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1. Explain how the immune system responds to the HPV vaccine to confer immunity and protect George against future HPV infections.
Human Papilloma Virus (HPV) Vaccine is injected via the intramuscular route which is easily accessible to lymphatic tissue and blood system. Once the HPV vaccine injected into George, antigens enter the body. Dendritic cells phagocytose the HPV antigen and process the vaccine material, present the endocytosed HPV antigens to CD4+ (T helper cells) using major histocompatibility complex (MHC) molecules. Surface recognition occurs in which selective molecular patterns specific to recognized pathogens. (Ryan & Ray, 2014).
CD4+ cells activate B cells and differentiate it into plasma cells to produce antibodies. B cells also produce memory cells. T helper cells also activate T killer cells (CD8+) to produce the cell-mediated immune response, where T killer cells recognize antigens and produce toxins to destroy these antigens. (Stanley, 2006).
The foreign proteins in the antigen break down very quickly and the immune response occurs in the body. This is called acquired immunity. (Ryan & Ray, 2014). Any foreign proteins left in the system is neutralized by new antibodies. If the same antigen enters the body next time, memory cells recognize them, and antibodies fight against them to prevent infection. Antibodies do not give long-term protection as they break down into specific amino acids within a few months. (Ryan & Ray, 2014).
2. Several large randomized clinical trials showed that most participants who received the HPV vaccine produced antibodies against HPV. Explain the significance of antibody production during the vaccination schedule in protecting George against potential HPV infections in the future.
Memory T cells and B cells are produced during the primary immune response. IgM antibodies produced in the initial response. During second time exposure to the same antigen, memory T helper cells get activated and stimulate memory T killer cells and memory B cells. Both these memory cells quickly divide into many immune cells. B cells produce new antibodies (IgG) to prevent infection and T killer cells destroy any body cells that might get infected. Thus, the secondary immune response occurs. Thus, HPV vaccine provides protection against future infections. (Ryan & Ray, 2014).
HPV vaccine scheduled for 3 doses and a booster dose. After each vaccine dose, antibody level increases until peak concentration is achieved one month after the 3rd vaccine. Then decline gradually but higher than those that naturally infected. (Mariani & Venuti, 2010).
Plasma cells are secreted with varying life spans, some migrate to the bone marrow surviving as long-lived and continuously producing antibodies. Thus, data suggest that HPV vaccine produces serological memory and reactive memory. (Stanley, 2010).
3. Discuss the rationale for including boys in the current national HPV vaccine program.
HPV is a double-stranded DNA virus, causes the most common sexually transmitted disease worldwide. Several studies noted that 75%-95% of male partners of HPV infected women are suffering from HPV infection. (Brayan, 2015).
In the USA, the incidence of HPV infection is higher in males than in females. Men develop HPV related cancers of the anus, the oral cavity and oropharynx. Men acquire the infection in the late teen ages and found to be in the same prevalence rate for further two decades. (Stanley, 2014).
HPV vaccine provides direct protection for vaccinated individuals from HPV infection and indirect protection to unvaccinated individuals through herd immunity.
2.Case Study on Hepatitis A Virus
1. Explain how the Hepatitis A virus infects and replicates within hepatocytes.
Viruses do not have a nucleus, cell membrane or ribosome. Viruses cannot replicate by itself. Viruses use the host cell’s genetic material to replicate and make viral proteins. (Jenkins & Tortora, 2013)
Hepatitis A virus (HAV) enters through oral route and enters the bloodstream through the intestinal tract, finally migrate to the liver parenchymal cells. These viruses reside inside hepatocytes and bind to the immunoglobulin-like region of the HAV cellular receptors on the cell surface. The envelope of the virus fuses with the plasma membrane of the hepatocytes. The nucleocapsid released into the cytoplasm. The nucleic acid separates from the protein coat and releases nucleic acid of the virus. (Hunt, 2015).
Then the HAV replicates slowly using virus-encoded RNA-dependent RNA polymerase. Over the time host cells gets packed with viruses, cell burst out and release contents into the surrounding fluid. (Ryan & Roy, 2014). The released viruses go to other hepatocytes and start replication. These viruses shed into the bile and pass through the stool. (Hunt, 2015).
