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A patient is rushed to the emergency due to a blockage of a vessel. His tissues in the
vicinity of the blockage are hypoxic. What are the immediate effects of this hypoxic state
on his cells? Are the disturbances reversible? These tissues would be considered
ischemic because there is not just a decrease in oxygen, but in blood supply overall.
Define edema and describe the inflammatory as well as the non-inflammatory causes of
edema.
-Inflammatory causes related to increased vascular permeability, due to damage of
endothelial cells, endothelial cell contraction, angiogenesis, leukocyte-dependent
cell damage.
-Non inflammatory causes: increased hydrostatic pressure, decreased colloid
osmotic pressure, obstruction of the lymphatics, retention of sodium due to kidney
pathologies. Note that these causes can also be induced by inflammatory changes
(eg. venule vasoconstriction inducing increased hydrostatic pressure; vascular
permeability causing loss of solutes inducing decreased osmotic pressure)
Outline the key differences between acute and chronic inflammation and give an example
of each.
Acute inflammation
- method of avoiding stress by sending inflammatory cells to an area of trauma
- via: vasodilation, change in blood flow, increased vascular permeability,
recruitment and activation of leukocytes, eg) bruise or cut
Chronic Inflammation
- simultaneous injury, inflammation and healing via mononuclear infiltration,
tissue destruction, ongoing repair, eg) atherosclerosis
What are two main intermediates of the inflammatory response pathway that cause fever?
IL-1 and Tumor-Necrosis Factor; there are others …
How does the previous two intermediates of inflammation cause an elevation of body
temperature (fever)?
They both influence the temperature set point of the hypothalamus.
List the 2 possible outcomes of acute inflammation and explain them when you would
expect each to occur.
Differentiate between labile, stable and permanent cells and state where you would
expect to find these types in the body.
Labile cells are cells that constantly divide and regenerate. It can be found in
haematopoietic cells
Stable cells are cells that have the ability to divide but only does so when told (ex.
skin cells)
What type of neoplasm involves the invasion and metastasis to not become incapsulated?
Malignant neoplasm; malignant neoplasms are generally unincapsulated, but not
always.
Although the two types of cell death share some mechanistic features, necrosis is
considered cell homicide where as apoptosis is programmed cell suicide.
Describe "healing by first intention" and list the processes within the first 24 hours, 3-7
days and subsequent weeks:
Healing by first intention is one of the simplest examples of wound repair and
occurs in the healing of a clean, uninfected surgical incision as in the case of
surgical sutures. Within the first 24 hours the injury fills with clotted blood, a scab
is formed by dehydration and neutrophils migrate toward the fibrin clot. There is
increased mitotic activity at the basal cells and the scab closes the wound to
protect the healing site.
What is the goal/ basis for the formation of granulomatous type inflammation?
To sequester a foreign substance that the body can't clear or digest.
Describe the process of brusing and what produces different coloured bruises.
When red blod cells are lysed after an injury or trauma, the free hemoglobin is
phagocytosed by macrophages. There are lysozymes in the macrophages that
break down the hemoglobin. A bruise is initially red from the blood under the
skin. As the bruise ages and gets broken down, it turns a bluish green due to
biliverdin, a breakdown product of heme. The bruise then turns yellow when there
is billirubin in the area, which is another breakdown product of heme.
Cancerous cells also often exhibit telomerase activity. Telomeres shorten after
each cell replication process. Eventually, there is a loss of telomeres and the
continued shortening of chromosome leads to chromosomal abnormalities. This
leads to the cell being signaled to apoptose. Telomerase replaces telomeres and
allows the cell to continue dividing.
Why does hypoxia result in increased Ca+ release from the structures within the cell?
Why will increased Ca+ levels kill the cell?
• Ca+ levels are tightly regulated within the cells.
• Ca+ is contained within organelles in the cells, such as the
sarcoplasmic/endoplasmic reticulum.
• ATP-dependent pumps actively transport Ca+ out of the cell, maintaining
the concentration gradient.
• Without oxygen (during hypoxia), ATP cannot be produced as effectively
(anaerobic glycolysis only). ATP-dependent Ca+ controls begin to fail,
and the Ca+ concentration gradient within the cell is compromised.
• Free Ca+ appears in the cytosol
• Being an important second-messanger, Ca+ triggers ALL Ca+ dependent
pathways simultaneously, including those that make holes in the cell
membrane.
• The cell membrane is destroyed, and the cell dies.
Which leukocytes are the first to the site of infection? In what type of infection are they
most numerous?
• Neutrophils; pyogenic infections.
What happens in the first 24 hrs of healing by first intention? 3-7 days? weeks?
