Physiology Final Revision PDF

Final Revision  Homeostasis Cells are capable of living, growing and performing their special functions so long as the proper concentrations of the constituents of the ECF are available. ➔The ECF is called internal environment of the Body. Definition: it is the maintenance of a constant...

Final Revision  Homeostasis Cells are capable of living, growing and performing their special functions so long as the proper concentrations of the constituents of the ECF are available. ➔The ECF is called internal environment of the Body. Definition: it is the maintenance of a constant condition in the internal environment  Homeostatic Mechanisms Stability comes from the ability of a system to measure any change (=variation), detect any errors when the system is not in balance and be able to counteract to correct any error to achieve balance again. To achieve this, we need: variable Variable Sensor sensor integrator Integrating Effector effector centre 1- Receptors = sensors or detectors Variable Sensor detect changes in the environment both outside and inside the body and provide information Integrating Effector centre 2- Controller = control centre or integrating centre receives the signal information from the sensors about the change ➔the integrator compares the sensor's input and the set point. If there is a difference between sensor's input (actual change) and the set point, it generates the signal necessary for correction of the error. 3-Effectors respond to signal from the centre to correct the error. Sensors Sensors measure controlled variables. Receptors are common sensors as they measure controlled variables by changing intracellular activity in response to extracellular changes. Nerve cells encode their information about controlled variables through the frequency of action potentials. Many sensors are specialised ion channels. 1) Negative Feedback Variable Sensor It provides a mechanism for change in relation to the size of the initial Effector Integrating variation. centre i.e. the bigger the change the bigger the negative feedback It causes the system to change in effect. the opposite direction from the stimulus Integrating Blood glucose centre Glucostat 2) Feed-forward Anticipatory changes are important Ex: when we eat ➔ forward signals are sent to allow the GI tract to be ready expecting glucose & stimulate insulin secretion allowing glucose uptake =The Incretin Effect when we eat salty food we get thirsty to drink water before the NaCl levels in the blood have had time to change. we put on warmer clothing before we get too cold, this an anticipatory behaviour. 3) Positive Feedback Also, present in the body, but they are not part of homeostatic mechanisms. They de-stabilise, rather than stabilise and accelerate transitions between different states, often amplifying signals. ➔change occurring in the same direction as the original stimulus. Positive feedback mechanisms usually control infrequent events such as blood clotting or childbirth Contractions of uterus during labour are stimulated by the baby’s head pressing on the cervix.  Levels of Control Whole body homeostasis Most whole body homeostatic mechanisms involve a joint action of autonomic nervous system, endocrine system and behavioural reactions such integrated responses include ionic balance, blood pressure, blood volume. Local homeostasis (organ-specific) In the lung when low oxygen levels ➔ blood vessels constrict and move blood flow to areas with higher oxygen levels to ↑oxygen uptake into the bloodstream. Cellular homeostasis After a nerve cell is activated and depolarised ➔ potassium channels open to normalise the resting membrane potential.  Membrane Transport Passive transport Active transport (With) (Against) Chemical driving force Electrical driving force Electrochemical  I) Passive Transport 1) Simple diffusion Diffusion is the result of the movement of molecules due to their thermal motion. 2) Facilitated diffusion For molecules where Permeability is very low Needs Carrier or Channel Proteins Driving force: ▪ Chemical force ▪ Electrochemical force Facilitated diffusion 1. Carriers 2. Ion channels Carriers are integral membrane proteins Selective for the transported molecule e.g. D-glucose is transported but not L-glucose Medium velocity 1000 molecules/sec Reversible and saturable Molecules move down the gradient  1. Carriers Carrier types Uniporter: transports only one molecule type Cotransporter: 1) Symporter (coupled transport of 2 different molecular types in the same direction) 2) Antiporter (coupled transport of 2 different molecular types in the opposite direction) 2. Ion channels Channels Mediate Inorganic Ion Transport Characterstics: Narrow, highly selective pores that can open and close Approximately 100 million ions can pass through it per second (105 times greater compared to any carrier) Cannot couple to energy source to perform active transport (always passive – downhill) All animal cells contain ion channels, not limited to neuron; each neuron might have more than 10 types of channel II- Active transport Primary active transport uses the energy source (ATP) to directly transport molecules. Secondary active transport uses the energy of a concentration or electrochemical gradient created by primary active transport. Osmosis: The movement of water through a semi-permeable membrane from a solution of low osmolarity to a solution of high osmolarity ➔ until osmotic equilibrium occurs. Osmotic Pressure: Is the pressure can stop osmosis.  Hypertonic solution: a solution ↑ EC osmolarity ➔ water moves out of the cell causing cell shrinking. Hypotonic solution: a solution ↓extracellular osmolarity ➔water moves into the cell. Isotonic solution: a solution causes no change in intracellular volume.  Molarity and Osmolarity 1 mole of a substance has a mass in grams equal to its molecular weight Example the molecular weight of NaCl is 58 therefore: 58g of NaCl = 1 mole 5.8 g of NaCl = 0.1 mols or 100 mmols The molar concentration of a substance is the number of moles of that substance in a litre Example 58g of NaCl (1 mol) dissolved in 1L is a 1M solution 5.8g of NaCl (100 mmol) dissolved in 1l is a 100 mM solution Molarity and Osmolarity One osmole is 1 gram molecular weight of osmotically active solute or the number of moles of a compound that contribute to the osmotic pressure of a solution. 180 grams of glucose, which is 1 gram molecular weight of glucose, is equal to 1 osmole of glucose because glucose does not dissociate into ions. If a solute dissociates into two ions, 1 gram molecular weight of the solute will become 2 osmoles because the number of osmotically active particles is now twice as great as is the case for the non-dissociated solute. When fully dissociated, 1 gram molecular weight of sodium chloride, 58.5 grams, is equal to 2 osmoles. Molarity and Osmolarity Osmolarity is defined as the sum of the molar concentration of all the solutes or the number of osmoles of solute per liter (L) of solution, it depends on the number of particles in a chemical solution, but not on the identity of those molecules Examples When 58g of NaCl (1 mol) is dissolved in 1L (a 1M solution) it dissociates in to 1 mole of Na+ ions and 1 mol of Cl- ions So the osmolarity of this solution is 1 molar (Na+) + 1 molar (Cl-) =2 osmolar 1 M solution of sodium sulfate, Na2SO4, dissociates into 2 sodium ions and 1 sulfate anion, so each mole of sodium sulfate becomes 3 osmoles in solution (3 Osm). Cell Permeability The movement of water through a semi-permeable membrane from a solution of low osmolarity to a solution of high osmolarity. 