MEDS2011 Learning Objectives

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The Human Lifespan

HUMAN LIFESPAN & MUSCULOSKELETAL DEVELOPMENT

Physiological Changes

1. Describe key contributors to increased human lifespan and our ageing population

In Short: Life expectancy has increased dramatically in the last 200 years through advances in lifestyle and medicine. With increasing lifespan is a larger population with more prevalent decline in bodily system function, lower rates or reproduction has decreased proportion of children.

Human lifespan has dramatically increased over the past two centuries due to a convergence of medical, social, and environmental advances. In the 1800s, life expectancy was around 40 years; today, it’s over 80 in developed nations.

Key contributors include:

• Public health improvements: Clean water, sanitation, sewer systems, and food safety have dramatically reduced infectious disease.

• Medical advancements: Vaccinations, antibiotics, surgical techniques, and critical care have saved millions of lives.

• Maternal and neonatal care: Decreased infant and maternal mortality through obstetric care, neonatal ICUs, and education.

• Nutrition and hygiene: Better access to food and hygiene reduces disease vulnerability and enhances childhood development.

• Health education: Awareness of hygiene, exercise, chronic disease prevention, and mental health has led to healthier lifestyles.

• Socioeconomic factors: Higher income, education levels, and social safety nets correlate with longer, healthier lives.

With increased lifespan and reduced birth rates, particularly in developed countries, we now face an ageing population: a demographic trend where a growing proportion of people are aged 65 and over. This shift increases demands on healthcare, aged care, and social systems.

▶️ Video overview on lifespan improvements 📈 Our World in Data – Life Expectancy

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2. Outline key components of human health which define lifespan specific to: cardiovascular, musculoskeletal, and nervous systems

As we age, each major body system undergoes characteristic changes. Understanding these changes helps predict health trajectories and identify intervention points.

Cardiovascular system

In short: compromised cardiac output

• Structural changes: Thickening and stiffening of arterial walls (arteriosclerosis), and ventricular hypertrophy (especially left ventricle).

• Functional decline: Maximal heart rate decreases with age (estimated by 220 – age). Blood vessels lose elasticity, raising blood pressure.

• Increased risk: These changes raise the risk of heart disease, heart failure, stroke, and hypertension.

Musculoskeletal (MSK) system

In short: reduced bone mass, muscle function, decreased joint integrity

• Bone density: Peaks in early adulthood, then gradually declines. Osteopenia and osteoporosis increase fracture risk.

• Muscle mass and strength: Peak around age 30, then decline through sarcopenia. Muscle fibres atrophy, and regeneration capacity drops.

• Joints: Cartilage thins, and ligaments stiffen, reducing flexibility and increasing wear-and-tear disorders like osteoarthritis.

Nervous system

In short: brain volume declines

• Brain volume: Peaks around age 20, then declines by ~3% per decade. Grey matter and white matter decrease with age.

• Cognitive function: Processing speed, working memory, and executive functions decline, though vocabulary and implicit memory remain stable.

• Neurodegenerative risk: Ageing increases risk for Alzheimer’s, Parkinson’s, and other forms of dementia.

🧠 Harvard article on brain ageing

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3. Explain differences between male vs female in chronic disease risk and life expectancy

In short: Despite having earlier decline in bone density, muscle strength and cognitive decline than men, women outlive men due to beinf more robust at all ages

On average, females live 4–6 years longer than males globally, though this gap is narrowing.

Biological and hormonal factors:

• Estrogen provides vascular protection in premenopausal women, delaying cardiovascular disease.

• Testosterone, while anabolic, may increase aggression, risk-taking, and cholesterol levels in men.

• Women experience earlier bone loss post-menopause due to estrogen decline.

Behavioural and social factors:

• Men are more likely to engage in high-risk behaviours (e.g., smoking, excessive alcohol use).

• Women are more likely to access healthcare services and adhere to preventative care.

Chronic disease risks:

• Men: Higher risk of heart attacks and earlier onset cardiovascular disease.

• Women: More prone to autoimmune conditions, osteoporosis, and longer periods of chronic disability.

📘 Why women live longer than men (Nature)

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4. Recall why non-human models are used to explore lifespan in research

In short: NHP closest to human, but need for shorter time explore ageing, C. elegans common model of lengevity, 2-3 week lifespan

Non-human models allow researchers to study complex biological processes under controlled, ethically permissible conditions. In lifespan and ageing research, they’re crucial due to their short life cycles, genetic manipulability, and conserved biological pathways.

Common models include:

• C. elegans (nematode worm):

  • 2–3 week lifespan.

  • Fully mapped neural system and genome.

  • Widely used to study genetic control of ageing, e.g., daf-2 and age-1 genes.

• Drosophila melanogaster (fruit fly):

  • Short lifespan (~30–50 days).

  • Useful for studying neurodegeneration and mitochondrial dysfunction.

• Mouse (Mus musculus):

  • Mammalian model with ~90% gene homology to humans.

  • Transgenic and knockout models for disease.

• Zebrafish: Transparent embryos allow real-time imaging of development.

• Non-human primates: Closest analogue to humans, but expensive, slow to age, and ethically restricted.

These models help investigate:

• Cellular ageing

• Genetic regulators (e.g., telomerase, sirtuins)

• Age-related diseases (e.g., Alzheimer’s)

• Drug and intervention testing (e.g., caloric restriction, rapamycin)

🧬 Video – How C. elegans helps in ageing research (MIT) 🧪 The Jackson Laboratory – Model organisms in ageing

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MUSCULOSKELETAL DEVELOPMENT

🦴 MSK Development: Conception to Birth

Gastrulation

At the end of 2nd week gestation: a bilayer embryonic disc is formed.

Consisting of epiblast (on dorsal side) and hypoblast (on ventral side)

Primitive streak is formed at the caudal end of the epiblast on the dorsal side (back/posterior of embryo)

During 3rd week gestation:

• Day 14-15: ingressing epiblast cells displace hypoblast to form definitive endoderm

• Day 16: ingressing epiblast cells migrate between endoderm nd epiblast to for intraembryonic mesoderm

• Three germ layers (ectoderm, mesoderm, endoderm) develop into the embryo

1. Mesoderm and Somite Development

• Mesodermal cells migrate cranially at the midline to form notochord

  • Notochord eventually releases signalling molecules

• Cells migrating from just lateral to notochord becomes paraxial mesoderm

  • paraxial mesoderm help in MSK development system

• The paraxial mesoderm forms somites, paired blocks along the neural tube.

• Each somite differentiates into:

  • Sclerotome → vertebrae and ribs / bones and cartilage

  • Dermatome → dermis of skin and muscle

  • Myotome → skeletal muscle

Cells at the dorsomedial and ventrolateral edges form precursors for muscle cells

Cells from these precursor groups migrate ventral to dermatome to create dermomyotome

Dermomyotomes cells that migrate:

• anteriorly = muscles of limbs and trunk (hypaxial muscles)

• posteriorly = intrinsic back muscles (epaxial muscles)

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2. Bone and Muscle Development

• Bone develops from mesenchymal stem cells derived from sclerotome.

• Muscle develops from myotome:

  • Epaxial (back muscles) and hypaxial (limb muscles)

  • Myoblasts → myotubes → myofibers

🦠 Myogenic regulatory factors (e.g., Myf5, MyoD) regulate muscle differentiation

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3. Intramembranous vs Endochondral Ossification

• Intramembranous: flat bones (skull, mandible) develop directly from mesenchyme

  • mesenchymal cells aggregrate to form ossification centre → differentiate into osteoprogenitor cells → osteoblasts → bone.

  • osteoblast secrete bone matrix (osteoid) of which undergoes mineralisation and entrapped osteoblasts become osteocytes.

Osteoblast produces the bone matrix and osteocytes maintains the bone matrix

Matrix produced increases –> Osteocytes increasingly separate from each other

Newly formed structure has structure of woven bone (immature) with thick trabeculae lined by osteoblast and endosteal cells

Further bone growth and remodelling: woven bone is replaced by compact bone in periphery (outer side) and spongy bone in between

Spaces beteen trabeculae become occupied by bone marrow cells that arrive with blood vessels

Intramembranous ossification

• Endochondral: long bones first form cartilage templates (chondrocytes) → replaced by bone.

  • Mesenchyme cells differentiate into chondrocytes, which then produce cartilage matrix

  • cartilage can grow in length and width and can calcify

  • marrow cavity created by blood vessels eroding and invading it

• Growth in length of long bones depend on the presence of epiphyseal growth plate

• As primary ossification centre develops, endochondral bone is formed on spicules of calcified cartilage

• A secondary ossification centre is established in the epiphyses

• When growth stops, the epiphyseal cartilage disappears and the metaphysis becomes merged with the epiphysis

🔧 Synovial Joint Development:

• Mesenchyme of the interzone between chondrifying bone primordia –> differentiates into fibroblastic tissue –> differentiaties into articular cartilage –>

• dense connective tissue in central region condenses to form synovial tissue –> lines the future joint cavity

• Inside connective tissue, tiny little bubbles called vacuoles start to form. These vacuoles slowly join together — like soap bubbles merging — to make a bigger space. That space becomes the synovial cavity.

