhanced contractile ability to constrict the airways.

3. Fibrosis:
-Will increase epithelium thickness through scar tissues. This thickened membrane is an impediment to diffusion and thus gas exchange.

Front 226

COPD Risk Factors

Back 226

The largest risk factor for developing COPD is cigarette smoking.

Front 227

Chronic Bronchitis

Back 227

This is a *bronchial infection* with hyper secretion of mucous and a chronic productive cough that lasts for at least 3 out of 12 months for a least 2 consecutive years.

Hint 227

Front 228

Emphysema

Back 228

This is a permanent *enlargement of the acinars* (functional lung units) with *alveolar wall destruction*.

The destruction of the alveolar walls and loss of elastin lead to the *loss of elastic recoil*
-reduced elasticity leads to increased compliance… this manifests as a "floppy" lung that has decreased expiratory capability

Hint 228

Front 229

How does tobacco induce COPD?

Back 229

1. Nicotine causes neutrophil aggregation. Neutrophils release elastase as part of their immune response package.

2. The ROS ("free radicals") inactivate α1-antitrypsin and other protease regulators. This is the functional, acquired variant of the genetic α1-antitrypsin deficiency.

Thus the increased elastase release from neutrophils combined with anti-protease deficiency causes protease activity derangement resulting in tissue damage.

Hint 229

Note that Chronic Bronchitis is associated with irritation, inflammation, and increased mucous. Contrast that with unregulated protease activity in emphysema, leading to alveolar loss.

Eventually, the pathologies coalesce into identical symptoms. *Cor Pulmonale* is right-sided heart failure as a result of pathology in the pulmonary vasculature. When lung problems induce heart dysfunctions, the mortality is very high.

Front 230

Absorption Atelectasis

Back 230

This is a *collapsed lung combined with fluid exudation*.

Alveoli are isolated by a mucous plug and closed *pore of Kohn*, resulting in atelectasis.

This can fill with stasis fluid, causing infection. The alveoli in West Zone 3 (the lowest lung layer) are the most susceptible to this disorder because of their *lower* ventilation/perfusion ratio.
-lower ventilation increases the probability of obstruction while higher perfusion increases the chances of fluid exudation and infection.

The prevention and treatment is to OPEN the pores of Kohn through deep breaths or positive pressure breathing, which bypasses the mucous plug and restores ventilation.

Front 231

Bronchiectasis

Back 231

This disorder involves *bronchial smooth muscle infection* and is primarily seen in immune-compromised and cystic fibrosis patients.

This is treated through an antibiotic regimen.

Front 232

Back 232

Front 233

Back 233

Front 234

Development of an Ovarian Follicle

Back 234

Girls are born with like 2 million primordial follicles (but we only use like 500 of them)

At midcycle, ovulation occurs, the follicle ruptures, and an egg is released.

The egg is the LARGEST cell in the human body!

The fimbriae of the fallopian tube coax the egg into the tube, where it meets the sperm in the ampulla region

Front 235

Menstrual Cycle

Back 235

Prior to ovulation, we have the Follicular Phase, where the follicle is developing, and also the Proliferative Phase of the Uterus, where the endometrium is growing.

Post-Ovulation, we have the Luteal Phase, in which LH induces the formation of the Corpus Luteum, which produces Progesterone to support the endometrium until implantation.

If implantation DOES occur, the chorion produces hCG to continue to support the corpus luteum such that progesterone levels are maintained.

If we DON'T have implantation, the Corpus Luteum degenerates, and the lack of progesterone induces the Secretory Phase of the endometrium and Menses occurs,

Front 236

Gonadotropes During Development

Back 236

During fetal development, high levels of gonadotropes allow for the development of primary sexual characteristics, including internal and external sex organs.

Gonadotrope levels remain high for the first six months of life to continue the development of primary sexual characteristics.

Then, levels remain low until puberty, where a rise in FSH and LH induces the development of secondary sex characteristics.

At the end of the reproductive years, when a woman has few quality follicles remaining, FSH and LH levels become very high as the body searches for additional follicles to develop.

