Class Questions - September 5th

Basic Pathology Questions 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. - Reduced ATP production due to decrease in oxygen results in a reduced ATPsodium pump activity. This in turn results in a net gain of sodium, resulting in a gain of water and cell swelling. -Anaerobic glycolosis increases, depletion of glycogen stores, accumulation of lactic acid thus lowering of intracellular pH. -Decrease in pH and ATP causes reduction in protein synthesis -If oxygen is restored to the tissues, the damage is reversible, however with persistent ischemia, irreversible injury will occur. - reduced ATP production also causes loss of ability to maintain Ca gradient  increased intracellular concentration and activation of multiple second-messenger cascades inducing damage to cells 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) Explain the 2 phases of indirect chemical injury. Phase I – makes more toxic - breaks down chemicals coming into the body Phase II – makes safe - neutralizes toxicity and excretes it as water soluble – this phase does not involved the actual excretion, but the water-solubility only Name 4 ways the body compensates during a state of shock. 1. sympathetic N.S. – vasoconstriction leads to increased blood flow to brain & heart 2. stress – vasoconstriction to increase blood pressure 3. kidneys – rennin/angiotensin/aldosterone – helps retain Na+ and therefore retain more water 4. ADH – secreted by pituitary gland and leads to peripheral vasoconstriction, therefore increasing blood pressure

Explain the cellular adaptations the uterus undergoes during pregnancy. a)Hypertrophy - increase in cell size and increase in size of the uterus b) Hyperplasia - increased number of cells in the uterus - both due to hormonal stimulation of estrogen leading to enlargement of muscle and increased blood flow. 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. Why do we tend to see leukocyte-dependent endothelial injury after an accumulation of leukocytes during the inflammatory response? An accumulation of leukocytes during the inflammatory response may cause release of toxic oxygen species and proteolytic enzymes, which then cause endothelial injury or detachment. Why is it common for patients with extensive hemorrhages to occasionally develop jaundice? Massive breakdown of red blood cells and systemic release of bilirubin from hemorrhages can cause jaundice. Compare the differences between apoptosis and necrosis in terms of triggers/causes, mechanisms and tissue reaction. Necrosis affects groups of neighboring cells via swelling, while apoptosis kills single cells through shrinkage and cell fragmentation. The causes of apoptosis can be external/exogenous through oxidative stress, trophic factors, toxins and stimuli such as TNF-@ or internally/endogenous from toxic substances (ex. Mutated SOD1) and byproducts of cell metabolism. Necrosis is mainly caused by exogenous stimuli such as radiation, toxics or just general disease processes. The mechanisms involved with

apoptosis includes programmed cascade of reactions, gene activation, endonucleases, and protease, whereas, in necrosis, it is energy independent, and ATP is depleted. Also, in necrosis, the membrane is destroyed, free radicals are involved and no protein synthesis or RNA transcription is needed. In terms of the tissue reaction, necrosis will cause inflammation to occur but none will be seen with apoptosis. Explain granulomatous inflammation Granulomatous inflammation is a distinctive form of chronic inflammation, and usually occurs from the presence of an indigestible foreign object from bacteria or other sources or from a cell-mediated immune reaction or a type 4 hypersensitivity reaction. The inflammation is controlled and terminated by chemical mediators such as macrophages, lymphocytes (T & B-cells), mast cells, eosinophils, and neutrophils which were released from damage tissue. These mediators are all sent and accumulate around the chronic inflammation from constant recruitment from the circulation or local proliferation. This persistent Tcell response leads to constant macrophage activation, which in turn leads to fibroblast activation. This will help form a protective wall of macrophages and scar/connective tissue, which forms a granuloma. List the 2 possible outcomes of acute inflammation and explain them when you would expect each to occur. The two possible outcomes of acute inflammation are resolution and scarring/fibrosis. Resolution occurs when full recovery is achieved and the area where inflammation occurred has resolved to normal. Scarring/fibrosis occurs when damage is so extensive that the body could not fully correct itself to its original state yet inflammation has subsided and repair has been made. 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) Permanent cells are cells without regenerative capability and therefore if destroyed cannot reproduce new ones (ex. cardiac, muscle cells) What type of neoplasm involves the invasion and metastasis to not become incapsulated? Malignant neoplasm; malignant neoplasms are generally unincapsulated, but not always. What pattern of inflammation involves the formation of pus? Suppurative through neutrophils, necrotic cells and edema