2. Describe the immune response to a hepatitis A infection.
Cell-mediated immune response activated in response to an HAV infection. When hepatocytes are infected with HAV, proteins from the virus are attached to the MHC proteins on the hepatocytic cell membrane. This alerts macrophages that this cell is infected and phagocytose the antigen, present it to the CD4+cells, which activates T killer cells and B cells. CD8+ cells recognize the antigen and attach itself to the infected body cells. (Ryan & Ray, 2014). T killer cells destroy infected cells by releasing perforin (a toxin). B cells produce antibodies which neutralize free viruses. B cells also form memory cells which help to prevent further infection. (Tortora & Derrickson, 2013). Once the immune system is not effective to counteract with HAV viruses, Hepatitis develops.
3.Discuss the significance of the elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme
AST & ALT are liver enzymes, the elevation of these enzymes indicates damage to the liver. The possible reasons include viral hepatitis, biliary tract obstruction, alcoholic fatty liver disease or autoimmune nonalcoholic fatty liver disease or toxicity due to use of hepatotoxic medications like paracetamol. Elevated levels of liver enzymes increase mortality related to liver disease especially for people with lower risk (like no familial history, nonalcoholic, no previous liver infection). (Tortora & Derrickson, 2014)
ALT should be greater than AST, to make AST: ALT ratio < 1. If this ratio is more than 1 indicates decreased hepatic clearance of AST with advancing liver disease, which makes a poor prognosis. Deficiency of pyridoxal 5’-phosphate decreases ALT synthesis to a greater extent.
Aminotransferase especially AST indicates liver disease as well as inborn errors of metabolism and acquired muscle disorder or hemolysis as these enzymes are present in striated muscles and red blood cells. The use of alcohol stimulates the synthesis and release of mitochondrial AST. (Malakouti, Kataria, Ali & Schenker, 2017)
3. Case Study on Whooping Cough
1. Identify the possible reasons for the continuing outbreaks of this infection.
Antimicrobial resistance to Bordetella pertussis is a possible risk factor for the outbreak of pertussis. Low pertussis vaccine coverage and not taking the full course of immunization are other reasons to point out continuing outbreak in low- and middle-income families. (CDC). Due to lack of awareness, delay in reporting possible and confirmed cases makes the spread of disease throughout the community. (Bryan, 2015).
2. Describe the early immune response to pertussis. Include the discussion of the effect of the Pertussis toxin produced by the Bordetella pertussis bacillus in your answer.
When Bordetella pertussis bacilli enter into the respiratory system, it is protected from innate immunity due to the presence of mucous lining on its wall. Chemical mediators of innate immunity are complement system and cationic proteins. Cationic proteins alter membrane permeability by acting on the bacterial plasma membrane. The complement system is directly entered the bacterial membrane and can opsonize bacteria for enhanced phagocytosis. It can activate polymorphonuclear cells and macrophages. (Mayer, 2015). Cytokines are released to the site of infection. (Jenkins &Tortora, 2013).
Neutrophils are unable to phagocytose these bacteria as no antibodies attached to it, thus specific immune response is initiated by macrophages, as it reaches to the site of infection. They phagocytose the bacteria and process the antigen and present it to the T helper cells residing in the lymphatic tissue. T helper cells activate B cells to produce plasma cells which produce antibodies. (Mayer & Nyland, 2015). These antibodies enter the circulation and the humoral response to a bacterial infection that results in antibodies attach to the bacteria and the activation of complement. The compliment and neutrophils can phagocytosis bacteria and eventually, bacteria get destroyed. (Ryan & Ray, 2014).
Pertussis Toxin (PT) acts on the pulmonary endothelial cells to inhibit neutrophil extravasation and influx into the airways. PT inhibits lipopolysaccharide signalling (LPS) which is a major stimulus for innate immunity in pertussis infection. PT reduce MHC class II molecules on the surface of human monocyte and modulate dendritic cell markers. PT mediated mechanism can increase the permeability of the blood-brain barrier to allow pathogenic T cells to access the central nervous system and thereby cause autoimmune encephalitis. (Carbonetti, 2010). PT also causes leukocytosis, insulinemia and hyperglycemia to cause systemic symptoms of pertussis. (Carbonetti, Artamonova, Mays & Zoe, 2003).
