Medical Quiz: Gangrene and Haemophilia

Homeostasis

• Cells function optimally when extracellular fluid (ECF) concentrations are appropriate.
• ECF is the body's internal environment.
• Homeostasis is maintaining consistent conditions within the internal environment.

Homeostatic Mechanisms

• Systems detect changes, identify errors, and counteract to restore balance.
• Essential components for homeostatic mechanisms include: a variable, sensor, integrator, and effector.

Components of Homeostatic Mechanisms

• Variable: The factor that needs to be regulated.
• Sensor: Detects changes in the variable.
• Integrator: Compares the sensor's input to the set point. This creates a corrective signal.
• Effector: Responds to the integrator's signal, returning the variable to the set point.

Receptors

• Receptors are common sensors that monitor variables through changes in intracellular activity.
• Nerve cells encode information about controlled variables through action potential frequency.
• Many sensors are specialized ion channels.

Feedback Mechanisms

• Negative feedback: Change in response to the initial variation, pushing it in the opposite direction. Larger variation results in a larger negative feedback effect.

• Blood glucose regulation is an example of negative feedback.

• Positive feedback: Amplifies signals in the same direction as the stimulus. Control infrequent events like blood clotting or childbirth.

Levels of Control

• Whole-body homeostasis: A combination of autonomic nervous system, endocrine system, and behavioral reactions that maintain ionic balance, blood pressure, and blood volume.
• Local homeostasis: Organ-specific mechanisms. For example, when the lung detects low oxygen levels, blood vessels constrict in the lung and flow is redirected to areas with higher oxygen levels, improving oxygen uptake. A nerve cell activated and depolarized causes potassium channels to open and return the resting membrane potential towards normal.

Membrane Transport

• Passive transport: (with the concentration gradient)

• Chemical driving force

• Electrical driving force

• Electrochemical driving force

• Active transport: (against the concentration gradient) Requires energy (ATP) and carrier proteins.

Passive Transport

• Simple diffusion: Molecules move from higher to lower concentration due to thermal motion. Small and nonpolar molecules readily diffuse across membranes.
• Facilitated diffusion: Molecules need carrier or channel proteins due to low permeability. These channels, too, follow a concentration gradient.

Facilitated Diffusion: Carriers

• Integral membrane proteins
• Selective for the transported molecule
• Reversible
• Saturable Different carrier types, uniporters (only one molecule type), or cotransporters (2 or more), exist.

Facilitated Diffusion: Ion Channels

• Narrow, highly selective pores
• Can open and close rapidly
• Allow passage of many ions per second
• Always passive (downhill) ion channels.

Active Transport

• Primary active transport: Directly uses ATP to move molecules.
• Secondary active transport: Uses energy from electrochemical gradients to move molecules.

Osmosis

• Movement of water across a semipermeable membrane from low to high osmolarity.
• Water moves to equalize the solute concentration across the membrane.
• Osmotic pressure: The pressure required to stop osmosis.

Solutions: Relative Osmolarity

• Hypertonic solution: Higher osmolarity than the cell, causing water to move out of the cell, leading to shrinkage.
• Hypotonic solution: Lower osmolarity, causing water to move into the cell and possible cell lysis.
• Isotonic solution: Same osmolarity as the cell, no net water movement.

Molarity/Osmolarity

• Molarity: Number of moles of a substance per liter of solution.
• Osmolarity: Sum of the molar concentrations of all dissolved substances; it depends on the number of particles.

Cell Permeability

• Movement of water across a semipermeable membrane from low to high osmolarity.

Obesity

• A complex disorder with multiple causes characterized by excess body fat.
• Types: Android (apple shape), Gynoid (pear shape).
• Measurements: Skinfold, BMI, waist circumference, waist-to-hip ratio.

Treatment of Obesity

• Dietary recommendations: Caloric restrictions (1200-1500 calories/day), low carbs in short-term but no long-term difference, fats, fiber, and protein contribute to satiety, protein especially important for lean body mass maintenance.
• Physical activity: Prevents weight gain, enhances weight loss, and promotes long-term adherence.
• Pharmacotherapy: Adjunctive support with diet and activity for BMI >30 and/or other risk factors. Generally used only when diet and exercise are unsuccessful, for risk reduction.
• Surgical treatment: For patients with BMI >40 and/or other risk factors, if dietary and/or exercise and/or drug therapy have been unsuccessful.

Physical Activity

• Any bodily movement produced by skeletal muscles, resulting in energy expenditure.
• Defined by duration, intensity, and frequency.
• Regular patterns involving moderate to vigorous intensity throughout the week.