Distinguish between necrosis and apoptosis and give one example of each process Necrosis refers to the morphological changes indicative of cell death caused by progressive enzymatic degradation , It may affect group of cells or part of a structure of an organ. Apoptosis is a pattern of cell death affecting single cells marked by shrinkage of the cell, condensation of chromatin and fragmentation of the cell into membrane bound bodies that are eliminated by phagocytosis. Although the two types of cell death share some mechanistic features, necrosis is considered cell homicide where as apoptosis is programmed cell suicide. The morphological appearance of necrosis is the result of enzymatic digestion and denaturation of proteins. It can be detected in a myocardial infarction. Apoptosis can be found in programmed cell destruction of cells during embryogenesis as it occurs in implantation, organogenesis and developmental involution 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. Between day 3 ands 7, neutrophils are replaced by macrophages and granulation tissue invades the incision space. Collagen fibers are laid down and the epithelial cell proliferation continues to close the dermis. In the weeks that follow the epithelium heals, a keratin layer forms the fibrous union of the dermis. By the end of the first month a scar forms, devoid of inflammatory cells and is covered by normal epidermis. What roll do proto-oncogenes play in the development in cancer? • Proto-oncogenes are normal genes found within the cell whose function is to code for proteins that help regulate the cell’s growth and differentiation. Since protooncogenes are responsible for maintaining the healthy growth and differentiation of each cell, any mutation to these genes may be detrimental to the cell’s normal function. • A mutation of a proto-oncogene can become an ONCOGENE, which, when expressed, can increase the malignancy of a tumor cell. • Ways in which an oncogene can change the cell are by losing the ability to selfregulate and/or increasing the enzymatic activity of the cell. This can cause the cell to lose its stability and thus will increase its chances of becoming malignant.

Is there a possible link between allergies and chronic disease, and the upregulation of heat shock proteins? • In order to answer this question, we must recognize that from an immunological standpoint, allergies (especially long-term allergies) can result in a heightened state of inflammation in the body. In general, allergies are indicative of an overactive immune system, and with chronic allergies, we may see an increased number of white blood cells due to the heightened immune response. • Also, we will also find that in most chronic disease, the immune system is overwhelmed with inflammation. Like allergies, the immune system is in an heightened state and there is a possibility of an increased amount of WBC and other signs of inflammation found in the blood. • Heat shock proteins are proteins whose expression is increased when cells are exposed to elevated temperatures. However, different types of environmental stress conditions can also trigger an upregulation of heat shock proteins, such as infection, hypoxia, and inflammation. • Since one of the triggers for an upregulation of heat shock proteins is inflammation, it would be expected to see an increase number of heat shock proteins in individuals suffering from allergies and chronic disease. 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. Suppurative inflammation is a combination of? Neutrophils, necrotic cells and edema which form pus. Why is edema a concern? - It increases blood pressure - It can decrease blood flow to extremities (resulting in compromised nutrient delivery to cells) - It is an excellent indicator that there is a problem within the body (likely affecting one or more systems) When is edema a serious problem? - When there is a loss of function - When there is significant pain - When there is swelling in a constricted space (ie concussion) - When it impairs wound healing and the ability to clear an infection What speaking of dysplasia, what are the 3 disturbances that occur? 1) variations in the size and shape of the cells. 2) enlargement irrecgularity and hyperchromatism of nuclei 3) disorderly arrangement of the cells within the epithelium. What are 4 disorders associated with Edema? 1. Arteriolar dilation 2. increased venous pressure

3. 4. 5. 6.

Hypervolemia Hyperproteinemia increased cappillary permeability Lymphatic obstruction