  *This synovial cavity gets filled with synovial fluid. The job of this fluid is to lubricate the joint — like oil in a machine — so your bones can move smoothly without rubbing or getting damaged.

• Joints form in the interzonal region between cartilage models.

• Formation includes:

  • Articular cartilage

  • Joint cavity

  • Synovial membrane

🦴 Animation: Bone ossification comparison

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👶 MSK Development: Birth to Adulthood

1. Determinants of Childhood Growth

• Genetics (height potential)

• Nutrition

• Hormones: GH, IGF-1, thyroid hormone, sex steroids

• Mechanical loading

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2. Mechanobiology Concept

• Cells sense mechanical stimuli and convert them to biological signals.

• Bone and muscle growth depend on strain, pressure, and shear forces.

• Wolff’s Law: bone remodels according to the mechanical load it experiences.

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3. Growth Plate Biology & Long Bone Growth

• Occurs via endochondral ossification at epiphyseal plates.

  • Epiphyses ossify in post-natal development: at birth they start as cartilage then later turn into bone

• Zones:

  • Resting

  • Proliferation - chondrocyte proliferation

  • Hypertrophy (swelling chondrocytes) & Calcification

  • Degradation & invasion: degradation of transverse septa and vascular invasion

  • Ossification (bone formation): new bone formation on calcified remnants by osteoblasts

  

  

🔬 IGF-1 and PTHrP regulate chondrocyte activity and plate elongation.

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4. Joint Changes with Growth

• Joints develop distinct zones (e.g., cartilage, bone, fibrous capsule).

  • usually the part of joint that connects (ball and socket) remain as cartilage to facilitate movement

• With age:

  • Synovium thins

  • Vascularity and cartilage hydration decline

  • Ossification centers fuse

• Articular joint cartilage thickens as bones grow in response to IGF-1 and BMP

• Increased thickness in joint leads to distinct zones:

  • Superficial Zone - fibres parallel to surface

  • Transitional zone - random fibres

  • Deep zone - fibres perpendicular to surface

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5. Muscle Types and Postnatal Growth

• Skeletal muscle:

  • Composed of Type I (slow) and Type II (fast) fibers

• Postnatal growth:

  • ↑ Muscle fiber hypertrophy

    • Muscle does not accrue more fibres as we grow but the volume of muscle fibres increases (hypertrophy)

  • ↑ Myonuclei via satellite cells

    • Hypertrophy is acheived by addition of nuclei which are recruited by muscle satellite cells

    • Fusion with muscle fibres to bring in nuclei to expanding cytoplasm

  • Muscle fascicle length increases with stretching

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6. Bones, Joints & Muscles Respond to Load

When we move, lift, or exercise, our bones, muscles, and joints feel mechanical load — a kind of pressure or stress. This load sends signals to the tissues, and they respond by getting stronger and thicker.

• Bone: loading stimulates osteoblasts, increases BMD

  • Osteoblasts (bone-building cells) make more bone when there’s load.

  • They lay down more ECM (extracellular matrix).

  • The ECM contains collagen (for flexibility) and minerals like calcium/hydroxyapatite crystals (for hardness).

  • Load helps keep the collagen-to-mineral ratio balanced, making bones both strong and slightly flexible.

• Cartilage (joints): maintains ECM integrity under moderate compression

  • Cartilage doesn’t have blood vessels, so it needs gentle loading to stay healthy.

  • Load helps maintain ECM integrity — this means the cartilage keeps its smooth surface and stays springy.

  • It also boosts the production of proteoglycans and collagen in the cartilage to protect joints.

• Muscle: resistance exercise stimulates protein synthesis, hypertrophy

  • Muscles get bigger through hypertrophy, which means the muscle fibers grow in size.

  • This happens when the muscle is used under load, like lifting weights.

  • The total muscle mass increases, helping support bones and joints better.

⚠️ Inactivity leads to:

• Osteopenia

• Sarcopenia

• Joint instability

In short: Load = signals for growth and repair. But no load (like in bedrest or space travel) = tissue breakdown.

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🧓 MSK System Through the Lifespan

1. Changes Through Lifespan

• Bone: peak BMD ~30 yrs → slow decline → rapid loss post-menopause

• Muscle: peaks in 20s–30s → gradual decline → sarcopenia

• Joints: thinning cartilage, decreased mobility, joint space narrowing

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2. Major Contributing Factors

• Hormonal changes (↓ estrogen, testosterone)

  • Cortisol can break down muscle proteins into amino acids if stress is chronic.

    • negatively regulates bone mass

    • drives inflammation in joints

  • Testosterone promotes muscle protein synthesis, reduces muscle protein breakdown –> increased bone mass

  • Progesterone (in women): work with estrogen to ↑ bone formation and ↑ bone mass. Can counteract effects of estrogen on muscle mass

  • Growth Hormone (GH) ↑ muscle growth by increasing protein synthesis and ↑ IGF-1

  • Insulin-Like Growth Factor 1 (IGF-1) works with GH to ↑ muscle cell growth, enhance muscle protein synthesis. IMPORTANT FOR REPAIR

• Physical inactivity

• Chronic diseases (e.g., osteoarthritis)

• Nutritional deficiencies

• Inflammation

• Menopause

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3. Causes of MSK Functional Decline

• Bone: osteoporosis → fractures

• Muscle: sarcopenia → falls

• Joint: arthritis → mobility loss

• Neuromuscular: decreased proprioception

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4. Consequences and Community Impact

• Individual:

  • Frailty, pain, disability, reduced independence

• Community:

  • High healthcare costs, rehabilitation needs, aged care burden

📊 Australia: falls/fractures cost billions annually, especially hip fractures in 70+

NEURODEVELOPMENT & NERVOUS SYSTEM

Nervous System

1. Describe the overall functional organisation of the nervous system, including the major subdivisions of the CNS and PNS and their broad functions (L1)

Source: L2.1 pg 5

The nervous system is broadly divided into:

• Central Nervous System (CNS): Composed of the brain and spinal cord. It is the integrative and command centre. The brain itself can be subdivided into:

  • Cerebrum (telencephalon): Includes the cortex (involved in perception, voluntary motor control, memory, decision making), basal ganglia (movement, motivation), and amygdala (emotions).

  • Diencephalon: Contains the thalamus (relay station) and hypothalamus (homeostasis, autonomic control).

• Midbrain (mesencephalon): Includes structures like the colliculi (visual/auditory reflexes) and substantia nigra (movement).

• Brainstem (metencephalon & myelencephalon): Includes:

  • Pons: Sensory and motor relay for the head.

  • Cerebellum: Coordination of movement and posture.

  • Medulla: Controls vital functions like breathing and heart rate.

• Spinal cord: Conveys motor output and sensory input for the trunk and limbs.

• Peripheral Nervous System (PNS): Connects the CNS to the body and is divided into:

  • Afferent (sensory) system: Receives input from the environment via skin, muscles, and special sense organs.

  • Efferent (motor) system: Delivers motor commands to:

    • Somatic effectors (skeletal muscles)

    • Autonomic effectors (smooth muscle, glands, enteric nervous system in the gut).

The CNS develops from the neural tube, and the PNS from the neural crest (covered in Objective 4).

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2. State the major cells of the nervous system, be aware of their approximate numbers/proportions (L1)

There are two major cell types:

• Neurons:

  • Estimated ~86 billion in the human brain.
  • Make up ~40–50% of brain cells.
  • Highly diverse in size, shape, neurotransmitter type, and function.
  • Electrically excitable; responsible for rapid, directional communication across long distances.
  • Most neurons are born in the first 5 months of gestation.
  • They communicate via chemical synapses, forming trillions of connections.

• Glial cells (“glue” cells):

  • Comprise the other ~50% of brain cells.

  • Types include:

    • Astrocytes: Support neurons, regulate extracellular environment, and maintain the blood-brain barrier.

    • Oligodendrocytes: Myelinate CNS axons.

    • Microglia: Immune surveillance and phagocytosis of debris and pathogens.

  • Glia are crucial for development, synapse regulation, and repair.

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Neurodevelopment

3. Describe the formation and differentiation of the neural tube and the relationship of the embryonic brain regions to the main divisions of the mature CNS (L1 & L2)

• Formation:

  • Begins with the neural plate, a thickening of ectoderm.

  • Lateral edges elevate to form neural folds, which meet and fuse to form the neural tube by day 28 post-conception.

