TOPIC 1: Functional properties of the excitable cells
TOPIC 2: Skeletal and smooth muscles.
TOPIC 3: Connective tissues
TOPIC 4: Cardiovascular system
TOPIC 5: Respiratory system
TOPIC 6: Gastrointestinal system
TOPIC 7: Urinary system
TOPIC 8: Calcium and phosphorus homeostasis, bone.
TOPIC 9: Skin
TOPIC 10: Acid-base balance
TOPIC 11: Nervous system metabolism and biochemistry of sensory transduction in special senses.
DETAILED learning objectives
FUNCTIONAL PROPERTIES OF THE EXCITABLE CELLS
Membrane excitability and communication between excitable cells.
Lectures will be focused on the physical principles of bioelectricity and on the exchanges of ions across the plasma membrane underlying the functional properties of the excitable cells: neurons and muscles. Specifically the following topics will be discussed: 1) the currents underlying the resting membrane potential, the graded potentials and the action potential. 2) Generation and transmission of graded potentials (post-synaptic and receptor potentials) and of the action potential. 3) Communication among excitable cells through the electrical and chemical synapses. 4) Activation of the skeletal muscle through the neuromuscular junction and of the smooth muscle. 5) Currents underlying the pace maker potential and myocardial action potential. 6) Spread of the excitation through the heart. Properties and types of ion channels and active transporters in neurons. Control of ion channels and functional states of gated channels. Role of trans-membrane ion movements in electrical excitability, signal propagation, and neurotransmission. Molecular composition and organization of myelin lipids and proteins and explain their roles, describe the channel distribution in the different compartments of a myelinated axon. Importance of intrinsic and adaptive myelination. Neurotransmitters and recognize criteria to identify them, the different chemical types of excitatory and inhibitory neurotransmitters. Bioactive peptides and their role in neurotransmission. The major neurotransmitters, their metabolism and regulation, neurotransmitter receptors, their types, action mechanisms and regulation, explain how chemical neurotransmission ends.
SKELETAL AND SMOOTH MUSCLES
Muscle contraction. Chemical composition of skeletal muscle and its peculiarities. Structure and properties of key sarcomere proteins, their molecular arrangements and functional properties. Neuronal signals to skeletal muscle, the sliding filament model of muscle contraction, and the molecular mechanisms underlying muscle relaxation. Integration of skeletal muscle contraction and metabolism, and coordinated regulation. Role of myoglobin, phosphocreatine and glycogen metabolism during exercise. Key molecules and metabolic integrations in aerobic and anaerobic exercise. Role of muscle proteins in glucose homeostasis.
Mechanical properties of skeletal muscle. Experimental approach to the study of the mechanical properties of the skeletal muscle: from the anatomical organization of the parts of the skeletal muscle to its biomechanical model. Functional behavior of the muscle during relaxation and contraction (total, active and passive force) in isometric condition. Modalities of skeletal muscle activation in experimental conditions and in situ: twitch, incomplete and complete tetanus and their relations with the active state. Functional behavior of the skeletal muscle in dynamic condition that is the relation between velocity of shortening and lengthening and the force exerted by the muscle. Skeletal muscle as a motor and as a brake.
Mechanical and electrical properties of the smooth muscle, including examples of hormones and drugs interacting with their receptors to modulate smooth muscle function.
Extracellular matrix and connective tissues, molecular composition and cells interactions. Types of collagen. Effects of the presence of collagen in tissues. Biosynthesis of collagen, with particular reference to assembly and factor requirement, including the role of vitamin C. Structural features and functional properties of elastin and proteoglycans.