3. Discuss the importance of this vaccination for Sally’s mother.
As Sally’s mother is pregnant, she is at risk of developing pertussis infection. Sally’s mother might have vaccinated in childhood and memory cells may be present in the bone marrow. If Sally’s mother is vaccinated this time, more antibodies, as well as memory cells, are produced against antigens. Antibodies bind with bacteria, neutrophils can phagocytose the bacteria with the presence of antibodies. Antibodies to the toxin can prevent the binding of the toxin to the host cells and making toxin ineffective. Compliment system neutralize antibody bound bacteria and eventually, bacteria die. Memory cells provide future protection. Immunization provides herd immunity as fetus being protected against infection.
4a. Cardiovascular Disease – Adult Case Study
1. Describe the development of atheroma and progression to atherosclerosis.
Low-density lipoprotein cholesterol (LDL-C) initiates and plays a major role in the development of atherosclerosis. When the levels of LDL-Cs are high, they are circulated through the arteries and gets trapped inside the arterial wall. (Porro, 2002). Depending on the size and concentration of the plasma cells and LDL-Cs pass through the leaky and dysfunctional endothelium into the subendothelial space. (Falk, 2006).
When LDL-C reaches the tunica intima layer of the arteries which gets oxidized due to the presence of oxygen free radicals released by activated endothelium. Vascular cell adhesion molecules -1(VCAM-1) are upregulated and monocytes and T-cells are recruited. (Falk, 2006).
As more and more oxidized LDL is formed which would damage the endothelium, which triggers to release endothelial leukocyte adhesion molecules. Leukocytes also come to the site of inflammation, but they eventually go off track and function differently. Macrophages engulf this oxidized LDL to form foam cells. (Porro, 2002).
Foam cells release more chemicals to attract macrophages to the site of inflammation. The release of growth factors by foam cells cause smooth muscle cell proliferation. Thus, collagen synthesis gets increased leading to hardening of the plaque and fibrous cap formation. (Falk, 2006). Eventually, foam cells die and release lipid contents including DNA into the intima.
Focal calcification in atherosclerotic plaque occurs as ages. Moreover, T helper cells bind with the adhesion receptors and enter the plaque area. At the same time more, macrophages are activated to the site and interferons are released which promotes further inflammation and making activated endothelial cells to attract more leukocyte. These plaques are attached to the arterial wall and are continuing to grow and leading to atherosclerosis. (Porro, 2002).
2. Explain how atherosclerosis contributes to coronary artery disease and the development of angina.
According to MOH, mortality rate and hospitalization rates for Ischemic heart disease (IHD) were more than twice and 1.3 times respectively higher among Maori than that of non-Maori. The reports state that IHD rate was increased by 29 million globally between 1990 and 2010. (Moran, Forouzanfar, Roth, et al).
Erythrocytes migrate to the plaque surface and cause rupture of the plaque followed by haemorrhage and thrombus formation inside the artery. (Falk, 2006). Fibrous plaque can be a serious as it gets broken, thrombi can form on the surface of the plaque. If these clots are large, they may block the artery and blood supply to the down the part of occlusion. If this occurs in a coronary artery, blood flow is restricted and decreases oxygen supply of the affected area. Thus, atherosclerosis leads to coronary artery disease. Thus, anaerobic metabolism takes place to produce lactic acid. This affects heart muscle contraction and causes pain to the affected area. This condition develops as angina. (Porro, 2002).
Ischemia of heart muscle also releases bradykinin and adenosine, which send signals to the brain through the afferent pathway to cause pain in different parts of the body called referred pain. In angina pain experienced in the jaw, left arm to the elbow, left hand and neck. (Falk,2006).
3. Describe the relationship between heart failure and peripheral oedema.
Congestive heart failure (CHF) is the inability of the heart to pump blood sufficiently out of the left ventricle to meet the metabolic demands of the body. Due to atherosclerosis and hypertension, arteries are narrowed, increases peripheral vascular resistance and causing hyper ventricular remodelling. Blood not pushed out effectively and pooled in the left ventricle. Thus, stroke volume (SV) and Cardiac output (CO) are decreased. (Tortora & Derrickson, 2014).
