Homeostasis and Its Mechanisms

Homeostasis

• Cells function optimally when the correct concentrations of extracellular fluid (ECF) components are present.
• ECF is the body's internal environment.
• Homeostasis maintains a stable internal environment.
• Key components of homeostasis include: variable, sensor, integrator, and effector.

Homeostatic Mechanisms

• Stability within a system is a result of measuring change (variation). The system detects errors and counteracts them to maintain balance.
• To achieve this, we need variable, sensor, integrator and effector.

Components of Homeostatic Mechanisms

• Receptors are sensors that detect changes in the environment (internal and external) and transmit the information.
• Receptors are frequently nerve cells that send information about changes in the controlled variable via frequency of action potentials. These sensors are often specialized ion channels.
• A controller (or integrator) receives the signal/input from sensors, compares the input to a set point and sends a corrective signal if needed.
• Effectors respond to the integrating center's signals to correct any errors and bring the variable back to its set point.

Types of Feedback

• Negative feedback: A change in the variable elicits a response to restore the variable to the set point. An example of negative feedback is blood glucose.
• Feed-forward: Events respond anticipatorily to a stimulus. An example of feed-forward is increased thirst when eating salty food.
• Positive feedback: A change in the variable elicits an even greater change in the same direction. Examples of positive feedback are blood clotting and childbirth.

Levels of Control

• Whole body response: Involves autonomic nervous system, endocrine system, and behavioural responses (ionic balance, blood pressure, blood volume).
• Local response: Organ-specific actions, such as constriction of blood vessels in the lungs when low oxygen levels are detected.
• Cellular response: When a nerve cell becomes activated and depolarised, potassium channels open to restore the resting membrane potential.

Membrane Transport

• Passive transport: Movement of molecules across a membrane without energy input. Includes simple diffusion (molecules move down their concentration gradient) and facilitated diffusion (molecules move down their concentration gradient with the help of protein channels).
• Active transport: Requires energy input to move molecules against their concentration gradient.

Osmosis

• Movement of water across a semi-permeable membrane from a solution of lower osmolarity to a solution of higher osmolarity until equilibrium occurs.
• Osmolarity is the number of osmoles of solute per liter of solution, reflecting the number of dissolved particles and therefore the water concentration.

Hypertonic, Hypotonic, and Isotonic Solutions

• Hypertonic: Higher osmolarity outside the cell; water moves out of the cell, causing cell shrinkage.
• Hypotonic: Lower osmolarity outside the cell; water moves into the cell, causing cell swelling.
• Isotonic: Equal osmolarity inside and outside the cell; no net change in water movement, resulting in no change in cell volume.

Molarity and Osmolarity

• A mole of a substance has a mass in grams equal to its molecular weight.
• Molar concentration is the number of moles of a substance per litre.
• One osmole is the number of moles of a substance that contributes to osmotic pressure.
• Osmolarity is the sum of the molar concentration of all the solutes.

Cell Permeability

• Movement of water across a semi-permeable membrane from lower osmolarity to higher osmolarity.

Obesity

• A complex disorder with multiple etiologies, characterised by excess body fat threatening socioeconomic, mental, or physical health.
• Types of obesity include android and gynoid.

Obesity Measures

• Skin fold measurements: Measuring skin folds at various body sites to estimate body fat percentage.
• Body Mass Index (BMI): A simple index of body fat calculated using weight and height.
• Calculation of BMI: weight (kg)/ height (m)^2.
• Waist circumference: Measurement of the waist to assess abdominal fat.
• Waist/hip ratio: Measurement of the waist and hip to indicate the distribution of body fat.

Treatment of Obesity

• Dietary recommendations: Caloric restrictions (1200-1500 calories/day), low-carb diets, high protein, fat, and fiber intake.
• Physical activity: Regular physical activity to enhance weight loss and prevent weight gain.
• Pharmacotherapy: Medications to enhance satiety, decrease fat absorption, increase energy expenditure, decrease appetite.
• Surgery: Bariatric surgery for individuals with significant obesity and comorbidities (BMI > 40 or BMI > 35 with associated conditions). The criteria are BMI >40 or BMI > 35 with associated health conditions.