At the same time, because there are in fact no follicles left, estrogen and progesterone levels fall precipitously, which induces menopause.

Hint 236

Front 237

HPV and Cervical Cancer

Back 237

HPV-16 and -18 lock out 2 important tumor suppressor proteins, causing certain cells to become more likely to mature and cause cervical cancer.

Hint 237

HPV tends to target the cells at the squamocolumnar junction, between the columnar cells of the cervix and the squamous cells of the vagina.
-this transitional area protrudes outward more into the pelvis in young adults as compared to infants or older women, which is likely a reason Gardasil was shown to be most effective in women between the ages of 13-25.

Front 238

Endometriosis

Back 238

Occurs when endometrial tissue implants somewhere other than the uterus.

Tissue that metastasizes to other areas of the body will still respond to hormones and proliferate and slough off each both

Front 239

Uterine Fibroids (leiomyomas)

Back 239

Fibroids are areas of smooth muscle that have become tumorous. They are completely benign tumors that are very common, especially in older women.

While they are NOT CANCEROUS, they are often uncomfortable and painful, and should be removed via hysterectomy in post-menopausal women. In women looking to preserve their fertility, surgeons can cut out fibroids individually in an attempt to maintain the uterus.

Front 240

Endometrial Cancer

Back 240

Unlike fibroids, this is cancer of the endometrial tissue, NOT the smooth muscle of the uterus.

This is the most common uterine cancer. Fortunately , there is a very good prognosis, because post-menopausal women are most commonly affected, and *the main clinical indicator is vaginal bleeding*, something obviously NOT normal in someone who has reached menopause.

Front 241

Salpingitis

Back 241

Inflammation of the fallopian tube.

Usually associated with pelvic inflammatory disease (PID).

Usually caused by infection, endometriosis, or ectopic pregnancy.

Front 242

Ovarian Tumors

Back 242

Most common ovarian origin is the *surface epithelial cells*, which cause 90% of malignant ovarian tumors.

Ovarian cancers have a pretty poor prognosis, because the ovary is so small, and can double in size many times before it can be palpated.

By the time ovarian cancer IS detected, it is often too late.

BRCA1 mutations greatly increase the risk ovarian cancer.

Hint 242

Front 243

Teratomas

Back 243

These are germ cells that wanted to become a person but didn't quite make it.

These are encapsulated tumors with tissue or organ components inside.

Teratomas are generally benign, but are still surgically removed

Front 244

Ectopic Pregnancy

Back 244

Any pregnancy outside the body of the uterus. Most common site is fallopian tube, which is most often caused by chlamydia. The egg is big and moves under the power of the cilia so if you have scar tissue its more likely to make the egg get stuck some place. Sperm has its own power to move so it isn't hindered. The fallopian tube cannot provide sufficient blood supply and nutrients for growth and development.

Front 245

Hydatidiform Mole (Molar Pregnancy)

Back 245

COMPLETE: there is not embryonic tissue, instead just have highly vesicular chorion. 2 sperm get in but no egg DNA. Empty egg, but 2 sperm get in and fertilize each other and start to develop. This produces lots of hCG (so positive pregnancy test), but shows up as static on an ultrasound.

PARTIAL: has a fetus in it! It is triploid bc 2 sperm get into a normal egg. We now have a 69 chromosome human.This doesn't work, so fetus usually doesn't go to term.
-FYI, seedless watermelons are triploid! Hence, no seed!

Front 246

Pre-Eclampsia

Back 246

Fairly common
Usually comes on late 2nd or early 3rd trimester
Fetus needs a lot of blood supply
Instead of nice deep penetration of blood supply we get shallower. Thus less surface area and thus less diffusion of nutrients. This becomes a problem late in pregnancy when the fetus has growth and has a much higher metabolic need. If fetus doesn't get enough nutrients it wants to increase blood flow thru placenta. So ti sends a signal to increase mom's blood pressure.
But the hypertension isnt high enough to drive proteinuria- something else is causing this

Front 247

Breast Cancer

Back 247

Hint 247

Usually in upper, outer quadrant

Front 248

Back 248

Front 249

Benign Prostatic Hyperplasia

Back 249

Every male gets BPH as they age. It doesn't cancer but it does cause problems peeing.