Exercise vs. Sports

• Exercise: Primarily for health and fitness improvement.
• Sports: Complex, organized, and often competitive forms of exercise.

Benefits of Exercise

• Weight management & improved self-image
• Reduced feelings of depression & anxiety, stress
• Improved daily tasks & work performance
• Enhanced cardiovascular function
• Reduced risk of colon cancer
• Reduced blood pressure

Types of Exercise

• Aerobic exercises: Continuous movement utilizing large muscle groups, performed at an intensity that increases heart, lung, and vascular system workload compared to resting levels. Improves cardio-respiratory fitness and strengthens heart and immune systems. - Examples include walking, jogging, bicycling, swimming, basketball, soccer, and jumping rope.
• Anaerobic exercises: Intense physical activity where the body's oxygen supply cannot meet energy demand. Strength training. Increases muscle size, tendon/bone/ligament strength, lean muscle mass and basal metabolic rate (BMR). Increase muscle mass, increases BMR, leads to increased fat loss.

Somatic Nerves

• Sensory: Transmit sensations of pain, temperature, and touch from skin and the face, through peripheral nerves, to the brain.
• Motor: Transmit signals from the brain to skeletal muscles causing voluntary movement.

Dermatome

• A specific area of skin innervated by a single sensory spinal nerve.

Autonomic Nervous System

• Involuntary: Regulates smooth muscle, cardiac muscle, and glands.
• Can be excitatory or inhibitory
• Controls vital processes- heart rate, digestion, body temperature, excretion, responses to stress.

Autonomic Ganglia

• Collections of nerve cells outside the CNS.
• Relay signals between preganglionic and postganglionic neurons.
• Distribution centers for autonomic drugs. Signals pass through ganglia as the ratio of pre-to-postganglionic fibres is 1:8.

Sympathetic Chain

• Synapses in paravertebral chain ganglia at the same level or different levels.
• Nerve pathways to various parts of the body through the spinal nerves, including splanchnic nerves, prevertebral ganglia, and effectors.

Adrenal Medulla

• Stimulation by sympathetic nerves leads to the release of epinephrine and norepinephrine.
• Important for body's response to stress.

Neurotransmitters and Receptors (ANS)

• Preganglionic: Acetylcholine
• Postganglionic (sympathetic): Norepinephrine (exceptions) ; Postganglionic (parasympathetic): Acetylcholine
• Receptors: Cholinergic receptors & Adrenergic receptors

Cell Adaptation

• Atrophy: Decrease in cell size due to loss of cell substance. Caused by a decreased workload of environmental stimuli; nutrition, blood supply etc.
• Hypertrophy: Increase in cell size, leads to increase in organ/tissue size and weight. Associated with increasing workload and/or hormonal stimuli
• Hyperplasia: Increase in cell number within an organ/tissue associated with increased workload. Cells capable of synthesizing DNA, thus, Nerve, cardiac and skeletal muscle cells don't exhibit hyperplasia to the same degree.
• Metaplasia: Reversal of cell type, where one mature differentiated cell type is replaced with another of the same category (epithelial or mesenchymal)

Leukoplakia

• White plaque on mucous membranes.
• Often related to chronic irritation; may be precancerous.

Reversible Cell Injury

• Disturbed water metabolism: Cloudy and vacuolar degeneration, hydropic degeneration.
• Disturbed fat metabolism: Fatty change/Steatosis.
• Disturbed mucopolysaccharide Metabolism: Mucoid and Myxomatous degeneration.

Irreversible Cell Injury (Cell Death)

• Necrosis: Localized death of cells in living tissue.
• Apoptosis: Programmed, regulated cell death.

Gangrene

• Massive necrosis (tissue death) followed by putrefaction.
• Types include dry, moist, and infective.
• Causes: arterial or venous occlusion, bacterial infection.

Portal Vessels

• Vessels linking two capillary networks.
• Examples include liver portal vessels and kidney portal vessels.

Pulmonary and Systemic Circulation

• Pulmonary circulation: Path of blood from the right ventricle to the lungs and back to the left atrium. Oxygenated blood through lungs.
• Systemic circulation: Path of oxygen-rich blood from the left ventricle to body tissues, returning to the right atrium.

Alveoli

• Tiny air sacs in the lungs with thin walls, surrounded by capillaries.
• Critical for gas exchange.

Gas Exchange

• Occurs at tissues (blood-tissue interchange) and lungs (blood-air interchange).
• Mechanism: Simple diffusion down a partial pressure gradient.