Blood. Molecular and ion composition of plasma. Similarities and differences among plasma, extracellular and intracellular fluids. Major plasma components: types, turnover and functional roles. Plasma carbohydrates, lipids, amino acids. Structure and function of albumin. Hypoalbuminemia. Turnover, functional properties and diagnostic importance of the different classes of plasma proteins. Hormonal control of erythropoiesis. Structural and functional properties of heme. Heme biosynthesis and catabolism, including bilirubin conjugation and excretion. Membrane and cytoskeletal properties of the erythrocytes. Hereditary spherocytosis. Metabolic requirements and metabolic specialties of red blood cells, in particular in relation to oxygen transport. Function of iron and maintenance of its homeostasis in humans. Toxicity of free iron, its consequences, and the body defenses against it. Measurement of blood viscosity. Determinants of blood viscosity in vitro and in vivo: temperature, hematocrit, red blood cells aggregation, axial migration. Effects of plasma proteins on red blood cells aggregations in normal and pathological conditions. Effects of axial migration on white cells-endothelial cells interactions. Erythrosedimentation rate. Polycythemia. Transport of oxygen and of carbon dioxide. Structure and function of hemoglobin and their relationships. Cooperative oxygen binding to heme and the physiological factors that influence it. Hemoglobin switching in human development, its control and role. Physiological variants of hemoglobin. Transport of carbon dioxide, carbon monoxide and nitric oxide by hemoglobin. Sickle cell anemia. Blood equilibrium curves for oxygen and carbon dioxide. Bohr and Haldane effects.
Vessels. Molecular and functional characteristics of endothelial cells, with particular reference to the molecular specialization of endothelial cell interactions, and their roles in endothelial barrier and transport properties, endothelial glycocalyx composition and its roles in endothelial properties, metabolic features of endothelial cells, major mechanisms of endothelial transport, different permeability of the endothelial barrier, endothelial control of vascular smooth muscle contraction and relaxation, and endothelial endocrine properties. Nitric oxide metabolism in endothelial cells and its effects in vessels and organism. Function and phases of hemostasis. Megakaryocyte maturation, platelets release and their control. Molecular specialization of platelets, their membrane and vesicle components, and their role in homeostasis. Describe the different steps of hemostasis. Blood clotting factors. Formation of hard clot. Role of vitamin K in blood coagulation. Fibrinolysis and natural anticoagulants. Protein C deficiency. Endothelial dysfunction in peripheral vascular disease. Elastic and resistive properties of the systemic and pulmonary circulation and of their parts. Role of passive and active tension in determining the radius of a vessel. Critical closing pressure and vascular instability Organization of the systemic and pulmonary circulation, with particular reference to the functional relations between the different parts. Physiological shunt. Distribution of blood volume and of surface area in the systemic and pulmonary circulation. Flow, pressure, blood velocity and cumulative cross-section in the different parts of the systemic and pulmonary circulation, also in the light of the equation of continuity, Bernoulli and Poiseuille equations. Turbulence and its hemodynamic effects. Carotid stenosis. Systolic, diastolic, pulse and mean arterial pressures and their determinants. Measurement technique for systolic and diastolic pressures. Mechanical behavior of arterial compartment using a simple RC model, and relation between the model's parameters (compliance and resistance) and arterial pressure. Age-related changes of arterial compliance and their consequences. Radial pulse, pulse wave velocity, its change in the arterial tree and its determinants. Role of arterial compliance and peripheral resistance in the genesis of a continuous capillary blood flow in the systemic circulation. Mechanisms of transcapillary exchange: diffusion, filtration, pinocytosis. Starling hypothesis and filtration changes in physiological and pathological situations. Lymphatics. Edema. Regulation of microcirculation by intrinsic and extrinsic mechanisms, and their relative importance in the different parts of the body. The veins as capacitance vessels. Starling resistor. Varicose veins. Mean systemic, pulmonary and circulatory filling pressures, and their determinants. Effects of venoconstriction, venodilation, changes in blood volume of mean systemic, pulmonary and circulatory filling pressures. Vascular function curves (also called venous return curves) and their determinants. Invasive assessment of hemodynamics. Characteristics and regulation of the cerebral, coronary, splanchnic, and skin circulation. Coronary stenosis. Hemodynamics of pulmonary circulation with particular reference to the effects of gravity and surrounding environment. Dependence of overall pulmonary vascular resistance on lung volume. Pulmonary hypertension. Characteristics of the renal circulation and their relations with renal blood flow distribution between the cortical and medullary part of the kidneys. Estimation of effective renal plasma flow and of renal blood flow by the clearance of p-amino-hyppuric acid. Relations between glomerular blood flow, the resistances of the afferent and efferent arterioles and the pressure in the peritubular capillaries. Intrarenal and extrarenal mechanisms of blood flow regulation. Tubuloglomerular feedback. Autoregulation.