  • Closure of the rostral (head) end occurs at days 24–26; failure leads to anencephaly.

  • Closure of the caudal (tail) end occurs at days 26–28; failure causes spina bifida.

• Differentiation:

  • The neural tube initially forms 3 vesicles:

    1. Prosencephalon (forebrain)

    2. Mesencephalon (midbrain)

    3. Rhombencephalon (hindbrain)

  • These later subdivide into 5 vesicles:

    • Telencephalon → cerebral cortex, basal ganglia, hippocampus, amygdala

    • Diencephalon → thalamus, hypothalamus, retina

    • Mesencephalon → midbrain

    • Metencephalon → pons and cerebellum

    • Myelencephalon → medulla

    • Caudally, the neural tube continues as the spinal cord

  • These segments also give rise to ventricular structures:

    • Lateral, third, cerebral aqueduct, and fourth ventricles.

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4. Describe the relationship between the neural crest and the formation of the PNS (L2)

• Neural crest cells originate from the borders of the neural folds and migrate extensively after the neural tube closes.

• They give rise to almost all of the PNS:

  • Sensory neurons (e.g., dorsal root ganglia, cranial sensory ganglia)

  • Autonomic neurons (sympathetic and parasympathetic ganglia)

  • Enteric neurons (gut nervous system)

  • Schwann cells (myelinate PNS axons)

• Their development is tightly regulated by local signalling molecules and transcription factors, ensuring appropriate differentiation and migration.

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5. Describe the relationship between neural early patterning and the formation of a simple neural circuit (L2)

Neural patterning is established by diffusible morphogens that form gradients in the neural tube:

• Sonic Hedgehog (Shh) from the notochord and floor plate (ventral/medial):

  • Specifies motor neuron identity.

  • Induces ventral structures in the spinal cord.

• Bone Morphogenetic Proteins (BMPs) from the roof plate and overlying ectoderm (dorsal/lateral):

  • Promote sensory neuron identity.

This dorsal-ventral gradient establishes progenitor domains that give rise to different classes of neurons, which later connect to form neural circuits:

• Sensory input enters dorsally through the dorsal root ganglia.

• Motor output exits ventrally via motor neurons in the anterior horn.

• These basic circuits underlie reflexes and set the foundation for more complex networks.

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6. Understand major processes which generate neural connectivity and their approximate timing (L3)

Neural connectivity involves several overlapping processes:

1. Neurogenesis (up to ~20 weeks gestation):

   • Neurons are born in the ventricular zone.
   • Most neurons are produced prenatally.

2. Migration (~8–24 weeks):

   • Radial glial scaffolding helps neurons migrate to their final positions.
   • Layers of the cortex are formed inside-out.

3. Axon guidance (~16 weeks onward):

   • Axons grow towards targets using growth cones that detect environmental cues.
   • Guidance molecules (e.g., netrins, slits, semaphorins) provide attractant or repellent signals.

4. Synaptogenesis (begins ~20 weeks, peaks after birth):

   • Exuberant synapse formation occurs.
   • Number of synapses dramatically overshoots adult levels.

5. Synaptic pruning and refinement (birth to adolescence):

   • Activity-dependent elimination of unnecessary synapses.
   • E.g., visual cortex matures by age 5, prefrontal cortex by ~25 years.

6. Myelination (begins ~30 weeks, continues into 20s):

   • Oligodendrocytes (CNS) and Schwann cells (PNS) myelinate axons.
   • Improves conduction speed and circuit reliability.

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Nervous System in Lifespan

7. Demonstrate an awareness of changes that occur in the nervous system across the lifespan and the factors that can influence them (L3)

Age-related brain changes:

• Structural:

  • Brain volume declines ~5% per decade after age 40.

  • Loss of grey and white matter.

  • Synaptic density and dendritic branching decrease.

  • Myelin is degraded.

• Functional:

  • Slower processing and reaction times.

  • Decline in working memory, executive function, and sensory acuity.

  • Decreased levels of neurotransmitters like dopamine and acetylcholine.

Factors influencing rate of ageing:

• Genetic: Some individuals have more robust synaptic maintenance (cognitive reserve).

• Lifestyle: Strong evidence supports that:

  • Physical exercise, education, good diet, sleep, and social engagement protect the brain.

  • Stress, inflammation, and toxins (alcohol/drugs) accelerate decline.

  • Enrichment (e.g., puzzles, music, travel) enhances resilience.

CARDIOVASCULAR SYSTEM — STRUCTURE, DEVELOPMENT, AND AGEING

Heart

1. Briefly describe the adult heart

Source: L3.1 pg 3

The adult human heart is a muscular organ roughly the size of a closed fist. It is responsible for pumping blood throughout the body via two main circuits:

• Pulmonary circulation: Right side of the heart sends deoxygenated blood to the lungs.

• Systemic circulation: Left side of the heart sends oxygenated blood to the body.

The heart consists of:

• 4 chambers:

  • Right atrium

  • Right ventricle

  • Left atrium

  • Left ventricle

• 4 valves to ensure unidirectional blood flow:

  • Atrioventricular (AV) valves: tricuspid (right), mitral (left)
  • Semilunar valves: pulmonary (right), aortic (left)

• Septum: Muscular wall separating left and right sides.

• Outflow tracts:

  • Pulmonary artery (from RV)

  • Aorta (from LV)

🫀 Visual reference: Interactive 3D model of the heart – Visible Body

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2. Describe the stages of embryological development of the heart structures

Heart development begins very early in embryogenesis and is completed by week 8 of gestation.

Key stages:

1. Formation of the primitive heart tube (~day 22):

   • Lateral plate mesoderm forms bilateral endocardial tubes → fuse at midline into a single heart tube.

   • When tube fuse together it primarily consists of 2 cell types:

   • endothelial cells - inside of the heart tube, allows blood to flow smoothly (no clotting)

   • myocardial cells - primary cells making up heart, responsible for heart beating so this heart tube is capable of beating

2. Heart tube looping (~day 23–28):

   • The straight heart tube elongates and loops rightward (D-looping) to bring future chambers into position.

3. Subdivision into regions:

   • Truncus arteriosus (TA) → ascending aorta and pulmonary trunk (aortic arch)

   • Bulbus cordis (BC) → right ventricle

   • Primitive ventricle (PV) → left ventricle

   • Primitive atrium (PA) → both atria

   • Sinus venosus (SV) → smooth part of right atrium and coronary sinus

   • Endocardial cushions between:

   • TA and BC

   • PV and PA

4. Septation (weeks 4–8):

   • AV septum (septum intermedium) forms from endocardial cushions to separate atria and ventricles.

   • Interventricular septum divides the lower chambers.

   • Atrial septation involves septum primum and septum secundum, with the foramen ovale allowing shunting in fetal life.

   • Chamber septation driven by mesenchymal cells in endocardial cushions

5. Outflow tract septation:

   • Spiral septation of the truncus arteriosus → separates pulmonary and systemic outflow via the aorticopulmonary septum.

🎥 Animation: Development of the Heart (3D)

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3. Identify fetal heart regions and relate them to adult heart

Source: L3.1 pg 11 –> insert diagram from this page

The fetal heart tube comprises several regions that correspond to adult heart structures:

Fetal Structure	Adult Derivative
Truncus arteriosus	Ascending aorta + pulmonary trunk
Bulbus cordis	Right ventricle
Primitive ventricle	Left ventricle
Primitive atrium	Left and right atria (muscular portions)
Sinus venosus	Right atrium (smooth part), coronary sinus

Special fetal features:

• Foramen ovale → fossa ovalis (postnatal closure)

• Ductus arteriosus (pulmonary trunk → aorta) → ligamentum arteriosum

• Ductus venosus (umbilical vein → IVC) → ligamentum venosum

🖼️ Diagram: Fetal to adult heart transition – Kenhub

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Vascular System

4. Briefly define the adult cardiovascular (circulatory) system

Source: L3.2 pg 3 –> insert diagram

The adult cardiovascular system is a closed-loop network responsible for transporting oxygen, nutrients, hormones, and waste products. It consists of:

• Heart – pump

• Arteries – carry blood away from the heart

• Veins – return blood to the heart

• Capillaries – exchange vessels between blood and tissue

There are two main circuits:

• Pulmonary circuit: Right heart → lungs → left heart

• Systemic circuit: Left heart → body → right heart

🧾 Diagram and animation – InnerBody’s Cardiovascular System

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5. Track development of the body’s major blood vessels

Vessel development occurs through:

• Vasculogenesis – formation of new vessels from angioblasts (de novo)

  • When endothelial progenitor cells come together to form a new tube/vessel

  • Heart tube and dorsal aortae are formed by vasculogenesis

• Angiogenesis – sprouting of new vessels (subvessels) from pre-existing ones

  Major developments:

  • Aortic arches (days 22–56) :

    1. Dorsal aorta and primitive heart tube fuse in the middle to later form descending aorta

    2. 6 pairs of aortic arches connect the truncus arteriosus (top of heart tube) to the dorsal aorta (kinda looks lke a rib structure)

    3. Arch I, II and V regresses

    1. 1st arch becomes part of maxillary arteries in the face

    2. 2nd and 5th arch just regress

  • 3rd → common carotids (vessels for brain, face, neck)

  • 4th → aortic arch for lower body (left) and right subclavian (right)

  • 6th → left pulmonary artery (left) and right pulmonary artery (right)

  • Vitelline arteries and veins :

  • Arteries → celiac, superior and inferior mesenteric arteries

  • Veins → hepatic portal system, part of the IVC

  • Umbilical arteries and veins:

  • Carry oxygenated (vein) and deoxygenated (artery) blood between fetus and placenta

  • Cardinal venous system:

    • Forms the superior vena cava, jugular veins, azygos system, renal and gonadal veins

Summary of Descending Aorta

Embryonic Branch	Adult Derivatives	Supplied Structures
Vitelline arteries	Celiac trunk, SMA, IMA	Foregut, midgut, hindgut
Dorsolateral branches	Intercostal arteries, lumbar arteries	Chest wall, spinal column, abdominal wall
Lateral branches	Adrenal, renal, gonadal arteries	Kidneys, adrenal glands, gonads
Iliac branches	Internal/external iliac, umbilical, sacral	Pelvis, legs, placenta (umbilical), lower spine

Great follow-up! Just like the aorta gives rise to arteries through embryonic remodeling, the venous system also begins as paired symmetrical veins and undergoes complex remodelling to form the adult systemic and portal veins.

Here’s a clear, structured breakdown:

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✅ DEVELOPMENT OF THE VENOUS SYSTEM

In early embryonic life, there are three main paired venous systems:

Vein Type	Function in embryo	Adult Derivatives
Vitelline veins	Drain the yolk sac	Hepatic portal system (e.g., portal vein)
Umbilical veins	Bring oxygenated blood from the placenta	Ligamentum teres (after birth)
Cardinal veins	Drain the embryo’s body	Systemic veins (e.g., SVC, IVC)

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1️⃣ Vitelline Veins → Portal Venous System

• Originate around the yolk sac

• Travel through the developing liver (hepatic sinusoids)

• Become:

  • Hepatic portal vein

  • Hepatic veins

  • Part of the inferior vena cava (IVC)

These veins form the gut-liver circulation that delivers absorbed nutrients to the liver.

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2️⃣ Umbilical Veins → Ligament of the Liver

• Two umbilical veins originally form (left and right)

• Only the left umbilical vein persists, carrying oxygenated blood from the placenta to the fetus

• Joins the ductus venosus (which bypasses liver) → into IVC

• After birth:

  • Umbilical vein closes → becomes ligamentum teres hepatis

  • Ductus venosus closes → becomes ligamentum venosum

📌 Both are visible as ligaments on the underside of the liver in adults.

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3️⃣ Cardinal Veins → Systemic Venous System

These veins drain the embryo’s body and evolve into the major veins of the trunk and limbs:

Embryonic Vein	Adult Derivative	Supplied Structures
Anterior cardinal veins	Internal jugular veins, superior vena cava (SVC)	Shoulders, arms, head
Posterior cardinal veins	Replaced by subcardinal and supracardinal systems	as below
Subcardinal veins	Part of IVC, renal veins, gonadal veins	adrenal, kidneys, reproductive organs
Supracardinal veins	Azygos system (azygos, hemiazygos)	Back, chest
Sacrocardinal veins		Legs

🔄 SVC and IVC are formed by a mix of these veins via asymmetric remodeling!

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💡 Visual Overview

• 🩸 Embryonic Venous System – UNSW Embryology

• 📽️ Video: Fetal circulation & venous development

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📝 Summary Table: Embryonic → Adult Veins

Embryonic Vein	Adult Structure
Vitelline veins	Hepatic portal vein, hepatic veins, part of IVC
Umbilical vein (left)	Ligamentum teres
Ductus venosus	Ligamentum venosum
Anterior cardinal	Internal jugular veins, SVC
Subcardinal veins	Renal and gonadal veins, part of IVC
Supracardinal veins	Azygos, hemiazygos veins

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Cardiovascular Changes Through Lifespan

6. Describe age-related physiological changes in the heart and cardiovascular system

Fetus vs Post-natal

🩻 1. Blood Vessel Maturation

During development, blood vessels begin as simple tubes, but they mature and strengthen over time. Two key processes help this:

🧱 a. Smooth Muscle Cell Recruitment

• Early vessels have only endothelial cells (the inner lining).

• Smooth muscle cells are later added to the outer layers (media).

• These give vessels the ability to contract or relax, helping control blood pressure and flow.

🧬 b. Elastin Deposition

• Elastin is a stretchy protein added to vessel walls — especially in large arteries like the aorta.

• It allows arteries to stretch and recoil with each heartbeat, helping smooth out blood flow.

📌 Mature vessels = strong walls + flexible function = better pressure regulation

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👶 2. Fetal vs Postnatal Circulation

Before birth, a fetus doesn’t use its lungs to get oxygen — it gets oxygen and nutrients from the placenta via the umbilical cord. Because of this, the fetal heart and blood vessels have special pathways that bypass the lungs and liver.

Here are the key differences:

🫁 a. Ductus Venosus

• Bypasses the liver.

• Blood from the umbilical vein goes straight into the inferior vena cava → right atrium.

🫀 b. Foramen Ovale

• A flap between the right atrium and left atrium.

• Allows blood to flow from right → left atrium, skipping the lungs.

🫁 c. Ductus Arteriosus

• Connects the pulmonary artery to the aorta.

• Shunts blood away from the lungs directly into systemic circulation.

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🌬️ 3. At Birth – Major Changes Happen

When a baby takes its first breath:

1. Lungs expand → blood flows into them for the first time

2. Oxygen levels rise → smooth muscle in ductus arteriosus contracts

3. Pressure in left atrium increases, closing the foramen ovale

4. Ductus venosus, ductus arteriosus, and foramen ovale all close and become ligaments

Fetal Structure	Becomes After Birth
Ductus venosus	Ligamentum venosum
Foramen ovale	septum
Ductus arteriosus	Ligamentum arteriosum
Umbilical vein	Ligamentum teres
Umbilical arteries	Medial umbilical ligaments

These changes turn fetal circulation into fully separated pulmonary and systemic circuits like adults.

Just need to know that the ductus venosus and ductus arteriosus regress postnatally

🩺 Summary:

Fetal circulation uses special shunts to bypass lungs and liver, since oxygen comes from the placenta. At birth, lungs take over, the shunts close, and the baby’s heart begins functioning like an adult’s.

Age-related changes

As humans age, the cardiovascular system undergoes both structural and functional changes:

• Heart rate:

  • Declines with age due to loss of pacemaker cells and reduced sensitivity of the autonomic nervous system.
  • Max HR = 220 – age

• Cardiac output (CO):

  • CO = HR × SV
  • Peaks in early adulthood, declines with age due to decreased stroke volume and HR.

• Myocardial stiffness:

  • Collagen accumulation in the heart muscle (fibrosis) reduces elasticity and diastolic filling.

• Vascular stiffening:

  • Elastic arteries become rigid due to fibrosis and reduced elastin.
  • Leads to systolic hypertension.

• Endothelial dysfunction:

  • Impaired vasodilation, inflammation, and thrombosis risk increases.

🫀 Heart and vascular ageing – American Heart Association

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7. Outline common cardiovascular conditions associated with aging

Aging increases susceptibility to various cardiovascular diseases:

• Hypertension: Most common; due to vascular stiffening and endothelial dysfunction.

• Atherosclerosis: Plaque buildup in arteries; can lead to MI or stroke.

• Heart failure with preserved ejection fraction (HFpEF): Common in older adults; linked to myocardial fibrosis.

• Arrhythmias (e.g., atrial fibrillation): Due to structural changes and loss of conduction system integrity.

• Valvular heart disease: Especially calcification of the aortic valve.

• Coronary artery disease (CAD): Leading cause of death globally.

🩺 Cardiovascular diseases in ageing – National Institute on Aging

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LONGEVITY, MORTALITY, HEALTHSPAN & CALORIE RESTRICTION

🩺 Mortality and Death

1. Describe key medical advances that have increased human lifespan

Key advances that significantly extended human lifespan include:

• Vaccinations (e.g., for measles, polio, diphtheria): lowered childhood mortality.

• Antibiotics: Controlled bacterial infections previously fatal (e.g., TB, pneumonia).