BLOOD

• Fluid part: Plasma (mostly water, proteins, salts, etc.), made mostly in liver (clotting factors, albumin, immunoglobulins).
• Cellular part: Red blood cells (erythrocytes), White blood cells (leukocytes), platelets (thrombocytes).

Hemoglobin

• Protein in red blood cells that binds and transports oxygen; gives blood its red colour.
• Consists of heme (with iron) and globin (protein).

Blood Groups (ABO)

• Standardized human blood group system (discovered 1901) based on antigens (A and B) on red blood cell membranes.
• Four major types: A, B, AB, O.
• Associated agglutinins against those antigens that are not present.

Rhesus (Rh) system

• Blood group system based on the presence or absence of the RhD antigen (most important).
• Rh-positive individuals have the RhD antigen; Rh-negative individuals do not.
• Antibodies against RhD antigen (agglutinins) can be formed if a Rh-negative individual receives Rh-positive blood; this is important in pregnancy where incompatibility can cause potential problems (Erythroblastosis Fetalis).

Erythroblastosis Fetalis

• Hemolytic disease of the newborn caused by Rh incompatibility between a mother and her fetus. Maternal antibodies against fetal RhD antigens cross the placenta and destroy fetal red blood cells.

Blood Transfusion

• Transferring blood or blood products from one person to another.
• Indications include hemorrhage, severe anemia, sickle-cell disease, bleeding disorders, and erythroblastosis fetalis.
• Precaution: Compatibility testing for ABO and Rh systems; cross-matching; good storage conditions.
• Dangers of transfusion include immediate reactions (hemolytic reactions, mechanical overload, hyperkalemia, citrate intoxication, bacterial contamination) and delayed reactions (transmission of infectious diseases).

Hypothalamus and Pituitary

• Anterior pituitary: Controls many body functions by releasing hormones (e.g., growth hormone, TSH, ACTH, LH, FSH, prolactin).
• Posterior pituitary: Stores and releases two hormones made by the hypothalamus (e.g., ADH(vasopressin),oxytocin).

Thyroid Disorders

• Hypothyroidism: Insufficient thyroid hormone production.
• Hyperthyroidism: Excessive thyroid hormone production.

Somatosensory Cortex

• Located in the postcentral gyrus of the parietal lobe.
• Receives sensory input from the body, processing pain, temperature, and touch.

Phantom Limb

• Painful sensations in a missing limb.
• Thought to be from activity of surviving nerves, with signals continuing in the brain. The brain will reorganize.

Inflammatory Pain

• Pain caused by inflammation or an injury.
• Controlled initially with NSAIDS that block nerve growth factor (NGF).

Neuropathic Pain

• Pain caused by damage or dysfunction of the somatosensory nervous system.
• Trigeminal neuralgia is a typical example, with sudden intense facial pain caused by irritation of the trigeminal nerve; pain may be difficult to treat but TAD (tricyclic antidepressants) may be successful.

Pain Pathways

• Ascending pathway: Information travels from receptors on the body to the brain involving cells outside and within the spinal cords.
• Descending pathway: The brain can modulate pain processing.

Behavioral Correlates of Primary and Central Sensitization

• Allodynia: Non-painful stimulus becomes painful.
• Hyperalgesia: Painful stimulus becomes even more painful.

Primary and Central Sensitization

• Primary sensitization: Peripheral neurons become more sensitive, generally C-fibers, pain caused by a thermal stimulus.
• Central sensitization: Dorsal horn neurons' sensitivity increases; generally triggered by mechanical stimuli.

Descending Pathways

• 1- Descending pain inhibitory pathways (e.g., anterior cingulate cortex to dorsal horn.
• 2- Descending pain facilitatory pathway (e.g., RVM to dorsal horn).

Opiates

• Treatment for chronic pain, but there is little to no risk of addiction as the opioid receptors are less likely to cause reward.

Normal Haemostasis

• The maintenance of blood within the blood vessels, preventing hemorrhage and thrombosis (formation of clots).
• Closely linked interactions of blood vessel walls, platelets, and coagulation factors.

Vasoconstriction

• Narrowing of blood vessels, occurs after vascular injury.
• Mechanisms: nervous reflexes (pain), local myogenic spasm (direct vessel wall damage), release of substances like thromboxane A2 and serotonin from tissues and platelets.

Primary Haemostasis

• Initial stage of hemostasis after vascular injury.
• Involves blood vessel exposure of collagen (subendothelial collagen). Platelet adhesion, via vessel wall factors (von Willebrand factor, or VWF) and subsequent activation and aggregation of platelets.

ADP and Thromboxane A2

• Factors in platelet aggregation, increasing stickiness, to lead to platelet aggregation.

