Year 2 exam revision concepts of disease, physiology and neuroscience PDF

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PhysiologyThe dive reflexThe dive reflex is a vast physiologic process, but its main mechanisms involve peripheral receptors, neuronal pathways, and chemoreceptors. A person holds their breath and submerges under water two things occur: the face gets wet and the oxygen content in the lungs becomes f...

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Physiology

The dive reflex The dive reflex is a vast physiologic process, but its main mechanisms involve peripheral receptors, neuronal pathways, and chemoreceptors. 1. A person holds their breath and submerges under water two things occur: the face gets wet and the oxygen content in the lungs becomes fixed. 2. Sensory information from the nasal region is relayed to the brainstem via the trigeminal nerve. The brainstem then sends efferent signals via the vagus nerve to specific target organs. 3. The vagus nerve primarily associates with the parasympathetic nervous system, and the result of this neuronal pathway is bradycardia. 4. The brainstem also sends out efferent signals to the peripheral vascular musculature which increases peripheral vascular resistance and results in blood shunting toward more vital organs. Chemoreceptors in the carotid bodies and aorta also play a role in the active physiologic changes as well. The carotid bodies sense regulation of partial pressure of oxygen in the lungs. When oxygen drops below a certain threshold, the carotid bodies send out an afferent signal to the brainstem that travels on the glossopharyngeal nerve. The resultant efferent signal from the brainstem travels on a number of sympathetic nerves that cause a marked increase in peripheral vasoconstriction that further save blood for vital organs including the brain and heart. The overarching goal of the detailed mechanism previously explained is to conserve oxygen while maintaining homeostasis within the body that is suitable for sustaining life.

Baroreceptor reflex The most important arterial baroreceptors are located in the carotid sinus and in the aortic arch. These receptors respond to stretching of the arterial wall so that if arterial pressure suddenly rises, the walls of these vessels passively expand, which increases the firing frequency of action potentials generated by the receptors. If arterial blood pressure suddenly falls, decreased stretch of the arterial walls leads to a decrease in receptor firing. The carotid sinus baroreceptors are innervated by the sinus nerve of Hering, which is a branch of the glossopharyngeal nerve (IX cranial nerve). The glossopharyngeal nerve synapses in the nucleus tractus solitarius (NTS) located in the medulla of the brainstem. The aortic arch baroreceptors are innervated by the aortic nerve, which then combines with the vagus nerve (cranial nerve X) traveling to the NTS. The NTS modulates the activity of sympathetic and parasympathetic (vagal) neurons in the medulla, which in turn regulate the autonomic control of the heart and blood vessels. Of these two sites for arterial baroreceptors, the carotid sinus is the most important for regulating arterial pressure. The carotid sinus receptors respond to pressures ranging from 60-180 mmHg (Figure 2). Receptors within the aortic arch have a higher threshold pressure and are less sensitive than the carotid sinus receptors. Maximal carotid sinus sensitivity occurs near the normal mean arterial pressure; therefore, very small changes in arterial pressure around this "set point" dramatically alters receptor firing In chronic hypertension the response curve shifts to right thereby increasing the set point. This explains, in part, how arterial pressure can remain elevated during chronic hypertension. Baroreceptors are sensitive to the rate of pressure change as well as to the steady or mean pressure. Therefore, at a given mean arterial pressure, decreasing the pulse pressure (systolic

minus diastolic pressure) decreases the baroreceptor firing rate. This is important during conditions such as hemorrhagic shock in which pulse pressure as well as mean pressure decreases. The combination of reduced mean pressure and reduced pulse pressure amplifies the baroreceptor response.

Although the baroreceptors can respond to either an increase or decrease in systemic arterial pressure, their most important role is responding to sudden reductions in arterial pressure 1. A person suddenly stands up or has a hemorrhage 2. A decrease in arterial pressure (mean, pulse or both) results in decreased baroreceptor firing. 3. Autonomic neurons within the medulla respond by increasing sympathetic outflow and decreasing parasympathetic (vagal) outflow. 4. Under normal physiological conditions, baroreceptor firing exerts a tonic inhibitory influence on sympathetic outflow from the medulla. Therefore, acute hypotension results in a disinhibition of sympathetic activity within the medulla, so that sympathetic activity originating within the rostral ventrolateral medulla increases. 5. These autonomic changes cause vasoconstriction (increased systemic vascular resistance, SVR), tachycardia and positive inotropy. The latter two changes increase cardiac output. Increases in cardiac output and SVR lead to a partial restoration of arterial pressure.