Due to increased pressure gradient blood flows back from atria to lungs causing pulmonary congestion leading to left-sided heart failure. The increased pressure in the pulmonary system affects right ventricle, as pressure increases in right atria or ventricle, venous return decreased. Thus, hydrostatic pressure is increased, and osmotic pressure is decreased, which pulls water into the interstitial cells instead of depositing in the subclavian vein through lymphatics and leads to peripheral oedema. (Casey, 2013). Excessive cardiac filling pressures lead to an increase in lung stiffness and pulmonary oedema. (Mckenzie & Cowlie, 2003).
Decreased blood volume and cardiac output in HF trigger sympathetic nervous system (SNS) to release noradrenaline, which increases heart rate and contractility. Continued stimulation of SNS causes ventricular remodelling in which the wall gets thickened. (King, Kingery & Casey, 2012). Eventually, this response becomes less responsive, AF and heart blocks are at risk. Decreased CO causes decreased perfusion to the kidneys which trigger RAAS. Aldosterone stimulates retention of sodium and water by kidneys to restore volume. Thus, experiences oedema. (Casey, 2013).
4. Outline the biological (or mechanism of) action of aspirin and discuss how it is expected to reduce Mr Scott’s risk of further major cardiovascular events.
Aspirin is an antiplatelet drug which inhibits vasoconstriction as well as platelet aggregation by blocking synthesis of thromboxane A2. It also reduces thrombus formation. Thus, aspirin is effective in reducing the risk of stroke, myocardial infarction, transient ischemic attacks and peripheral arteries disease in Mr Scott. (Tortora & Derrickson, 2014).
5Acid Base Case Study
1. State the type of acid-base imbalance.
2. Explain the origin of the acid-base imbalance. (Include the bicarbonate equation in your explanation and direction of chemical flow).
Respiratory acidosis occurs due to chronic smoking or any other respiratory pathology. The gas exchange will be impaired. Thus, the amount of O2 reaching the alveoli decreased, CO2 increased in the alveoli. The severe deficiency of O2 depresses the activity of central chemoreceptors causing a decrease in breathing rate and rhythm. (Tortora & Derrickson, 2014).
Alveolar hypoventilation leading to accumulation of carbon dioxide (CO2), which lower the pH. Thus, hypoventilation causes hypercapnia and hypoxia. The increased levels of CO2 cause an increase in hydrogen ions and a slight increase in bicarbonate. Thus, the chemical reaction takes place towards the right side of the equation. Bicarbonate acts as a buffer to overcome acidosis and maintain normal pH. (Woodrow, 2004).
CO2 + H2O ———-> H2CO3- -> HCO3- + H+
CO2 diffuses into the capillary blood and combines with water to form carbonic acid (H2CO3) in the presence of carbonic anhydrase enzyme. Carbonic acid quickly breaks down into H+ and bicarbonate ion.
3. Is there any compensation occurring? If so, describe the type of compensation.
Based on the ABG values respiratory acidosis with partial metabolic compensation occurs. Bicarbonate buffer system is activated. (Tortora & Derrickson, 2014).
Initially, in PCT, H+ reacts with bicarbonate to form H2CO3 which dissociate into CO2 and water. CO2 then diffuse into tubular cells and joins with water to form H2CO3, which again dissociate into H+ and bicarbonate in the presence of CA. The H+ is excreted into the urine joined to an ammonium ion (NH4+). The HCO3- is reabsorbed, re-enters the plasma and becomes part of the bicarbonate buffer and is then available to soak up any extra H+ formed. (Woodrow, 2004). Then this allows kidneys to compensate and secrete more hydrogen ions into the urine and increase the reabsorption of HCO3- into the plasma. The renal system responds slowly (over several hours to a few days) and can regulate alkaline substances. (Simpson, 2004).
4. Explain the effect of this acid-base imbalance on oxygen delivery to tissues.
Bohr effect enables the body to adjust to the different conditions and making oxygen supply to the needed tissues. The Bohr effect increases the efficiency of O2 transport through the blood. In an acidic environment, H+ bind with amino acids Hb and CO2 back to lungs where H+ is converted to CO2 and expelled. Here, the affinity of Hb for O2 is low. So, Hb releases O2 very easily to the surrounding cells to meet oxygen demands. During exercise (lactic acid produced) and fever (increased metabolism) more oxygen delivered to the cells via Bohr effect. (Tortora & Derrickson, 2014).
