Monday, 11 January 2016

Food Sensitivities

This is for my personal use, though it should help anyone in a similar boat.

Since cutting out dairy and gluten four days ago the heavy breathing that I used to get in the mornings, afternoons and evenings has greatly subsided. However, it seems to have made a bit of a comeback today (Monday 11th January 2016) and yesterday (Sunday 10th January 2016). I also felt very tired earlier in the afternoon which is a symptom I haven't had in a month or so.

This may be due to a sensitivity to fried foods as I ate chips on Saturday and Sunday night. It may also be totally unrelated to food and just a part of recovering from fatigue. I shall see how I feel tomorrow and whether or not the heavy breathing is present then as today I will only be eating fruits, vegetables, noodles, meat and some herbal and fruit drinks.

Saturday, 13 June 2015

Question 5: How might a patient's white blood cell count be affected by a drug that reduces cell division, and how may this person be treated differently to compensate for this effect?

*These posts are from coursework answers for my degree, but the Figures that are referred to in the text didn't scan well and have already been handed in. These long posts would probably not interest most people but if you enjoy quite in-depth reading of scientific problems then this may be for you.

Question 5: If a patient with an inoperable cancer is treated using a drug that reduces the rate of cell division, how might the patient’s white blood cell count change?  How might the patient’s environment be modified to compensate for the effects of these changes?


If a drug that reduces the rate of cell division is given to a cancer patient, one would expect a decrease in that person’s white blood cell count (Prinjha, and Tarakhovsky, 2013).This is because not only would the cancer cells have their rate of cell division stunted, but the immune cells would also.
A drug which inhibits cancer cell growth and is given to a patient with an inoperable cancer is likely to be a form of targeted therapy in regard to cancer treatment. These drugs are more specialised in choosing cancer cells to exhibit their effects. Older drugs find it harder to differentiate between healthy and cancerous cells, and given that their effect usually increases depending on the rate of cell reproduction (advantageous because cancer cells tend to rapidly reproduce), these older drugs commonly cause much harm to fast-growing cells such as the skin and digestive tract. However, targeted therapies still have substantial side-effects, particularly fatigue, nausea, skin and clotting problems as well as elevated blood pressure. These forms of drugs, however, would have less effect upon the white blood cell count than ordinary drugs (National Cancer Institute, 2014).
Chan, Koh and Li (2012), state that cancerous cells are most vulnerable during mitosis and that the use of drugs centred on cell division is therefore of high importance to cancer treatment. They also state that drugs producing antimitotic effects tend to be highly specific, but that the body reacts unpredictably when exposed to them.
According to Schmidt (2000 pp. 112-115), the production of thymidylate and dihydrofolate are of substantial importance in the role of DNA synthesis. Given that cancer is fundamentally a cellular error causing uncontrolled replication, the inhibition of DNA synthesis plays a pivotal role in treating cancer. A compound called 5-fluorouridine bears strong similarity to the substrate acted upon by thymidylate synthase, once it has been phosphorylated by a nucleoside kinase (the only difference is that this product contains a fluorine where the natural substrate, dUMP, contains hydrogen). However, once this end-product (called 5-fluorouridine monophosphate) binds with thymidylate synthase, the fluorine stays bonded to the enzyme, causing it to no longer function. Since the 5-fluorouridine monophosphate reacts with the enzyme, and the enzyme can no longer function afterwards, it is called a “suicide substrate”. DNA necessary for cell division can also be reduced by decreasing the reduction of dihydrofolate to tetrahydrofolate. When N5,N10-methylene tetrahydrofolate donates a methyl group to deoxy-UMP under the supervision of the thymidylate synthase enzyme, thymidylate (deoxy-TMP) is formed. This reaction is illustrated in figure 5.1.