150 mM NaCl 50 mM NaCl 300 mM NaCl “isotonic” “hypotonic” “hypertonic” Definition of obesity: Obesity is a heterogeneous complex disorder of multiple etiologies characterized by excess body fat threatening socioeconomic, mental or physical health. Types of obesity:  Obesity Measures 1) Skinfold measurements Skinfold caliper from selected sites Use of formulas to calculate % of body fat 2) Body Mass Index (BMI) BMI = wt/ (ht)2 in meter Normal weight = 18.5-24.9 Overweight = 25-29.9 Obesity = BMI of 30 or greater 3) Waist circumference 4) Waist/ Hip ratio  Treatment of Obesity 1) Dietary Recommendations: ▪ Caloric restrictions-1200-1500/day to promote weight loss ▪ Low carb-more weight loss in short-term; no difference in losses in long-term ▪ Fat, Fiber, and Protein all shown to be helpful in satiety. ▪ Protein especially important in maintaining lean body tissue during weight loss Treatment of obesity: 2)Physical Activity: prevents weight gain enhances weight loss Ultimate goal in behavioral interventions is to promote long term adherence Treatment of obesity: 3) Pharmacotherapy for Weight Loss When to use? Adjunct to diet & physical activity at BMI ≥ 30 Or, BMI ≥ 27 with other risk factors Should not be used for cosmetic weight loss Only for risk reduction Use only when 6-month trial of diet & physical activity fails to achieve weight loss  Treatment of obesity: 3) Pharmacotherapy for Weight Loss It includes: Enhancing satiety Decreasing fat absorption ➔ ↓Fat soluble vitamins absorption (S/E) Increasing energy expenditure Decrease appetite ➔↑ blood pressure (S/E) Note: These drugs are only modestly effective 2 to 10 kilogram loss Most occurs in the first 6 months If patient does not lose 2 kilograms in the first 4 weeks, success is unlikely If the first 6 months is successful, continue Treatment of obesity: 4) Surgical Treatment: Bypass surgery criteria are: BMI>40 OR BMI>35 with comorbidities  Physical activity Bodily movement produced by skeletal muscles that results in energy expenditure ❑Defined by its duration, intensity, and frequency ❑Duration is the amount of time spent participating in a physical activity session ❑Intensity is the rate of energy expenditure ❑Frequency is the number of physical activity sessions during a specific time period (one week). Regular pattern = activities are performed in some order if moderate-intensity activities are chosen ➔ daily, 5 days or more. Ifweek vigorous-intensity activities are chosen➔3 or more days of the. Differentiate between exercise & sports Exercise A form of physical activity done primarily to improve one’s health and fitness. Sports Is complex, institutionalized and competitive exercise. CDC 1999  Benefits of Exercise: ▪ Helps weight control &Improves self-image ▪ Reduces feelings of depression and anxiety ➔ Good Management of stress ▪ Increases ability to perform tasks of daily living ➔Improves work performance ▪ builds and maintains healthy bones, muscles, and joints. ▪ Enhances cardiovascular function &Reduces many cardiovascular diseases ▪ Reduces the risk of developing colon cancer. ▪ reduces blood pressure in people who already have high blood pressure. ▪ Mitigates the debilitating effects of old-age or retains a more desirable level of health for a longer period of time Why we should do exercise: Increased prevalence of ischemic heart diseases in the world. Childhood obesity has reached epidemic proportions all over the world Children are eating more and exercising less, as more time is spent watching television or using computers coupled with poor dietary habits ➔ significant increases in the number of children with Type II diabetes and ischemic heart diseases.  Types of Exercise: I - Aerobic Exercise Continuous movement uses big muscle groups performed at an intensity that causes the heart, lungs, and vascular system to work harder than at rest + blood supply to muscles and ability to use oxygen ➔Cardio respiratory Fitness is built through aerobic exercise ➔ it strengthens the heart, respiratory system, muscles, and immune system (CDC physical activity report 1999)  Types of Exercise: I - Aerobic Exercise Outdoor Activities Indoor Activities Walking Treadmill machine Jogging/running Stair climbing machine Bicycling Stationary bike Swimming Aerobics, boxing... Basketball Soccer Jumping Rope  Types of Exercise: II- Anaerobic Exercise Intense physical activity in which the body’s supply of oxygen to produce energy does not meet demand. = Strength Training + muscle size + tendon, bone, and ligament strength + lean muscle mass throughout. + Basal Metabolic Rate (minimum amount of energy needed to maintain normal body functions) Increase muscle mass = Increase basal metabolic rate= increase fat loss  Types of Exercise: II- Anaerobic Exercise Isometric – little or no Isotonic – repeated movements movement, using weights; Ex: push-ups, Ex: pushing against wall. weights  Somatic nerves Sensory Motor Somatic sensory fibres from include somatic spinal and the body’s skin ➔ spinal cranial motor efferents cord via peripheral nerves Somatic descending motor tracts from the brain synapse Somatic sensory fibres from with cranial neurons and then the face ➔ brain via cranial travel peripherally as motor nerves fibres in cranial nerves Posterior Function: relay sensations of Somatic descending motor root pain, temperature, and touch tracts from the brain synapse with spinal neurons in the spinal cord then travel anterior peripherally as spinal motor root nerves Dermatome: It is a skin area supplied by a sensory spinal nerve Each spinal nerve innervates a “segmental field” of the skin Except C1 ( Purely motor)  Autonomic NS Somatic NS Involuntary Voluntary Supply Smooth muscle, cardiac muscle and glands Supply Skeletal muscle Can be excitatory or inhibitory Always excitatory Autonomic sensory fibres relay sensory signals from Somatic sensory fibres relay sensations numerous visceral receptors to CNS of pain, temperature, and touch from the skin via peripheral nerves and cranial nerves to the CNS Autonomic efferent arise from thoracic, and upper Somatic Efferent motor spinal nerves arise from all the three lumbar segments (sympathetic) and middle sacral spinal cord segments and as efferent fibers in some segments and cranial nerves III, VII, IX, X cranial nerves to muscles (III, IV, V, VI, XI, XII) (parasympathetic)  Resting membrane Potential (RMP) = the potential difference between the outer and inner surfaces of the cell membrane during rest ▪ The outer surface of the cell membrane