6a. Renal Disease – Adult Case Study
1. Describe the normal changes in the kidney associated with ageing.
As age advances and capillary wall permeability increases. Moreover, podocyte injury increases which change tubular reabsorption. The number of functioning nephrons and podocytes decrease and lead to decreased glomerular filtration rate (GFR). (Denic, Glassock & Rule, 2016).
The oxidative stress due to ageing causes a decrease in nitric oxide (NO) production, leading t low renal perfusion. Thus, endothelial damage causes and at risk of developing atherosclerosis and hypertension. (Weinstein & Anderson, 2010).
Fat deposition occurs in kidneys over the time, causes injury to the nephrons and can progress to glomerulosclerosis. This decreases total kidney volume. Initially glomerular hypertrophy occurs to compensate kidney volume, but eventually, kidney function declines. Thus, the surface area available for filtration is reduced and GFR reduced (Denic, Glassock & Rule, 2016).
2. Discuss how dehydration could have contributed to Mrs Murphy’s diagnosis of acute kidney injury.
Acute kidney injury occurred in Mrs Murphy due to the increased age, dehydration secondary to less water intake as well as the use of NSAIDS.
Low renal perfusion due to dehydration causes sodium retention. (Shah, Anjum & Little, 2004).
Changes in the renin-angiotensin-aldosterone mechanism (RAAS) and nitric oxide (NO) play role in acute kidney injury in older adults. With advancing age, NO production is decreased and endothelial dysfunction occurs. (Weinstein & Anderson, 2010).
NSAIDs inhibit production of renal prostaglandins and renal perfusion id reduced. Usually, metabolites of NSAIDs are excreted through the kidney, but in acute kidney injury waste products are retained. (Medsafe, 2013). When these chemicals are filtered through the glomerulus, the endothelial damage occurs. Macrophages secrete more TNF that leading to inflammation and oedema in the glomerular basement membrane. (Lines & Lewington, 2009).
Thus, over the time, ongoing inflammation leads to sclerosis of the capillary beds. Then the capillary pores become less permeable and prevent plasma from filtering. Acute kidney injury is confirmed by the rapid decline in GFR over hours to days. (Schetz, Dasta, Goldstein & et. al, 2005).
3. Describe the implication of Mrs Murphey’s low glomerular filtration rate on the normal homeostatic action of the renin-angiotensin-aldosterone system.
Decreased perfusion pressure in the presence of NSAIDs decreases vasodilatory prostaglandins which increase angiotensin II. Inflammatory response causes a reduction in renal blood flow. (Denic, Glassock & Rule, 2016). RAAS activated by hypoperfusion. RAAS cannot function effectively in case of renal injury. GFR decreased due to nonfunctioning nephrons, less blood id filtered through the nephrons. (Metheny, 2012). Thus, age-related decline in creatinine clearance occurs. And so, reduction urinary creatinine excretion occurs. The incidence of microalbuminuria and proteinuria increases with age. (Weinstein & Anderson, 2010).
When dehydrated osmolarity is increased, high blood osmotic pressure stimulates hypothalamic osmoreceptors to synthesis and release ADH. Kidneys retain more water which decreases urine output. Aldosterone secreted from the adrenal gland in response to dehydration also reduce urinary sodium and water excretion by increasing tubular reabsorption of sodium in exchange for potassium and hydrogen ions. (Tortora & Derrickson, 2014).
7. Type 1 Diabetes Case Study
1. Gene variants from the human leukocyte antigen (HLA) gene complex that encodes the major histocompatibility complex (MHC) are associated with type 1 diabetes.7,8 Explain the effects of these genetic variants on the MHC located on the pancreatic beta cells in people with type 1 diabetes.
Heredity plays a role in the development of TID (Hemminki, Li X, Sundquist & et al, 2009). In general, the incidence of T1D increases with age, the incidence peak is at puberty. (Soltesz, Patterson & Dahlquist, 2007).
Polymorphism within the HLA gene is associated with increased susceptibility to T1DM. Based on MHC expression assay detected TID risk associated HLA-DQ encode with unstable MHC proteins whereas TID protective haplotypes encode with most stable HLA-DQ proteins. HLA instability mediates the development of the autoimmune disorder. (Miyadera, Ohashi, Lernmark & et al, 2015).