Physical Activity

• Defined by its duration, intensity, and frequency. Regular physical activity involves activities performed in an organised way, with the chosen intensity dictating the frequency.

Exercise vs. Sports

• Exercise is physical activity aimed at improving health and fitness.
• Sports are complex, institutionalized, and competitive forms of exercise.

Benefits of Exercise

• Weight control. Reducing feelings of depression and anxiety.
• Increased ability to perform daily tasks. Improvements in work performance.
• Healthy bones, muscles, and joints.
• Enhanced cardiovascular function and reduction in cardiovascular diseases.
• Reduced risk of colon cancer.
• Reduced blood pressure in people with high blood pressure.
• Mitigating effects of age and improved health for a longer time.

Action Potentials

• Action potential results from a rapid sequence of changes in the membrane potential.
• Depolarization occurs due to the influx of sodium ions. Re-polarization occurs due to the efflux of potassium ions.

Chemical Synapses

• A chemical synapse is a junction between two neurons. When transmitted from one neuron to the next, the electrical signal converts to a chemical signal. This chemical signal then causes more electrical signals in the next neuron.
• Neurotransmitters are chemical messengers that carry the signal across the synaptic cleft between neurons.

Blood Cell Development

• Blood cells develop from hematopoietic stem cells. The stages are detailed in the provided document.

Receptors

• Receptors are protein-based cells that detect changes in their external environment.
• Receptors may include nerves that relay sensations of pain, temperature, and touch.

T-Cells

• T-cells are lymphocytes involved in the immune response—they have a variety of roles within the immune system.

B-Cells

• B-cells are lymphocytes that play a vital role in the immune system.

Monocyte-Dendritic Cell Lineage

• Monocytes act as antigen-presenting cells, triggering an immune response to foreign intruders.
• Monocytes develop into macrophages to engulf foreign pathogens.

Macrophage

• Macrophages are antigen-presenting cells that aid in inflammatory processes and wound healing. They also play a key role in phagocytosis (engulfing foreign particles).

Dendritic Cells

• Dendritic cells are antigen-presenting cells that patrol tissues, seeking out and presenting foreign invaders to the immune system.

Neutrophils

• Neutrophils are white blood cells that fight infection by killing and digesting bacteria and fungi.

Neutrophil Disorders

• Both neutropenia (low neutrophil count) and neutrophilia (high neutrophil count) are classified as neutrophil disorders, which are caused by viral and bacterial infections, certain medications and cancers.

Eosinophils

• Eosinophils are involved in the immune response to certain pathogens, such as parasites, and in reactions to allergies and asthma, by releasing various factors to mediate the immune response.

Basophils

• Basophils are specialized white blood cells, crucial to the immune response, known for releasing histamine in allergic reactions and contributing to immediate hypersensitivity reactions to foreign particles.

Mast Cells

• Mast cells are granulated cells that play a key role in the immune system, particularly in mediating inflammation and allergic responses, releasing various factors including histamine.

Homeostasis (blood)

• Haemostasis involves mechanisms to prevent blood loss, keep blood within vessels. It involves interaction between the blood vessels, platelets, and coagulation factors.

Vasoconstriction

• Nervous reflexes caused by pain impulses due to trauma. This results in contraction of the nearby injured blood vessels.
• Local myogenic spasm caused by direct damage to the vascular wall and release of local substances such as thromboxane A2 & serotonin from traumatized tissues and platelets.

Primary Haemostasis

• Injured blood vessel → Collagen exposure → Platelet adhesion to collagen → Platelet activation & degranulation → Platelet aggregation → formation of initial platelet plug.

ADP & Thromboxane A2

• ADP causes platelets to become sticky, promoting platelet aggregation.
• Thromboxane A2 powerfully stimulates platelet aggregation and secretion of platelet granules.

Extrinsic & Intrinsic Pathways (Coagulation)

• Extrinsic pathway is triggered by tissue damage and involves tissue factor.
• Intrinsic pathway is triggered by blood vessel damage and involves various circulating plasma clotting factors.
• Both pathways converge into a common pathway, resulting in the formation of fibrin, a crucial component of the blood clot.