Respiratory system response to exercise Pulmonary ventilation increases almost immediately, largely through stimulation of the respiratory centers in the brain stem from the motor cortex and through feedback from the proprioceptors in the muscles and joints of the active limbs. During prolonged exercise, or at higher rates of work, increases in CO2 production, hydrogen ions (H+), and body and blood temperatures stimulate further increases in pulmonary ventilation. At low work intensities, the increase in ventilation is mostly the result of increases in tidal volume. At higher intensities, the respiratory rate also increases.

CV response in anticipation of exercise Cardiac output increases in anticipation of exercise by ‘central command’ responses: 1. Cerebral cortex 2. CV centre ventolateral medulla 3. ↑ HR ↓ vagal tone ↓ baroreceptor reflex sensitivity ↑ sympathetic outflow ↑ CO ↑ SV 4. ↑ blood flow to working muscles

CV responses during exercise Feedback from receptors in muscles and joints increase HR Central command input to upregulates CVS Venous pooling reduces to increase end diastolic volume Systolic arterial pressure increases Arterioles dilate in working muscles Muscle bed capillaries are recruited Altitude (Gilbert-Kawai et al. 2014)

Describe the CV responses to endurance exercise/regular aerobic exercise Cardiac output (Q) is the blood volume pumped by the left ventricle of the heart per minute (HR x SV). An increased maximal cardiac output is one of the most important adaptations to endurance exercise. It is facilitated by increased in cardiac size, improved contractile force, and increased blood volume. These factors result in more ventricular filling and stroke volume increase. Increased cardiac size and contractile force is the result of cardiac muscle fibre hypertrophy. A positive correlation between VO2 max and cardiomyocyte volume was observed by (Kemi et al. 2004), with ventricular cardiomyocyte volume increasing by 20% with training. They also observed faster relaxation and contraction, as well as increased shortening by 30-40%. Greater ventricular wall thickness and muscle mass allows for increased force of contraction, increasing the volume of blood emptied by ventricular contraction.

Increased VO2 is also facilitated by plasma volume (PV) and red blood cell volume (RBCV) elevations, as described by (Montero and Lundby 2018). They noted an increase in plasma volume after only a small number of training sessions, which decreases the haematocrit. Renal erythropoietin (EPO) is then released to expand RBCV by up to 10%. Other contributors to renal EPO production are angiotensin II and vasopressin, both of which are increased after just one endurance training session. Another possible explanation for endurance training-induced erythropoiesis is the transient increase in cortisol and catecholamines following training. (Professional athletes may have a RBCV of up to 40% higher than untrained individuals.) Other adaptations to accommodate the higher oxygen demand during exercise include increased muscular perfusion capacity. This is facilitated by an increased number of arterioles and capillaries to improve oxygen delivery, as well as increased diameter of elastic arteries to reduce resistance to flow. A decreased in elastic artery wall thickness increases arterial compliance. Another way the CV system responds to long term training is by decreasing the resting heart rate. This is facilitated by decreased cardiac sympathetic activity and increased cardiac parasympathetic activity. Endurance training also leads to a reduction in submaximal exercise heart rate due to decreased sympathetic innervation to the heart (Carter et al. 2003). (Kemi et al. 2004) also found that many of the changes acquired after 2-3 months of aerobic exercise training are lost after 2-4 of detraining, which demonstrates the adaptable nature of the cardiovascular system. Calcium sensitivity in heart Decreased blood pressure volume of ventricular cavities Secondary effects • Muscle fibres contain more mitochondria Vascular smooth muscle cells: • ↑ sensitivity to [Ca] • ↑ release of NO [x4 in response to ACh] • ↑ relaxation Metabolic adaptations to exercise (Flores-Opazo et al. 2020) glut4 upregulation

Resistance exercise The cardiovascular and respiratory responses to episodes of resistance exercise are mostly similar to those associated with endurance exercise. One notable exception is the exaggerated blood pressure response that occurs during resistance exercise. Part of this response can be explained by the fact that resistance exercise usually involves muscle mass that develops considerable force. Such high, isolated force leads to compression of the smaller arteries and results in substantial increases in total peripheral resistance (Coyle 1991)