Heart. Contractile proteins and ion channels in the myocardium (also in comparison with the skeletal muscle). Cardiac metabolism (energetic fuels, regulation, and specialization). Fatty acid metabolism and regulation in the heart, and the cardiac role of lipoprotein lipase, carnitine, and CPK. Cardiac metabolic adaptation in physiological conditions and hypoxia. Structure and action mechanism of natriuretic peptides and control of their secretion by the heart. Conditions/stimuli leading to heart remodeling, and its consequences. Electrical properties of the myocardium and of its parts. Genesis and conduction of the cardiac action potential in physiological conditions. Principles of electrocardiography. Common alterations of heart rhythm investigated with electrocardiography, atrioventricular conduction blocks, premature depolarizations, ectopic tachyarrhythmias, flutter and fibrillation. Mechanical events in terms of the main hemodynamic parameters, and their relations with the electrocardiogram. Effects of heart rate on the duration of the systole and diastole (and therefore of diastolic filling). Cardiac valves. Sounds and murmurs detected by auscultation. Major valvular heart diseases. Description of the cardiac events of the cardiac cycle in terms of pressure-volume (PV) loops. Relation between the PV loops and the mechanical characteristics of the ventricle described in terms of isovolumic, isobaric maxima curves and end-diastolic pressure-volume relation, or in terms of end-systolic pressure-volume relation and end-diastolic pressure-volume relation. Pericardium. Determinants of stroke volume, end-diastolic and end-systolic volume for the left and right ventricle. Preload and afterload. Contractility and its clinical estimators. Ejection fraction. Heterometric regulation of the heart: the Frank Starling mechanism and its relevance in the cardiovascular system in physiological and pathological conditions. Use of the PV plane to explain the Frank Starling mechanism. Cardiac function curves and their determinants, including pleural pressure. Cardiac output as the product of heart rate and stroke volume. Measurement of cardiac output (indicator dilution methods, Fick's method and echocardiography). Control of heart rate and contractility (intrinsic and extrinsic, heterometric and homometric).
Coupling between the different parts of the cardiovascular system, regulation and integrated responses. Coupling between the systemic circulation and the heart-lung. Use of Guyton's equilibrium diagram in order to represent the cardiovascular system in conditions of increased or decreased pre or post capillary resistance, constriction or dilation of capacitance vessels, changes of intravascular volume, changes of heart rate or contractility, changes of the passive properties of the heart or of the pericardium. Coupling between the right and left ventricle through the pulmonary circulation. Effects of alterations of the right and left ventricles and of the systemic and pulmonary circulation on the cardiovascular system. Reflexes and hormones controlling the function of the cardiovascular system, baroreflex, Bainbridge reflex, reflexes originating from the low pressure receptors, adrenaline, angiotensin II, atrial peptides. Physiopathology of heart failure and shock. Compensation of hypovolemia.
GASTROINTESTINAL SYSTEM AND ADIPOSE TISSUE
Motility. Motility of esophagus, stomach, small and large intestine. Intrinsic and extrinsic regulation of motility. Effects of nervous and hormonal stimulation. Expulsive maneuvers. Defecation. Gastroesophageal reflux.
Exocrine and endocrine properties of the gastrointestinal system. Composition, elaboration, and control mechanisms of the digestive secretions including saliva, gastric, pancreatic and intestinal juice, and bile. Metabolic properties of the gastro-enteric system. Structural properties, regulation and physiological actions of gastro-enteric hormones. Cystic fibrosis at the pancreas.