Since the tetrahydrofolate compound in this reaction is oxidised to dihydrofolate, the converse of this (reduction of dihydrofolate by dihydrofolate reductase (DHFR)), will consequently lead indirectly to thymidylate production. Thus, the inhibition of DHFR will also reduce thymidylate production. Substrates which are competitive inhibitors of folates are called folate antagonists, where an antagonist is a substance that binds to a receptor, without producing the receptor’s activity. Thus, a substance binding to a folate-receptor, may not produce the same effect as a folate-containing substance binding to it. The antagonists in this example will attempt to out-compete the folate substrates involved in activating the DHFR enzymes, thus preventing the chemical reactions leading initially to the reduction of dihydrofolate to tetrahydrofolate and eventually to the production of thymidylate, which would increase DNA synthesis and allow cell division to occur.
From Schmidt (2000, p. 230), information is given about the G1 phase of cell division. This particular phase is actually a point of non-division, in which various biochemical reactions take place, but the cell does not actively divide. Many animal cells can spend years in the G1 phase without dividing, which makes it highly important in cancer treatment. If the G1 phase could be clearly understood, then cells could be encouraged to remain within it, not dividing, and consequently not resulting in cancer formation. An unfortunate consequence of decreasing cell division non-specifically however, is that all cells in the body which take in a particular drug that decreases cell division will have their rate of replication decreased. This makes it more difficult for the body to combat infections which are not affected by the drugs, given that the body cells may be subjected to division-inhibition for many weeks or months before encountering a new infection, its immune cells are likely to be lower in number and therefore not be as capable of combating the threat.
If the number of white blood cells that a patient has, decreases, then that person is more susceptible to all possible infections as these cells fight them.
Among the white blood cells or leukocytes, the form most important during consideration of possible infections is the neutrophil. This is the type of white blood cell most abundant in plasma, constituting roughly 54-62% of the overall number of circulating leukocytes (Mescher 2013, p. 235). Neutrophils are relatively small phagocytic immune cells that are produced in vast quantities every day (roughly 126 billion enter the digestive tract daily, according to Seeley, VanPutte, Regan and Russo, 2011, p. 791), and are often the first of the immune cells to reach infected regions in great numbers. Once at an infected site, neutrophils are responsible for increasing immune cell activity and inflammation at this area. This is brought about by their release of cytokines which encourage the proliferation and differentiation of immune cells, and by chemotactic agents, respectively (Seeley, VanPutte, Regan and Russo, 2011, p. 792).
The test for abundance of circulating neutrophils is called the absolute neutrophil count (ANC), and is considered the most important risk factor for both bacterial and fungal infections, according to Johnston and Spence (eds, 2003, p. 253). The diagnosis of neutropenia (a deficiency of neutrophils), is stated as an ANC of less than 500 per millilitre of plasma, or expected to fall to this level within the next 24 hours of being tested. These writers also state that risk increases as neutrophil count decreases, and that the rate at which neutrophil count is decreasing, as well as how long neutropenia has presented, also play a pivotal role in contracting bacterial and fungal infections. The more rapidly neutrophil count is falling, and the longer a person has had neutropenia, the more likelihood there is of becoming infected, and the more severe the infection is likely to be. Thus, it is highly important to consider neutropenia, although B-cell and T-cell function is also compromised in cancer treatment, usually due to chemotherapy, but further exacerbation can occur via concomitant utilisation of steroids (Johnston and Spence, eds, 2003, p. 246). These authors also explain that the use of catheters in immunocompromised cancer patients poses a significant risk of subsequent infection, this is due to the ease with which microbial colonies can form within the synthetic catheter, possibly migrating into the host and causing infection. Therefore, it is of the utmost importance that catheters be monitored and if possible, sampled, in order to gauge microbial growth.
There are many other types of immune cell that are important in the response to infection. This first section deals with those cells which are an integral part of the innate immune system, i.e. the branch of the immune system acts in a non-specific manner:
Neutrophils fall into this category but are explained in detail above.
Monocytes are white blood cells that circulate the body and are enticed by chemo-attractants to enter damaged tissue and differentiate into macrophages which are important for consuming toxic substances and cells that may damage the body, they may also stimulate B-cell and T-cell activity during infection (Seeley, VanPutte, Regan and Russo, 2011, p. 791). Macrophages are roughly 5 times the size of monocytes, and have additional lysozymes and mitochondria. They are larger, longer-lasting, and are capable of engulfing larger particles than neutrophils, though they appear at the site of infection a little later than neutrophils. Thus, they are most used in the later stages of infection. Their large size makes them ideal for engulfing cellular debris, and even whole neutrophils which have died earlier on during the immune response. Macrophages may also secrete various substances such as interferons, complement, and prostaglandins. The roles of interferons and complement are discussed elsewhere, but prostaglandins have a variety of actions, perhaps most importantly of which are its function in increasing the permeability of blood vessels (which can allow immune cells to permeate vascular and reach infected or damaged tissue, and also in causing vasodilation, again allowing immune cells to reach a particular site by aiding blood flow to the affected region. This is shown by Seeley, VanPutte, Regan and Russo, 2011, pp. 789, 792.
Both basophils (motile) and mast cells (nonmotile) are immune cells that promote inflammation within tissues through the release of various chemicals, e.g. leukotrienes and histamine. This inflammatory response can increase blood flow to the area, signal other leukocytes to arrive on the scene, and encourage the formation of either a platelet plug or clot to seal off the affected region to further damage and/or infection. Conversely, eosinophils are motile immune cells that enter tissues and inhibit the inflammatory response. They do this by breaking down the substances secreted by the basophil and mast cells. Therefore, eosinophils are produced in larger quantities during immune reactions where a large inflammatory response occurs, such as in allergies. Additionally, eosinophils have the ability to kill some forms of parasites (Seeley, VanPutte, Regan and Russo, 2011, pp. 791-793).
Finally, NK (natural killer) cells are important in the attack on cancer cells. NK cells contain enzymes that can chemically lyse or split tumour cells, preventing the growth spread of cancer, one of their preferred mechanisms of actions is to chemically lyse the plasma membrane of harmful cells (Seeley, VanPutte, Regan and Russo, 2011, p. 791-792).
The adaptive immune system then, deals with specific and personalised threats to the body. This branch of the immune system is capable of responding to a specific substance, called an antigen. These antigens may be produced by the body, for example, a tumour cell (a self-antigen), or produced by a foreign invader or microbe which has found its way into the body and may cause harm (a foreign antigen). Within the umbrella term of adaptive immunity, there are two main categories of immune response; cell-mediated immunity and antibody-mediated immunity. Antibody-mediated immunity is brought about by the production of antibodies (these are released by cells that result from the differentiation of B-cells) that bind with antigens to form antigen-antibody complexes that inhibit the actions of harmful cells. On the other hand, cell-mediated immunity arises from the activity of T-cells, which can destroy whole cells instead of inhibiting vital components. This is highly useful for infections from viruses, which essentially ‘hijack’ the biochemical reactions of a cell for their own needs (Seeley, VanPutte, Regan and Russo, 2011, p. 794-806).
The adaptive immune system almost entirely consists of B-cells and T-cells to combat infection:
B-cells can be stimulated by antigens on the cell surface membrane of a pathogen and differentiate to produce either a plasma cell or memory B-cell. The plasma cell in this scenario would produce antibodies complementary in shape to the harmful antigen which would inhibit the effectiveness of the pathogen and signal for its lytic destruction by neutrophils, eosinophils, macrophages or monocytes. The memory B-cells formed by differentiated of B-cells can promote a rapid and lasting immune reaction to a specific form of pathogen. If this pathogen were to enter the body, memory B-cells would mass-produce antibodies that would inhibit its actions. (Seeley, VanPutte, Regan and Russo, 2011, pp.791, 803).
There are many types of T-cells; delayed hypersensitivity T-cells promote inflammation through the release of cytokines, helper T-cells stimulate the activity of effector T-cells and B-cells, Suppressor T-cells do the opposite, inhibiting the action of both T-cells (effector forms) and B-cells, and lastly, memory T-cells are similar to memory B-cells in their ability to maintain a lasting immunity towards a particular antigen that has been previously encountered. (Seeley, VanPutte, Regan and Russo, 2011, p. 791).
Finally, dendritic cells activate both B-cells and T-cells after recognition of a harmful antigen (Seeley, VanPutte, Regan and Russo, 2011, p. 791).
Another area of concern is the mucous membrane throughout the digestive tract. This membrane can become inflamed and mouth, stomach and other ulcers can result from the use of both chemotherapy and radiotherapy (depending on where the latter is targeted to), these ulcers and general damage to the mucous membrane can facilitate the harbouring of pathogens which can infect the body (Johnston and Spence, eds, 2003, p. 253). Further to this, though beyond the scope of this essay, is the effect of the underlying cause or simultaneous condition with regard to cancer. Chronic lung or liver diseases as well as AIDS, can independently compromise immune function, which would only be worsened by cancer treatment.
Care must be taken to ensure proper health of skin, teeth and the general oral cavity. Healthy skin and mucous membranes in the oral cavity produce secretions that prevent bacterial infection. For example, skin secretes oils and has an acidic pH due to the actions of sebaceous and sweat glands. Saliva in the oral cavity contains many antimicrobial agents, including the protein lysozyme, which destroys the cells walls of bacteria. These are some examples of nonspecific barriers (methods that provide a broad-spectrum of defence not limited to a single pathogen at a time). See Houghton Mifflin Harcourt (2014). Broken skin, infected gums and rotting teeth can all harbour bacteria that can lead to an infection the immunocompromised patient. Antibiotics may be taken to control overall and in particular, digestive bacteria, lest these should turn pathological.
According to Pack (2001, pp. 210-212), there are three types of barrier preventing infections to the body. These are the nonspecific barriers, the nonspecific defences, and the specific defences of the body. Many of the nonspecific barriers have already been covered, these are; skin, sweat, proteins such as lysozyme, cilia, digestive juices, and commensals (symbiotic organisms exist in and on the human body that can compete against harmful microbes). These barriers prevent the inward movement of harmful substances and microbes into the body.
The nonspecific defences are responsible for nonspecific removal and destruction of threats that have found their way into the body. Examples include phagocytes (white blood cells that engulf and digest pathogens, neutrophils, eosinophils, macrophages and monocytes are included in this category). Natural killer cells, are also on the list, as well as interferons and a defensive chemical called “complement”. Interferons are released by cells that are infected by viruses, and help the immune system recognise when a viral infection has occurred. Interferon is also aptly named for its ability to interfere with the production of viruses (Seeley, VanPutte, Regan and Russo, 2011, p. 789). Complement is a compound formed by roughly 20 proteins bonded together which attracts phagocytic immune cells to the site of an infection, as well as lysing cells by its own actions (Pack, 2001, p. 211).
The immune system forms the specific defence system against foreign microbes (Pack, 2001, p. 213). Some of the nonspecific defences such as natural killer cells and phagocytes are used for specific defence, particularly when an antigen has become part of an antigen-antibody complex and immune cells are signalled to engulf it.
On page 254 (Johnston and Spence, eds, 2003), the authors make known the vices of surgical removal of the human spleen, which can take place occasionally as part of cancer treatment. They state that the spleen is necessary for removal of opsonized pathogens (those bound by antibodies in the preparation of phagocytosis) and erythrocytes which have been infected with parasites. Surgical removal of the spleen also reduces the body’s ability to develop immune reactions to previously unencountered antigens. According to Pack (2001, pp. 204-209), the spleen is the largest organ in the lymphatic system. It contains two distinct regions; the white pulp and the red pulp. The white pulp contains many lymphocytes (T cells and B cells), as well as reticular fibres, whereas the red pulp contains many venous sinuses that act as a reservoir of red blood cells. The spleen has several main functions; filtering the blood of pathogens and debris from dead and aged cells, the destruction of old erythrocytes and subsequent recycling of organelles and nutrients, acting as a reserve for blood, and providing a site of T cell and B proliferation (T cells reproduce before returning to attack non-self cells and B cells produce antibodies and plasma cells which go on to inactivate harmful antigens. Thus, its removal can have dangerous consequences.
The above effects combined produce a patient who is highly susceptible to infection. They mention several bacteria whose infections are more commonly and severely present in immunocompromised patients, there are; Streptococcus pnuemoniae, Capnocytophaga canimorsus and Babesia microti (a bacterium that presents with malaria-like symptoms such as fever, chills, sweating, and head and body aches information that is elaborated upon by the Centers for Disease Control and Prevention, 2014a).
Wigglesworth (2003) gives a lot of information on the use of environment changes for immunosuppressed patients. If such patients are currently residing in a hospital then they can be separated from the main hospital population and wads, usually by keeping them in a single room. Hygiene is of particular importance to ensure that no pathogens are transferred from care workers to the patient. Hand-washing is a must in this scenario.
According to the University of Utah Health Care (2003), proper hand-washing is the most important action in the prevention of infectious diseases. The amount of visitors that a person meets during the day and the foods that they eat must be monitored to ensure there is little risk of infection. Certain foods are considered high-risk when it comes to patients with a weakened immune system, extra care must be taken to avoid these foods. Soft cheeses and anything made with raw eggs are a hazard for such patients. Therefore, mayonnaise was also be avoided.
Additionally, the use of vaccinations before a person is likely to become immunocompromised can decrease the likelihood of infection. This has been proposed as a strategy for persons likely to exhibit lower immune function for a number of different reasons including cancer and HIV (Tolan, et al, 2013).
The Centers for Disease Control and Prevention recommend that any sign of fever in patients receiving chemotherapy be treated as an emergency, even if it is the only symptom (Centers for Disease Control and Prevention, 2014b). Further safety precautions can be taken to reduce the chance of infection can be taken. One can avoid sharing any personal items, such as cups or utensils or anything that requires insertion into the mouth, e.g. toothbrushes. Daily washing should be done with unscented lotions. Lotions which are scented can damage or dry the skin, allowing pathogens to colonise or pass through this layer. Meat and eggs must be cooked thoroughly, raw fruit and vegetables must be washed carefully, gloves should be worn around pets and for gardening, and care must be taken to avoid damaging the gums during tooth-brushing (thus a soft toothbrush is highly recommended), see Centers for Disease Control and Prevention, 2014c. This same source provides ample knowledge of the warning signs of infection in order to warn immunocompromised patients. Some of the more noticeable signs are; a fever of >38oC for over one hour, sore throat, burning or other pain upon urination, shortness of breath, diarrhoea, vomiting and increased urination.
Finally, the Centers for Disease Control and Prevention also note that white blood cell usually drops to its lowest value as a result of chemotherapy around 7 to 12 days after the chemotherapy dose has finished, and from this point the low count can last for around a week before increasing again. This lowest point is when most vigilance is required in protecting oneself from infection, as the immune system will be most weakened and unable to respond adequately (Centers for Disease Control and Prevention, 2014d).