Describe the physiological responses to a fall in blood pressure It is essential that the cardiovascular system responds to hypotension and restores blood pressure to the range of 120/80 mmHg in order to provide sufficient renal blood supply. This is because the kidneys have the highest flow rate and resistance. Cardiovascular compensatory mechanisms The cardiovascular system responds to hypotension in two main ways; alteration of cardiac output, and alteration of blood vessel tone. These responses are facilitated by the baroreceptor reflex, as described in figure 1. An arterial pressure decrease causes a reduction in baroreceptor firing, and which is relayed to the cardiovascular control centre of the medulla oblongata, which responds by increasing sympathetic innervation and decreasing vagal tone. When blood pressure is in the normal range, baroreceptor firing inhibits sympathetic outflow from the medulla to the heart, therefore a fall in blood pressure causes disinhibition of sympathetic outflow. This results in positive inotropy and positive chronotropy which increase cardiac output, as well as constriction of peripheral blood vessels to increase resistance, resulting in increased arterial pressure. Renal compensatory mechanisms The endocrine system facilitates long term adaptations to blood pressure. Modification of extracellular volume is a key method of blood pressure regulation. The kidneys can respond to a fall in blood pressure by altering urinary fluid loss by the Renin-Angiotensin-Aldosterone system (RAAS) and by secretion of antidiuretic hormone (ADH). Juxtaglomerular cells are the main storage site for renin, which is then released in response to a decrease in the pressure of the afferent arteriole, facilitated by sympathetic innervation. ((An increase in afferent arteriole pressure results in inhibition of renin release)). A decrease in the sodium chloride concentration of the tubular fluid is detected by cells in the macula densa, resulting in the release of renin. A reduction in pressure of the afferent arteriole causes reduction of glomerular filtration rate, decreasing the sodium chloride concentration in the distal tubule. This is a critical response for renin increase in the event of hypotension in order to restore blood pressure. When it enters the bloodstream, renin cleaves angiotensinogen to form angiotensin I. This is then converted to angiotensin II by angiotensin converting enzyme (ACE), mainly found in the vascular endothelium of lungs. Angiotensin II is a potent vasoconstrictor that acts via AT 1 to increase arterial pressure and systemic vascular resistance. It also increases the sensation of thirst. In addition, angiotensin II increases sympathetic adrenergic stimulation by increasing the release of the neurotransmitter norepinephrine (NE). NE binds to alpha receptors, causing constriction of arteries to increase blood pressure. In addition, angiotensin II stimulates aldosterone release from the adrenal cortex

resulting in increased renal sodium reabsorption, and vasopressin release from the posterior pituitary to increase renal water reabsorption. Anti-diuretic hormone (ADH), or arginine vasopressin (AVP), is released in released in response to angiotensin II, hyperosmolarity, sympathetic stimulation, or decreased atrial receptor firing. AVP is synthesised by magnocellular neurons in the supraoptic and paraventricular nucleus hypothalamus, and travels to the posterior pituitary, which secretes it into the bloodstream. The predominant physiological function of AVP is to regulate water reabsorption in the kidneys, but it is also a potent vasoconstrictor when it binds to V1 receptors. Magnocellular neurons project their axons to the posterior pituitary (the neurohypophysis). Their axon terminals in the neurohypophysis contain granules. These granules are membrane-bound and release vasopressin in response to an action potential, which open calcium channels, causing an influx of calcium. Therefore the hypothalamus directly regulates AVP release. Vasopressin binds to V2 receptors in the collecting duct, inducing the insertion of aquaporin 2 in the apical membrane. This allows water to enter collecting duct cells, and water then leaves via AQP3/4 and enters the bloodstream, increasing blood volume, in turn increasing blood pressure

Concepts of Disease

Describe the process of cancerous tumour formation and development Tumours can be classified into benign or malignant. Malignant tumours, known as cancer, are differentiated from benign by their ability to metastasize. Most cancers arise from a single progenitor that proliferates uncontrollably, which is demonstrated by the same pattern of x-inactivation throughout malignant tumours. The hallmarks of cancer are growth signalling autonomy, evasion of growth inhibitory systems and apoptosis, angiogenesis, maintaining replicative immortality, and invasion and metastasis. This essay will aim to outline the mechanisms behind these six hallmarks, and how they contribute to carcinogenesis. Growth signalling autonomy Epidermal growth factor abnormality can be caused by -increased ligand production (EGF) -increased EGFR receptor levels -mutations causing permanently active variant receptors Evasion of growth inhibitory systems Growth inhibitory systems are evaded in cancer cells to allow for uncontrolled replication and avoidance of growth arrest. Approximately 70% of mutations found in cancerous tumours are related to tumour suppressor (TS) inactivation, as described by (Amin et al. 2015). They state the importance of tumour suppressor genes in preventing the formation of cancer cells in response to