Role of the digestive apparatus and adipose tissue in the metabolic homeostasis. Digestive and absorption processes. The integrative role of the CNS in caloric homeostasis and food intake. Overview of nutritional requirements and the role of nutrition in homeostasis. Factors influencing food intake and energy expenditure. Molecular mechanisms underlying hunger and satiety and their function in homeostasis. Hormonal mechanism of eating behavior. Interplay among hormones and the autonomic nervous system allows for the control of caloric homeostasis and appetite. Energy balance, caloric homeostasis and its neuro- and hormonal regulation. Obesity. Diabetic hyperphagia. Key properties and molecular specialization of the liver. Coordination between the liver and the body for energetic substrate usage. Monosaccharide metabolism in the liver and hepatic role in the maintenance of blood glucose. Hepatic lipid metabolism and its role in homeostasis. Essential role of the liver in the amino acid and protein metabolism. Metabolic compartmentalization of hepatic metabolism. Detoxification pathways in the liver. Phase I reactions, and role of the microsomal electron transport chain. Inducible properties of phase I enzymes. Phase II reactions, and different types of conjugation reactions. Ethanol structure, absorption, and tissue distribution. Enzymatic mechanisms of ethanol oxidation and their properties. Effects of ethanol oxidation on the liver and the toxic effects of chronic ethanol consumption. Liver cirrhosis. Endocrine pancreas. Endocrine properties of the islets of Langerhans. Structure, biosynthesis and secretion of insulin, glucagon, amylin, somatostatin, pancreatic polypeptide and ghrelin. Mechanisms controlling the release of pancreatic hormones and their interconnections. Adipose tissue. Key storage role of adipose tissue and its crucial functions in body's homeostasis. Origin and properties of different adipocytes. Lipogenesis and lipolysis in the white adipose tissue, and their hormonal control. Endocrine properties of adipose tissue, and the different compounds secreted by adipocytes. Biochemical and functional differences between white and brown adipocytes. Contribution of brown adipocytes to thermogenesis, and their nervous control.
Statics of the respiratory system. Spirometric and plethysmographic measurements of clinical interest. Quasi-static properties of the respiratory system: pressure-volume curves the respiratory system as a whole and partitioning of quasi-static elastic properties in those of the lung and of the chest-wall. Respiratory, pulmonary and chest wall compliance. Volume changes and elastic work of breathing at rest and during exercise. Surface phenomena in the lungs. Surfactant composition (lipids and proteins), metabolism, secretion and dynamics. Functions, of the surfactant, with particular reference to the regulation of surface tension and maintenance of mechanical homogeneity of lung units. Respiratory distress syndrome in the newborn. Pulmonary interdependence. Mechanics of the pleural space and the mechanisms of gases and fluids removal. Changes of the lung PV curves in emphysema and fibrosis.
Dynamics of the respiratory system. Organization of the airways. Molecular composition and properties of airway mucus. Structure, synthesis and assembly of airway mucins. Mechanisms for removal of foreign particles in the lungs Components and mechanism of the mucociliary escalator. Role of ion channels in lung properties. Lung CFTR and its properties. Cystic fibrosis in the lung. Characteristics of upper and lower airways. Contributions of different airways generation to total airway resistance. Effect of pulmonary interdependence on airway diameter. Respiratory mechanics during spontaneous ventilation and measurement and partitioning of respiratory work. Campbell diagram. Organization and characteristics of respiratory muscles. Distribution of ventilation and perfusion in relation to posture. Onion skin diagram. Expiratory flow limitation in health and disease. Obstructive and restrictive syndromes. COPD and emphysema. Effects of orthosympathetic and parasympathetic stimulation on the tracheobronchial tree.
Gas exchange. Composition of inspired, expired and alveolar air. Anatomical and physiological dead space and their measurement (Fowler's and Bohr's methods). Total, dead space and alveolar ventilation. Characteristics and function of the alveolar-capillary barrier. Respiratory gases diffusion across the alveolar-capillary barrier during rest and exercise. Diffusion capacity for carbon monoxide. Measurement of oxygen consumption, carbon dioxide production and respiratory exchange ratio by indirect calorimetry. Relation between respiratory exchange ratio and metabolism. Estimation of energy consumption by indirect calorimetry. "Ideal" lung. Alveolar gases equations. Representation of gas exchange in the Fenn's diagram. Effects of changes of metabolism, ventilation and cardiac output on the alveolar air, arterial blood, and mixed venous blood points. "Real" lung. Ventilation-perfusion ratio and its distribution in health and disease. Hypoxic vasoconstriction and hypercapnic bronchodilation. Three compartment model. Ideal point. Alveolar-arterial oxygen gradient. Gas exchange during disease. Hypoxemia, its definition and its causes: shunt, diffusion limitation, ventilation perfusion mismatch and hypoventilation. Effects of oxygen enriched mixtures on hypoxemia. Cyanosis. Gas exchange during exercise. ARDS.