Question 5 References:
Centres for Disease Control and Prevention, 2014a. Babesiosis FAQs, [online] Available at: <> [Accessed 13 April 2015].
Centres for Disease Control and Prevention, 2014b.Emergency Room Personnel, [online] Available at: < > [Accessed 13 April 2015].
Centres for Disease Control and Prevention, 2014c. How can I prevent an infection? [online] Available at: < > [Accessed 13 April 2015]. 
Centres for Disease Control and Prevention, 2014d. Protect: Know the Signs and Symptoms of Infection, [online] Available at: <> [Accessed 13 April 2015].
Chan, K.S., Koh, C.G., and Li, H.Y., 2012. Mitosis-targeted anti-cancer therapies: where they stand. [online] Available at: <> [Accessed 7 April 2015]. 
Houghton Mifflin Harcourt 2014. Nonspecific Barriers, [online] Available at: <> [Accessed 7 April 2015]. 
Johnston, P.G., and Spence, R.A.J., eds. 2003, Oncologic Emergencies. United States, New York: Oxford University Press Inc.
Mescher, A.L., 2013. Junqueira’s Basic Histology Text & Atlas, 13th ed. China: The McGraw-Hill Companies.

National Cancer Institute, 2014. Targeted Cancer Therapies, [online] Available at: <> [Accessed 7 April 2015].
Pack, P.E., 2001.  Anatomy and Physiology, Hoboken, NJ: Wiley Publishing, Inc.
Prinjha, R., and Tarahovsky, A., 2013. Chromatin targeting drugs in cancer and immunity. [online] Available at: <> [Accessed 7 April 2015].
Schmidt, F., 2000. Biochemistry II, New York, NY: Wiley Publishing, Inc.
Tolan, R.W., Brook, I., Windle, M.L., Domachowske, J., Rauch, D., and Steele, R.W. 2013. Infections in the Immunocompromised Host, [online] Available at: <> [Accessed 7 April 2015].
University of Utah Health Care, 2003. Prevention of Infectious Diseases, [online] Available at: <> [Accessed 7 April 2015].
Wigglesworth, N., 2003. The use of protective isolation, [online] Available at: <> [Accessed 7 April 2015].

Question 4: Discuss causes, effects and treatments of atherosclerosis

*These posts are from coursework answers for my degree, but the Figures that are referred to in the text didn't scan well and have already been handed in. These long posts would probably not interest most people but if you enjoy quite in-depth reading of scientific problems then this may be for you.

Question 4: Atherosclerosis in the coronary circulation causes heart disease; discuss the causes of atherosclerosis and its effect on the cardiovascular system. How are stents used to treat atherosclerosis?


Atherosclerosis is the build-up of plaque formed primarily by white blood cells and cholesterol within the innermost membrane of an artery wall, called the tunica intima (Seeley, VanPutte, Regan and Russo, 2011, p. 725). This accumulation of plaque is a slow process, often taking years or decades to present with any symptoms, if at all, to the person suffering from it. It is important to note that oxidised low-density lipoproteins (ox-LDLs) are considered more atherogenic than native LDLs. This is agreed upon in many works, for example; Samsioe (1994), Panza, and Cannon, eds. (1999, pp. 89-92), and Kummerow, (2013). Dr. Kummerow, in particular, gives much weight to the pathological effects of oxidised cholesterols, known as oxysterols. He believes that the intake of oxysterols via fried foods, excess vegetable oils (especially partially hydrogenated vegetable oils) and cigarette smoking play a far greater role than simple dietary cholesterol. This will be a part of the original thought later on in this essay.
Schmidt (2000, p. 38), explains that as cells take in LDL cholesterol to satisfy their metabolic requirements, they begin to exhibit fewer cell membrane receptor sites for LDLs. Therefore, if a high concentration of LDL cholesterol exists in the bloodstream, then cells will take in as much as they need, down-regulate their receptor sites, and the remaining cholesterol will be free to circulate the body. This means that more of the cholesterol will be free to travel the circulatory system and become deposited in walls of blood vessels, leading to an increased risk of arterial diseases. The use of receptors on cell surface membranes in order to take in a specific molecule or nutrient is an example of receptor-mediated endocytosis (Pack, 2001, pp. 26-27). When this occurs, a vesicle is formed as the cell membrane folds inwards around the substance being received. Once the substance is safely inside of the cell, the vesicle can break-down, releasing, in this case, the LDL.
 The resultant problems associated with atherosclerotic lesions are typically due to the narrowing of blood vessels (stenosis), this decreases the available size of lumen for blood to travel through, leading to a reduction in blood supply to tissues (ischemia). There are many causes of atherosclerosis, these include: Hypercholesterolemia or dyslipidemia (particularly increased LDL [low-density lipoprotein] concentrations, but decreased levels of HDL [high-density lipoproteins that appear to offer a protective effect against plaque build-up] are also a risk factor [Carmena, Duriez and Fruchart, 2004]). Habitual cigarette smoking (Lin, et al,. 1992) has also been found as a potential factor in disease progression. Mitchell, et al. (2007, p.345) show that diabetes, elevated C-reactive protein in serum, growing older, male gender, genetic faults that produce high levels of cholesterol and family members who have suffered from atherosclerosis and its related cardiovascular incidences (more detail further on in this essay), were more likely to get the disease. Concomitant disorders also include obesity and insulin resistance (as well as type 2 diabetes), as shown by Hotamisligil (2010).
The above factors will be touched upon briefly, however a lot of this write-up will be dedicated to biochemical pathways within the body that both decrease and contribute to atherosclerosis, and how a down-regulation of antiatherogenic chemicals can lead to this disease.
Some of the more microscopic changes that occur to bring about atherosclerosis include but are not limited to the following: Monocyte and macrophage adhesion to endothelial cells, platelet aggregation, reduced endothelial nitric oxide levels, high endothelial permeability increasing the migration of lipoproteins into the walls of arteries, and increased vascular smooth muscle cell proliferation, this rapid reproduction rate greatly speeds up the aging process (Panza, and Cannon, eds., 1999, p. 44).
One of the largest factors in the occurrence and progression of atherosclerosis is the movement of lipoproteins, primarily LDLs, into the arterial wall, where they can then deposit cholesterol which can become oxidised. HDL is considered protective in this situation as it bonds to cholesterol and carries it to the liver. This is one of the main reasons why proportions of varying types of lipoproteins is an important study in these diseases, in particular, having low HDL and high LDL is considered a strong factor in the onset of atherosclerosis (American Heart Association, 2014a).
Mescher (2013, pp. 234-239) shows that the whole blood consists of approximately 1% leukocytes and platelets combined (white blood cells) which are usually inactive while circulating the body. Their activity is apparent however, when they are signalled to sites of infection, inflammation or general damage. Here they will migrate into tissues and exert (generally) appropriate action. In the case of atherosclerosis, the prime white blood cell to be considered is the monocyte, an agranulocytic blood cell that, among many other functions, modulates the concentrations of LDLs in the arterial wall, it has this capability because it is a precursor of the macrophage (an immune cell of the mononuclear [one nucleus] phagocyte system, that engulfs cellular remnants and infectious agents, among other substances and living matter). Whenever LDLs and particularly oxidised LDLs are present in the arterial wall, monocytes (a form of leukocyte) are coaxed into adherence to the endothelial cells by the presence of a protein, VCAM-1 (vascular cell adhesion molecule 1 or vascular cell adhesion protein 1, as shown by the National Center for Biotechnology Information, 2015). Without this protein, the monocyte would continue its journey around the body without stopping. Instead, the monocyte will migrate into the endothelium experiencing LDL-induced inflammation and will differentiate into a macrophage, in order to phagocytise the offending molecule and carry it away.