• Improved sanitation and clean water: Reduced infectious disease spread.

• Advanced diagnostics and surgery: Enabled earlier detection and treatment of conditions.

• Preventive medicine and public health campaigns: Smoking cessation, dietary guidelines.

• Chronic disease management: Statins, antihypertensives, insulin, and heart medications improved survival.

📊 Interactive resource: Our World in Data – Life Expectancy

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2. Outline the major causes of death in Australia

According to the 2022 ABS report:

• Top causes:

  • Ischaemic heart disease

  • Dementia (including Alzheimer’s)

  • Cerebrovascular disease (e.g., stroke)

  • Lung cancer

  • Chronic lower respiratory diseases

  • Diabetes mellitus

Chronic non-communicable diseases (NCDs) now dominate mortality, replacing infectious diseases due to public health progress.

🗂️ Australian Bureau of Statistics – Causes of Death

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3. Explain how longitudinal studies have identified key risk factors for disease

The Framingham Heart Study is a landmark prospective cohort study started in 1948 to understand heart disease. Over decades, it identified risk factors that are now well-known:

• High blood pressure

• High cholesterol

• Smoking

• Obesity

• Diabetes

• Sedentary lifestyle

Longitudinal studies follow individuals over time, allowing researchers to correlate lifestyle factors with disease incidence, which short-term studies cannot.

🧪 Framingham Heart Study summary – Nature Rev. Cardiology (2019)

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🧬 Healthspan

4. Explain the difference between healthspan and lifespan

• Lifespan: Total years lived.

• Healthspan: Years lived in good health, free of significant disease or disability.

Goal: Extend healthspan to match increasing lifespan — i.e., live longer and healthier, not just longer with chronic disease.

📈 Visual: Healthspan vs Lifespan explained – Nature

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5. Describe the prevalence and impact of obesity on human health

• Over 60% of Australian adults are overweight or obese.

• Obesity contributes to:

  • Type 2 diabetes

  • Cardiovascular disease

  • Stroke

  • Certain cancers

  • Osteoarthritis

  • Depression

Obesity reduces healthspan and lifespan, with higher all-cause mortality and disease burden.

📊 Australian data: AIHW – Overweight and Obesity

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6. Outline the positive impacts of exercise on human longevity

• Physical activity lowers risk for:

  • CVD

  • Type 2 diabetes

  • Depression

  • Certain cancers

• Exercise improves:

  • Insulin sensitivity

  • Lipid profile

  • Blood pressure

  • Inflammatory markers

  • Cognitive function

• Regular moderate-intensity activity (150–300 min/week) significantly reduces all-cause mortality.

📄 Study: Exercise reduces mortality – Lee et al. (2022), Circulation

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🧠 Longevity

Source: L4.3 pg 7

7. Explain key functions of the insulin signalling pathway

• Insulin binds its receptor, triggering phosphorylation of IRS proteins.

• Activates PI3K/Akt pathway, which promotes:

  • Glucose uptake

  • Glycogen and lipid synthesis

  • Inhibition of gluconeogenesis

• Akt also inhibits FOXO transcription factors, reducing stress resistance and promoting growth.

🔬 Insulin Signalling Video – Drew Berry

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8. Describe how insulin/IGF-1 signalling can control gene expression

• Via the PI3K/Akt cascade, insulin/IGF-1 inhibits FOXO transcription factors.

• When IGF-1 is low, FOXO enters the nucleus and upregulates genes for:

  • Stress resistance

  • Autophagy

  • DNA repair

  • Longevity

Reduced insulin/IGF-1 = increased FOXO activity = lifespan extension (in model organisms).

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9. Explain the roles different model organisms can have in longevity studies

• C. elegans: Easy to manipulate genetically, short lifespan (2–3 weeks). Found daf-2 mutants live twice as long.

• Drosophila: Short-lived, conserved metabolic pathways.

• Mice: Mammalian models. Useful for caloric restriction, rapamycin, and gene knockout studies.

• Yeast: Simpler pathways; used in autophagy research.

These models show evolutionarily conserved roles of insulin/IGF-1 and mTOR in ageing.

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10. Outline the effects of the insulin/IGF-1 signalling and mTOR pathways on longevity

Spurce: L4.3 pg 14

• Insulin/IGF-1 inhibition → activates FOXO → extends lifespan

• mTOR pathway:

  • Activated by amino acids (especially leucine) and insulin

  • Promotes cell growth and inhibits autophagy

  • Inhibition via rapamycin has been shown to extend lifespan in mice

These pathways integrate nutrient sensing with cellular maintenance.

🧪 Review: mTOR and longevity – Nature (2009)

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🥗 Calorie Restriction

11. Outline different diets that can mediate calorie restriction

• Calorie Restriction (CR): 20–40% reduction in caloric intake without malnutrition.

• Intermittent Fasting (IF): Time-restricted eating or alternate-day fasting.

• Fasting Mimicking Diets (FMD): Low-calorie, low-protein, low-carb cycles mimicking fasting.

• Ketogenic diets and protein restriction may also mimic some CR effects.

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12. Explain important caveats of calorie restriction studies in model organisms

• Lab animals are genetically homogeneous and pathogen-free.

• CR often improves health under controlled conditions, but translation to humans is complex.

• Long-term CR in humans may have:

  • Negative effects (e.g., infertility, bone loss)

  • Compliance issues

  • Nutrient deficiencies if not monitored

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13. Outline some of the published effects of calorie restriction on longevity in animal models

• Mice and rats: CR increases lifespan by up to 50%, delays tumour formation.

• Monkeys: Mixed results — CR improves healthspan but not always lifespan.

• C. elegans and Drosophila: Lifespan extension is robust and repeatable.

Mechanisms include:

• Enhanced autophagy

• Reduced oxidative stress

• Improved metabolic health

• Lower inflammation

📄 Calorie Restriction in Monkeys – Science (2009)

DISEASE, GENETICS, LIFESTYLE, AND VULNERABLE POPULATIONS

Intro to Disease

1. Define aetiology, pathogenesis, and morphology

• Aetiology: The cause of a disease. Can be:

  • Genetic (e.g., BRCA mutation in breast cancer)
  • Environmental (e.g., tobacco in lung cancer)
  • Multifactorial

• Pathogenesis: The sequence of events from the initial cause to the manifestation of the disease. Example:

  • Bacterial pneumonia: infection → inflammation → alveolar consolidation

• Morphology: The structural changes in cells or tissues due to disease. Can be:

  • Microscopic (e.g., neutrophils in alveoli)
  • Macroscopic (e.g., lung consolidation visible on X-ray)

📘 Source: Robbins Pathological Basis of Disease

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2. Approaches to disease classification and their limitations

Classification types:

• Congenital vs Acquired
• Genetic vs Environmental
• Infectious vs Non-communicable
• Neoplastic vs Non-neoplastic
• Systemic vs Organ-specific

Limitations:

• Overlap between categories (e.g., autoimmune diseases can be genetic and acquired)
• Not always predictive of clinical outcomes
• Some diseases defy clear categorisation (e.g., mixed pathologies)

📚 Explore: WHO ICD-11

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3. Systematic approach to disease process and lesion assessment

When evaluating a lesion:

1. Identify the cause (aetiology)
2. Trace pathogenesis – how the lesion developed
3. Describe morphology – what the lesion looks like microscopically/macroscopically
4. Link to clinical manifestations – symptoms and signs

🔍 Example:

• Lobar pneumonia

  • Aetiology: Streptococcus pneumoniae
  • Pathogenesis: bacterial proliferation → inflammation
  • Morphology: alveoli filled with neutrophils
  • Clinical signs: fever, cough, crackles, hypoxia

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🧬 Genetics on Disease

4. Scope and impact of genetic disorders

• ~8% of the population affected
• Contribute to early miscarriages, congenital anomalies, adult-onset diseases
• Can present at any life stage (e.g., Down syndrome in infancy, Huntington’s in mid-life)

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5. Three main categories of human genetic disease

1. Chromosomal disorders: Numerical or structural changes

   • Trisomy 21 (Down syndrome), Turner syndrome (45,X)

2. Single-gene disorders (monogenic):

   • Autosomal dominant (e.g., Marfan syndrome)
   • Autosomal recessive (e.g., cystic fibrosis)
   • X-linked (e.g., Duchenne muscular dystrophy)

3. Polygenic/multifactorial:

   • Multiple genes + environmental triggers
   • Examples: Type 2 diabetes, hypertension

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6. Inheritance patterns of single-gene disorders

• Autosomal Dominant (AD):

  • One mutant allele causes disease
  • Affects structural proteins (e.g., fibrillin in Marfan syndrome)
  • 50% transmission risk

• Autosomal Recessive (AR):

  • Two mutant alleles required
  • Often enzyme defects (e.g., PKU, CF)

• X-linked Recessive:

  • Mostly affects males
  • Females are carriers with variable expression (e.g., Fragile X syndrome)

🧬 Visuals: Garvan Genetics Inheritance

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7. Molecular mechanisms of genetic disease

• Point mutations, insertions, deletions
• Copy number variations
• Trinucleotide repeat expansions (e.g., Huntington’s)
• Non-coding RNA and epigenetic changes

These affect protein function, gene regulation, and developmental processes.