Peptidome HLA b associated with T1D. (Eichmann, de Ru, van Veelen & et al, 2014). The cellular proteins are made by using cell’s DNA if the gene in a DNA is abnormal that makes abnormal protein. (Mayer & Nyland, 2015.) The human leukocyte antigen (HLA) gene on chromosome 6 transcribes for the MHC on the beta cell. HLA gene used to make MHC proteins on the beta cells are abnormal. These abnormal MHC proteins are recognized by macrophages and trigger primary immune response resulting in the destruction of the beta cells. (Ryan & Ray, 2014).
2. Describe the autoimmune processes that lead to the destruction of the beta cells.
Viral infections are considered as the trigger for the development of T1D. (Van der Werf N, Kroese, Rozing & et al, 2007). TID occurs due to autoimmune destruction of beta cells in the islets of Langerhans, as beta cells are responsible for insulin production. (Rickels, orbLeslie & Elliott, 1994). In a susceptible host, environmental factors operate over the years to induce the immune process to destroy the beta cell. (Leslie & Elliott, 1994).
This disease is slow and progressive, primary seen in children. Levels of antibodies increased over the years. Evidence suggests that B cells play a crucial role in this pathogenesis. (Zipris, 2009). Macrophages discover, phagocytose abnormal MHC proteins on the cell membrane of beta cells and goes to the lymph nodes. Secretes interleukin and present this to the T helper cells, which stimulates T killer cells and B cells, which go to the pancreas to find these abnormal cells. (Ryan & Ray, 2014).
CD8⁺ T cells differentiate into effector T cells in islets and kill beta cells via the perforin-granzyme pathway. B cells produce antibodies against beta cells and specific anti-insulin. These antibodies bind with these insulins. (Graham, Sutherland, Mannering & et al, 2012).
Memory T and B cells are made. Memory cells recognize beta cells as abnormal and destroy them. Typically, when most all the beta cells are destroyed, and no insulin is produced. Thus, need exogenous insulin and diagnosis of TID is confirmed.
3. Moana is admitted to hospital and commenced on intravenous saline and potassium and an insulin infusion. Discuss the rationale for adding potassium to the intravenous fluids despite the elevation in Moana’s serum K+.
DKA causes metabolic acidosis, where plasma hydrogen ion levels increase causing potassium hydrogen exchange, which maintains hemodynamic stability. Thus, potassium being lost through kidneys. (Nyenwe & Kitabchi, 2011).
Even though potassium levels are high, but insulin replacement causes a reduction in potassium level. A prospective study revealed that in course of the therapy 63% developed hypokalaemia. (De Ruyter & Harrison, 2007).
8. Type 2 Diabetes and Related Complications Case Study
1. Describe the effect of insulin resistance on the: a) Liver and b) Pancreas
When liver cells become filled with fat, it produces cytokines to prevent further fat deposition and to prevent energy molecules from entering the liver. (Savage, Petersen & Shulman, 2005). ATP production is decreased as no glucose enters the cell. Insulin receptors do not function. Liver cells release stored glucose into the plasma. Triglycerides are released from adipose tissue. Macrophages engulf excess fat and release tumour necrotic factors (TNF), which makes atherogenic lipoproteins like LDL & VLDL. (Savage, Petersen & Shulman, 2005). Eventually liver becomes IR. (Larter & Farrell, 2006).
Liver cells signal pancreas to become insulin resistant. VLDL-C deposited into beta cells, which cause inflammation and dysfunction of it. Over the time insulin secretion decreases. Beta cells stop insulin secretion instead filled up with fat. No enough insulin to bind with insulin receptors and no glucose enters. Thus, beta cells become insulin resistant. (Savage, Petersen & Shulman, 2005).
2. Discuss the effect of hypertension on the vascular endothelium and its association with microvascular disease.
The high pressure within all the arteries causes damage to the endothelial layer of the artery leading to inflammation, thickening of endothelium, platelet activation and formation of atherosclerosis. This may block blood supply to the distal arteries. (Tortora & Derrickson, 2014.)
Hypertension causes endothelial dysfunction and cardiovascular complications. (Daly, Kenealy, Arroll & et.al, 2014).