If this process becomes chronic, i.e. many LDLs are constantly permeating the endothelium and causing inflammation, then a high concentration of macrophages will exist within the endothelium in order to try and remove these LDLs. This accumulation of monocytes is called extravasation (Mescher, 2013, p. 245). Unfortunately, the presence of so many macrophages and resultant inflammatory response leads to disproportionate tissue damage within the artery. As the macrophages engulf lipoproteins they begin to change size and shape, and are termed “foam cells” (Oh, et al., 2012). The change in appearance is due to the high concentration of lipoproteins within the macrophages. When this occurs, the atherosclerotic lesion begins to look like a fatty streak. This point in the progression of atherosclerosis is usually not severe enough to induce significantly restricted blood flow within the artery to the point of producing symptoms, but the artery becomes more rigid and susceptible to damage.
Thus, we can see that endothelial permeability to low-density lipoproteins is a prime factor in atherosclerosis. If the endothelium did not allow LDL to move into it, then there would be no need for macrophages to enter either, possibly preventing atherosclerosis from even beginning.
As time goes on, macrophages begin to die and release chemicals that further exacerbate inflammation, leading to a greater immune response within the area. This causes more monocytes to be signalled to the vessel wall and differentiate into macrophages, furthering the progression of plaque formation. This occurs primarily between the tunica intima and tunica media (American Heart Association, 2014a). Also over time, calcium deposits build up due to poor clearance of cellular debris from these deceased cells. This is because the atherosclerotic plaque proves too great a physical barrier to facilitate their removal. Further to this, if the atherosclerotic plaque ruptures, possibly due to the high blood pressure in the artery and weak structural strength of the plaque, then a clot may form. A clot is the entrapment of blood cells, fluid and platelets by fibrin (a protein that encourages clotting).
Another name for a blood clot is coagulation, and the proteins involved in its production are called either coagulation or clotting factors, which are contained in blood plasma. Under ordinary conditions, these factors remain inactivated, however, when damage occurs to tissue, such as a weakened blood vessel in our case of atherosclerosis, the coagulation factors become more active. The initiation of clotting can occur via an extrinsic or intrinsic pathway, though both link into a later route of chemical reactions called the common pathway (Seeley, VanPutte, Regan and Russo, 2011, pp. 660-661).
The extrinsic pathway of clotting starts due to the presence of chemicals that are not contained within the bloodstream. This could be from the release of thromboplastin (other names for this chemical are factor III or tissue factor) as a result of tissue damage. If calcium ions react with thromboplastin, the result is a compound containing factor VII which can react to activate another chemical called factor X. This is the point where the common pathway begins at the end of the extrinsic pathway (Seeley, VanPutte, Regan and Russo, 2011, p. 661).
The intrinsic pathway starts off differently, with chemicals that are contained within the blood stream, such as collagen which can be exposed when blood vessels are injured. Whenever a chemical called plasma factor XII reacts with this collagen, the factor XII becomes active. Consequently, factor XI is activated, leading to stimulation of factor IX, which binds with various other molecules, such as factor VIII, phospholipids contained within platelets, and positive calcium ions. The result of this is that factor X becomes acitivated, and this is the point where the common pathway begins, just like at the end of the extrinsic pathway (Seeley, VanPutte, Regan and Russo, 2011, pp. 661-662).
At the beginning of the common pathway, prothrombinase is formed by the binding of factors X and V, along with phospholipids from platelets, and calcium ions. Prothrombinase is capable of converting a protein dissolved in plasma, called prothrombin, into thrombin, an enzyme highly important in clot formation. This enzyme produces a protein called fibrin from fibrinogen (another protein dissolved in plasma). The fibrin formed is responsible for the entrapment of platelets, blood cells and fluids that make up a blood clot. Blood clotting is a relatively rare example of positive feedback in the human body, because its presence can lead to the production of its own precursors (e.g. factor XI and prothrombinase). Vitamin K is necessary for clot formation, and its deficiency can lead to excessive bleeding (Seeley, VanPutte, Regan and Russo, 2011, p. 662).
When a clot is attached to an arterial wall it is called a thrombus. After a clot has formed and attached itself, it starts to become denser due to clot retraction. This occurs because platelets, arranged as extensions to fibrinogen (which are bonded to fibrinogen receptors on cells of the blood vessel wall), begin to contract through the use of actin and myosin filaments, effectively pulling on the fibrinogen and drawing the clot into a more compact structure. This process liberates serum (a fluid similar to plasma, but which doesn’t contain some clotting factors, as well as fibrinogen). As a result of this, the injured blood vessel is more tightly sealed up, allowing it to recover more easily, and reducing the possibility of infection (Seeley, VanPutte, Regan and Russo, 2011, p. 663).
Figure 4.1 shows the development of atherosclerotic plaque and subsequent clot formation. Here we see that the plaque itself is enough to cause significant narrowing of the blood vessel, however, due to rupture of plaque, a thrombus has started to form. This thrombus is further restricting blood flow through the artery and will be discussed further blow. The diagram also shows that the plaque is developing between the tunica intima (innermost membrane of the artery, and one that separates other tissue layers from the lumen) and the tunica media. (Seeley, VanPutte, Regan and Russo, 2011, p. 725).
A fundamental chemical involved in atherosclerosis is nitric oxide. A reading of the literature greatly brought up the antiatherogenic importance of this small, highly-reactive free radical. Its production is decreased in atherosclerosis (Panza, and Cannon, eds., 1999, p. 20) and this has a strong effect in the progression of the disease, as will be elaborated on below.
It is important to note before continuing that the following substances either inhibit nitric oxide (NO) directly, either in production (which occurs via the nitric oxide synthase enzyme), release or functional effect:
Endothelin-1, abbreviated to ET-1. This is a petide composed of 21 amino acids that is produced in the endothelium, one of its main effects is as a vasoconstrictor. ET-1 has been shown to be elevated in atherosclerosis and likely contributes to the disease. Its vasoconstriction effects are roughly a hundred times stronger than noradrenaline per unit of concentration. Oxidised low-density lipoproteins increase its release, explaining its increased production during atherosclerosis. It also attracts monocytes to atherogenic lesions because it has chemoattractant effects (Panza, and Cannon, eds., 1999, pp. 97-109).