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️ Disease Prevention

8. Difference between macronutrients and micronutrients

• Macronutrients: Carbs, proteins, fats

  • Provide energy and building blocks
  • Imbalance → malnutrition or obesity

• Micronutrients: Vitamins, minerals

  • Needed in trace amounts
  • Deficiencies → anaemia (iron), scurvy (vitamin C), rickets (vitamin D)

🩸 Case example: Iron deficiency anaemia → low Hb, MCV, ferritin; common in women/pregnancy

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9. Benefits of physical activity

• Reduces risk of CVD, obesity, type 2 diabetes, cancer
• Improves insulin sensitivity, mental health, and sleep
• Physical inactivity is a major risk factor for global mortality

🧠 Reference: Australian Activity Guidelines

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10. Sleep function and hygiene

• Sleep supports:

  • Tissue repair
  • Cognitive consolidation
  • Emotional regulation

• Poor sleep → higher risks of:

  • CVD, diabetes, depression
  • Road/work accidents

• Sleep hygiene tips:

  • Consistent schedule, avoid caffeine, quiet/dark room, no screens before bed

🌐 Sleep Hygiene Guide

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👥 Vulnerable Populations and Health Equity

11. Define a vulnerable population

Groups at greater risk for poor health outcomes due to:

• Limited access to care
• Socioeconomic disadvantage
• Cultural and linguistic barriers
• Disability
• Geographic isolation

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12. Additional risk factors for low SES and remote populations

• Fewer healthcare facilities
• Inadequate transport
• Food insecurity
• Higher exposure to environmental hazards
• Lower health literacy

🔗 WHO – Health Literacy

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13. Indigenous health and healthcare access

• Indigenous health is holistic: physical, emotional, cultural, community-based

• Disparities:

  • Lower life expectancy
  • Higher rates of chronic diseases
  • Reduced access to screening and treatment

• Barriers: cost, distance, cultural mismatch, discrimination

• Solutions:

  • Indigenous-led health services
  • Culturally safe care
  • Community partnerships

📄 Learn more: AIHW Indigenous Health Summary

NEUROLOGICAL CONDITIONS: PARKINSON DISEASE, SPINA BIFIDA, EPILEPSY

🟣 PARKINSON DISEASE

1. Clinical symptoms and pathological hallmarks

Clinical symptoms:

• Motor: bradykinesia (slowness), resting tremor, rigidity, postural instability

• Non-motor: sleep disturbances (e.g. REM Sleep Behaviour Disorder), anosmia, constipation, cognitive impairment, depression

Pathological hallmarks:

• Progressive loss of dopamine neurons in the substantia nigra (part of the basal ganglia)

• Formation of Lewy bodies: intracellular aggregates of misfolded α-synuclein protein

🧠 Visual: Alpha-synuclein animation – Khan Academy

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2. Aetiology and risk factors

• ~90% idiopathic (no known cause), ~10% familial (linked to mutations in α-synuclein (SNCA), LRRK2, PARK2 etc.)

• Risk factors:

  • Ageing (most significant)

  • Male sex

  • Pesticide exposure

  • Head trauma

  • People with REM sleep behaviour disorder

  • Rural living

  • Inverse association: smoking and caffeine (possibly protective)

🧬 It is a multifactorial disorder involving gene-environment interactions.

• Decreasing the risk factors:

  • exercise

  • Mediterranean diet (rich in fruits and veggies and saturated fats like olive oil)

  • smoking - possibly the nicotine in it

In healthy brain α-synuclein is a soluble protein found in axon terminals. Responsible for:

• vesicle tracking

• activating receptors

• plasticity (formation and removal) of synapses

In Parkinson’s synuclein becomes abnormal and insoluble and deposits in cell bodies to form Lewy bodies

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3. Basal ganglia circuit degeneration and symptomatology

Source: L6.1 pg 8

How Basal Ganglia Degeneration Causes Symptoms

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🧠 What is the Basal Ganglia?

The basal ganglia is a group of deep brain structures that help control movement by regulating how the motor cortex sends movement signals to muscles.

Major parts include:

• Striatum (caudate + putamen)
• Globus pallidus (internal and external)
• Subthalamic nucleus (STN)
• Substantia nigra (includes dopamine-producing neurons)

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🔄 Two Major Movement Pathways:

1. Direct Pathway = promotes movement
2. Indirect Pathway = inhibits movement

Both pathways need dopamine from the substantia nigra pars compacta (SNc) to function normally:

• Dopamine excites the direct pathway (via D1 receptors) → ⬆ movement
• Dopamine inhibits the indirect pathway (via D2 receptors) → ⬇ inhibition

🧠 Together: dopamine helps you start and control smooth, purposeful movements.

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What Happens in Parkinson’s Disease?

• Dopaminergic neurons in the substantia nigra die.

• This leads to:

  • ⬇ activation of the direct pathway

  • ⬆ activation of the indirect pathway

• Result = reduced movement output from the motor cortex.

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Symptoms from This Circuit Imbalance:

Pathway Effect	Clinical Symptom
Weak direct pathway	Slowness (bradykinesia), can’t initiate movement
Overactive indirect path	Rigidity, postural instability
Loss of fine motor control	Tremors (due to abnormal feedback loops)

🧠 Think of the brain like a “movement gate”:

• Normally: dopamine “opens the gate” so you can move.
• In Parkinson’s: the gate is stuck, so everything slows down.

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🔵 SPINA BIFIDA

4. Pathophysiology and major subtypes

Pathophysiology of Spina Bifida

Spina bifida is a type of neural tube defect (NTD) where the spinal column does not close completely during early embryonic development.

• The neural tube forms by day 22–28 of gestation.
• If the caudal (lower) end of the tube fails to close, it results in spina bifida.
• This defect affects the vertebrae, and sometimes the spinal cord and meninges.

🔗 Main cause: Folic acid deficiency before or during early pregnancy Other risk factors: genetics, maternal diabetes, medications (e.g. valproate), obesity

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Major Subtypes of Spina Bifida

Subtype	Description	Severity
Spina Bifida Occulta	Mildest form; vertebrae fail to close but no protrusion of spinal cord or meninges. Often found incidentally.	Mild
Meningocele	Meninges protrude through the vertebral defect, forming a fluid-filled sac. The spinal cord remains in place.	Moderate
Myelomeningocele	Most severe form. Both spinal cord and meninges herniate through the vertebral opening. Often causes paralysis and bowel/bladder dysfunction.	Severe

📸 Myelomeningocele is the classic “open back” lesion seen on prenatal ultrasound.

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What Else Can Be Affected?

• Hydrocephalus: often due to associated Chiari II malformation (herniation of brain tissue into the spinal canal)

• Orthopaedic problems: foot deformities, scoliosis

• Bladder/bowel dysfunction

• Learning difficulties (in some children)

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5. Treatments and management

🏥 1. Initial Diagnosis and Early Intervention

• Prenatal Diagnosis:

  • Ultrasound (detects open neural tube defects)
  • Maternal serum AFP (α-fetoprotein) screening

• Postnatal Diagnosis:

  • Physical examination
  • MRI or CT to assess the spinal lesion

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2. Surgical Treatment

a. Postnatal Surgery

• Standard approach for myelomeningocele.

• Performed within 48 hours of birth.

• Aims to:

  • Close the spinal defect
  • Prevent infection (like meningitis)
  • Protect exposed neural tissue

b. Fetal Surgery (In Utero Repair)

• Done during 19–26 weeks gestation.

• Improves:

  • Motor outcomes
  • Reduces the need for a ventricular shunt for hydrocephalus

• ⚠️ Higher maternal risks and preterm delivery

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3. Management of Hydrocephalus

• ~80% of myelomeningocele cases develop hydrocephalus.