is positively charged while the inner side of the cell membrane is negatively charged ▪ RMP in excitable tissues ranges between -70 to -90 mV Causes of resting membrane potential: 1. Selective Permeability (Main factor)➔Continuous potassium efflux through transmembrane protein channels out of the cell. This efflux causes accumulation of positive (+) charges on the outer surface of the cell membrane 2. Sodium-Potassium pump It extrudes 3 sodium ions out of the cell in exchange for 2 potassium ions intruded into the cell ➔accumulation of positive (+) charges outside the cell  Action potential Membrane potential (mv) All voltage-gated Na+ channels are closed +35 ion Depolarization 0 Repolarizat All voltage-gated K+ channels are open All voltage-gated Na+ channels are open Some of the voltage-gated Na+ channels start to open -65 -70 Stimulus After hyperpolarization Time(ms)  Ionic Changes during action potential 1. During depolarization, there is sudden marked increase in membrane permeability to sodium ➔ rapid massive sodium influx ➔ reversal of polarity of the cell membrane 2. During repolarization , there is marked increase in cell permeability to potassium ➔rapid potassium efflux  Propagation of Action Potential in unmyelinated nerves Once initiated, an action potential is self- propagated along the cell membrane of the excitable tissue Self propagation of the action potential occurs by local current flow from the active point (depolarized area) to the inactive (resting.i.e. polarized) point Propagation of Action Potential in myelinated nerves Saltatory conduction Advantages of saltatory conduction 1- Faster: only at node of Ranvier 2-Economic: less ATP used Propagation of Action Potential in myelinated nerves by saltatory conduction Chemical synapse  Development of different blood cells from hematopoietic stem cell to mature cells NGU M. Assaf 49  T- cell development T cell progenitor cells leave the bone marrow and settle in the thymus. They will produce thymocyte cells that differentiate into T- helper cells and T- cytotoxic cells T-helper T- cytotoxic NGU 50  B-cells Bone marrow of higher vertebrates The bursa of Fabricius is a sac-like lymphatic organ present only in birds and situated dorsal to the cloaca. It was first described by Hieronymus Fabricius NGU M. Assaf 51  Monocyte- dendritic cell lineage The monocyte Act as antigen presenting cells (APCs), as Antibody- Dependent Cytotoxic Cells (ADCC) , and promote inflammation Gives rise to tissue histiocytes activated to become macrophages NGU M. Assaf 52  Macrophage Functions as antigen presenting cell (APC), in inflammation (M1), and in regulation of wound healing (M2) Has a major role in phagocytosis of foreign antigens NGU M. Assaf 53  Dendritic Cell This cell is mainly an antigen presenting cell, yet also phagocytic. It inhabits the tissues looking for foreign intruders to present NGU M. Assaf 54  Neutrophils Function in antimicrobial activity, inflammation response, and antibody-dependent cell-mediated cytotoxicity (ADCC) Enzymes within granules function in killing and digesting bacteria and fungi NGU M. Assaf 55  Neutrophil disorders Neutropenia: A lower than normal number of neutrophils in the blood Causes: Congenital Viral infections Certain medicines Cancer treatments such as chemotherapy and radiation Bone marrow disorders Medical conditions that can affect the immune system NGU M. Assaf 56  Neutrophil disorders Neutrophelia: increase in circulating neutrophils above that expected in a healthy individual of the same age, sex, race and physiological status. Causes: Bacterial and fungal infections Surgery Inflammation ( gout, rheumatoid arthritis,…) Malignancy Physiological NGU M. Assaf 57  Eosinophils Active in the immune response to asthma, allergies, and parasites NGU M. Assaf 58  Basophil An IgE responsive cell in the circulation. It is characterized by cytoplasmic granules which, when released, function in destruction of parasites and also in allergic reactions. The cell releases histamine and platelet activator and other chemical signals. NGU M. Assaf 59  Mast Cell Like the related basophils, these cells function in inflammation and allergic response. When mature, they become granulated and are found in tissues, not in peripheral blood. The cell granules release histamine and other factors NGU M. Assaf 60  Somatic Nervous System Autonomic Nervous System Mode of action Voluntary Involuntary Effector Skeletal muscle Smooth muscle, cardiac muscle and glands Effect Always excitatory Can be excitatory or inhibitory Site of efferent All the spinal cord Thoracic and upper three lumbar (sympathetic) origin and middle sacral segments and cranial nerves III, VII, IX, X (parasympathetic) Reflex arc The efferent neuron arises from The efferent preganglionic fiber arises from the the anterior horn of the spinal lateral horn of the spinal cord and synapses cord with autonomic ganglia outside the central nervous system CNS Chemical Acetylcholine Acetyl choline transmitter Or Norepinephrine The functions of the A.N.S Preparation of the body to face emergencies (stresses) Regulation of the process of food digestion Regulation of the body temperature Regulation of the heart rate and blood pressure Control of some hormonal secretion as catecholamines Regulation of vital excretory processes as micturition & defecation  Comparison between Sympathetic and Para-sympathetic Nervous Systems Sympathetic Para-sympathetic Action In Stress, catabolic Rest & digest, anabolic Distribution Generalized Localized Origin Thoraco-lumbar Cranio-sacral Ganglion Lateral, collateral Terminal Autonomic ganglia Definition It is a collection of nerve cells outside the C.N.S. It contains the nerve fiber of the pre- ganglionic neurons and cells of the post- ganglionic neurons Function of Autonomic Ganglia ▪ Relay stations for the preganglionic fibers ▪ Site of action of autonomic drugs ▪ Distribution centers: as the ratio of pre to postganglionic fibers is 1:8. ➔Postganglionic nerves arise in the ganglia and are distributed to various organs Sympathetic Chain 1. Synapse in paravertebral chain ganglia at same level or different level Pass through paravertebral ganglia and synapse in prevertebral ganglion 67 Adrenal Medulla Stimulation of the sympathetic nerves to the adrenal medullae causes large quantities of epinephrine and norepinephrine to be released into the circulating blood➔ to all tissues of the body (80 % epinephrine and 20 % norepinephrine) Neurotransmitters And Receptors In Autonomic Nervous System The neurotransmitter released from all autonomic preganglionic fibers is acetylcholine The neurotransmitter released from postganglionic sympathetic fibers is norepinephrine (with some exceptions) Postganglionic sympathetic fibers that innervate sweat glands and blood vessels of skeletal muscles secrete acetylcholine  The neurotransmitter released from postganglionic parasympathetic fibers is acetylcholine Receptors that bind acetylcholine are called cholinergic receptors Receptors that bind norepinephrine and epinephrine (released by the