Coagulation Pathways

• Intrinsic pathway and Extrinsic pathway converge resulting in a common pathway → leading to thrombin.

Fibrinolysis

• Breakdown of fibrin (a key component of blood clots). t-PA (tissue plasminogen activator) activates the conversion of plasminogen to plasmin, which degrades fibrinogen into fibrin degradation products (FDPs).

Therapeutic Fibrinolysis

• Treating thrombosis with recombinant t-PA (tissue plasminogen activator) as used in myocardial infarction, stroke, and massive pulmonary embolism.

Natural Anticlotting Mechanisms

• Smooth endothelium: Prevents intrinsic pathway activation.
• Rapid blood flow: Removes and inactivates activated clotting factors.
• Prostacyclin (PGI2): Inhibits platelet aggregation and phospholipid release.
• Tissue factor pathway inhibitor (TFPI): Initial inhibitor of coagulation.
• Antithrombin III (heparin cofactor I): inactivates clots by inactivating coagulation factors.

Fibrinolytic System

• Facilitates thrombin inactivation and inactivates factors Va and VIIa.

Template Bleeding Time

• Time taken for a puncture wound to stop bleeding, without clot formation.
• Used to assess platelet function.

Thrombocytopenia (platelet dysfunction)

• Reduction in the number of circulating platelets.
• Symptoms include easy/spontaneous bruising, petechiae/purpura, epistaxes, menorrhagia, prolonged bleeding, bleeding at operation sites, intravascular sites. (all related to problems in the coagulation cascade).

Global Tests of Haemostasis

• Prothrombin time (PT): Tests extrinsic pathway efficiency.
• Activated partial thromboplastin time (PTT): Tests intrinsic pathway efficiency. (Measures clotting time after activation of the contact factors).
• Thrombin time (TT): Measures final common pathway; affected by fibrinogen concentration.

Prolonged PT

• Congenital: Coagulation factor deficiencies (VII, X, V, II, I).
• Acquired: Liver disease, warfarin therapy, Vitamin K deficiency.

Haemophilia

• Genetic disorder related to deficiencies in coagulation factors.
• Type A: Factor VIII deficiency; Type B: Factor IX deficiency.
• Transmission: Sex-linked (X chromosome).
• Symptoms: prolonged bleeding after operations, injuries and/or muscular hematomas in infants/toddlers.
• Diagnosis: Coagulation screen abnormalities (e.g. prolonged PTT); factor assays.
• Treatment: Giving deficient factor (e.g., factor concentrates).

Virchow's Triad

• Endothelial injury, Abnormal blood flow, and Hypercoagulability: contributing factors to thrombosis formation; increased blood clotting tendency.

Risk Factors for VTE

• Age, immobility, surgery, obesity, dehydration, active cancer, history of VTE, HRT, pregnancy, oral contraceptive pills (OCPs).

Kidney Function

• Filtration, Reabsorption, and Secretion occur in the kidneys.

Definitions (Kidney Functions)

• Lumen: Region inside a hollow organ/tube
• Apical membrane: Part of a cell membrane exposed to the outer environment/lumen
• Interstitium: Space between cells
• Capillary: Small blood vessel (blood exchange site)
• Transcellular transport: Movement of substances through cells (rather than in-between cells).
• Paracellular transport: Movement of substances between adjacent cells.
• Tight junction: Zone between cells sealing the paracellular space.
• Basolateral membrane: Part of a cell membrane facing away from the outer environment.

Body Calcium and Phosphate Homeostasis

• Calcium (Ca2+) and phosphate (Pi) levels in extracellular fluid are regulated by the intestines, kidneys, and skeleton.
• Kidneys excrete Ca2+ and Pi in the same amount entering the body through the gut.
• Intestinal Ca2+ and Pi absorption increase due to calcitriol (1,25(OH)2D3, a vitamin D metabolite)

The Kidney and Vitamin D3

• Vitamin D3 undergoes a series of enzymatic activations, and one major activation occurs in the kidneys, resulting in calcitriol (1,25(OH)2D3).

Formation of Red Blood Cells

• Erythropoiesis: Formation of red blood cells.
• Haematopoiesis: Formation of all blood cells (including erythrocytes in bone marrow).

Factors for Erythropoiesis

• Erythropoietin
• Iron
• Vitamin B12
• Folic acid
• Ascorbic acid (vitamin C)
• Pyridoxine (vitamin B6)
• Amino acids

Red Blood Cells

• Abundant in blood, 4.5 - 6.1 million/µL
• Contain hemoglobin which binds O2 and CO2.
• Biconcave shape providing large surface area for gas exchange.