• Managed with:

  • Ventriculoperitoneal (VP) shunt to drain excess CSF
  • Or newer options like endoscopic third ventriculostomy (ETV)

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4. Orthopaedic and Mobility Support

• Common issues: clubfoot, scoliosis, hip dislocation

• Interventions include:

  • Bracing
  • Physiotherapy
  • Orthopaedic surgery
  • Use of wheelchairs or walkers

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5. Bladder and Bowel Management

• Neurogenic bladder is common → risk of UTIs and renal damage

• Interventions:

  • Clean intermittent catheterisation (CIC)
  • Anticholinergic medications to reduce bladder pressure
  • Bowel programs with dietary fibre, enemas, or laxatives

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6. Multidisciplinary Lifelong Care

Involves:

• Neurologists, neurosurgeons
• Urologists, orthopaedic surgeons
• Physiotherapists, occupational therapists
• Social workers, psychologists
• Special education support

Average life expectancy now ~50+ years with good quality of life when supported

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Summary of Management Areas

Area	Management Approach
Neural tube defect	Surgical closure (postnatal or prenatal)
Hydrocephalus	VP shunt or ETV
Bladder/bowel	CIC, medications, bowel routines
Mobility	Bracing, physio, wheelchairs
Orthopaedic issues	Surgery, assistive devices
Long-term care	Multidisciplinary team & community support

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6. Public health risk factor management

🎯 Why Folic Acid?

• Folic acid (vitamin B9) is essential for neural tube closure during early embryonic development (around day 22–28 of gestation).
• A deficiency in folic acid greatly increases the risk of neural tube defects (NTDs), including spina bifida.

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🏥 Public Health Interventions

1. Periconceptional Supplementation

• Recommendation: All women of childbearing age take 400–500 micrograms (µg) of folic acid daily.
• Start at least 1 month before conception and continue through the first trimester.

✅ This can reduce the risk of NTDs by up to 70%.

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2. Folic Acid Food Fortification

• Mandatory fortification of staple foods (e.g. wheat flour, bread) with folic acid is one of the most effective population-level strategies.
• Australia introduced mandatory fortification of bread-making flour in 2009.

📉 Result: Significant drop in NTD rates, particularly in:

• Indigenous populations
• Women with unplanned pregnancies

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3. Public Awareness Campaigns

• Government and NGOs run campaigns to:

  • Educate about folic acid’s role in pregnancy
  • Promote prenatal vitamins
  • Target groups with low supplement use, e.g., adolescents, rural populations

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4. High-Risk Supplementation

• Women with previous pregnancies affected by spina bifida or NTDs are advised to take a higher dose: 4–5 mg/day (under medical supervision).

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Outcomes of Public Health Measures

Measure	Impact
Supplementation campaigns	Increases maternal folate intake
Mandatory fortification	Decreases population-wide NTD rates
Targeted interventions	Helps high-risk or underserved populations

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🌍 Global Note:

• The WHO recommends folic acid supplementation in countries with high NTD prevalence.
• Over 80 countries have implemented mandatory folic acid food fortification.

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🔴 EPILEPSY

7. Difference between seizures and epilepsy

What is a Seizure?

A seizure is a sudden, abnormal burst of electrical activity in the brain.

• This can cause changes in:

  • Movement (e.g. shaking, muscle stiffness)

  • Sensation (e.g. strange smells or visual flashes)

  • Behaviour or awareness (e.g. staring, confusion, blackout)

➡️ A seizure is usually brief, often lasting seconds to a few minutes.

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What is Epilepsy?

Epilepsy is a chronic neurological condition in which a person has a tendency to experience recurrent, unprovoked seizures.

• “Unprovoked” means the seizures are not caused by a temporary trigger like low blood sugar or fever.

• Diagnosis typically requires:

  • Two or more unprovoked seizures, occurring at least 24 hours apart, OR

  • One unprovoked seizure with a high risk of recurrence

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Key Difference

Term	What it Means
Seizure	A single event – sudden abnormal brain activity
Epilepsy	A condition where the brain is prone to seizures

🧠 Not everyone who has a seizure has epilepsy. For example:

• A seizure from high fever = febrile seizure, not epilepsy

• A seizure from head trauma or alcohol withdrawal = acute symptomatic seizure

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Types of Seizures and Their Clinical Manifestations

Seizures are broadly classified into focal and generalized seizures based on where in the brain they start.

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Focal Seizures (Start in One Hemisphere)

Focal Aware Seizure (Simple Partial)

• Person is fully conscious.

• May experience:

  • Jerking in one part of the body (e.g., hand or face)
  • Unusual sensations (e.g., tingling, visual or auditory hallucinations)
  • Emotional changes (e.g., fear, déjà vu)

Focal Impaired Awareness Seizure (Complex Partial)

• Consciousness is impaired or altered.

• May include:

  • Staring blankly
  • Repetitive behaviours (e.g., lip smacking, hand rubbing)
  • Confusion after the seizure

Focal to Bilateral Tonic-Clonic Seizure

• Starts in one hemisphere, then spreads to both.
• Begins like a focal seizure but evolves into bilateral convulsions.

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Generalized Seizures (Start in Both Hemispheres Simultaneously)

Generalized Tonic-Clonic Seizure (Grand Mal)

• Most dramatic type.

• Tonic phase: body stiffens

• Clonic phase: rhythmic jerking of limbs

• Often includes:

  • Loss of consciousness
  • Crying out, incontinence
  • Postictal confusion or fatigue

Absence Seizure (Petit Mal)

• Sudden brief loss of awareness, often in children.

• Characterized by:

  • Blank staring
  • Eyelid fluttering
  • No postictal confusion

Myoclonic Seizure

• Brief, shock-like jerks of muscles (e.g., shoulders, arms).
• No loss of consciousness.
• Can be mistaken for a sudden startle.

Atonic Seizure (Drop Attack)

• Sudden loss of muscle tone → person may collapse or fall.
• Very brief, high risk of injury.
• Often seen in severe epilepsy syndromes.

Tonic Seizure

• Sudden muscle stiffening, often during sleep.
• No jerking (no clonic phase).
• May cause person to fall if standing.

Clonic Seizure

• Repeated rhythmic jerking movements.
• Less common than tonic-clonic seizures.

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8. Classification of seizures and syndromes

Classification of Epileptic Seizures

Seizures are classified based on where in the brain they begin and how they present clinically. The two major categories are focal and generalized seizures.

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Focal Seizures

These start in one area (or one hemisphere) of the brain.

• Focal Aware Seizure:

  • Consciousness is preserved.
  • May involve motor, sensory, autonomic, or emotional symptoms.

• Focal Impaired Awareness Seizure:

  • Altered awareness or confusion.
  • Often involves automatisms (e.g., lip smacking, repetitive movements).

• Focal to Bilateral Tonic-Clonic Seizure:

  • Begins as focal, then spreads to both hemispheres, causing full-body convulsions.

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Generalized Seizures

These start in both hemispheres at once and affect the entire brain.

• Tonic-Clonic (Grand Mal):

  • Stiffening (tonic) followed by rhythmic jerking (clonic), with loss of consciousness.

• Absence (Petit Mal):

  • Brief lapses in awareness, blank staring, eyelid fluttering.
  • Common in children.

• Myoclonic:

  • Sudden, brief muscle jerks without loss of consciousness.

• Atonic:

  • Sudden loss of muscle tone, often causing falls.

• Tonic:

  • Muscle stiffening without clonic jerking.

• Clonic:

  • Rhythmic jerking without a preceding tonic phase.

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9. Risk factors for epilepsy

Epilepsy can develop due to a wide range of genetic, structural, metabolic, infectious, immune, and unknown causes. A seizure trigger is something that can provoke a seizure in a person who already has epilepsy.

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Genetic Causes

• Some epilepsy syndromes are inherited or linked to gene mutations (e.g. SCN1A in Dravet syndrome).
• Family history of epilepsy increases risk.
• Idiopathic generalized epilepsies often have a genetic basis without structural brain abnormalities.

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Structural Causes

• Head trauma: Traumatic brain injuries (TBIs) can lead to post-traumatic epilepsy.
• Stroke: Ischemic or hemorrhagic stroke can cause seizures, especially in older adults.
• Brain tumors: Can irritate surrounding neurons, leading to seizure activity.
• Congenital brain malformations: Cortical dysplasia, tuberous sclerosis, etc.

---

Infectious Causes

• Infections that affect the brain can provoke seizures:

  • Meningitis
  • Encephalitis
  • Neurocysticercosis (in endemic areas)
  • HIV/AIDS-related CNS infections

---

Immune-Related Causes

• Autoimmune encephalitis (e.g. anti-NMDA receptor encephalitis)
• Multiple sclerosis and other neuroinflammatory disorders can also increase seizure risk.

---

Metabolic and Other Causes

• Electrolyte imbalances: e.g. low sodium, low calcium
• Hypoglycemia (low blood sugar)
• Drug or alcohol withdrawal
• Sleep deprivation
• High fever in infants and young children (febrile seizures)

---

Common Triggers in People with Epilepsy

• Flashing lights (photosensitivity)
• Stress and anxiety
• Missed medication doses
• Illness or fever
• Alcohol consumption or withdrawal
• Hormonal changes (e.g. during menstruation)

---

10. Pathophysiology of epilepsy

• Seizures result from neuronal hyperexcitability and hypersynchronous firing
• Imbalance between excitatory (glutamate) and inhibitory (GABA) neurotransmission
• Genetic mutations affect ion channels (e.g., Na+, K+, Ca2+)

🧪 Neurotransmission animation Certainly! Here’s a student-friendly breakdown of the pathophysiology of epilepsy, using only ##### as the highest-level subheading, suitable for R Markdown formatting:

Epilepsy arises when there is an imbalance in the brain’s electrical activity, causing hyperexcitable neurons to fire abnormally and synchronously. This leads to seizure generation.