adrenal medulla or given from external source) are called adrenergic receptors  CELL STRESS CELL ADAPTATION INJURY Hyper- Hyper- Reversible Irreversible Atrophy Metaplasia trophy plasia Degeneration Cell death M.Assaf 71 Types of adaptation 1. Atrophy 2. Hypertrophy Physiological or Pathological 3. Hyperplasia Generalized or Localized 4. Metaplasia M. Assaf NGU 72  ATROPHY [Meaning: from Greek: A= without ; Trophe= nourishment/ food] Definition: Decrease in the size of the cell by loss of cell substance When a sufficient number of cells is involved, the entire tissue or organ diminishes in size, thus becomes atrophic Mechanism: Altered balance between protein synthesis & degradation within cells ↓cell anabolism or ↑ cell catabolism → ↓ cell organelles M. Assaf NGU 73 Adaptation Atrophy When nutrition, blood supply or other cell stimulants are decreased the cell retreats to a smaller size to achieve a new equilibrium. M. Assaf NGU 74 Types of atrophy: A. Physiological atrophy: a. Generalised: senile atrophy b. Localized: i. Atrophy of thymus gland after puberty. ii. Breast & ovaries after menopause B. Pathological atrophy: a. Generalized atrophy: i. Chronic malnutrition ii. Chronic diseases (tuberculosis and malignancy) b. Localized atrophy: i. Disuse atrophy: Prolonged immobilization ii. Neurogenic atrophy: Poliomyelitis iii.Pressure atrophy: Atrophy of vertebrae due to pressure by aortic aneurysm iv.Ischemic (Vascular) atrophy: Renal atrophy due to atherosclerosis of renal artery v. Hormonal atrophy: Breast atrophy after ovariectomy Hypertrophy Meaning: hyper = exceeding/ beyond , trophy= nourishment Definition: ↑ size of cells→ ↑ size & weight of organ (or tissue) Etiology: 1. ↑ functional demands → ↑ protein synthesis 2. Specific hormonal stimulation ↑Workload → synthesis of more proteins to achieve a balance between the demands and the cells functional capacity M. Assaf NGU 76 Types: Physiological hypertrophy: e.g. body builders and pregnant uterus. Pathological hypertrophy: Adaptive hypertrophy: Increased intraluminal pressure in a hollow organ e.g. hypertrophy of the urinary bladder due to prostatic enlargement and gastric hypertrophy as a result of pyloric stenosis. Compensatory hypertrophy: Hypertrophy of one kidney following nephrectomy of the other Hyperplasia Meaning: Hyper: beyond/exceeding ; plasis= formation Definition: ↑ number of cells in an organ → ↑ in its size and weight It takes place in cells capable of synthesizing DNA, thus: nerve, cardiac & skeletal muscle cells reveal little/absent hyperplasia Types: 1. Physiological hyperplasia 2. Pathological hyperplasia M. Assaf NGU 78 1. Physiological hyperplasia a. Hormonal hyperplasia: 1. Breast and genitalia at puberty 2. Proliferative endometrium after menstruation due to estrogen stimulation b. Compensatory hyperplasia: 1. Liver cell hyperplasia following partial hepatectomy 2. Bone marrow hyperplasia following hemorrhage M. Assaf NGU 79  Pathological hyperplasia: a. Hormonal hyperplasia: e.g. Endometrial hyperplasia Benign prostatic hyperplasia Hyperplasia of thyroid epithelium in thyrotoxicosis. b. Irritation hyperplasia: e.g. i. Hyperplasia of lymphoid tissue in infections ii. Epidermal hyperplasia due to chronic irritation  Metaplasia Definition: It is a reversible change in which one adult “mature, differentiated” cell type is replaced by another of the same category (epithelial or mesenchymal) Why? To adapt to environmental changes M. Assaf NGU 81 Types of metaplasia Epithelial Mesenchymal Connective Squamous tissue Glandular M. Assaf NGU 82  Types of metaplasia: Epithelial metaplasia: Squamous metaplasia: Change of any type of epithelium into the more resistant stratified squamous epithelium. Cause: chronic irritation Examples: a. The respiratory pseudostratified columnar ciliated epithelium is transformed into the more resistant stratified squamous epithelium due to cigarette smoking. b. The transitional epithelium of the urinary bladder is changed into stratified squamous epithelium through chronic irritation by stones or bilharzia ova.  Columnar (Intestinal) metaplasia: Gastric mucosa at the edge of chronic peptic ulcer is changed into intestinal type epithelium. The lower third of the eosophageal stratified squamous epithelium is transferred into gastric type mucosa(columnar metaplasia) in cases of gastric reflux. Connective tissue metaplasia At sites of healing injury, fibroblasts may be transformed into chondroblasts or osteoblasts with formation of cartilage or bone outside the skeleton e.g. myositis ossificans.  Leukoplakia Might follow squamous metaplasia Definition, according to the WHO: A white plaque (or patch) on the mucous membrane that cannot be removed by scraping and cannot be classified clinically or microscopically as any disease entity. M. Assaf NGU 85  Leukoplakia Common sites: tongue, vulva, U. bladder Related to chronic irritation Precancerous ( can lead to Squamous cell carcinoma) Microscopy: Urinary Bladder: squamous metaplasia with excessive keratinization Tongue& vulva: Hyperplasia with keratinization M. Assaf NGU 86 Classification of reversible cell injury Changes associated with Disturbed Disturbed Disturbed fat water Mucopolysacch Hyaline change metabolism metabolism arides M.Assaf 87  Changes associated with disturbed water metabolism Reversible cell damage characterized by accumulation of water inside cells. Named according to the degree of water accumulation: mild → cloudy swelling moderate → vacuolar degeneration severe → hydropic degeneration Vacuolar Hydropic degeneration degeneration M. Assaf 88 Changes associated with disturbances of fat metabolism Fatty change “Steatosis” It denotes abnormal accumulation of fat inside cells Causes: 1.Bacterial toxins (diphtheria) 2.Chemical toxins 3.Malnutrition and chronic alcoholism Hepatic cells showing droplets of fat inside cytoplasm M.Assaf 89 Fatty change Organs affected: Liver, kidney, heart Gross: organ↑size, pale yellow, soft Microscopic: fat globules distend the cell (1)→ unit to a single large one pushing the nucleus “signet ring cell”(2) 2 2 1 1 1 2 M.Assaf 90 Obesity Excessive accumulation of fats in normal sites due to over nourishment along with sedentary life or to disturbance of endocrine glands. Lipomatosis Localized accumulation of fat not necessarily associated with marked obesity. M.Assaf 91 Changes associated with disturbed mucopolysaccharide metabolism Mucoid degeneration +++ accumulated mucin within epithelial cells Myxomatous degeneration +++ accumulated MPS in connective tissue M.Assaf 92  Irreversible cell injury (Cell death) Necrosis Apoptosis Local death of a Regulated, group of cells programmed cell inside the living death tissue M.Assaf 93  Difference between necrosis and apoptosis Necrosis Apoptosis Physiologic or pathologic? Pathologic Both Adjacent inflammation Present Absent, only phagocytosis Cell size Enlarged Reduced Nucleus Pyknosis→ karyorrhexis→ Nuclear fragmentation karyolysis Cell membrane Disruption Intact M.Assaf 94 GANGRENE Definition: Massive necrosis followed by putrefaction Causes of