24 hrs - clot of blood is filled; surface gets dehydrated; neutrophils enter site;
mitosis occurs @ basilar region of skin; dermal section of basement membrane
closes; macrophages stimulated by fibroblasts
3-7 days - epidermis gets mitosis and closes; mitosis in keratin cells too
weeks - get fibrous healing
Discuss the difference between Ischemia and Hypoxia. Which is the most common type
of cell injury in clinical medicine? Which one of the two mentioned injures tissue faster?
The most common type of cell injury is Ischemia, and it is typically occurring
because of diminished blood flow in a particular tissue’s vascular bed. This is
opposite to hypoxia, where the glycolytic energy generation can continue. Ischemia
also compromises the delivery of substrates for glycolysis causing anaerobic energy
generation to cease in ischemic tissues after potential substrates are exhausted or
when glycolysis is inhibited by the accumulation of metabolites that would normally
be removed by blood flow. Given this we can see that ischemia injures tissues faster
then hypoxia.
What are free radicals? What happens when they are generated in cells? What special
type of reactions do they initiate? Discuss three ways in which free radicals may be
generated.
Free radicals are chemical species with a single unpaired electron in an outer orbital.
This chemical state is unstable and readily reacts with inorganic and organic
chemicals. When free radicals are generated in cells, they attack and degrade nucleic
acids and many membrane molecules. Free radicals initiate autocatalytic reactions.
This means that molecules that react with free radicals are converted into free
radicals, increasing the degree of damage. Free radicals may be generated by nitric
oxide, absorption of radiant energy, and enzymatic metabolism of exogenous
chemicals.
By what process does chemical injury indirectly affect the body?
Many chemicals that enter the body must first be converted to reactive toxic
metabolites before they can act on target cells. This modification that must occur
is usually accomplished by the P-450 mixed function oxidase which is in the
smooth endoplasmic reticulum of the liver and other organs.
A middle-aged man was snowboarding when he took a nasty fall and broke his right leg
in several places. Subsequently he was in the hospital for a week had to remain in a cast
for two months. During this period of time his mobility was greatly reduced and he
found that when the cast was removed he noticed that his right leg looked much smaller
and he had some problems walking and maintaining balance. What is the process that
has occurred and why?
He has suffered from Atrophy due to immobilization of the right leg. Atrophy is
the wasting or shrinkage of cells/tissues due to the loss of substance and this can
be caused by lessened function or immobilization. It can be an adaptive process
where the cells retreat to a smaller size in order to survive. One of the main ways
that the cells decrease their size is through protein degradation through either
lysosomes, which have autophagic vacuoles, or the Ubiquiting-proteosome
pathway.
Ciara was suffering from a cold when she got a bad splinter on the plantar surface of her
second toe and it went deep enough to cause bleeding. She pulled the splinter out but
was in a hurry and did not wash the area clean. A few weeks later she noticed that the
toes was red, swollen and painful to the touch. The toe kept on getting worse but she still
thought it was insignificant and thought it would resolve on it’s own. Soon the whole
foot was swollen and Ciara started experiencing a fever, dizziness, confusion, and the
skin of her legs and abdomen were warm and flushed. She finally went to the emergency
room and what did the doctors diagnose her problem as?
When the splinter penetrated the skin and drew blood bacteria was able to enter
the wound as well as the circulatory system. The patient did not clean out the
wound therefore letting it fester with wood, possible wood fragments, and
bacteria. She was already suffering from a cold and therefore her immune
function was already compromised and could not effectively take care of the
wound caused by the splinter. Even though her body was showing her that
something was wrong she did nothing about it until the infection kept on getting
worse with the bacteria multiplying in her blood stream. When she went to the
hospital she was suffering from a case of septic shock, and since her vital organs
were still working she has probably just entered the progressive stage.
When are Heat Shock Proteins expressed and in response to what factor? Describe 2
functions of Heat Shock Proteins.
Heat Shock Proteins are expressed under various conditions of cellular stress (eg.
environmental stress, toxins) and in response to Heat Shock Factor. Two functions
of HSP include helpingnewly synthesized proteins to fold and in acting as
molecular chaperones.
As a naturopath, where can we encourage free radical neutralization and why would we
want to do this?
We can encourage neutralization by ensuring enough functional ie. reduced GSH
in the body (you mentioned in class that GSH requires selenium, therefore we
could encourage more selenium in diet or through supplements- although there
may be even more ways that I don't know about yet). This is important because
the presence of free radicals can damage tissues in the body, especially through
things like lipid peroxidation. Keep in mind that in many cases we depend on free
radicals to protect us; the task is clearing them when their job is complete, and
avoiding the accumulation of excessive free radicals due to less-than-optimal
lifestyle choices (smoking, consuming smoked meats, sun exposure, consuming
toxic substances, etc.). There are multiple ways to minimize free radical load on
the body – both reducing production by lifestyle, and stacking our systems with
antioxidants – GSH is an important one, and we can provide a few different
precursors. As was mentioned in class, the best defence is a diet high in brightly
coloured fruits and veggies.