stress factors and mutagens. These genes induce cell cycle arrest and apoptosis to inhibit replication of cells with DNA damage. Therefore, the inactivation of tumour suppressors plays a crucial role in carcinogenesis. An example of a TS gene is p53 Evasion of apoptosis Healthy cells respond to certain stress factors and noxious stimuli by activating apoptotic pathways. Internal stress factors result in the intrinsic (mitochondrial) apoptotic route being activated. BAX is a pro-apoptotic protein that create pores in the outer mitochondrial matrix, releasing cytochrome C into the cell’s cytoplasm. Mitochondria cannot produce ATP in the absence of cytochrome C, and its presence in the cytosol induces a caspase cascade, resulting in cell death. However, this apoptotic pathway is often disrupted in cancer cells, promoting their survival. Mouse models were used by (Hübner et al. 2008) to demonstrate that inactivation of caspase causes evasion of apoptosis and increased tumour growth. This is evidence that evasion of apoptosis is essential for tumour formation. There are several ways that cancer cells can modify routes of apoptosis, as described by (Fernald and Kurokawa 2013). They found that cancer cells can alter levels of expression of apoptotic genes or carry out translational, post-translational or transcriptional modifications. They also described the role of BAX breakdown as a last resort to evade apoptosis. Angiogenesis Tumours produce VEGF in response to hypoxia blood vessels produce nitric oxide in order to become unstable and dilate endothalial cells sprout from the original vessel pericyte stabilise new vessels Maintaining replicative immortality Cancer cells produce telomerase to maintain telomere length Invasion and Metastasis (Chaffer and Weinberg 2011) The stages of metastasis: 1) invasion 2) intravasion 3) transport- tumour cells in blood 4) extravasion 5) metastatic colonisation- tumour colony formed

Discuss the mechanisms that contribute to an inflammatory response, focusing on inducers, sensors, mediators, and effectors

Inflammation is instigated by inducers. Endogenous inducers eg damage associate molecular patterns (DAMPS). Exogenous inducers include pathogen associated molecular patterns (PAMPS). Sensors detect inducers. The main type of sensors involved in inflammation are pattern recognition receptors, which include toll-like receptors (TLRs) and Nodlike (NLRs). PAMPS bind to TLRs and activate the NFKB pathway, resulting in the release of both cytokines and chemokines. DAMPS bind to NLRs which trigger pro-cytokine cleavage to cytokines via caspase enzymes. 5 cardinal signs Effectors include macrophages, neutrophils and phagocytes, which are recruited via signal transduction. (actions of macrophages, neutrophils and phagocytes). Acute phase proteins are synthesized by the liver, including fibrinogen, haptoglobin, and C-reactive protein. (Actions of acute phase proteins). An increase in vascular permeability is facilitated by endothelial cells, allowing immune cells to be recruited to the site of infection. Complement system and adaptive immune system

Explain how mutations can affect the role of protooncogenes and how such changes help promote and maintain cancer. Include examples of three specific protooncogenes to support your answer. Explain how mutations can affect the role of proto-

oncogenes and how such changes help promote and maintain cancer. Include examples of three specific protooncogenes to support your answer. Explain how mutations can affect the role of protooncogenes and how such changes help promote and maintain cancer. Include examples of three specific protooncogenes to support your answer. Explain how mutations can affect the role of proto-

oncogenes and how such changes help promote and maintain cancer. Include examples of three specific protooncogenes to support your answer. Cholera and Salmonella Gastroenteritis is a highly detrimental to global health and is attributed to a staggering 1.7-5 billion cases per year and approximately 1.3 million deaths per year, according to (Amicizia et al. 2019). They also estimated that around 25% of infant deaths in south-east Asia and Africa are the result of diarrheal disease, which is likely due to poor sanitation and medical care, and lack of clean water. Many pathogens can cause gastroenteritis, but two very prevalent etiological agents are Salmonella Typhimurium (S. typhimurium) and Vibrio Cholerae. This essay will aim to characterise these diseases and compare their pathologies, as well as treatments. Salmonella Salmonella enterica is a gram negative, facultatively anaerobic, motile bacterium that causes fever and diarrhoea, most commonly transmitted by the ingestion of contaminated food or water. Salmonella enterica serovar Typhimurium is a common serotype. Fol...