Front 250

Prostate Cancer

Back 250

Prostate Cancer is much less common, and not very likely to be the cause of death. More likely to dies from something else first.

The earlier you see it in a man, the more aggressive the cancer is (i.e. in a 50 year old man)

Problem with removing prostate is that you dont want to damage the surrounding nerves.

Front 251

BPH vs. Prostate Cancer

Back 251

BPH starts in central zone (near urethra) and is likely to cause compression and urinary disturbances early on.

Prostate cancer usually starts in peripheral zone, so it doesn't cause compression, and therefore you don't get the early indicator! Uh oh…

Front 252

Anatomy of the Eye

Back 252

From outermost to innermost, light enters eye through the cornea, lens, anterior chamber of the eye, ball of the eye, and finally hits the retina in the back of the eye.

Hint 252

On the outside of the eyes, we have the SCLERA, or the whites of our eyes. The sclera is tough and made up of layers.

On the inside, there is the RETINA and the FOVEA within the MACULA.

Rods and Cones are concentrated in the fovea!!!

Along the back of the eye, we also have the optic disk, which is where the optic nerve (all axons of retinal cells) and blood vessels are.

The optic nerve is also our blind spot!!!

Front 253

Lens

Back 253

The lens is flexible, which allows us to focus light at different distances.

It is composed of living epithelial cells which produce transparent proteins, creating the very clear lens fiber.

The lens can become cloudy with age, due to UV light damage

Front 254

Retina

Back 254

The retina contains photoreceptors (rods and cones).

Rods respond to light and see only black/white. Cones see colors.

The retina also contains ganglion neurons and interconnecting neurons (which "interconnect" the ganglion neurons to the rods/cones)

Front 255

Visual Processing

Back 255

Light passes thru the ganglion neurons and interconnecting neurons in order to reach the rods and cones.

When a rod gets excited by light, it HYPERpolarizes! But, note that rods and cones DO NOT fire action potentials!!

This information gets passed to the ganglion cells through the interconnecting neurons and *the ganglion cells will fire APs along their long axons down the optic nerve.

Front 256

Photoreceptors

Back 256

Rods contain G-protein Coupled Receptors which contain 11-cis retinal (bent).

When light hits it, it becomes 11-all-trans retinal (straight_, which activates the Tα part of the GPRC, which stimulates phosphodiesterase. This enzyme breaks down cGMP.

Hint 256

In addition to GPCR's, photoreceptors also contain cGMP-gated sodium channels and voltage-gated calcium channels, which in the dark are kept open by the high levels of cGAMP. This allows Na+ and Ca2+ to follow their concentration gradients into the cell and keeps the cell depolarized (Vm= -45 mV).

However, in light, cGMP levels fall and the cGMP-gated channels close. Na+ and Ca2+ can no longer enter the cell, Na continues to be pumped out through the Na/K pump, and K continues to leak out thru the K+ leak channels. So, the cell will hyper polarize to -75mV

Front 257

Cell Distribution in the Eye

Back 257

In the middle of our eye, we have the macula ("spot"), which contains the fovea ("ditch").

*In the fovea, there is a higher density of rods and cones, but no ganglion cell axons.*
-essentially, there is an unobstructed path towards the photoreceptors, which allows for super fine vision in the middle of our eye, and poorer vision in the periphery.

This isn't a problem tho, bc our peripheral vision is still very good at detecting movement or changes!

Front 258

Visual Fields and Neuronal Pathways

Back 258

Optic Nerve→ Optic Chiasm→ Lateral Geniculate Body of Thalamus→ Optic Radiations→ Visual Cortex of Occipital Lobe

Hint 258

In the visual system, we have HEMI-DESCUSSATION- only half of the fibers cross.

The OUTER/Temporal/Peripheral visual fields project images on the INNER/Nasal portions of each retina.

The INNER/Medial/Center visual fields project images on the OUTER portion of each retina.

The fibers from the nasal portion of each retina cross over to the opposite side at the optic chiasma and terminate in the lateral geniculate nuclei (LGN). The fibers from the outer portion of the retina remain on the ipsilateral side and also terminate on the LGN.