Steatosois occurs mainly in which organ and why is it most likely to occur in this organ?
What other organs can it be seen in?
Mainly occurs in the liver because it is a filter organ and involved in metabolism
of lipids specifically. It can also be seen in the heart, kidneys and skeletal muscle.
What are three typical tissue changes during an acute inflammatory process?
Increased vascular permeability to allow chemical mediators out of the immediate
area, increased leukocytes to the tissue, decreased osmotic pressure and increased
hydrostatic pressure which allows white blood cells to enter tissue.
What are two different types of chemical mediators, give an example and describe their
action.
-local (histamine) vs. systemic (Factor XII, complement activation system)– both
act by binding to cell surface receptors, and increase action within the target cells
OR they stimulate the formation of opposing molecules.
While at work one evening Lori cut herself when attempting to cut lemons. This caused a
painful episode of blood outflow from one of her fingers. What is the term used to
describe the clotting of blood that needs to occur, and describe the healing process
involved, assuming Lori is a healthy adult.
- Hemostasis = clotting of blood
- After the vessel is injured, vasoconstriction occurs, therefore less blood loss.
- Platelets become activated and form a hemostatic plug
- Lastly, coagulation occurs, involving the laying down of fibrin between
platelets, forming a secondary clot.
- Finally the blood components need to halt the clot formation so that it does
not cascade throughout the blood stream; the coagulation cascade also
activates antithrombotic mechanisms that control clotting, and ultimately
breaks down the clot once the vessel is healed.
What is cachexia? Why does chronic disease cause cachexia?
It is weight loss, wasting of muscle , loss of appetite and general debility that
occurs with chronic disease. This reason why is is not completely understood.
The cytokines that cause cachexia are produced mainly by cells of the immune
system, especially macrophages. Most cachexia is believed to be caused by
diminished consumption of nutrients rather than by a hypermetabolic state.
Typically the opposite – cachexia tends to involve an accelerated basal metabolic
rate, inducing wasting regardless of caloric intake. But it is true that many
individuals with chronic diseases do consume less. Cachexia may indicate cancer,
infectious disease or an autoimmune condition.
What are some of the key chemical mediators that are signalled to arrive upon acute
injury? Explain the process of acute inflammation.
Acute inflammation involves trauma or initial injury, where local arteriolar
vasodilation occurs, yielding initial higher pressure and more blood filtering
through cell walls into the tissues. Increased vascular permeability also leads to
leakage of proteins into tissue, changing the osmotic pressure and thus attracting
more solutes into the blood. RBC's concentrate in vessels which slows the flow of
blood. Ultimately stasis occurs, allowing the leukocytes to marginate, migrate
and become activated. There are many chemical mediators involved in this
process as cells rely on chemotaxis via concentration gradients:
- Mast cells, basophils and platelets all contain histamine, which affects
vascular permeability.
- Plasma proteases help activate the Hageman factor - pain, clotting and
coagulation
- Pro/antiinflammatory fatty acids eg omega 6 arachadonic acid & omega 3
fatty acids
- Platelet activating factor
- Cytokines eg interleukins and TNF - utilize macrophages
- Nitric oxide
- Lysosomal constituents
We must keep in mind that the inflammatory process is a protective mechanism of
the body that allows inflammatory cells to get to the area of trauma.
Why is pathology important in naturopathic medicine?
It is important to know the cause and effect of disease and the functional and
structural changes that occur in order to recognize, diagnose, and treat according
to our principle “treat the root cause”
Because a disease can manifest itself in many ways, it is important to know the
cellular changes that occur that are causing certain signs and symptoms and treat
the underlying cause
We can always continue to philosophize about this – it’s a very key concept.
What are the two main process involved in acute inflammation, and briefly describe
them.
The two major processes are vascular changes and cellular events. Vascular
changes are characterized by vasodilation of blood vessels, increased vascular
permeability, and changes in blood flow. Cellular events are characterized by a
sequence of events that will lead to the movement of white blood cells from inside
the blood vessel to the extravascular space. These events include: 1) margination
and rolling 2) adhesion and trasmigration and 3) chemotaxis and activation
Pete is a 56 year old male. He enjoys the outdoors and is often found sunning himself by
the pool. He has recently found an odd shaped mole on the left side of his upper back.