What is the purpose of chemical mediators in the blood? They circulate in blood all the time, keeping processes "in check". The mediators are activated when trauma occurs and bind to the surface receptors to elicit the appropriate response. Generally, these mediators are molecules of communication; they are activated by injurious stimuli and bind to cell surface receptors; it is up to the cell to determine the appropriate response (based on the receptor type). What is a reperfusion injury? A reperfusion injury is when blood re-enters an ischemic area. This brings in extra white blood cells to the injury site, which can cause damage to the tissue when inflammatory mediators and free radicals are released . The blood also brings in oxygen that can cause oxidative damage to the cells or cellular parts. Also flushes the damaged cells with more calcium which can exacerbate Cadependent enzyme damage. 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. What is the course of a tumour from benign to malignant? Benign tumours go through two other stages prior to being labeled malignant. The first is pre-malignant. The next is carcinoma in situ. In this stage, there is no invasion of surrounding tissues. Because of this, carcinoma in situ will not necessarily form a tumour. However, it is a precursor that if left untreated may become malignant. Benign tumours do not necessarily progress toward malignancy, but cells that are dysplastic are warning signs. How do cancer cells avoid normal cell aging and death? Often TP53 is mutated. TP53 is responsible for signaling cell DNA repair. If DNA damage is beyond repair, then TP53 signals cell apoptosis. If this gene is mutated, then the damaged cell will continue proliferating. 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. Explain the two types of calcium deposition. 1. Dystrophic: The accumulation of calcium phosphate occurs as a crystal in areas of necrosis, commonly in the blood vessels. 2. Metastatic: Calcium deposition occurs due to hypercalcemia. Explain the difference between hyperemia and congestion. Hyperemia is the accumulation of blood in an area due to increased flow; where congestion is an increase of blood in an area due to a decreased ability to clear blood. 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 Which causes more damage to tissues and why: Ischemia or Hypoxia? During hypoxia, the tissue cannot receive oxygen. During ischemia, the body cannot receive oxygen as well as various other nutrients. Also, ischemic tissue cannot be flushed of wastes. Therefore, ischemia is a more harmful condition. This really depends; ischemia tends to have a greater impact on the specific

tissues involved; however, if hypoxia is due to low oxygen in the blood systemically, this is much more harmful than local ischemia (assuming it’s not in the heart or brain). What happens during the resolution phase of inflammation? - lymphatics pick up fluid and proteins - monocytes mature into macrophages, which pinocytose and phagocytose neutrophils and other debris How does endothelial cell contraction contribute to vasular permeability? The endothelial cells lining the blood vessels contract cell by cell creating space between them.(The cells contract away from each other) allowing fluid and cells to leak or move out of the vessels and into the tissues. What is the difference between hyperplasia and metaplasia? Hyperplasia is an increase in the number of cells, the term is reserved for things that are non-malignant. The mechanism can be hormonal(Thyroid hormone), compensatory(liver regenration), or pathogenic(cancer, thickening of endometrium). Metaplasia is when a cell or group of cells change type. It is a reversible process. It occurs when the cell or group of cells cannot handle a stressor. Usually it is followed by dysplasia and often neuroplasia. 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. Give three examples of intracellular accumulations of abnormal exogenous substances: a) heavy metals, b) tatoos, c) fat soluble vitamins Describe the metastatic casacde. The metastatic cascade enables tumor spreading, and can be divided for ease into 4 main steps. The first step involves tumor cell detachment and thus the creation of individual tumor cells. This occurs when the intercellular junctions between each tumor cell loosen through disruption of E-cadherin function. The second step involves the use of the multiple receptors on tumor cells (more than are found on noncancerous cells) that effectively bind the tumor cell to the ECM. The third step in the metastatic cascade, that of ECM degredation, occurs when proteolytic enzyme activity essentially dissolves the ECM, enabling tumor cells to be released from it. This leads to the fourth and final step: movement (or migration) of the tumor cells to varied locations in the body. This migration is powered by tumor cell cytokine activity, growth factors, and other chemical signals. Discuss the major causes of thrombosis, as per Virchow's triad. Virchow's triad effectively presents the 3 major causes of thrombosis in the body: injury to the endothelium, blood flow changes, and coagulability of the blood. Injury to the endothelium constitutes any disturbance to blood vessel endothelium. This disturbance does not necessarily result from physical injury or trauma to the site; it can also result from other factors including endothelial scarring as a result of bacterial injury or surgical changes (ie., synthetic valves in the heart); hypertension; or toxin absorption (ie., from smoking). Thrombosis can also result from blood turbulence, with blood stasis being a primary example. Blood stasis changes blood's laminar flow, encouraging platelets to cling to endothelial walls and thus cause problems in clotting factor distribution. The third cause of thrombosis is the extent of blood coagulability. Although this cause is the