The LGN then transmits this information to the visual cortex of the occipital lobe, the adjacent neurons will allow our brains to *make sure our eyes are converging on the same image*. If not, they will send that conflicting info back to the frontal field that controls the eyes until the eyes converge at the same image.
-this reinforcement of information also allows for depth perception!

Front 259

Visual Pathway Lesions

Back 259

Front 260

Extra-Ocular Muscles

Back 260

There are 6 extra-ocular muscles that move the eye.

They are controlled by cranial nerves 3, 4, and 6.

Front 261

Eye Pathophysiology:
-Strabismus
-Amblyopia
-Nystagmus

Back 261

Strabismus:
-Failure of eyes to converge. Essentially, the eyes are looking at 2 different things. Recall that in the primary cortex, neurons next to each other are supposed to look at the same things, but in this case, they are not. This results is DIPLOPIA, or crossed eyes/double vision, which conflicts with the message that the brain is getting.

Ambylopia:
-Lazy eye; blindness of one eye without any physical problem of the eye.
-The brain won't be happy with this and will choose to "ignore" one eye.

Nystagmus:
-Alternating smooth and jerky movements (can be normal or pathological). If pathological, it is usually caused by vestibular system problems.

Front 262

Alterations in Refraction

Back 262

As you grow, so do your eyes. They grow into a shape that is most comfortable for whatever you are looking at

Myopia: (near sighted)
-parallel rays of light are brought to a focus in front of the retina.

Hyperopia: (far sighted)
-parallel rays of light come to a focus behind the retina in the unaccommodative eye.

Simple Myopic Astigmatism:
-the vertical bundle of rays is focused on the retina; the horizontal rays are focused in front of the retina.
-in astigmatism, the lens is not symmetrically shaped, so it is difficult to focus light anywhere.

Presbyopia:
-usually involves a loss of near vision (older people).
-due to loss of accommodation, eyes are "stuck" in distance vision.

Front 263

Leading Causes of Blindness

Back 263

Front 264

Cataracts

Back 264

Clouding of the lens.

Occur in older people and in diabetics.
Caused by protein glycosylation.

Front 265

Glaucoma

Back 265

INcreased pressure in the anterior chamber (located right behind the cornea), which pushes the lens back, which increases pressure in the eyeball, which increases pressure on the optic disk, which damages the optic nerve.

Hint 265

Test for glaucoma with the puff test:
-bounce puff of air on lens
-if you have increased pressure, the lens will be harder, so puff of air will bounce well (like an overinflated basketball)

Once detected, glaucoma is very easy to treat with drugs

Front 266

Macula Degeneration

Back 266

Degeneration of macula causes central blindness. Lose vision only in the middle of our visual field where most of our visual power lies.

Front 267

Diabetic Retinopathy

Back 267

Increased vascular permeability and angiogenesis destroys retina.

Front 268

Back 268

The auricle/pinna on the outside down to your external auditory meatus make up your external ear.

Middle ear: made up of your tympanic membrane (which marks the end of external ear), then the auditory ossicles that include the malleus, incus, and stapes. The stapes ends on your oval window.

Inner Ear begins as your oval window. This includes your cochlea, used for hearing, and the semicircular canals with trickles and saccades, used for balance. The oval window is the beginning of the cochlea and has a corresponding round window.

The middle ear is filled with endolymph, and inner ear is filled with perilymph. Both have similar chemical composition to interstitial fluid.

Front 269

The Inner Ear

Back 269

Front 270

The Pathway of Sound

Back 270

Auditory (compression waves) travel down the external auditory meatus and vibrate the tympanic membrane, which transfers vibration to auditory ossicles causing vibrations to be transferred to where the cochlea vibrates

Front 271

Vestibular System

Back 271

Contributes to balance, due to acceleration not position. remember that there are 2 types of acceleration: linear and rotational.

Front 272

Which parts of the vestibular system detect linear acceleration?

Back 272

Saccule & Utricle

We have two detectors that work to detect 1.5 dimensions, due to their curvature, thus allowing the varied curved receptors to feel acceleration in 3 dimensions.