Control of breathing. Neural mechanisms responsible for the generation of the breathing pattern. Modulation of the output of the central pattern generator by information from central and peripheral chemoreceptors, slow adapting, fast adapting, irritant and J pulmonary receptors, muscle and joints proprioceptors and temperature. Hering Breuer reflex. Ventilatory response to changes of arterial carbon dioxide, oxygen partial pressures and pH. Ventilatory adaptation to high altitude.
Renal functions and metabolism. renal functions and role of the kidneys in the body's homeostasis. Energy requirements of the kidney, and its adaptations in physiopathological conditions. Importance of the kidney in the biosynthesis of nitrogenous compounds. Role of the kidney in glucose homeostasis in physiological conditions, during starvation, and its hormonal regulation. Diabetes mellitus. Renal metabolism of amino acids and mechanisms of ammonia excretion, including their role in starvation and acidosis. Renal participation in hormonal regulation. Renal glycosuria.
Glomerular filtration, tubular reabsorption and secretion. Molecular strategies for glomerular filtration. Molecular structure and organization of the glomerular filter. Glomerular filtration rate, net filtration pressure and coefficient of ultrafiltration and their determinants. Relations between glomerular blood flow, resistances of the afferent and efferent arterioles and glomerular filtration rate. Intrarenal and extrarenal mechanisms of glomerular filtration rate regulation. Tubuloglomerular feedback. Clearance. Measurement of glomerular filtration rate by inulin clearance, by creatinine clearance and estimation of glomerular filtration rate by creatinine plasma level. Comparison between the clearance of a freely filtered substance with that of inulin in order to gain information about net secretion or absorption of that substance. Changes of ultrafiltrate osmolarity and volume along the nephron. Major inorganic and organic components of the urine and importance of their excretion. Molecular strategies for tubular specialization: compartmentalization of specific transporters in proximal tubule, Henle's loop, distal tubule and collecting duct. Molecular mechanisms of renal reabsorption of organic molecules (proteins, amino acids, vitamins, monosaccharides, urea, uric acid), ions (sodium, chloride, bicarbonates, potassium, calcium, magnesium and inorganic phosphorus) and water. Extracellular matrix of the kidney. Renal treatment of urea and ammonia. Renal elimination of exogenous and endogenous organic acids and bases and the role of pH. Sodium balance and the role of the kidneys in its maintenance. Primary aldosteronism. Proteinuric kidney disease. Nephrotic syndrome. Regulation of sodium reabsorption by intrarenal and extrarenal factors. Renin-angiotensin-aldosterone system and its renal and systemic actions. Water balance and the role of antidiuretic hormone in its maintenance. Countercurrent medullary multiplier. Regulation of antidiuretic hormone secretion by osmoreceptors and baroreceptors. Potassium homeostasis. Distribution of potassium in the body compartments and how redistribution of potassium can maintain a constant plasma concentration. Hypo and hyperkalemia and their effects. Determinants of potassium secretion in the cortical collecting duct. Mechanisms of action of the main classes of diuretics. Effects of diuretics on potassium balance. Regulatory mechanisms of arterial pressure in short, middle and long term. Micturition.
PHYSIOLOGICAL EFFECTS OF POSTURAL CHANGES
Effects of gravity on the cardiovascular, respiratory and urinary systems. Concept of hydrostatic indifference point/level. Hydrostatic indifference point/level in the systemic and pulmonary circulation. Hemodynamic changes and reflex activation during the postural change. Role of the skeletal muscles. Effects of postural changes on urine production. Effects of postural changes on pulmonary perfusion and ventilation.