least commonly seen in cases of thrombosis, it still deserves discussion as one of the potential causes. Hypercoagulability of the blood involves more predisposition to thrombi formation. This can can result from either genetic-based or acquired disruptions of homeostasis. What dietary component/substance has the ability to influence the production of inflammatory mediators? Omega-6 fatty acids (in excess) 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. How do heat shock proteins help cells recover from injury? Heat shock proteins are good at helping the cellular proteins stay in a functional form. After cellular injury there is an increase in the number of HSPs to help refold the increased denatured proteins within the cell. 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. How do white blood cells find sites of injury and inflammation? They move up a chemical gradient in a process called chemotaxis. 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. Why would metastatic tumor cells undergo anaplasia? It is important to realize that the less differentiated a cell is, the more susceptible it is to mutations and other factors, such as growth factors, cytokines, chemical mediators etc. When cells revert to a more primitive form, as they do in anaplasia, they are becoming more lethal and mitogenic. When such fast growth occurs and many abnormal mitoses occur, cells are highly more susceptible to mutations, and thus produce an even more dangerous generation of offspring. This cycle perpetuates itself; the strange looking cells that become dangerously less differentiated in anaplasia lead to even more abnormal cells as mitosis progresses. The metastatic tumor cells can now undergo angiogenesis, invade and destroy local tissue via the matrix, and spread then all over the body. 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 is smoker’s cough? Why do they have it?  It is adaptive response in the upper respiratory tract (metaplasia) from mucussecreting epithelium (ciliated columnar cells) to stratified squamous epithelium  This change in cell type no longer allows the trachea to fulfill its role in filtering foreign substances out effectively via cilia beating and mucous secretion and thus individuals who smoke have a more difficult time expelling these substances and hence the characteristic dry, hoarse sounding “smoker’s cough” What aspects of a cell are most vulnerable to damage? There are four main areas that are vulnerable to damage. The integrity of the cell membrane is very vulnerable. This can be very damaging because it could upset the fine ionic balance between the interior and exterior of the cell. The process of ATP generation can also be altered of stopped through damage to the mitochondria. Protein synthesis can also be vulnerable to damage. Lastly, the DNA contained within the nucleus can also be a target. 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 A 65 year old man suffered from tachycardia, hypertension, peripheral vasoconstriction, dizziness and mental confusion. He breathing became irregular and he was rushed to the hospital. What is the diagnosis? What is the most likely cause and why? He would most likely be diagnosed with ischemic stoke. It is most likely caused by coagulation necrosis in the brain stimulated by hypoxia. It is most likely that a blood clot has blocked the flow of blood, causing tissue ischemia distal to the clot. Solid DDX question – less relevant for pathology. 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. What is the significance of an oxidative burst in the phagocytotic phase of the inflammatory process? The oxidative burst is part of the killing and degradation phase of phagocytosis (Three phases). In an oxidate burst there is a sudden increase in oxygen consumption, glycogen catabolism, increased oxidation and production of reactive oxygen metabolites. This secretion of free radicals kills bacteria, but it is important to note that these free radicals will go on to kill healthy cells if not properly mediated. List three differences between healing by first and second intention: 1. First intention healing involves fewer tissue defects with less volume of necrotic debris and fibrin than healing by second intention. Second intention wounds are not cleaning cut like first intention wounds. The debris from second intention wounds must be removed prior to effective healing. 2. There are large amounts of granulation in second intention wounds vs. first intention wounds. 3. Wounds of second intention experience wound contracting to improve the integrity of the injury. Scars often result from 2nd intention healings than first intention because the area that is healed is bigger and more massive. 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.

What are contributing factors to an increase in vascular permeability? Vascular permeability can be a result of many different factors such as postcapillary venule contraction causing a local increase in blood volume, direct endothelial cell injury causing fluid from blood to leak from the vessel, and leukocyte- dependent cell injury causing the release of cytokines which act to increase vascular permeability. Increased transcytosis which disrupts the fluid

balance within the vessel causing leakyness of vessels, and angiogenesis of new vessels can increase vascular permeability since these newly generated vessels are leaky they have tendency to release more fluid into the extracellular space. Describe the process of how thrombosis can develop into an embolism? A thrombosis is inappropriate clotting within blood vessels which can be caused by endothelial injury, stasis or turbulence, or hypercoagulability. This clotting could be dislodged from the vessel wall and be considered an embolism. This can be quite serious since it could block off a small vessel resulting many problems such as reduced oxygen delievery, and necrosis of tissue. What are 5 examples of cellular events that promote vascular permeability: Five examples that promote vascular permeability are: 1. endothelial cell contraction that then creates spaces between the cells, (this can be very short lived, 15-30 minutes), 2. direct endothelial cell injury, 3. leukocyte-dependent cell injury, 4. increased transcytosis (the movement of substances across a cell via receptors), 5. leakage due to angiogenesis because newly formed blood vessels don’t have the required integrity as a well establish/formed blood vessel wall. 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 a compliment system? This is a system that functions for defence against microbial agents in both innate and adaptive immunity. The complement components in high concentration cause increased vascular permeability,chemotaxis, and opsonisation. 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 areas of a cell are susceptible to free radical damage? - the cellular proteins - DNA - cell membranes What could cause easy bruising and bleeding in an individual?