Supporting cells are anchored to the head, so as the head moves, the receptors move with it.

Otoliths (ear stones) move with acceleration on the gelatinous layer (i.e. with acceleration forward, they move backward), which causes movement of the gelatinous layer.

Hint 272

This gelatinous movement causes hair cells to bend based on the direction and extent of acceleration. This hair cell movement translates into AP firing frequency in the attached sensory neurons.

If the hair cells bend a particular direction they increase firing rate, and if they move the other way they decrease firing rate from the resting firing rate.

These changes in firing frequency reveal acceleration to the brain, based on the bending of hair cells.

Front 273

Which parts of the vestibular system detect rotational acceleration?

Back 273

Semicircular Ducts

Detect rotational acceleration in 3 dimensions of the xyz planes. Thus there are 3 semicircular canals orthogonal to each other to measure rotational acceleration.

The combination of the signals from the 3 canals is combined to make a unified sensation. Also, your right and left vestibular system should have the same acceleration, unless your head has exploded where your right and left are moving in opposite directions.

With acceleration, fluid moves past the cupula, causing movement of the hair cells. Again, the hair cell movement causes firing of nerves, whose AP frequency correlates to rotational acceleration

Front 274

Vertigo

Back 274

Vestibular Pathology

A balance problem

Front 275

The Cochlea and Hearing

Back 275

There are two scala: the scala vestibuli starts at the oval window, and the scala tympani ends at the round window.

The vibrations in the middle ear and endolymph (pink) vibrate; it causes the oval window to pop in, causing vibrations in the cochlear perilymph, which pushes through the scala out to the round window.

Hint 275

These vibrations in the cochlea create certain standing waves of varying frequency. The peaks of these standing waves cause vibration of hair cells between the scala, which send the information down the auditory nerve then to the primary auditor complex, where tonicopic separation will separate out the frequencies and the association area of the brain will attach the sound to an object in the memory.

High frequencies are detected near the oval and round window. Lower frequencies are detected near the helicotrema

The hairs at these different areas are sensitive to different frequency peaks.

Note that the fluid moves in the opposite direction in scala vestibule and tympani!

Front 276

Hearing Range and Audiograms

Back 276

Our absolute hearing range is from ~ 60Hz to 20 kHz, but our normal hearing range is from around 100-8000Hz.

The threshold of hearing in a normal person is 0dB.

An Audiogram shoes frequency predominance of common sounds and letter sounds.

Front 277

Hearing Loss

Back 277

Conductive Loss:
-due to change in ear function

Sensoneural Loss:
-due to cochlear or brain damage causing hearing loss

Hint 277

Front 278

Obstructive Lung Disease

Back 278

Patient can't fully exhale. So they attempt to maintain gas exchange with rapid, short inspirations

Hint 278

Front 279

Compare the lung volume of a normal vs. obstructive disease patient

Back 279

Obstructive Patient will have:

1. Increased Functional Reserve Capacity and Reserve Volume, even after maximum expiration

2. Decreased Tidal Volume

The resulting trapped air increases inspiratory resistance and requires higher pressure to inflate the lungs

Hint 279

This is a Flow-Volume Loop

The obstructed patient will have:

1. increased overall lung volume
2. decreased inspiratory/expiratory flow

Front 280

What is the mechanism behind COPD air trapping?

What are the consequences of air trapping?

Back 280

Physiological insults destroy bronchial elastin protein fibers.
-These fibers are important in maintaining a patent airway by resisting the deformations induced by various pressure changes associated with inspiration and expiration as well as smooth muscle constriction.

With compromised elastin fibers, the airway OVEREXPANDS upon INSPIRATION, but COLLAPSES upon EXPIRATION, trapping air.

This elastin destruction is coupled with *mucous plugs* which exacerbate the obstruction.
-mucous production is increased upon epithelial irritation from pollutants or smoking.

Hint 280

The consequences of air trapping is decreased gas exchange and thus retained CO2.

Prolonged/excessive CO2 retention leads to metabolic acidosis, compensated by renal production of bicarbonate.