The capillaries in the retina, kidney and peripheral nerves are more susceptible to damage due to hypertension or elevated blood sugar. As blood supply through these areas is damaged which causes diabetic retinopathy, diabetic nephropathy and peripheral neuropathy. (AMA)
3. Explain the biological action (or mechanism of action) of betaloc and its effect on mean arterial pressure.
Betaloc is a beta blocker, acts by blocking beta 1 adrenergic receptors on the heart muscle and the blood vessels. This decreases phase 4 and prolongs repolarization phase3. Thus, slow down potassium release and reduce sodium uptake. (Marx, Hockberger & Walls, 2014). As a result, heart rate (HR) and oxygen demand are reduced. This reduces the workload of the heart. It also widens the blood vessels thereby reducing peripheral vascular resistance. As HR is maintained under control and SV increased, which makes CO normal. Moreover, the mean arterial pressure (MAP) is based on CO and resistance to the blood flow. Thus, the MAP is reduced. (Medsafe).
4. State the numbers-needed-to-treat (NNT) to achieve ‘tight’ blood pressure control in people, like Mr Asavili with type 2 diabetes, to prevent one person from having a major microvascular complication. (Include an appropriate reference to validate your answer).
This study is done in England, to determine the effectiveness of tight blood pressure (BP) control in patients with T2DM to prevent microvascular and macrovascular complications. (UKPDS 38).
Experimental group (tight BP control) =758
Control group (less tight control) =390
Microvascular Event rate in control group = 54/390 x 100 =0.138×100=13.8
Microvascular event rate in experimental group= 68/758 x 100 =0.08×100=8
Absolute reduction risk (ARR)=0.138-0.08=0.058
Number needed to treat (NNT) =1/ARR =1/0.058=17.2
The number of patients who needed to be treated over 10 years to prevent one patient from developing microvascular complication was 17.
9. Asthma Case Study
1. In New Zealand, dust mite faeces are a common trigger for an asthma attack.9 Explain how dust mite faeces activate an immune response in a person with a history of asthma.
Asthma is a major health problem in New Zealand, generating large costs to the health services and industry (Holt & Pearce, 2000). Allergen exposure is an important exacerbation trigger for a substantial proportion of asthmatic patients. (Bates & Cydulka, 2013).
House dust mite-specific immunoglobulin E and longitudinal exhaled nitric oxide measurements in children with atopic asthma (Lee, Yang, Park & et. al, 2015). It has shown that IgE antibodies specific to different allergens can differentially influence the quantity of total IgE. (Erwin, Ronmark, Wickens & et. al, 2007).
Eosinophils are nonphagocytic cells that participate in allergic reactions along with basophils and mast cells. (Ghaffar, 2015). Those susceptible to Asthma eosinophils move into the lung tissue and reacts to allergens when get exposed. These eosinophils release many cytokines especially tumour necrosis factor which stimulates the primary immune response. The eosinophils activate the dendritic cells, which take up the allergen and send it to T helper cells. Interleukin also signals while B cells are activated, in which IgE antibodies are produced. These antibodies bind with mast cells to release histamines. At the same time, CD4+ also activates eosinophils to release more cytokines. The inflammatory and immune changes in the lungs lead to acute and chronic changes in the lungs. (Ryan & Ray, 2014).
2. Describe the acute pathological changes that occur in the lungs during an asthma attack.
Asthma is a hyperimmune response to an allergen. It represents parasympathetic response, bronchoconstriction prevents entry of allergen into the airway. When the immune and inflammatory responses activate during an asthma attack, the parasympathetic nervous system stimulated to cause bronchoconstriction. This causes involuntary contraction of smooth bronchial muscles. Due to inflammatory of airways, airways become edematous and airway remodelling occurs. Due to hyperplasia of goblet cells, mucus production increased which subsequently cause plugging of smooth airways. Airway resistance increases, especially in the mid-sized bronchi. This leads to breathing difficulty and air hunger. (Ryan & Ray, 2014).
3. Flixotide is used to reduce chronic changes that typically occur in children, like James, who have a history of asthma. a. Describe the typical chronic changes that occur in the lung parenchyma and b. Explain how Flixotide impacts on these changes.
In asthmatic patients, major basic protein (MBP) is released by eosinophils causes chronic changes in the lungs. MBP damages epithelial cells lining the bronchi over the time and cause inflammation. Smooth muscle hypertrophy occurs. Collagen deposition is increased in the basement membrane of the epithelial lining which prevents expansion while during respiration. (Sutherland & Martin, 2003).