Easy bruising could be related to a platelet disorder, whereas easy bleeding with the inability to coagulate. Both platelet and coagulation disorders can coexist and thus, both conditions can be seen in an individual. Other signs would include epistaxis, gingival bleeding etc. These conditions can also be related to the integrity of the vessel walls; you could see easy bruising and easy bleeding with both platelet and coagulation factor disorders. In TCM, consider the function of the Spleen (controls blood). Outline and explain the five themes of biochemical damage. 1. ATP depletion – essential to all cellular functions, as it is the primary energy source of the cell, and thus decreases may lead to problems with essential cellular function leading to inactivity or even death 2. Oxygen deprivation or Free radical generation – oxygen depletion may lead to ATP depletion and its associated problems; free radicals may damage the cell membrane or other components, thus leading to overall cellular damage or death 3. Calcium homeostasis – very important 2nd messenger (imbalance can lead to chaotic cellular cascades or even lack of cellular signalling depending on the changes to the homeostatic balance) 4. Membrane permeability – can lead to changes in ion balance, which can alter cellular signalling or function; tends to be the primary cause of irreversible cell damage 5. Mitochondrial damage – associated with ATP depletion, as mitochondria are the power house of cellular respiration and ATP generation, thus damage could decrease or inactivate ATP generation and lead to its associated problems Describe a granuloma and explain how it is formed. A granuloma is a mass or nodule of chronically inflamed tissue with granulations that is usually associated with an infective process, especially when there are foreign entities that the body can’t remove (e.g. Tuberculosis). It is formed when the body produces a persistent T-cell response, which leads to persistant macrophage activation, and fibroblast activation. Ultimately scar tissue is formed (as related to the granulations) and a protective wall of macrophages forms around the scar. Finally, this mass becomes necrotic at the centre, leading to a caseous granuloma. Describe the fuction of pseudopod with regard to chemotasis 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? List three types of necrosis and explain their causes. ⇒ Coagulative necrosis: caused by hypoxia. Mycoardial infarction is a prime example. ⇒ Liquefactive necrosis: caused by bacterial or sometimes fungal infections which provide powerful stimulation of white blood cells.

⇒ Caseous necrosis: encountered mostly in foci of tuberculous infections. The term is derived from a cheesy, white gross appearance of the necrotic area. 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. Why is inflammation so important in the body’s ability to fight cancer? Immune cells are in fact equipped to recognize the foreign antigen presented by most tumour cells, however without the warning signals and wake up call provided by the inflammatory response the immune system is unaware that these tumour cells exist. A good analogy is that the immune system is in the dark and can only recognize the tumour cells they are specific for if the lights are turned on. Of course, it is the inflammatory response that serves the function of turning the lights on. 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 What are the differences between Benign and Malignant Neoplasm? Benign: - Well differentiated - Resembles normal cells - Slow growth (few mitosis) - Localized and discrete - Tend to be encapsulated - Is unable to metastasize Malignant: - Poorly differentiated - Abnormal cells - Fast growth (many mitosis) - Invades local tissue - Not encapsulated - Able to metastasize