Angiotensin II or Ang II is also implicated in the development of atherosclerosis and reduction of nitric oxide. This is a peptide hormone that also has vasoconstrictive effects. Its administration has been shown to increase the size of atherosclerotic lesions in mice deficient in apolipoprotein E (this is a molecule that breaks down lipoproteins, and without it, mice as well as humans, have a much greater risk of developing atherosclerosis, Daugherty, A., Manning, M.W., and Cassis, L.A. 2000).  Nitric oxide also inhibits the effects of Ang II in the vasculature (Toda, N., Ayajiki, K., and Okamura, T. 2007).
Asymmetrical di-methylarginine (ADMA), this is a circulating amino acid that is similar in structure to L-arginine. As l-arginine is a precursor to nitric oxide, ADMA is able to interfere with this metabolic pathway, by interacting with its components, namely the nitric oxide synthase enzyme (NOS).
NG-monomethyl-L-arginine (L-NMMA) as well as L-nitroarginine methylester (L-NAME) share a similar effect, by competing with L-arginine for the active site of the NOS enzyme (Panza,  and Cannon, eds., 1999, p. 165). This occurs because the production of nitric oxide from L-arginine results from the oxidation of the terminal containing a guanidine-nitrogen bond, which is also contained within the inhibitors mentioned above.
Implicated as well in the down-regulation of various aspects of nitric oxide are many reactive oxygen species (ROS) including the superoxide anion (O2-) and hydrogen peroxide (H2O2). This is due to the effect of these species to rapidly and chemically alter nitric oxide. Panza, and Cannon, eds. (1999, p. 134) show that the reaction between the superoxide anion and nitric oxide produces the peroxynitrite anion, a relatively stable ion compared to the particular radicals in this example of its creation. The peroxynitrite anion loses many of the qualities of nitric oxide, but retains a small ability to cause vasodilation, unfortunately it is also damaging to cells and therefore needs to be detoxified (Panza, and Cannon, eds., 1999, p. 23).
The following substances in some way enhance the effect, production or release of NO:
Estrogen, via its effect of up-regulating the eNOS enzyme (Chambliss, K.L., and Shaul, P.W. 2013). Interestingly, estrogen has also been shown to alter lipid profile in humans. Specifically, estrogen has been shown to reduce both total and LDL-cholesterol levels while raising HDL. Evidence is currently gathering which points towards an additional antiatherosclerotic effect of estrogen, namely in the inhibition of lipid oxidation, this is based on an overall review of the literature by Samsioe, 1994. As mentioned above, oxidised lipids are considered more important in the onset and progression of atherosclerosis.
L-arginine is also important (as mentioned above, L-arginine is a precursor for NO).
The peroxynitrite anion (the actual formation of this anion actually greatly reduces the effect of NO because it is formed via the reaction of nitric oxide with the superoxide anion and attenuates the vasodilatory effects of NO, however, the presence of the peroxynitrite anion itself still contributes to some of NO’s effects, this information is referenced above in the text about reactive oxygen species).
The cysteine-containing NO donor SPM-5185, as demonstrated in (Panza, and Cannon, eds., 1999, p. 22).
Finally, antioxidants such as vitamin C (in some trials), and the enzyme superoxide dismutase (SOD) as shown in (Panza, and Cannon, eds., 1999, p. 135).
When talking about nitric oxide in relation to atherosclerosis, the endothelium of arteries is the primary point of interest. Thus, the notation eNO (for endothelial nitric oxide) and eNOS (short for endothelial nitric oxide synthase) can be used interchangeably with NO and NOS for this topic.
eNO is highly important in alleviating and preventing atherosclerosis because it first of all decreases endothelial permeability. As covered previously, when the endothelium is highly permeable, more low-density lipoproteins are allowed to pass through it into the arterial wall, and this is what requires macrophage activity. In decreasing endothelial permeability, the whole onset of atherosclerosis could be abated. Much of the information regarding nitric oxide as shown above is available in the works of Panza, and Cannon, (1999) where it is backed up by hundreds of in-text citations.
The eNO radical also reduces monocyte adhesion to cells of the endothelium, seemingly by inhibiting the expression of VCAM-1. This would prevent the influx of monocytes and subsequent differentiation into macrophages, thus inhibiting foam cell occurrence. eNO also attenuates platelet aggregability, as shown by Panza, and Cannon, eds. (1999, pp. 120-122). The cohesion of platelets at the site of inflammation of endothelium can lead to a thrombosis (a clot attached to a blood vessel) that starves cells and tissue further down the vessel of oxygen. If the cells further downstream of the thrombosis are cardiac muscle cells (myocardium) then the result can range from angina to a heart attack.
This next section details the possible adverse effects associated with atherosclerosis. It is important to note that each issue may occur as both a result of the build of plaque directly, but also indirectly, as plaque formation can lead to blood clots that cause and/or exacerbate many cardiovascular incidents. As plaque builds up between the tunica intima and the lumen there is a possibility of plaque rupture. This is shown on the atherosclerosis webpage of the American Heart Association (2014b). The subsequent effect of this is that a stationary clot (thrombus) in the wall of the affected blood vessel may further reduce the size of the lumen and ability of blood to through the vessel. This can cause or contribute to all of the problems shown below, for the same reason as a gradual build-up of plaque, for it limits the blood flow to areas of the body downstream from the affected blood vessel.
Alternatively, the blood clot formed at the rupture site of plaque can dislodge from the arterial wall and become free-floating. In this case it is called an embolus and can cause an embolism (a substance that produces obstruction within a blood vessel). This can cause the same effect as a thrombus, but the embolism can float around and block a vessel located in the distal systemic circulation (Kumar, Abbas, and Fausto, 2004). This is also briefly pointed out in the work of Seeley, VanPutte, Regan and Russo, 2011, p. 663.
Angina pectoris usually presents as a pain in the chest, though it may also appear in the lower jaw, neck and possibly also the left arm or shoulder. It is caused by anaerobic respiration in the heart. It can arise from atherosclerosis due to narrowing of blood vessels within the coronary circulation. This causes restricted blood and oxygen flow to the cardiac muscle. Unable to respire aerobically but still requiring energy, the cardiac muscle cells must survive on anaerobic respiration due to hypoxic conditions. Unfortunately, this respiratory pathway causes a build-up of acidic by-products that raise acidity (and lower pH) in the affected area. This causes a pain response to be stimulated. This situation is exacerbated by any process demanding additional cardiac output, for example physical and mental stress. On the other hand, relaxation would have the opposite effect by reducing cardiac exertion. Vasodilation via chemical intervention (nitro-glycerine or free radical NO) or placement of a stent can increase the blood flow through the affected artery and improve oxygen of the cardiac muscle as well as improving the removal rate of acidic by-products of respiration. A clot could also cause this issue as a result of atherosclerotic plaque rupture. The formation of a clot in a blood vessel in this situation would further restrict blood flow through the vessel, provided that the clot doesn’t cause severe obstruction. Angina pectoris is a relatively minor condition, provided that it is only short-lasting. Normally if the blood flow is restored, there is only mild permanent damage to cardiac tissue.
Myocardial infarction (heart attack), is caused by a more lengthened condition of hypoxia (or even anoxia). In this circumstance, instead of just pain, the cardiac cells may die in large numbers in affected areas. Atherosclerosis increases the possibility of myocardial infarction because the resultant lesions can greatly reduce the size of the lumen of coronary arteries, thus increasing blood pressure and possible clot formation (thrombus). This thrombus further narrows the blood vessel and exacerbates cell hypoxia, perhaps leading to total anoxia in some areas, depending on severity. This leads to cell death in the cardiac tissue. The above information on angina pectoris and myocardial infarction can be found in the work of Seeley, VanPutte, Regan and Russo (2011), p. 686.
Stenosis can also lead to enlargement of certain regions of the heart, such as the left ventricle. Because the left ventricle is required to pump blood around the whole body via the aorta, if there is stenosis in the aorta as a result of atherosclerotic plaque, then there is increased resistance to the contraction of the left ventricle. This means that the left ventricle must work harder in order to overcome the resistance, otherwise the whole body will become affected by hypoxia due to decreased blood supply. This can lead to hypertrophy of the left ventricle, an increase in size of the muscles located here. The ventricular hypertrophy allows the left ventricle to have more contractile force and push more red blood cells through the stenosed aorta and into the systemic circulation. It was mentioned in question 2 that the arterial stenosis causes an increase in ventricular afterload which the left ventricle must overcome (Jardins, 2008, p. 210). The increased force through the aorta increases systolic pressure. This information was found from Seeley, VanPutte, Regan and Russo, 2011, Appendix G, A-34 9 a-f.
A stent can be used to treat atherosclerosis. In this case, the stent is typically made of metal and is transported into the artery which is clogged with atherosclerotic plaque. This occurs during a procedure called angioplasty in which an empty balloon is inserted via catheter into the blood vessel which has narrowed. Once inside the vessel, the balloon is inflated in order to open it up and reduce stenosis. This occurs because the pressure of the balloon is both able to forcibly widen the blood vessel and also in squeezing the atherosclerotic plaque so that it takes up less space within the lumen of the blood vessel. At this point, if the catheter also contains a stent, as it would in the case of atherosclerosis, then this stent can hold the vessel open to the extent that the balloon did. Thus, even when the inflating balloon has left the blood vessel, it stays open to the same extent via the stent. Therefore, the stent provides a more long-term ability to reduce stenosis. This has the same effect as a vasodilator in holding the blood vessel open. So far, only the mechanical properties of the stent have been touched upon. However, a stent can also produce pharmacological effects as well. This is achieved by coating the outer surface of a stent with medication which slowly releases into the arterial wall and/or blood stream. Stents that have this capacity are called drug-eluting-stents (DES). Blood which would ordinarily be forced through a narrower space in the vessel, possibly leading to a blood clot or greatly increased blood turbulence, is now free to travel through at the normal speed and pressure. This can decrease the likelihood of cardiovascular incidences, such as those covered above.  Additional lifestyle measures must also be taken however, as over time the stent itself can become clogged if the underlying cause of arterial stenosis is not removed. This process of repeated narrowing of the blood vessels after a measure has been taken to reduce it is called restenosis. This information is shown clearly on the stent webpage of the American Heart Association (2014c). Figure 4.2 shows the placement of a stent in the coronary artery. As can be seen from this diagram, the stent is made of a metal mesh and is pressing against the atherosclerotic plaque, thus opening up the lumen of this blood vessel. Once the stent has been placed via the catheter, both it and the guide wire are removed, leaving the stent to hold the artery open.
This portion of the essay is dedicated to thought not seen in work by other sources on atherosclerosis. Any relation to previous work done by any author on this topic is purely coincidental.
It is possible that some of the development of atherosclerosis is due to increased ventilation and oxidative stress during mental stress. Granted modern society has many problems when it comes to eating nutrient-depleted, high-fat foods and breathing indoor air, but with many economic factors causing significant stress and subsequent increases in respiration occurring as part of the fight-or-flight reaction, various bodily changes are likely to occur. For example, it is possible that prolonged mental stress and resultant over-breathing reduce the bodily carbon dioxide levels and inhibit the Bohr Effect, leading to an increased need for erythrocytes and a permanent shifting towards elevated ventilation. This would also increase the level of oxygen dissolved in blood plasma, as a result of air pressure within the lung during inspiration. From this, more oxygen would travel through the bloodstream, and cause oxidative stress throughout the body. This would exacerbate the peroxidation of lipoproteins and oxysterol production, thus contributing towards atherosclerosis.
Another possible related mechanism for atherosclerosis is mouth-breathing. Because nitric oxide is also produced within the nose, nose-breathing may also allow significant quantities of nitric oxide to diffuse into the blood stream, which may perhaps be unlikely given that it is a highly-reactive free radical, but it could bind to haemoglobin, as opposed to travelling freely, see Seeley, VanPutte, Regan and Russo, (2011) p. 653. The aforementioned reaction between the superoxide anion and nitric oxide would readily result, decreasing the amount of oxygen available for lipid peroxidation and subsequent atherosclerotic plaque formation in blood vessels. Research into the use of cancer cell growth inhibitors brought up the topic of iron-mediated reactive oxygen species production (Galaris, and Pantopoulos, 2008). This abstract points towards iron accumulation as being a cause of reactive oxygen species formation with toxic effects. It is possible that this could further add to lipid peroxidation, with formation of oxidised LDLs capable of atherogenesis.