Erythrocytes (Why biconcave disc)

• Shape provides large surface area for gas exchange.
• Enables red cells to bend and flex when moving through smaller blood vessels.

Haemoglobin

• Complex protein found in abundance in red blood cells.
• Binds and transports oxygen in the blood.

Blood Groups

• ABO system: Distinguishes blood based on antigens A, B, and/or absence on red blood cell surfaces, associated with plasma antibodies.
• Rh system: Blood group based on the presence or absence of the RhD antigen (the most important).

Causes of Anemia

• Reduced production of red blood cells: bone marrow failure, reduced available essential nutrients (required for haemoglobin synthesis)
• Blood loss: trauma from accidents, surgeries etc., menorrhagia and heavy menstrual blood flows.
• Increased red cell destruction: red cell breakdown occurs before expected 120-130 days, or autoimmune reactions occur against the red blood cells.

Anemia-Morphological Classification

• Microcytic: Small red blood cells (MCV<80 fL), associated with iron deficiency and thalassemia.
• Normocytic: Normal-sized red blood cells (MCV=80-99 fL), associated with blood loss, chronic diseases, and more.
• Macrocytic: Large red blood cells (MCV>99-100 fL), associated with deficiencies in folate/Vit B12, liver disease, or more.

Microcytic Anemia

• Defect in haem synthesis: Iron deficiency, anemia of chronic disease
• Defect in globin synthesis (thalassemia): Alpha and Beta thalassemia.

Macrocytic Anemia

• Vitamin B12 or folate deficiency: Due to absorption issue, insufficient intake etc.
• Liver disease and ethanol toxicity: associated with decreased synthesis.
• Increased reticulocytes: The precursor cells to red blood cells, with 20% being larger than mature red blood cells

Normocytic Normochromic Anemia

• Recent blood loss
• Early stages of iron deficiency or anemia of chronic diseases;
• Renal failure
• Bone marrow failure/suppression or infiltration.
• Hypersplenism: e.g., portal cirrhosis.
• Pooling of red cells in the spleen.

Hemolytic Anemia

• Inherited: Abnormal red cell membrane (e.g., hereditary spherocytosis), abnormal hemoglobin (e.g., sickle cell anemia), defects in glycolytic pathways (e.g., pyruvate kinase deficiency), defects in enzymes of pentose shunt (e.g., G6PD deficiency).
• Acquired: Damage to red cell membrane (e.g., autoimmune hemolytic anemia), or injury to red blood cells (e.g., microangiopathic hemolytic anemia).

Skeletal Muscle Tubular System

• Transverse tubules (T tubules): Invaginations of the sarcolemma (cell membrane) that bring extracellular fluid inside the muscle fibers.
• Sarcoplasmic reticulum (SR): Network of channels surrounding myofibrils, stores calcium ions important for muscle contractions.

Muscles: Excitability and Motor Units

• Muscles are excitable tissues that respond to signals from the nervous system.
• Motor units: Consists of a motor neuron and the muscle fibers it innervates;
• A single motor neuron initiates contraction in multiple muscle fibers in the same unit, leading to coordinated muscle actions.

Neuromuscular Transmission

• The sequence of events involved converting electrical nerve signals into mechanical muscle contractions.

Isotonic vs. Isometric Muscle Contractions

• Isotonic: Muscle length changes during contraction, more energy consumed, relatively more efficient, external work being done.
• Isometric: Muscle length stays constant during contraction, less energy consumed, very little external work being done, relatively less efficient.

Muscle Fatigue

• Decreased strength, Prolonged duration and/or Incomplete relaxation (contracture)
• Causes include: Metabolic accumulation (e.g. lactic acid), depletion of ATP & creatine phosphate, interruptions to blood supply, reduced neuromuscular transmission.

Myasthenia Gravis

• Autoimmune disease causing muscle weakness or tiredness easily. Antibodies attack acetylcholine receptors, causing disruption to normal neuromuscular transmission, leading to paralysis and death may result if severe or not treated properly.

Hierarchical Model of Motor Control

• Organization of motor control as occurring through multiple interconnected levels. The three types include reflexive movements (spinal cord level), rhythmic movements (spinal cord and brainstem level), and voluntary movements (originating from the motor cortex).

Brain and Spinal Cord in Motor Control

• Motor Idea: originates from association areas in cortex.
• Motor Plan: Formed by the output from the association motor cortex and basal ganglia.
• Execution: The brain stem converts motor plan into commands to the spinal cord which result in movement.