necrosis: A. Arterial occlusion B. Venous occlusion C. Bacterial infection “infective gangrene” M.Assaf 95 A. Arterial occlusion: examples include 1. Thrombosis 2. Embolism 3. Strangulation 4. Vascular compression B. Venous occlusion: gangrene if no bypass is present C. Putrefaction: Saprophytes “bacteria” → act on dead tissues Dead tissues hydrogen sulphide Hydrogen sulphide + Iron “from HB” → Iron sulphide “black” # What is the cause of the black coloration of the gangrenous tissue? M.Assaf 96 Types of gangrene 1. Dry gangrene : a. Senile gangrene b. Raynaud’s disease 2. Moist gangrene: a. Intestinal gangrene b. Diabetic gangrene c. Bed sores d. Gangrene of limbs “ crush injury& tight tourniquet” 3.Infective gangrene 4. Gas gangrene M.Assaf 97 Sequence of events in dry gangrene 2. Progress of gangrene: a. Distal to occlusion: pale cold area (ischemia) → red (escape of blood from necrotic capillaries)→ black (H sulphide) b. In the adjacent area there is irritation with thrombosis and progression of gangrene till an area with collateral circulation is reached→ gangrene stops c. Line of demarcation between gangrenous and healthy tissue A red zone of acute inflammation d. Line of separation: A groove in the area of inflammation → deepens → dead part separates from the healthy tissue e. Stump: conical, Why? Because gangrene spreads higher up in skin & SC tissue (less arterial blood supply) than muscle and bones. M.Assaf 98 Moist gangrene Sudden occlusion of artery and vein Site: internal organs ( intestine), extremities in severe crush wounds. No evaporation of fluid → rapid putrefaction→ toxemia Poor line of demarcation Absent line of separation Rapid spread of gangrene Q.: Compare between dry and moist gangrene M.Assaf 99 Bed “pressure” Sores Bed ridden→ thrombosis of vessels → tissue necrosis → ulcers over bony prominences Bed sore on a pressure point Infective gangrene Bacteria are the cause of necrosis& putrefaction Lung gangrene on top of lung abscess Cancrum oris cheeks of debilitated children “bacteria: Treponema vincenti” Severe toxemia M.Assaf 101 Cancrum Oris “Noma” According to the WHO: necrotizing ulcerative Stomatitis. Gangrene from within out and into the bones (maxilla, mandible, nose)  Gas Gangrene Infective gangrene characterized by liberation of gases (CO2 and hydrogen sulphide) Involved bacteria: the clostridia family (anaerobic, gram positive bacteria) Predisposing factors: compound fractures, penetrating injury and agricultural accidents Agricultural accidents→ deep wounds contaminated by manure containing anaerobic spores → vascular damage→ local ischemia → germination of spores. M.Assaf 103  Portal vessels Artery Are “Vessels connecting 2 exchange sites” = between 2 capillary networks Vein e.g.: 1- Liver portal vessels 2-Kidney  Pulmonary and Systemic Circulations Pulmonary circulation: Path of blood from right ventricle through the lungs and back to the heart Systemic circulation: Path of Oxygen-rich blood pumped by the left ventricle to all organ systems to supply nutrients and return of the blood to the right atrium  Alveoli Very thin walled sacs Number: 300.000.000 Each alveolus is encircled by 1000 capillaries Gas Exchange Sites of Gas exchange: - At tissues (between blood & tissues) - At the lungs (between blood & air) Mechanism of Gas exchange: - Simple diffusion ➔ down partial pressure Gradient (from high to low partial pressure) Gas exchange in the lung In the lungs: - Venous blood enters pulmonary capillaries - Air enters alveoli O2 diffuses from alveoli to blood of pulmonary capillaries CO2 diffuses from blood circulating in the pulmonary capillaries to alveoli  BLOOD consists of: Fluid part Cellular elements = Plasma Red blood cells "Erythrocytes" White blood cells "Leucocytes" Largely made in the liver Platelets "Thrombocytes" -Clotting Factors -Albumin All made in the bone marrow -Immunoglobulin Reticulocytes All blood cells are formed from a common stem cell by a process referred to as HAEMOPOIESIS, which occurs in the bone marrow. HEMOGLOBIN [Hb] Red pigment , appears red when combined with O2 and bluish when deoxygenated. The Hb molecule consists of: 1. The globin portion: protein of 4 highly folded polypeptide chains, forming 2 pairs. Each pair is one type of polypeptide chains. 2. The heme moiety: 4 iron-containing protoporphyrin bound to one of the polypeptides. Each hemoglobin molecule can pick up 4 O2 molecules. BLOOD GROUPS 1) ABO system-classic blood groups: discovered by Landsteiner in 1901 ❖ The membranes of human RBCs contain agglutinogens A- and B-agglutinogens (glycoprotein) ❖ Agglutinogens present in many tissues (epithelial and endothelial cells), and secretions (salivary glands, kidney, liver, lungs) ❖4 major groups: A, B, AB and O. ❖Other clinically important groups (Duffy, Kell, Kidd and S) Antibodies against red cell agglutinogens (agglutinins): Present in plasma. Naturally occurring antibodies to the antigens that the person does not express Agglutinins against A and B- Frequency in UK: 42% 8% 47% 3% agglutinogens [anti-A (α) and anti-B (β)] occur 3-6 months from birth Antibodies are IgM and can agglutinate and activate complement  2) Rhesus (Rh) system: named for the first studied in Rhesus monkey not been found in tissues other than red cells. "D" is the most important antigenic component. Rh-positive ➔ agglutinogen D, found in 85 – 90% of population. Rh-negative ➔ the individual has no D-antigen and forms the anti-D agglutinin when injected with D+ve cells. The anti-D-antibodies (agglutinin) are not naturally present in Rh-negative individuals. Erythroblastosis Fetalis: (Hemolytic disease of the New-born) due to Rh-incompatibility between mother and fetus blood. if RhD -ve mother has anti-D - and in next pregnancy, her foetus is RhD +ve ➔mother’s IgG anti-D antibodies can cross placenta ➔ causes haemolysis of fetal red cells ➔ if severe: hydrops fetalis, death Treatment: Exchange transfusion, to replace the newborn’s blood with Rh –ve blood. Prevention BLOOD TRANSFUSION The process of transferring blood or blood-based products from person into the circulatory system of another person Indications: 1. hemorrhage 2. In severe anemia (to restore Hb level). 3. People suffering from sickle-cell disease may require frequent blood transfusions. 4. In bleeding attacks due to disturbances in clotting mechanisms or platelet function (transfusion of clotting factors). 5. In erythroblastosis fetalis.  Whole Blood Red Cells Platelets Plasma fresh frozen plasma Cryoprecipitate albumin Coagulation Factors  A) Immune Transfusion Reactions Acute - Acute haemolytic transfusion reactions - Anaphylaxis Delayed - Delayed Haemolytic transfusion reactions - Post transfusion purpura - Neonatal immune disorders including Rh disease of the newborn  Acute Transfusion reaction Agglutinated RBCs form clumps blocking capillaries ➔pain and tightness of the chest immediately. The clumps are hemolyzed, releasing Hb into plasma ➔ jaundice. ➔Free Hb is liberated into the plasma. ➔renal tubular damage and renal failure and may be death. Histamine release causing vasodilatation, resulting in hypotension. B) Non Immune Transfusion Reactions Infective : bacterial, viral, prion Iron Overload: - 200mg Fe per unit of Packed RBC - Major cause of morbidity and mortality in people with transfusion dependent diseases Precautions before blood transfusion: 1. Blood typing: the donor's blood should be compatible with that of the recipient regarding ABO system and Rh factor. 