Flixotide is an inhaled corticosteroid (ICS) and an effective antiasthmatic agent that can reverse specific chronic inflammation. It reduces airway responsiveness to allergens like dust, fog, chemicals. Flixotide limits the narrowing of airway upon long-term use. Eventually reduces the number of mast cells, eosinophils and T-lymphocytes in the body. Flixotide reverses shedding of epithelial cells, goblet cell hyperplasia and basement membrane thickening. It can regain extracellular matrix over time. (Chung, Caramori & Adcock, 2009).
10a. COPD Adult Case Study
1. Discuss the underlying pathology of emphysema and its effects on the: a) Alveoli b) Small airways c) Respiratory membrane and diffusion of CO2 and O2
In emphysema immune response activated upon inhalation of noxious substances like cigarette smoke and cytokines and other immune mediators are released. (Sutherland & Martin, 2003). Macrophages activate T killer cells to release Tumor necrosis factor-α. (TNF-α), which stimulates synthesis of enzymes called matrix metalloproteinases (MMP) responsible for the destruction of elastin. (Macnee, Vestbo & Agusti, 2016).
Macrophages also stimulate neutrophils to release proteases like Neutrophil elastase causes excess mucus production leading to mucus gland hyperplasia and causes alveolar destruction. (Corriveau & Fagan, 2018). Due to the destruction of elastin, alveolar walls, alveolar attachments and walls of the airways are destroyed. Lung capacity is increased due to air trapping inside the lungs, which reduces the diffusing capacity of CO2 in the lung. (Segal, Weiden & Horowitz, 2015).
Oxidative stress activates TNF κB which promotes cytokine release. This leads to alveolar destruction. It increases neutrophil influx into the lungs, leading to airway obstruction. (Sharafkhaneh, Hanania & Kim, 2008).
The airway is narrowed due to an increased number of goblet cells, mucosal thickening, ciliary dysfunction and destruction of alveolar cells. (Tabatabai & Gruber, 2018). Loss of pulmonary vascular bed, arterial vasoconstriction lead to hypoxemia and hypercapnia. (Corriveau & Fagan, 2018). Inflammation causes oedema of the respiratory membrane which impairs gas exchange. (West, 2012).
Transforming growth factor (TGF)-β acts on epithelial cells which release fibroblast and cause fibrosis of small airways and bronchial smooth muscle. As alveolar thickness increases which decreases surface area for gas exchange. (Sutherland & Martin, 2003).
2. Describe the effects of dynamic lung hyperinflation associated with emphysema which leads to breathlessness and limited physical activity.
In emphysema, the destruction of alveolar attachments in the airways, cause early closure of airway during the expiration. Thus, air trapped inside and gets hyperinflation of the alveoli. Moreover, the collapse of the airways occurs. (Baraldo, Turato & Saetta, 2012).
In emphysema, as pulmonary capillary is destructed. This leads to ventilation-perfusion mismatch. Alveolar hypoxia occurs, and which increases vascular resistance. Airflow limitation causes limitation in physical activity. (Kent, Mitchell & McNicholas, 2011).
Work of breathing increases with activity. Dyspnea leads to reduced activity, deconditioning and progressive disability. (Corriveau & Fagan, 2018). Due to increased work of breathing, oxygen demand increases, which causes physiological stress (Bates & Cydulka, 2013).
Skeletal muscle dysfunction is one complication of COPD. COPD affects quadriceps muscle which causes a reduction in muscle strength, muscle fibre atrophy occurs, muscle weakness reduces exercise capacity. (Kent, Mitchell & McNicholas, 2011).
3What is Mr Seddon’s BMI and explain why a low BMI is associated with emphysema.
BMI= Weight in kg = 60 = 19.59
(Height in metres)2 (1.75×1.75)2
Mr Seddon has a normal BMI. In emphysema, exertional dyspnea occurs for a long time, they use accessory muscles for breathing which causes increased use of calories for breathing. Thus, weight loss occurs. (Beasley & Travis, 2015). The effects of oxidative stress and inflammatory mediators in emphysema causes weight loss over time and muscular wasting and metabolic derangements. (Tabatabai & Gruber, 2018).
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