What is the difference between Edema and Hyperemia and what are 2 types of hyperemia? Edema is swelling of any organ or tissue due to accumulation of excess fluid, without an increase of the number of cells in the affected tissue. It is an increase of extracellular fluid in any organ. Similarly, Hyperemia is also the swelling of any organ or tissue but due to blood accumulation at a certain area. So edema is increased fluid in the interstitial space of a tissue; hyperemia is an increased volume of blood in the tissue. Hyperemia can lead to edema. The 2 types of Hyperemia are active in which blood collects in an organ due to increased blood flow, and passive, in which blood collects in an organ due to an obstruction in the outflowing veins. What you have defined as “passive hyperemia” is actually called “congestion”. Hyperemia is an increased blood flow to an area. 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. Where are lymphatics most concentrated? The GUT. 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 Membrane permeability because the maintenance of a selective semi permeable membrane is vital to a cells survival. If the membrane is disrupted, the cell will lose the ability to maintain its concentration gradients and substances will travel across the membrane freely, rendering the cell unable to function. On the other hand, ATP can be replaced while free radical damage and mitochondrial damage can be repaired. 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. Differentiate between benign and malignant neoplasms (tumors). • Benign neoplasms are well differentiated and resemble normal cells. They grow at a slow rate with few mitoses. They do not metastasize and tend to be encapsulated, localized and discrete. On the other hand malignant tumors are not well differentiated and are considered abnormal cells. They have many mitoses and therefore grow at a faster rate, making them to be more problematic than benign tumors. Another characteristic making malignant tumors dangerous is their ability to invade local tissues and therefore metastasize. This ability is attributed to it not being encapsulated. 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. Shock is a serious medical condition. Describe the four stages of shock. 1. Initial - This is where the hypoperfusional states causes hypoxia. The mitochondria is unablle to produce adenosine triphosphate. Due to this lack of oxygen, the cell membrane is damaged and the cells undergo anaerobic respiration. This causes a build-up of lactic and pyruvic acid which results in systemic lowered pH (metabolic acidosis). These compounds are not removed by the liver becuase of the lack of oxygen. 2. Compensatory - This stage is characterised by the body employing physiological mechanisms, including neural, hormonal and bio-chemical mechanisms in an attempt to reverse the condition. Because of acidosis, the person will begin to hyperventilate in an attempt to inspire more oxygen. The baroreceptors in the arteries detect hypotension, and cause the release of adrenaline and noradrenaline. This causes vasoconstriction resulting in an increase in blood pressure and heart rate. These hormones cause vasoconstriction of the kidneys, gi tract and other organs to divert blood to the heart, lungs and brain. The lack of blood to the renal system causes the characteristic low urine production. 3. Progressive -Compensatory mechanisms begin to fail. Due to the decreased perfusion of the cells, sodium ions build up within while potassium ions leak out. As anaerobic metabolism continues, increasing the body's metabolic acidosis, the arteriolar and precapillary sphincters constrict keeping that blood inside the capillaries. Due to this, the hydrostatic pressure will increase and, combined with histamine release, this will lead to leakage of fluid and protein into the surrounding tissues. As this fluid is lost, the blood concentration and viscosity increases. The prolonged vasoconstriction will also cause the vital organs to be compromised due to reduced perfusion. 4. Refractory - At this stage, the vital organs have failed and the shock can no longer be reversed. Brain damage and cell death have occurred and death will occur imminently. After injury, will all cells repair themselves? Different cells undergo different mitotic patterns. Cell Types

E.g.

Labile cells (always regenerate) Stable cells (sometimes regenerate) Permanent cells (don’t regeneratre)

Epidermis, Intestinal, Bone Marrow Liver Parenchymal cells Cardiac & Skeletal muscle cells, Nerve cells

What role does Telomere shortening play in aging? A telomere is a region of highly repetitive DNA at the end of a linear chromosome that functions as a disposable buffer. Each time a cell divides the telomere shortens a little more until the telomere or "buffer" region becomes too short causing the it to enter cellular senescence or causing apoptosis. Does the inflammatory process serve as a protective mechanism? If so how? Inflammation is the first response of the immune system to infection or irritation. White blood cells, or leukocytes are sent to the site of inflammation and act as phagocytes, picking up bacteria and cellular debris. They may also aid by walling off an infection and preventing its spread. However, chronic inflammation is not beneficial as it will lead to tissue destruction as can acute inflammation if inappropriate or uncontrolled. As in everything else in life, balance is the key! Identify the causes of each of the five signs of inflammation? Heat is caused by an increased in blood flow. Redness is caused by the dilation of blood vessels. Swelling is caused by the extravascular accumulation of fluid and hyperemia and congestion of blood. Pain is due to the increased pressure exerted by the accumulation of interstitial fluid and to chemical mediators irritating nerve endings. Loss of function is due to chemical and structural changes to the tissue or organ and likely due to pain, as well as limited range of motion from swelling (stiffness). Which is least likely site for Infarction A) Skin B) Spleen C) Liver D) Kidney E) Bone C) Liver has dual blood supply so is least likely to undergo infarction. The other organ least likely to undergo infarctio are lungs. In hypoxic damage of cells all may occur except A) Cell swelling B) Disappearence of nuclei (Karyolysis ) C) Leakage of Sodium from cells D) Leakage of calicum into cells E) Loss of potassium from cells C) Sodium enters the cells because its concentration is higher in extra cellular fluid.

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. Describe the differences between a hemorrhage, hematoma and hemostasis. Hemorrhage – blood leaving the vessel; due to a ruptured vessel, trauma or erosion; open or closed Hematoma – a localized collection of extravasated blood, usually clotted, in an organ, space or tissue Hemostasis – normal & appropriate accumulation and clotting of the blood