He cannot recall when it appeared or how long it may have been there. Although he
doesn’t remember it there last summer. He complains that it is sore and doesn’t seem to
heal. Upon examination, the skin appears open and irregular. Given the above
information, what predictions can you formulate?
It is most likely a neoplastic growth on the surface of the skin on his upper back.
I believe this because it appears, by Pete’s indications, to have grown recently and
quickly. It also appears to be spreading. Since the growth is irregular in shape it
may have malignant qualities and should be looked at immediately.
Drescribe, through the telomere theory of cell aging, how activation of telemerase could
promote cancer.
• According to the telomere theory, at the terminal end of each cell's DNA is
repeating, non-transcribed, segments that are progressively lost/shortened with
each DNA replication during cell division. Therefore, each cell has a finite
amount of replication that it can undergo, after which, the cell dies (it has
aged). In cancer, there is a theory that telomerase adds telomere segments to the
terminating end of DNA causing the cell to divide infinitely (or as long as
telomerase exerts it's effects). Thus, division is uncontrollable, the defining
characteristic of cancer.
In carcinogenesis is the genetic damage lethal or non-lethal (and explain why) and what
genes are affected:
The genetic damage in carcinogenesis is non-lethal in order to modify what is
required in the cell to inhibit normal responses to inadequate cell development,
and to promote the growth and development of the carcinogenic cell. The genes
that are affected are growth-promoting genes, growth-inhibiting genes, apoptosis
genes, and repair genes. If the damage was lethal, the mutated cell would never
regenerate a key concept for oncology.
What is the function of the TP53 gene and how does it relate to formation of tumors?
TP53 is a tumour suppressor gene that recognizes damage to the nucleus of cells
and signals cells to either fix damage or undergo apoptosis. Tumours arise from
mutations in such genes where cells with damaged nuclueses are allowed to
continue growing.
What can happen to a wound if the epidermis heals before the dermis?
What are some factors that can determine the severity of an embolus?
Why/how do some wounds not leave scars? (does it depend on the level of dermis
penetrated?) Definitely – if the cells are not damaged beyond repair (ie. the basal cells
are intact, and the dermal appendages are not damaged), then the cells will regenerate (ie.
replace themselves with normal tissue). However, if cells are not able to regenerate, then
the healing will be done using fibrosis (collagen tissue) a scar.
In the progression of a tumour how does the principal of survival of the fittest play out?
When an immune response is made against a tumour it imposes selection on the
tumour cell population. Variant cells that have low expression of tumour Ags or
mutant eptiopes will no longer be recognized by the immune system and the
tumour will evade the immune response. Moreover, the longer a cancer grows,
expands its population and colonizes different sites and environments within the
body, the more genetic variation it acquires and the less likely it become that the
immune response can fight the tumour with success.
What are the types of cellular adaptation? Give one cause or mechanism for each one.
Atrophy Shrinking of cells; Decreased workload / loss of innervation /
diminished blood supply
Hypertrophy Enlargement of cells; Increased physiological demand / increased
hormonal stimulation
Hyperplasia Mutiplication of cells; Hormonal stimulation such as in breast
growth at puberty; or compensatory, is hyperplasia when a portion of tissue is
removed or diseased; or pathological, most of these cases are due to excessive
hormonal stimulation and can be a fertile soil for cancerous proliferation.
Metaplasia when cells sensitive to a particular type of stress are replaced for
another type that is better able to deal with the stress.
Describe the difference between a thrombus and an embolus. What is one possible
consequence of each and briefly describe the mechanism of potential damage?
Thrombus is a blood clot which forms in and adheres to the endothelial lining of a
blood vessel while an embolus refers to any inappropriate substance, including a
thrombus, foreign object, bit of tissue, or air or gas bubble, flowing through the
blood stream until it becomes lodged it a blood vessel causing an embolism.
In both cases, a thrombus or embolism can result in an infarction (ie. cardiac
infarction) in which blood flow to an area of tissue stops or is substantially
decreased. A thrombus will decrease the diameter of a blood vessel or possible
occlude it, the more common mechanism of damage would be the progression of
a thromus to embolus. In either case, lack of nutrient delivery and waste removal
will lead to tissue necrosis and compromised function. In the case of the heart,
the walls of the heart will loose the ability to contract and pump blood out of the
heart, decreasing cardiac out put substantially.
Describe one difference between an ischemic and hypoxic insult on an organ tissue.
Both an ischemic and hypoxic insult may result in decreased oxygen to cells in
the area of an affected organ. Ischemia limits nutrient influx and waste efflux
(does not result in tissue necrosis – Infarction) due to vasoconstriction, a
thrombus, or an embolism, which leads to the accumulation of metabolites.