Question 4 References:
American Heart Association, 2014a. Cholesterol and CAD. [online] Available at: <> [Accessed 4 April 2015].

American Heart Association, 2014b. Atherosclerosis. [online] Available at: <> [Accessed 4 April 2015].

American Heart Association, 2014c. Stent. [online] Available at: <> [Accessed 4 April 2015].

Carmena, R., Duriez, P., and Fruchart, J.C., 2004. Atherosclerosis: Evolving Vascular Biology and Clinical Implications, Cicrulation, [online] Available at: <> [Accessed 1 April 2015].

Chambliss, K.L., and Shaul, P.W., 2013. Estrogen Modulation of Endothelial Nitric Oxide Synthase. Endocrine Reviews. [online] Available at: <> [Accessed 4 April 2015].
Daugherty, A., Manning, M.W., and Cassis, L.A., 2000. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. The Journal of Clinical Investigation. [online] Available at: <> [Accessed 4 April 2015].
Galaris, D., and Pantopoulos, K., 2008. Oxidative Stress and Iron Homeostasis: Mechanistic and Health Aspects. Critical Reviews in Clinical Laboratory Sciences. [e-journal] 45(1), pp.1-23, Abstract only. Available through: Informa Healthcare website <> [Accessed 7 April 2015].
Hotamisligil, G.S., 2010. Endoplasmic reticulum stress and atherosclerosis. Nature Medicine [online] Available at: <> [Accessed 4 April 2015].

Kumar V., Abbas A.K., and Fausto N., 2004. Robbins & Cotran Pathologic Basis of Disease: With STUDENT CONSULT Online Access. 7th ed. Philadelphia: Saunders.

Kummerow, F.A., 2013. Clinical Lipidology. Future Medicine. [online] Available at: <> [Accessed 4 April 2015].
Lin S.J., Hong C.Y., Chang M.S., Chiang B.N. and Chien S., 1992. Long-term nicotine exposure increases aortic endothelial cell death and enhances transendothelial macromolecular transport in rats. Arteriosclerosis, Thrombosis, and Vascular Biology [online]. Available at: <> [Accessed 1 April 2015].

Mescher, A.L., 2013. Junqueira’s Basic Histology Text & Atlas, 13th ed. China: The McGraw-Hill Companies.
Mitchell, R.S., Kumar, V., Abbas, A.K., and Fausto, N., 2007. Robbins Basic Pathology: With STUDENT CONSULT Online Access. 8th ed. Philadelphia: Saunders.

National Centre for Biotechnology Information, 2015. VCAM1 vascular cell adhesion molecule 1 [Homo sapiens (human)] [online] Available at: <> [Accessed 4 April 2015].

Oh, J., Riek, A.E., Weng, S., Petty, M., Kim, D., Colonna, M., Cella, M. and Mizrachi, C.B., 2012. Endoplasmic Reticulum Stress Controls M2 Macrophage Differentiation and Foam Cell Formation. The Journal of Biological Chemistry, [online] Available at: <> [Accessed 4 April 2015].

Pack, P.E., 2001.  Anatomy and Physiology, Hoboken, NJ: Wiley Publishing, Inc.
Panza, J.A. and Cannon, R.O., eds., 1999. Endothelium, Nitric Oxide, and Atherosclerosis. Armonk, NY: Futura Publishing Company, Inc.

Samsioe, G., 1994. Cardioprotection by estrogens: mechanisms of action—the lipids. [online] Available at: <> [Accessed 4 April 2015].
Seeley, R.R, VanPutte, C.L., Regan, J. and Russo, A.F., 2011. Seeley’s Anatomy & Physiology, 9th ed. New York, NY: McGraw-Hill.
Schmidt, F., 2000. Biochemistry II, New York, NY: Wiley Publishing, Inc.
Toda, N., Ayajiki, K., and Okamura, T. 2007. Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation. Pharmacological Reviews. [online] Available at: <> [Accessed 4 April 2015].

Question 3: Multiple questions on a patient with chronic lung disease and shortness of breath

*These posts are from coursework answers for my degree, but the Figures that are referred to in the text didn't scan well and have already been handed in. These long posts would probably not interest most people but if you enjoy quite in-depth reading of scientific problems then this may be for you.

Question 3: Davy Smith is a 65-year-old male with a 50-year history of smoking 2 packets of cigarettes a day. Over the past 5 years, he has become increasingly short of breath. At first, he noticed this only when exercising, but now he is even short of breath at rest. Over the past two years, he has had several bouts of lower respiratory tract infection treated successfully with antibiotics. His shortness of breath hasn't subsided, and his breathing is assisted by use of his accessory muscles of respiration. Pulmonary function testing revealed the graph below:

a.      Based on the graph, fill in the following data:
The tidal volume: ____________
The inspiratory reserve volume: ______________
The expiratory reserve volume: _______________
The forced vital capacity: ______________
b.      Describe the microscopic changes that are occurring in Davy's lungs. What effect do these microscopic changes have on Davy’s ability to transfer oxygen and carbon dioxide in the lungs?
c.       Blood testing showed Davy’s hematocrit to be 59% (normal = 42-50%). Why was his hematocrit so high?
d.      Why is Davy susceptible to lower respiratory tract infections?


Part a:

Each box on the graph is roughly 125 cc of volume.
The tidal volume is the amount of air breathed in during a relax breath. On the graph this is roughly 4 boxes in height.  4x125 = 500 cc.
Therefore, the tidal volume is 500 cc in volume.
The inspiratory reserve volume is the extra air that can be inhaled after a relaxed inhalation. Thus it is the difference between the height of the forced inhalation and that of the normal inhalation on the graph. This is approximately 14 boxes in height. 14x125 = 1750 cc.
Therefore, the inspiratory reserve volume is 1750 cc in volume.
The expiratory reserve volume is the extra air that can be exhaled after a relaxed exhalation. So it is the difference between the height of the forced exhalation and that of the normal exhalation on the graph. This is approximately 3.5 boxes in height. 3.5x125= 437.5 cc.
Therefore, the expiratory reserve volume is 437.5 cc in volume.
The forced vital capacity is the total volume of air which can be exhaled after a full inhalation. This is can calculated as either the difference between the highest and lowest points of the graph, or by adding up the tidal volume, inspiratory reserve volume and expiratory reserve volume. This is roughly 21.5 boxes in height. 21.5x125 = 2687.5 cc
Therefore, the forced vital capacity is 2687.5 cc in volume.
(Bass, 1974 p.7).
The work of Bass showed how to calculate volumes from a lung function graph, however much of its other work may be outdated so it was only used for this initial piece of work.