CALCIUM AND PHOSPHORUS HOMEOSTASIS
Molecular composition of bone. Bone mineral. Molecular mechanisms underlying bone remodeling and their regulation. Collagen I biosynthesis, assembly and factor requirement, including the role of vitamin C. Molecular specialization and metabolic properties of osteoclasts and osteoblasts. Formation of hydroxyapatite crystals, the role of matrix vesicles and alkaline phosphatase in bone mineralization. Role of osteocalcin and osteonectin in bone remodeling, and the hormonal properties of uncarboxylated osteocalcin. Role of bone molecules as biochemical markers of bone remodeling. Structure, properties and metabolism of cartilages. Vitamin C deficiency. "Brittle" bone disease. Calcium balance and homeostasis. Importance of dietary calcium. Calcium absorption and factors influencing it. Renal treatment of calcium. Different forms of calcium in plasma and their functional roles. Structure, regulation and action mechanisms of calcitonin, parathyroid hormone, and calcitriol. Role of intestine, bone and kidney in calcium homeostasis. Rickets. Phosphorus homeostasis. Differences between calcium and phosphate in plasma and in cells. Role of intestine, bone and kidney in phosphate homeostasis. Renal treatment of inorganic phosphorus. Hormonal control of phosphate homeostasis. FGF23-Klotho signaling as endocrine axis in plasma phosphate regulation. FGF23-mediated hypophosphatemic rickets.
Key properties of the skin. Structure and function of skin keratins and desmosomes. Protein and lipid molecules of the cornified envelope and their functional properties. Mechanisms of the epidermal barrier and skin permeability. Different mechanisms of skin perception. Skin interrelationships with other organs/tissues and the skin endocrine properties. Molecular pathways of skin pigmentation and control. Photoaging. Internal core temperature.
Chemistry of acids and bases in aqueous solutions. Dependence of the ionization state and transmembrane distribution of weak electrolytes on the pH of the solution. Passive reabsorption and secretion of weak acids and bases. Definition of buffer solution and related properties. Intracellular and extracellular buffer systems of the body. Differences between an open and a closed buffer system. Representation of the acid base status on the Davenport diagram and its use to describe the acid-base disorders and their compensations. Open and close buffer systems. Bicarbonates, hemoglobin, proteins and inorganic phosphorus. Respiratory compensation for a non-respiratory acid base disorder. Non-respiratory compensation for a respiratory acid base disorder. Role of the kidneys in the maintenance of acid-base balance. Renal treatment of bicarbonates. Ex-novo production of bicarbonates: titrable acids and glutamine metabolism. Role of the liver in glutamine metabolism. Effects of kidney or liver disease on acid-base balance. Conditions which may induce the kidneys to maintain or produce a state of metabolic alkalosis. Effects of diuretics on acid-base balance. Hemogasanalysis and interpretation acid-base and respiratory disorders. Measurement of blood gas components: pH, pCO2, HCO3-.
NERVOUS SYSTEM METABOLISM, AND BIOCHEMISTRY OF SPECIAL SENSES
Brain molecular composition & differences between grey & white matter, energy requirements and fuels of the nervous system, glucose transport and metabolism in neurons and glial cells, the functional glucose imaging of the brain, metabolic and functional cross-talk between neurons and glial cells, monocarboxylate transport and role in brain metabolism, brain amino acid metabolism and ammonia neurotoxicity, cholesterol metabolism and role in the nervous system.
Vision - The molecular mechanisms of light perception; photoreceptor cells: rods and cones, functional properties and retinal localization, structural and molecular features of the outer segment, molecular structure and functional properties of the ribbon synapses; photoreceptor molecules: opsins: biochemical properties and differences between rods and cones, 11-cis retinal: origin, role and location in the photoreceptor structure; the visual cascade: photo-transduction, molecular mechanism and electrical events, termination and regeneration of the photo-pigment.
Perceiving the chemical stimuli: the molecular mechanisms of taste and olfaction, perception and transformation of chemical stimuli, taste: stimuli, receptors and molecular mechanisms for perception; taste transduction and hormonal regulation of taste; olfaction: odorants, olfactory receptors, and odorant decoding by combinatory mechanisms; olfactory signal transduction