Hypoxia only refers to an inadequate amount of oxygen in the blood and
subsequent delivery to tissue cells and does not result in an accumulation of
metabolites..
With regards to chemical injury, chemicals can impact cells either directly or indirectly.
In case of indirect chemical injury, most chemicals need to be converted to reactive
toxins to act on target cells. Which system is required to be able to accomplish the
conversion?
P450 system
What is the name of a chemical mediator that is found in mast cells, basophils and
platelets and is triggered by physical injury, IgE reactions, anaphylatoxins, and other
cytokines? This chemical mediator causes immediate arteriolar dilation and venular
permeability.
Histamine
How does cell ‘necrosis’ differ from cell ‘apoptosis’ in terms of the stimuli that initiate
each process?
Necrosis is initiated by factors exogenous to the cell, while Apoptosis is stimulated by
factors that are either endogenous or exogenous to the cell.
What are three conditions that can result in abnormal intracellular accumulation of fat,
cholesterol, protein, glycogen or pigment?
1) Production exceeds elimination
2) Defects in the metabolic pathway
3) Abnormal exogenous substances.
What cells are lipofuscins found in? lysosomes Lysosomes are organelles within a cell.
What is margination?
Leukocyte accumulation at periphery of vessels, which allows leukocytes to stick to
endothelial surface in clotting process so that leukocytes can transmigrate through
intracellular junction where chemotaxis can occur and G protein-mediated activation
of PIP2 2nd messenger system.
Which three systems are set into play once Hageman Factor has been activated?
1. Kinin System, 2. Clotting System, and 3. Coagulation system.
Which 3 factors are involved with assessing tumor progression (ie. The stages of severity
of a tumor)?
TNM T=tumor size (graded on 1-4 for severity), N=lymph node involvement
(graded on scale of 1-3), and M=presence or absence of metastasis.
Out of the following themes of biochemical damage, which one is most likely to result in
irreversible damage and why?
ATP Depletion
Free Radical Damage
Mitochondrial Damage
Membrane Permeability
Describe is the purpose of acute inflammation and the means by which the vascular
system accomplishes it.
Acute inflammation occurs within minutes of the assault or injury in order to send
inflammatory cells to the damaged area, ultimately to control the damage and
begin healing. In order to accomplish this, the vascular system undergoes
vasodilation, increases blood flow to the area and locally increases vascular
permeability. These changes allow large amounts of blood containing
inflammatory cells to reach the damaged area as quickly as possible.
What is a free radical and how does it cause damage to living cells?
Free radicals are chemical species that have an unpaired electron. They react
readily with other substances in an effort to obtain an electron thereby becoming
stable. When generated in cells they attack and degrade nucleic acids and many
membrane molecules, including integral proteins. Also, as free radicals react with
molecules, those molecules become free radicals themselves, thereby creating a
cycle of destruction.
Why do chemical mediators not constantly produce an inflammation response if they are
found circulating in plasma or produced locally?
Because they are circulating in inactive forms. Mediators at the site of injury
activate.
Define the term 'hypertrophy'. Provide an example each of physiologic hypertrophy and
pathologic hypertrophy.
Hypertrophy is the enlargement of an organ or part due to the increase in size of
the cells composing it; the overgrowth meets a demand for increased functional
activity. It can be both physiologic or pathologic. An example of physiologic
hypertrophy of the uterus during pregnancy occurs due to estrogen stimulation of
smooth muscle. Another example is how a weight lifter can develop their muscles
by increasing the cell size of individual skeletal muscle cells by increasing
workload. Pathologic hypertrophy occurs when there is cardiac enlargement due
to hypertension or due to aortic valve disease. The enlargement of cardiac
myocytes after an acute myocardial infarction is another example of pathologic
hypertrophy.
A 22 year old male was rushed into emergency for severe trauma to the left arm suffered
while wake boarding in the Muskokas. He presented with what first appeared to be
severe atrophy of the biceps brachii, accompanied by sever hypertrophy and bruising of
the forearm. Upon further examination the doctor learned that the patient had become
entangled in the wakeboarding rope and subsequently severed his brachial artery, as well
as the heads of his biceps brachii muscle, thus displacing it into the forearm. Using at
least 3 of the basic pathology terms studied in class briefly describe what this patient
might be experiencing pathologically in this case.
ischemia: tissues of the arm are cut off from blood supply
edema: of the forearm
effusion: massive effusion of blood and lymph into forearm
hemorrhage
shock
I like this question, but I would want a more elaborate response; what is the process that
led to the edema, ischemia, etc.