Part b:

It is likely that Mr. Smith is suffering from chronic obstructive pulmonary disease. This is a chronic lung disease that is usually caused by cigarette smoking. Given that Mr. Smith has a history of 100 pack-years of cigarette smoking (packets of cigarettes per day multiplied by years of duration, i.e. 2 packets daily x 50 years = 100 pack-years) this particular pulmonary condition is highly likely. It encompasses other respiratory diseases such as chronic bronchitis, emphysema and possibly also chronic obstructive airways disease. The repeated lower respiratory tract infections also point to this diagnosis so Mr. Smith is certainly at risk of the disease and he has the decreased lung function test to match. With regard to the microscopic changes occurring in Davy’s lungs, there is probably dilation and enlargement of the bronchioles, which is only partially reversible, i.e. much of the damage at this stage of illness is likely to be permanent (Mescher, 2013 p. 361). Alveoli are also enlarged in this condition as shown in Figure 3.1. This is due to the walls separating each alveolus gradually being destroyed over the years. Alveolar enlargement can occur because cigarette smoking provokes an inflammatory immune response which causes the release of various proteases (enzymes that break-down proteins, in this case these enzymes are mostly elastase and trypsin, and the immune cells they are most associated with are neutrophils, however macrophages are also involved in alveolar destruction), in the lungs from immune cells (Davies and Moore, 2003 pp. 26-28). This can break down the elastic protein in alveoli (called elastin) and render them inflexible (Seeley, VanPutte, Regan, and Russo, 2011, pp. 830-862).  In healthy persons the use of these enzymes is inhibited by a chemical called alpha-1-antitrypsin. This stops the immune cell-induced damage from continuing. However, in smokers and persons with a genetic fault causing an alpha-1-antitrypsin deficiency, the damage goes largely unchecked and pulmonary destruction ensues. In smokers the lack of alpha-1-antitrypsin activity is attributed to its reaction with free radicals in cigarette smoke, rendering it ineffective. What can then result from this is that instead of having very many alveoli, the alveoli can break down their walls to the extent that they form one larger air sac (Mayo Foundation for Medical Education and Research, 2015a). This results in a much lowered surface area for the diffusion of gases both into and out of the lungs which causes many of the reduced volumes seen on the lung function test (Mayo Foundation for Medical Education and Research, 2015b). Chronic bronchitis obstructs the larger airways of the respiratory tract while emphysema causes the same effect in small airways, as well as air-trapping in the alveoli (The McGraw-Hill Companies, 2000). The differences between healthy alveoli and those affected by emphysema are shown in Figure 3.2. Initially, the damage will reduce the amount of oxygen diffusing into the bloodstream, leading to an increase in ventilation. This hyperventilation lowers the concentration of carbon dioxide in the blood, while attempting to compensate for lowered oxygen. Usually, there is still some decrease in blood oxygen levels despite the hyperventilation. As the damage progresses however, there comes a point when the respiratory tract is so compromised that eventually carbon dioxide will accumulate in the bloodstream because it cannot diffuse out of the lungs at this stage and oxygen in the blood becomes significantly more decreased as well. The conditions of elevated carbon dioxide and decreased oxygen in the blood are termed hypercapnia and hypoxemia respectively (University of Maryland Medical Center, 2013).  The inability to adequately remove air from the lungs explains the elevated residual volume in Mr. Smith’s lungs. The use of accessory muscles of respiration helps to create more pressure in the lungs to expel air during expiration.
One beneficial effect of the elevated level of carbon dioxide in the blood is that oxygen is unloaded more readily from haemoglobin. This is known as the Bohr Effect and may occur due to the conversion of carbon dioxide to carbonic acid with simultaneous release of a hydrogen ion which reduces the blood pH. This effect is very useful during exercise because the increased carbon dioxide concentrations in the blood cause subsequent reduction in pH (which also occurs via other metabolic by-products, e.g. lactic acid) will cause preferential off-loading of oxygen to cells that are respiring more vigorously. This allows cells that are under the heaviest workload to receive adequate amounts of oxygen from haemoglobin (Razani, B., 2014). This means that in the case of Mr. Smith, his body actually requires less oxygen to reach his erythrocytes, (i.e. not as high an oxygen saturation in the blood is required) because it is off-loaded to other cells and tissue within his body more readily. A similar effect also occurs as the concentration of a substance called 2, 3-Diphosphoglycerate (2,3-DPG) increases. This is a compound that is formed as a result of anaerobic glycolysis, therefore its production increases under hypoxic / hypoxemic conditions. It is important to note that hypoxia and hypoxemia are not equivalents. Rather, hypoxemia is the state of reduced oxygen content in the blood stream of arteries (or a pathologically low arterial oxygen tension), whereas hypoxia is a condition in which too little oxygen is delivered to tissues. It can therefore be possible, though unlikely, that hypoxemia may exist in a patient, but compensatory mechanisms may be sufficient to encourage oxygen dissociation from haemoglobin in order to oxygenate tissues adequately. The aforementioned 2, 3-DPG however, increases under hypoxic conditions (given its production occurs under anaerobic conditions), and consequently, increases tissue oxygenation in a similar way to the Bohr Effect (Jardins, 2008, p.236).
Figure 3.3 shows the oxygen-haemoglobin dissociation curve. Note that when exercising, erythrocytes will off-load oxygen more readily to respiring tissue (possibly due to any number of reasons, for example, increased CO2 or 2, 3-DPG production as well as increase in temperature) which explains the point labelled deoxygenated blood on the graph. At rest, tissues respire more slowly, and produce less CO2, 2, 3-DPG, heat and other metabolic by-products that encourage the dissociation of oxygen from haemoglobin. The dashed curve to the right of the continuously drawn curve shows what would happen if any or all of the following components were increased: CO2, 2, 3-DPG, acidity, and temperature, though more possibilities exist. This produces an effect known as a “right-shift”, which means that a higher pressure of oxygen is required to produce the same oxygen saturation percentage compared to normal conditions. This means that under right-shift conditions, haemoglobin loses oxygen more readily, and consequently, respiring tissue receives oxygen in greater amounts.
Figure 3.4 shows the diffusion of carbon dioxide and oxygen into and out of an alveolus. This forms a diagrammatic representation for the equation of Fick’s Law of diffusion, which is also shown in this figure. Relating this to the case at hand, the reduced ability to both remove carbon dioxide from and deliver oxygen to the alveoli in Mr. Smith’s lungs results in a higher partial pressure of carbon dioxide and lower partial pressure of oxygen in these air sacs. A consequence of this is that less carbon dioxide will diffuse out of the bloodstream and into each alveolus, while less oxygen will diffuse from the atmosphere into the same region. This is because the difference in partial pressure between the blood stream and alveoli, relating to carbon dioxide, is smaller for Mr. Smith than a regular person. Similarly, the partial pressure difference of oxygen between the atmosphere and the diseased alveoli will be smaller as well. Thus, less carbon dioxide is encouraged to diffuse into the alveoli and be removed from the lungs in expiration, and less oxygen will diffuse into the lungs during inspiration (Jardins, 2008, p. 139). This explains why Mr. Smith is forced to use his accessory muscles of respiration.
The use of accessory muscles of respiration can improve the delivery of gases both from the atmosphere to the lungs and vice versa. Firstly, the accessory muscles of inspiration must be considered. The largest muscles of this category are the scalenus, sternocleidomastoid, pectoralis major, trapezius, and external intercostal muscles. Without getting into excessive detail, the overall function of these muscles is to help decrease the pressure within the lungs to such a level below atmospheric pressure that gases flow more readily into the alveoli, diffusing via a pressure and concentration gradient. As the concentration of any gas increases in a given area, so also does its tension. Therefore, the fact that Mr. Smith is having difficulty ventilating his lungs, means that the concentration of oxygen normally extracted from the alveoli into the blood stream has decreased (therefore, both alveolar partial pressure and concentration of oxygen have decreased) and Mr. Smith’s blood carbon dioxide levels have increased (regarding both partial pressure and concentration of arterial carbon dioxide). Thus, for inspiration, the lower the pressure inside the lungs, relative to the surrounding atmosphere, the greater the diffusion gradient for gases moving from the atmosphere into the lungs (and consequently alveoli). Therefore, the result of using the accessory muscles of inspiration is to increase oxygen supply to the blood stream. A person who is using their accessory muscles of inspiration while breathing will be quite noticeable, with much of their upper chest expanding and elevating during each inhale and some shrugging occurring also (Jardins, 2008, pp. 54-58). Conversely, the accessory muscles of expiration will increase the pressure within the lungs, relative to that of the surrounding atmosphere. This helps compensate for airway resistance, such as that seen in COPD. The primary accessory muscles of expiration are the rectus and transversus abdominis muscles, the external and internal abdominis obliquus muscles and the internal intercostal muscles. The basic movement of these muscles during expiration is of compression. The abdomen becomes compressed, and the diaphragm is pushed into the thoracic cage, increasing the pressure in the lungs well above atmospheric pressure and causing a diffusion of gases out of the alveoli into the surrounding environment (Jardins, 2008, pp. 59-61).
Part c:
Haematocrit is the proportionate measure of red blood cells compared to the overall blood volume (Seeley, VanPutte, Regan, and Russo, 2011, p 668).Thus, if Davy’s haematocrit was 59% then this is the percentage of his blood which was composed of red blood cells.
Red blood cells are used strongly in the transfer of various gases both to and from the lungs, and from and to cells. Therefore, an elevated level of red blood cells would occur in an individual who had trouble dealing with both the build-up of gases, and the inadequate diffusion of gases into the blood. In the case of Davy, he is suffering from both hypoxemia and hypercapnia. Therefore, he will need additional red blood cells to carry oxygen from his lungs. This sets up a steeper concentration gradient between the alveoli of the lungs and the bloodstream, thus allowing more oxygen to diffuse into the blood and be carried to various cells. Approximately 98.5% of the oxygen in our blood is bonded to haemoglobin to form oxyhaemoglobin, the remainder is dissolved in plasma (Seeley, VanPutte, Regan, and Russo, 2011, p 652) and tends to be ignored in calculations of arterial oxygen content.