2. Cross matching test: should be done "The donor's cells are added to the recipient plasma and the donor's plasma tested with the recipient cells". ➔to avoid incompatibility due to any subgroup, or due to increased concentration of agglutinins in the donor's plasma. Precautions before blood transfusion: 3. A healthy donor must be carefully chosen with no history of serious diseases such as: Hepatitis, HIV or AIDS, Malaria and Syphilis. 4. Good storage of the blood with the addition of acid citrate (to prevent its clotting) and glucose (as a nutrient to the RBCs). The blood should be kept at a temperature of 4º C in the blood banks and not freezed, otherwise the RBCs will be destroyed. The blood should not be used after 5 weeks.  Dangers of Blood Transfusion: I- Immediate: Hemolytic reactions. Mechanical overloading of the circulation in cardiac diseases. Hyperkalemia: due to its release from old hemolysed cells ➔sudden death. Citrate intoxication with massive transfusion due to excessive citrate infusion ➔hypocalcemia and acidosis. Bacterial contamination: specially with cold-growing gram-negative bacilli ➔shock associated with fever. Prolonged storage at room temperature (>4 hours) encourages the growth of contaminating bacteria. II- Delayed: Transmission of diseases e.g. AIDs, hepatitis, jaundice, malaria and syphilis. Hypothalamus & Anterior pituitary pituitary Growth hormone: Stimulates growth of bone and tissue and is also involved in emotional well-being.) Thyroid-stimulating hormone (TSH): Stimulates the thyroid gland to produce thyroid hormones Adrenocorticotropin hormone (ACTH): Stimulates the adrenal gland to produce steroid hormones Luteinizing hormone (LH) and follicle-stimulating hormone (FSH):Hormones that control sexual function and production of the sex hormones Prolactin: Hormone that stimulates milk production in females Posterior pituitary Antidiuretic hormone (vasopressin): Controls water loss by the kidneys Oxytocin: Contracts the uterus during childbirth and stimulates milk production Growth hormone abnormality Growth hormone Acromegaly is growth Gigantism is excess Dwarfism is growth hormone excess that production of growth hormone deficiency occurs after the hormone before the in children , short epiphysis closure epiphysis closure stature  Thyroid Disorders Hypothyroidism Hyperthyroidism  Somatosensory cortex Somatosensory cortex is present in the postcentral gyrus of the lateral parietal lobe of the brain The primary somatosensory cortex contains a representation of the opposite side of the body Afferents from every body part send their information to a designated area of the somatosensory cortex The greater the cutaneous receptors of this body part, the larger is its brain’s representation area  Phantom limb Amputee patients commonly continue to experience sensation in limbs that have been surgically removed These sensations may be painless feelings of tingling, temperature, or itching, in which case the term “phantom sensation” is used If patients experience squeezing, throbbing, or burning pain coming from their amputated limb, and this is called “phantom pain” This pain is not mainly coming from the remaining stump of the amputated limb It is caused by continuous signals from the nerve endings of the missed part, in addition to changes happening in the cortex after the actual body part is no longer present  Inflammatory pain Pain arising as a consequence of inflammation to the body usually follows injury It is well controlled initially by drugs such as ibuprofen (non- steroidal anti-inflammatory drugs: NSAIDS) and newer drugs that block nerve growth factor (NGF) driven sensitization  Neuropathic pain Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system It is poorly controlled by drugs but some success with tricyclic antidepressants e.g. Trigeminal neuralgia Trigeminal neuralgia is a condition characterized by episodes of unilateral intense facial pain that lasts from a few seconds to several minutes or hours The pain occurs in areas of the face where the trigeminal nerve supplies normal sensation: cheek, jaw, teeth, gums and lips, and sometimes the eye or forehead  Neuropathic pain (cont.) Trigeminal neuralgia causes sudden, sharp and very severe pain, usually only on one side of the face The pain is described as feeling like stabbing electric shocks, burning, crushing, exploding or shooting pain Patients describe areas on the face as being so sensitive that lightly touching the face or even air currents can trigger an episode of pain However, in many patients, the pain is generated spontaneously without any apparent stimulation Rational approaches to the control of pain understanding the neurobiology How are pain-related networks organized and controlled? Pain pathway: 1. Receptors 2. Peripheral sensory nerves (unmyelinated C fibers or myelinated A delta fibers) 3. 1st order neuron : ipsilateral (same side) dorsal root ganglia (DRG) 4. 2nd order neuron: ipsilateral dorsal horn of spinal cord 5. 3rd order neuron: contralateral Thalamus 6. Fibers ascends to the contralateral cortex Pain pathway Pain Pathway (cont.): How does the pain information reaches the brain? 2nd order neuron: Dorsal horn neuron 3rd order neuron : thalamic nucleus From the ipsilateral dorsal horn of Axons of projection neurons in laminae the spinal cord axons cross to the I and V carried in the lateral contralateral side forming two major spinothalamic tract end in 3rd order neurons of the thalamus which relay ascending pain pathways : the pain information to the sensory cortex and cingulate gyrus The lamina I pathway The lamina V pathway During their pathway, axons from the Forming the paleospinothalamic dorsal horn target several brain regions: and neospinothalamic tracts rostromedial-ventral medulla (RVM) and periaqueductal grey area (PAG) in collectively called the lateral spino- midbrain (slide 17) thalamic tract Behavioral correlates of primary and central sensitization Allodynia: touch becomes painful Hyperalgesia: painful stimulation becomes more painful  Primary and central sensitization Primary sensitization Central sensitization Mainly C fibers Dorsal horn neuron Mainly triggered by a Mainly triggered by a thermal stimulus mechanical stimulus C fibers DRG Descending pathways 1.Descending pain inhibitory pathways from: anterior cingulate cortex (ACC) to PAG (encephalin) to RVM (off neurons and raphe magnus nucleus) to dorsal horn neurons Raphe magnus nucleus have serotonergic axons (releasing serotonin) projecting to dorsal horn for pain modulation Opiate analgesia 2. Descending pain facilitatory pathway from RVM (ON neurons) and their ablation prevents