Fibrinolysis

• Degradation and breakdown of clots via tissue plasminogen activator (tPA) and plasmin.
• Involves various factors including plasminogen and plasminogen activator inhibitor-1 (PAI-1).

Therapeutic Fibrinolysis

• Recombinant tissue-type plasminogen activator (rt-PA) for dissolving blood clots in myocardial infarction, stroke, and massive pulmonary embolism.

Natural Anticlotting Mechanisms

• Smooth endothelial lining of vessels prevents the activation of the intrinsic pathway.
• Rapid blood flow removes activated clotting factors.
• Prostacyclin (PGI2) inhibits platelet aggregation and phospholipid release.
• Tissue factor pathway inhibitor (TFPI) inactivates the tissue factor pathway.
• Antithrombin III inhibits factors II, IX, X, XI, XII.

Fibrinolytic System

• Thrombo-modulin interacts with Thrombin
• Protein C and Protein S inactivate factors Va or VIIIa, thus regulating blood clotting.

Template Bleeding time

• measures the time needed for a blood clot to form after a small, controlled injury—specifically a puncture wound.

Causes of Prolonged Bleeding Time

• Thrombocytopenia (reduced platelet count)
• Platelet function defect (e.g., aspirin)
• von Willebrand disease.

Causes if Thrombocytopenia (Reduced Platelet count)

• Failure of platelet production
• Increased destruction of platelets
• Increased consumption of platelets

Thrombocytopenia/Platelet Dysfunction Symptoms

• Easy bruising
• Petechiae (small, red spots) or purpura
• Epistaxis (nosebleeds)
• Menorrhagia (heavy menstrual bleeding)
• Prolonged bleeding after minor trauma
• Operative bleeding (in surgeries)

Global tests of Haemostasis

• Prothrombin time (PT): Measures the time it takes for blood to clot in the presence of tissue factor (an external trigger)
• Activated partial thromboplastin time (aPTT): Measures the time it takes for blood to clot in the absence of tissue factor (an internal trigger)
• Thrombin time (TT): Measures the final stage of coagulation using thrombin.

Prolonged Prothrombin Time (PT) Causes

• Congenital coagulation factor deficiencies
• Acquired deficiencies (liver disease, warfarin therapy, vitamin K deficiency)
• Other factors impacting clotting.

Haemophilia

• Haemophilia is an inherited bleeding disorder characterized by the deficiency in clotting factors, resulting in prolonged clotting times.
• Haemophilia A: Factor VIII deficiency; Haemophilia B: Factor IX deficiency.
• Sex-linked, meaning carried on the X chromosome.
• Females are carriers and usually asymptomatic.
• Males are typically affected.

Haemophilia: Infantile/Childhood Symptoms

• Post-circumcision bleeding
• Intramuscular haematoma
• Recurrent painful bleeding in joints (haemarthrosis)
• Bleeding into muscles forming pseudo-tumours
• Prolonged bleeding following surgeries.

Haemophilia: Adults Symptoms

• Recurrent spontaneous painful bleeds in joints.
• Prolonged life threatening operative bleeding and post-operative bleeding.

Haemophilia Diagnosis

• Abnormal coagulation screening tests.
• Prolonged aPTT.
• Normal PT and TT.
• Factor assays to measure deficient factors.

Haemophilia Treatment

• Give the patient the missing clotting factor.
• Prophylactic factor concentrates (e.g. 'normal boys')

Virchow's Triad

• Endothelial injury; Abnormal blood flow; Hypercoagulability; contributing factors to thrombosis.

Risk Factors for VTE

• Age; Obesity; Dehydration; Active cancer; Medical conditions; Pregnancy; Abnormal clotting; Surgery; History of VTE; HRT or birth control pills.

Kidney Function

• The kidneys are responsible for filtering blood, maintaining electrolyte balance, and excreting wastes and excess substances, such as calcium and phosphate.

Body Calcium and Phosphorus Homeostasis

• Calcium and phosphorus levels in the extracellular fluid are regulated by the digestive system, kidneys, and skeleton.
• Kidneys are responsible for regulating phosphorus levels.
• Calcium and phosphorus absorption from the gut increase with calcitriol.
• Key pathways for regulating calcium homeostasis include the vitamin D pathway.