There are numerous equations for approximating oxygen delivery and content within the body. Shown below is an equation for oxygen content in arteries (Gutierrez, and Theodorou, 2009).
CaO2, shorthand for the content or amount of oxygen in the arterial blood, is calculated by the following equation:
CaO2 ~ [Hb](SO2)x1.34
Where ~ means roughly equal to (because here we are neglecting the amount of dissolved oxygen within plasma [roughly 1.5 to 2%], and instead focusing entirely on oxygen bonded to haemoglobin), [Hb] is the concentration of haemoglobin in the blood, and SO2 is the fractional oxygen saturation of haemoglobin.
Thus, we can see that the oxygen content of arterial blood is proportional to the concentration of haemoglobin, and also to the fractional oxygen saturation of haemoglobin. This means that if either haemoglobin concentration or oxygen saturation increases while the other remains the same, then oxygen content of arterial blood will also increase. Also, if CaO2 remains the same value, then [Hb] and SO2 are inversely proportional to each other. This means that as one quantity increases, the other will decrease in order to achieve the same result for CaO2. Therefore, if we assume CaO2 to be an unchanging quantity, then we can clearly see that if oxygen saturation of haemoglobin decreases, then the concentration of haemoglobin must increase.
In the case of Davy Smith, his ability to extract oxygen from alveoli has greatly decreased. Even with a normal tidal volume of 500 cc, his blood is still not receiving an adequate supply of oxygen. This means that in our equation SO2 has decreased. Mr Smith’s body will still need to utilise roughly the same amount of oxygen, provided that compensatory mechanisms are not in place to reduce overall metabolic rate. Thus, the concentration of haemoglobin (also known as the haematocrit) will have to increase in order to supply to the same demand for oxygen content. This particular form of increased erythrocyte production (i.e. from hypoxic lung disease) is called either secondary erythrocytosis or secondary polycthemia (Seeley, VanPutte, Regan, and Russo, 2011, p. 669). This means that if Davy Smith was to somehow have his lung condition cured, then his haematocrit would drop to normal levels. However, while his condition remains, his kidneys will secrete more erythropoietin in response to decreased oxygen delivery.
Carbon dioxide is also a highly important consideration in this situation. As Davy Smith’s lung function deteriorates, his carbon dioxide levels will continue to increase. This accumulation of carbon dioxide must be dealt with. The body will naturally convert much of its extracellular carbon dioxide into bicarbonate ions (roughly 66% takes this form). Of the remaining 34%, 7% will be dissolved in plasma and the remaining 27% will bind to haemoglobin. The formed complex is called the carbaminohemoglobin molecule (Mescher, 2013, p. 236). Thus, elevated carbon dioxide levels will cause increased erythrocyte concentrations in order to bond the plasma carbon dioxide and transport it away from cells.
A more serious gas in the body that requires an elevated haematocrit level is carbon monoxide. Carbon monoxide is a poisonous gas found in cigarette smoke among other sources, especially those involving combustion of carbon-containing compounds in a region of inadequate oxygen (incomplete combustion) which has a very high affinity for haemoglobin and bonds to form carboxyhaemoglobin. Once carboxyhaemoglobin has formed, it is unlikely that the carbon monoxide will dissociate again in the lifespan of the red blood cell, usually it stays bonded until the red blood cell is broken down by the body. During this time the haemoglobin is unable to bind to oxygen or carbon dioxide molecules, or anything else for that matter. Thus, carbon monoxide essentially disables the effect of haemoglobin towards other molecules and requires increased red blood cell concentrations. It has been found that the blood of chronic smokers contains between 5 and 15% carboxyhaemoglobin. This alone provides a strong reason for the elevated red blood cell concentration found in Davy Smith (Seeley, VanPutte, Regan, and Russo, 2011, pp 653-655).
Part d:
Davy is susceptible to lower respiratory tract infections. This could be due to the act of smoking tobacco which has been reported to damage cilia in the lungs (Mueller, 1997). Cilia are microscopic projections that protrude from cells and sweep away various substances and microbes that can damage the body. When these are damaged, various toxins and microbes can enter the lower respiratory tract in greater numbers, requiring a stronger immune system to combat it.
Further to this, differences in bacterial populations within regions of the respiratory tract between smokers and non-smokers have been found. The exact location of these bacterial colonies is unlikely to be of concern, considering that as long as they are present somewhere in the respiratory tract, they may allow pathological microbes to travel past them into lower regions, whereas bacterial populations in healthy non-smokers would have some sort of inhibitory effect. Brook, and Gober (2005) found that the nasopharyngeal flora of smokers contained more potential pathogens than non0smokers, as well as fewer beneficial bacteria which might inhibit their growth and harm. Fujimori, et al. (1995) also found that healthy smokers had higher levels of Streptococcus Aureus (S. Aureus) and lower levels of alpha-streptococci (the forms which inhibit S. Aureus), as compared to healthy non-smokers. Forms of alpha-streptococci that inhibit another potential pathogen called S. pyogenes were similar in both healthy smokers and non-smokers. This indicates that smokers are more susceptible to infections via Streptococcus Aureus.
A review of many studies by Arcavi, and Benowitz (2004) revealed some interesting data about smokers. Several studies that were examined showed decreases of 10-20% in serum Immunoglobulins IgA, IgG and IgM. These are all vital antibodies that play a major role in the response against infection. These same authors also found that specific antibody responses to influenza (both as an unaltered virus and as vaccine) and Aspergillus fumigatus were decreased in smokers.
Additionally, the act of smoking can cause excessive mucus production and due to the impaired function of the damaged cilia in the respiratory tract, this mucus can build up without being removed. Mr. Smith likely has a “smoker’s cough”, a heavy cough which attempts to dislodge and remove this built-up mucus. Unfortunately, this accumulating mucus in the bronchial tree provides vital nutrients for pathological microbes that take up residence in the lungs. Thus, Mr. Smith is more susceptible to lower respiratory tract infections. Antibiotics are likely only to act as a short-term aid, with recurrent infections being a part of his life in the long-term (The McGraw-Hill Companies, 2000).

Question 3 References:
Arcavi, L., and Benowitz, N.L., 2004. Cigarette Smoking and Infection. [online] Available at: <> [Accessed 6 April 2015].
Bass, B.H., 1974. Lung Function Tests An introduction. 4th ed. London: H.K. Lewis & Co. Ltd.
Brook, I., and Gober, A.E., 2005. Recovery of potential pathogens and interfering bacteria in the nasopharynx of smokers and nonsmokers. [online] Available at: <> [Accessed 6 April 2015].
Davies, A., and Moore, C., 2003 The Respiratory System. Spain: Churchill Livingstone.
Fujimori I., Goto R., Kikushima K., Ogino J., Hisamatsu K., Murakami Y., and Yamada T. 1995.
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Jardins, T.D., 2008. Cardiopulmonary Anatomy & Physiology Essentials of Respiratory Care, 5th ed. Delmar, USA: Nelson Education, Ltd.

Mayo Foundation for Medical Education and Research, 2015a. Diseases and Conditions Emphysema. [online] Available at: <> [Accessed 6 April 2015].

Mayo Foundation for Medical Education and Research, 2015b. Diseases and Conditions Emphysema. [online] Available at: <> [Accessed 6 April 2015].

Mescher, A.L., 2013. Junqueira’s Basic Histology Text & Atlas, 13th ed. China: The McGraw-Hill Companies.

Mueller, D.M., 1997. Smoking Any Substance Raises Risk of Lung Infections, [online] Available at: <> [Accessed 6 April 2015].
Razani, B., 2014. Bohr Effect. [online] Available at: <> [Accessed 6 April 2015].
Seeley, R.R, VanPutte, C.L., Regan, J. and Russo, A.F., 2011. Seeley’s Anatomy & Physiology, 9th ed. New York, USA: McGraw-Hill.

The McGraw-Hill Companies, 2000. Case History 13: Restrictive and Obstructive Lung Disease, [online] Available at: <> [Accessed 7 April 2015].   
University of Maryland Medical Center, 2013. Chronic obstructive pulmonary disease. [online] Available at: <> [Accessed 6 April 2015].