maintenance of chronic pain  What about opiates ? So should opiates be given to chronic pain patients ? Yes Is there a risk of addiction ? Very little This is mainly due to the diminished ability of opiates to produce positive reinforcement by the presence of chronic pain Also the efficacy of opioids in stimulating the dopaminergic system (reward system) is suppressed in neuropathic pain Opioids are substances that act on opioid receptors to produce morphine-like effects Opioids include opiates, an older term that refers to such drugs derived from opium, including morphine itself Normal Haemostasis Haemostasis is the mechanism by which blood is kept inside the blood vessel (i.e No haemorrhage) and in fluid state (i.e. No thrombosis) Normal Haemostasis The normal homeostatic response to vascular damage depends on closely linked interaction between Coagulation Blood vessel platelets factors wall Vasoconstriction occurs after vascular injury. What is the mechanism of vasoconstriction? -Nervous reflexes :induced by pain impulses due to trauma. -Local myogenic spasm : induced by direct damage to the vascular wall.. -Releasing of local substances from traumatized tissues and platelets e.g. thromboxane A2 & serotonin  Primary Haemostasis: - Injured blood vessel - Exposure of collagen (Subendothelial Collagen) - Adhesion: Platelet adhesion via von Willebrand factor (VWF) - Activation and degranulation of platelets - Aggregation ofplatelets  ADP: -Itcauses platelets surface to become sticky → adhere to the first layer of aggregated platelet. -More ADP is released from these newly aggregated platelets, which causes more platelets to aggregate (Positive feedback) → building up a plug of platelets. Thromboxane A2 : powerfully stimulates platelet aggregation & secretion of - platelet granules.  Extrinsic tenase complex Intrinsic tenase complex Prothrombinase complex original ‘waterfall' model of blood coagulation cascade. How do the extrinsic and the intrinsic pathways interact togather ? Evidence suggests that tissue factor (TF) exposure constitutes the principal trigger of physiological haemostasis in vivo. The TF:FVIIa complex is then able to active FX to Fxa (extrinsic tenase complex) In combination with its cofactor FVa, FXa is then able to convert prothrombin into thrombin. ( prothrombinase complex) Critically, the small thrombin spark generated by initial TF exposure is then able to back activate FXI to FXIa, FVIII to FVIIIa and FV to FVa (illustrated by green lines). The net effect of this positive feedback loop amplification is that a secondary large amount of thrombin is generated.  EXTRINSIC FIBRINOLYSIS Tissue – plasminogen t-PA activator PAI-1 Plasminogen activator inhibitor-1 PLASMINOGEN PLASMIN FIBRIN(OGEN) FIBRIN(OGEN) DEGRADATION PRODUCTS (FDPs)  Therapeutic fibrinolysis Recombinant t-PAs: main indications Myocardial infarction Stroke Massive pulmonary embolism N.B. Increased risk of bleeding, therefore careful clinical assessment The natural anticlotting mechanisms 1- Smooth endothelial lining of the vessel, prevents activation of intrinsic pathway. 2- Rapid blood flow facilitates the removal of activated clotting factors by the circulating blood and their inactivation by the liver 3- Prostacyclin (PGI2): produced by healthy endothelium, inhibits platelet aggregation and phospholipid release that initiate coagulation The natural anticlotting mechanisms 4- The first inhibitor to act is tissue factor pathway inhibitor (TFPI) which inactivates the initiation phase of coagulation by forming a quaternary complex with factor VIIa, Xa and tissue factor 5- Anti-thrombin III (heparin cofactor I): It causes inactivation of factors II, IX, X, XI, XII. Its action is facilitated by heparin.  Fibrinolytic System produced by all endothelial cells, Thrombin Thrombo-modulin except cerebral microcirculation ++ Protein C & protein S Inactivate factors Va and VIIIa  Template bleeding time It is the time needed for closure of a puncture wound without clot formation  Causes of a prolonged bleeding time 1- Thrombocytopenia 2- Platelet function defect (e.g. Aspirin) 3- von Willebrand disease 4- Vascular defect – Ehlers Danlos syndrome ( will be studied in coming modules) (defect in collagen type III, lethal vascular problems due to fragile vessels)  Causes of thrombocytopenia (reduced platelet count) 1- Failure of platelet production by bone marrow 2- Increased destruction of platelets ( e.g. autoimmune) 3- Increased consumption of platelets (e.g.disseminated intravascular coagulopathy)  Thrombocytopenia or platelet dysfunction - SYMPTOMS Easy +/- spontaneous bruising Petechiae/purpura Epistaxes (nose bleeds) Menorrhagia (heavy periods) Prolonged bleeding following minor trauma Operative bleeding Intramuscular haematoma (rare) Intracranial haemorrhage (rare) Joint bleeds (very rare)  Global tests of haemostasis Tissue factor Prothrombin time (PT): Extrinsic It tests the clotting time in the presence of optimal concentration of tissue extract (tissue factor) It indicates the overall efficiency of extrinsic clotting system Normal range 11-14 seconds  Global tests of haemostasis Activated partial thromboplastin time (PTT): Intrinsic It tests the clotting time after the activation of the contact factors but without the addition of tissue thromboplastin (TF) It indicates the overall efficiency of intrinsic pathway The normal range is 26-40 seconds  Thrombin Global tests of haemostasis Thrombin time (TT): Thrombin is added and clotting time is measured. Fibrinogen It is affected by the concentration of fibrinogen Prolonged Prothrombin Time (PT) ◼ CONGENITAL Coagulation factor deficiencies: VII, X, V, II, I ◼ ACQUIRED Liver disease Warfarin therapy Vitamin K deficiency (II, VII, IX, X) others Haemophilia Haemophilia A = Factor VIII deficiency Haemophilia B = Factor IX deficiency Sex linked - ie gene on X chromosome Females carriers – usually asymptomatic Males affected 33% arise by new mutation  Haemophilia Clinical Features A- Infants – post-circumcision bleeding – intramuscular haematoma B- Toddlers children adults – recurrent spontaneous painful bleeds large joints (haemarthroses) – Muscles pseudo-tumours – prolonged life-threatening peri/post- operative bleeding Haemophilia Diagnosis Coagulation screen abnormal – APTT prolonged (>40 seconds) ( Normal 24-40 seconds) – PT and TT normal Factor assay or measurement: Low plasma factor VIII in haemphilia A or low plasma factor IX in haemophilia B  Haemophilia Treatment of haemophilia Give the patient the deficient factor: for example: prophylactic recombinant factor concentrates, can be ‘normal boys’ Virchow‘s triad What are the risk factors for VTE? Significantly ↓ mobility Age Surgery > 60 years Certain Obesity medical conditions Risk factors Abnormal Dehydration clotting conditions Active Pregnancy cancer History HRT or of VTE The ‘pill’ (list not exhaustive) Aff. Art. Eff. Art. Filtration Peritub. Cap. Reabsorption Secretion EX. Renal pelvis, ureter Transcellular transport Paracellular transport Factors necessary for erythropoiesis 1. Erythropoietin 