Vitamin D3

• Vitamin D3 is activated by the kidneys with the 1a-hydroxylase enzyme.
• Key function includes regulation of calcium.

Red Blood Cells (Erythrocytes)

• Most abundant blood cells.
• Biconcave discs (enhances diffusion).
• Lack nuclei.
• No organelles.

Erythropoiesis Factors

• Erythropoietin (EPO) is a hormone that controls the production of red blood cells in the bone marrow.

Why do red blood cells suffer anaemia?

• Reduced production of red blood cells and/or haemoglobin in the bone marrow
• Blood loss (hemorrhage).
• Reduced survival of red blood cells in the circulation.

Red Blood Cell Under Microscope

• Salmon-colored
• Mean cell volume (MCV)
• Mean cell hemoglobin (MCH)
• Central pallor

Anemia-Morphology Classification

• Microcytic; Normocytic; Macrocytic

Microcytic Anaemia Causes

• Defect in haem synthesis (e.g., iron deficiency)
• Defect in globin synthesis (e.g., thalassemia).

Microcytic Hypochromic Aneamia

• Smaller red blood cells
• Low hemoglobin (low MCH)
• Increased central pallor.

Macrocytic Anaemia Causes

• Vitamin B12 or folic acid deficiency (nutritional or malabsorption)
• Liver disease or ethanol toxicity
• Some drugs interfere with DNA synthesis.

B12 Deficiency

• Nutritional (vegetarians)
• Gastric, such as pernicious anaemia, with anti-bodies to IF and/or GPC

Folate Deficiency

• Nutritional deficiencies—in those with malabsorption in the small intestine
• Excess requirement—in pregnancy

Normocytic Normochromic Anemia Causes

• Recent blood loss.
• Early stages of iron deficiency.
• Anaemia of chronic disease
• Renal failure.
• Bone marrow failure.
• Bone marrow infiltration (tumours).
• Hypersplenism (e.g. portal cirrhosis)
• Pooling of red blood cells in the spleen.

Haemolytic Anaemia

• Inheretd: Abnormal red blood cell membranes; abnormal haemoglobin; defective glycolysis; defective enzyme pathways (such as pentose shunt).
• Acquired: Damage to red blood cell membranes; or damage to the whole red cell.

Skeletal Muscle Tubular System

• The transverse tubules (T tubules) are invaginations of the muscle cell membrane that extend into the muscle fiber. They contain extracellular fluid.
• Sarcoplasmic reticulum (SR) is a network of membrane-bound structures surrounding myofibrils. It stores calcium.

Muscles

• Muscles are excitable tissues with the capacity to generate and transmit electrical signals called action potentials.
• Motor neurons control the contraction of several muscle fibers, and this combined system is referred to as a motor unit.

Summary of Events during Neuromuscular Transmission

• Action potential in presynaptic motor axon terminals.
• Increase in Ca2+ permeability. Influx of Ca2+.
• Release of acetylcholine (ACh).
• Diffusion of ACh to post-junctional membrane.
• Combination of ACh with specific receptors on post-junctional membrane.
• Increase in permeability of postsynaptic membrane to sodium.
• This causes an action potential to transmit to muscles resulting in muscle contractions.

Isotonic Contraction

• Muscle length changes.
• Tension remains constant.

Isometric Contraction

• Muscle length does not change.
• Tension increases.

Muscle Fatigue

• Decreased muscle strength.
• Prolonged duration.
• Incomplete relaxation (contracture).
• Causes include metabolite accumulation, ATP depletion, decreased blood supply and impaired neuromuscular transmission.

Myasthenia Gravis

• Autoimmune disease affecting neuromuscular junction
• Antibodies attack acetylcholine receptors
• Symptoms: Muscle weakness, often affecting the eyes, face, and limbs
• Treatment: Acetylcholinesterase inhibitors
• Prevent destruction of ACh
• Allow more ACh to stimulate muscle contraction

A Hierarchical Model of Motor Control

• Three types of movements; Reflex, rhythmic and voluntary.

Brain and Spinal Cord in Motor Control

• Motor Idea → Association cortex and basal ganglia.
• Motor Plan → Motor cortex—cerebellum.
• Execution → Brain stem—spinal cord.