2. Iron 3. Vitamin B12 (cyanocobalamin) 4. Folic Acid (folate) 5. Ascorbic acid (Vitamin C) 6. Pyridoxine (Vitamin B6) 7. Amino acids Red Blood Cells (Erythrocytes) Most abundant blood cells In , 1µL of blood contains 4.5-6.1 million RBCs In , 1µL of blood contains 4.2-5.5 million RBCs Contains the red pigment hemoglobin which binds and transports O2 and CO2 Each RBC is a biconcave disc Diameter → 8 µm Thickness → 2.5 µm Erythrocytes Why a biconcave disc? Provides a large surface area for O2 entry/exit Enables them to bend and flex when entering small capillaries RBCs lack a nucleus and most organelles. Instead they are simply membranous bags of hemoglobin. Here, we have an RBC bending to fit thru a small capillary Hemoglobin The O2 binding and transporting protein found in extreme abundance in RBCs Hb levels are reported in grams/dL or gm/dL 13-17g/dL in adult 12-15g/dL in adult Types of hemoglobin? HB= Hemoglobin Haematinics: Substances required for normal erythropoiesis Hormones: – Stem cell factor, IL3, GM-CSF (granulocyte macrophage- colony stimulating factor), EPO, thyroxine. Vitamins : – B12, folic acid, vitamin C,E,B1,B6 Amino acids Metals – iron, cobalt, manganese Why you may suffer anaemia? Blood loss Reduced production Reduced survival Pooling of red cells of red of red cells in the in a very large cells/haemoglobin circulation spleen in the bone marrow < 120 days  Red cell under microscope Salmon coloured Mean cell volume=MCV Mean cell hemoglobin=MCH Central pallor Anemia- Morphologic Classification microcytic (MCV< 80 fL) : iron deficiency, lead toxicity and thalassemia Normocytic (MCV = 80-99 fl) : blood loss, hemolysis, chronic disease, infiltrative, sequestration macrocytic (MCV >99-100 fL) : Vit B12 and folate def, liver disease, uremia, hypothyroid, aplastic anemia, dyserythropoeisis Microcytic Anaemia Common causes of a microcytic anaemia – Defect in haem synthesis Iron deficiency Anaemia of chronic disease (sometimes) – Defect in globin synthesis (thalassaemia) Defect in α chain synthesis (α thalassaemia) Defect in β chain synthesis (β thalassaemia)  Smaller=Low MCV=Microcytic Low hemoglobin content= low Microcytic hypochromic MCH=hypochromic Increased central pallor Increased central pallor Macrocytic anaemia causes: Vitamin B12 or folic acid deficiency Use of drugs interfering with DNA synthesis Liver disease and ethanol toxicity Increase reticulocytes – 20% larger than mature red cells – Blood loss – Haemolytic anaemia B12 DEFICIENCY: FOLATE -Nutritional DEFICENCY: (vegetarians) Vitami Nutritional -gastric eg. pernicious n B12 anaemia (PA) (antibodies stomach Mal- Intrinsi to IF and/or GPC) absorption c factor (small intestine) Gastric excess parietal cell requirement SMALL INTESTINE B12/IF complex absorbed Intrinsic factor (IF) is made by gastric parietal cells (GPC). It binds to dietary B12 and the IF B12 complex is absorbed in terminal ileum. Normocytic normochromic anaemia Recent blood loss Failure of production of red cells – Early stages of iron deficiency or anaemia of chronic disease – Renal failure – Bone marrow failure or suppression (will be studied later) – Bone marrow infiltration(will be studied later) Hypersplenism, e.g. portal cirrhosis (will be studied later) Pooling of red cells in the spleen Haemolytic Anaemia INHERITED ACQUIRED Abnormal red cell Damage to red cell membrane, e.g. hereditary membrane, e.g Autoimmune spherocytosis hemolytic anaemia Abnormal Hb, e.g. sickle Damage to whole red cell, cell anaemia e.g, Microangipathic hemolytic anaemia Defect in glycolytic pathway, e.g. pyruvate kinase deficiency Defect in enzymes of pentose Remember!! This is an intro to anaemia and all the above types of anaemia will be studied in shunt, e.g. G6PD deficiency relevant modules Skeletal muscle tubular system 1- The Transverse tubule (T) It is an invagination of the muscle membrane containing extracellular fluid at the junction of the A and I bands 2- The sarcoplasmic reticulum It is a network of channels surrounding each myofibril containing calcium (Ca2+) Its end expand to contact T tubules at the junction between A & I bands  Muscles are excitable tissues Muscles receive inputs from motor neurons of the spinal cord (or brainstem) Each motoneuron controls the contraction of several muscle fibers The motor neuron and its associated muscle fibres is the motor unit a large motor unit with several Summary of events that occurs during neuromuscular transmission Action potential in presynaptic motor axon terminals ↓ Increase in Ca2+ permeability and influx of Ca2+ into axon terminal ↓ Release of acetylcholine from synaptic vesicles into the synaptic cleft ↓ Diffusion of acetylcholine to post-junctional membrane ↓ Combination of acetylcholine with specific receptors on post-junctional membrane ↓ Increase in permeability of post-junctional membrane to Na+  Under resting conditions, myosin binding sites over actin is covered by tropomyosin and troponin Ca++ binds troponin, troponin undergoes conformational change causing tropomyosin to move away from its position covering the myosin binding site on actin Uncovered, the binding site on actin combines with cross bridges from thick filaments and contraction begins Isotonic Contraction Isometric Contraction Length of the muscle changes Length is constant (elastic components show no series of elastic component significant stretching) are stretched Tension remains constant Tension rises More sliding of filaments Less sliding of filaments Lasts longer Last shorter More energy consumed Less energy consumed External work isdone No external work is done Mechanical efficiency 20-25% Mechanical efficiency 0% Muscle fatigue Muscle fatigue is characterized by: -Decreased strength -Prolonged duration -Incomplete relaxation (contracture) Causes: 1. Accumulation of metabolites (lactic acid) 2. Depletion of ATP, creatine phosphate & glycogen 3. Interruption of blood supply 4. Diminished neuromuscular transmission  Myasthenia Gravis Definition: Myasthenia gravis is a serious and sometimes fatal disease in which skeletal muscles are weak and tire easily Cause: It is believed that the disease is an autoimmune disease in which patients have developed antibodies against their own muscle acetylcholine-activated receptors. If the disease is intense enough, the patient dies of paralysis, particularly of respiratory muscles Treatment: The disease can be ameliorated by administration of drugs, such as neostigmine, that is capable of inactivating acetylcholinesterase. This allows accumulation of adequate amounts of A Ch to affect normal muscular activity  The motor system produces three types of movement:  Reflexive - spinal cord and brainstem  Rhythmic - central pattern generators - spinal cord and brainstem  Voluntary - from motor cortex  An hierarchical model of voluntary movement control: 1. Idea 2. Motor Plan 3. Subroutines 4. Execution of sub-routines 5. Movement  Brain and spinal cord in motor control Motor Idea association cortex & basal ganglia Motor Plan motor cortex- cerebellum Execution brain stem- spinal cord