---

Neuronal Hyperexcitability

• In a healthy brain, neurons fire in a controlled manner.

• In epilepsy, certain neurons become hyperexcitable, meaning they are more likely to fire inappropriately.

• Causes of hyperexcitability include:

  • Genetic ion channel mutations (channelopathies)
  • Neuronal injury or malformation
  • Imbalance between excitatory and inhibitory neurotransmission

---

Excitatory and Inhibitory Imbalance

• Glutamate is the brain’s main excitatory neurotransmitter.

• GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter.

• Epileptic seizures can result from:

  • Too much glutamatergic activity
  • Too little GABAergic inhibition
  • Dysfunction of ion channels that regulate neuron firing (e.g., Na⁺, K⁺, Ca²⁺ channels)

---

Paroxysmal Depolarizing Shift (PDS)

• A hallmark of epileptic activity in individual neurons.

• PDS is a sudden, prolonged depolarization of the neuronal membrane, leading to:

  • A burst of action potentials
  • Followed by afterhyperpolarization

• Multiple neurons firing PDS simultaneously = seizure

---

Synchronous Neuronal Firing

• In seizures, many neurons fire at the same time in a rhythmic pattern.
• This synchronous activity is what produces abnormal waveforms on an EEG.
• Local (focal) synchronous activity can sometimes spread to become generalized.

---

Key Mechanisms

• Ion channel mutations (e.g. sodium or potassium channelopathies)
• Structural brain injury causing disorganized neuronal circuits
• Impaired function of inhibitory interneurons
• Altered synaptic plasticity and receptor expression

---

11. Epilepsy in special populations

• Affects quality of life: social stigma, medication side effects, driving restrictions

• Special concerns:

  • Children: cognitive and developmental delays
  • Adults: employment, mental health
  • Elderly: polypharmacy, misdiagnosis (e.g., focal seizures mistaken for confusion)

Long-term care requires multidisciplinary support (neurologists, psychiatrists, social workers)

🧠 More info: Purple Day for Epilepsy

AGEING MUSCULOSKELETAL SYSTEM: OSTEOPOROSIS, SARCOPENIA, FRACTURES, OSTEOARTHRITIS

🦴 OSTEOPOROSIS

1. Understand the mechanisms behind osteoporosis

Osteoporosis is a disease where bone resorption exceeds bone formation, leading to reduced bone mass and microarchitectural deterioration.

• Increased osteoclast activity: Driven by RANKL, inhibited by OPG

• Decreased osteoblast function: Reduced matrix deposition and mineralization

• Key regulators: Estrogen, mechanical load, calcium, and vitamin D

• Osteocytes release both resorptive (RANKL) and inhibitory (sclerostin) signals for bone remodelling.

🔗 WHO Overview on Osteoporosis

---

2. Explain how nutrition impacts bone health in the ageing population

As we age, our bones naturally lose density, becoming more fragile and prone to fractures. Nutrition plays a critical role in maintaining bone strength and reducing the risk of osteoporosis and fractures in older adults.

---

1. Calcium

• Most important mineral for bones — about 99% of the body’s calcium is stored in bone.

• Required for:

  • Bone mineralisation
  • Maintaining bone density

• Ageing effect: Reduced calcium absorption from the gut due to lower vitamin D levels.

📌 Recommendation: 1000–1300 mg/day in older adults

---

2. Vitamin D

• Helps the body absorb calcium from the intestine.
• Also involved in bone remodeling and mineral balance.
• Older adults often have lower sun exposure and less skin synthesis, increasing deficiency risk.

📌 Deficiency can lead to osteomalacia (soft bones) and contribute to osteoporosis.

---

3. Protein

• Essential for:

  • Collagen matrix formation (the scaffold of bone)
  • Maintaining muscle mass (which supports skeletal health)

• Inadequate protein intake is linked to increased fracture risk.

📌 However, too much protein without adequate calcium may increase calcium loss in urine.

---

🧃 4. Other Key Nutrients

• Magnesium: Helps with bone structure and calcium metabolism.
• Phosphorus: Important for bone mineralisation, but excessive intake (e.g., from soft drinks) can be harmful.
• Vitamin K: Involved in bone matrix protein synthesis (e.g., osteocalcin).
• Zinc: Important for bone tissue renewal.

---

🚫 5. Poor Dietary Habits That Harm Bones

• Low calcium and vitamin D intake = weaker bones.
• Excess salt and caffeine = increased calcium excretion.
• Excessive alcohol = interferes with calcium balance and bone-forming cells.
• Smoking = decreases estrogen and blood supply to bones.

---

Summary

Nutrient	Role in Bone Health	Deficiency Effect
Calcium	Bone mineralisation	Bone loss, osteoporosis
Vitamin D	Calcium absorption and bone remodeling	Osteomalacia, fracture risk
Protein	Builds collagen matrix, supports muscle	Weak bones, poor healing
Vitamin K	Activates bone proteins (e.g., osteocalcin)	Impaired mineral binding
Magnesium/Zinc	Bone structure, cell turnover	Reduced density, slow healing

---

3. Impact of hormone deprivation on bone health

The impacts of hormone deprivation on bone health are especially important in the context of ageing, menopause, and andropause. Here’s a clear breakdown of how this works:

---

🧬 Key Hormones That Maintain Bone Health

• Estrogen (in females)
• Testosterone (in males, also converted to estrogen in bone tissue)
• Parathyroid hormone (PTH) and calcitonin (regulate calcium)
• Growth hormone and IGF-1 (support bone formation)

---

🚺 Estrogen Deprivation (e.g., post-menopause)

What happens:

• Estrogen inhibits bone resorption (bone breakdown) by suppressing osteoclast activity.

• When estrogen levels drop sharply after menopause:

  • Osteoclasts become more active → ↑ bone resorption
  • Osteoblast activity can’t keep up → net bone loss

Impacts:

• Rapid decrease in bone mineral density (BMD) — especially in the first 5–10 years after menopause
• ↑ Risk of osteoporosis and fragility fractures (e.g. hip, spine, wrist)

📊 Women can lose up to 20% of bone mass within 5–7 years after menopause.

---

🚹 Testosterone Deprivation (e.g., ageing males or hormone therapy)

What happens:

• Testosterone helps maintain BMD directly and through conversion to estrogen via aromatase.

• In older men or men undergoing androgen deprivation therapy (e.g., for prostate cancer):

  • ↓ Testosterone → ↓ bone formation, ↑ bone resorption
  • This leads to osteopenia or osteoporosis

---

💔 Consequences of Hormone Deprivation

Effect	Mechanism
↑ Bone resorption	Overactive osteoclasts (due to low estrogen/testosterone)
↓ Bone formation	Reduced osteoblast activity
↓ Bone mass and BMD	Net bone loss over time
↑ Fracture risk	Weak, porous bones
↓ Bone quality (microarchitecture)	Trabecular thinning, cortical porosity

---

Clinical Management

• Hormone replacement therapy (HRT) in postmenopausal women can slow bone loss.
• Testosterone therapy may be considered in men with clinical hypogonadism.
• Alternatives: bisphosphonates, denosumab, SERMs, calcium/vitamin D, weight-bearing exercise

---

💪 SARCOPENIA

1. Describe common causes of sarcopenia

Sarcopenia is the age-related loss of skeletal muscle mass, strength, and function. It increases the risk of falls, frailty, and disability in older adults.

---

🔍 Common Causes of Sarcopenia

1. Ageing

• Natural ageing leads to:

  • Reduced muscle protein synthesis
  • Loss of motor neurons that innervate muscle fibers
  • Decrease in hormones like growth hormone, testosterone, and IGF-1

• Result: gradual shrinkage and atrophy of muscle fibers, especially type II (fast-twitch) fibers

2. Physical Inactivity

• “Use it or lose it” principle.

• Sedentary lifestyle leads to:

  • Muscle disuse atrophy
  • Reduced mitochondrial function and muscle endurance

3. Inadequate Nutrition

• Especially low protein intake or caloric deficiency

• Older adults often have:

  • Poor appetite (anorexia of ageing)
  • Reduced nutrient absorption

• Deficiencies in vitamin D, leucine, and B12 can also worsen muscle loss

4. Chronic Illness

• Diseases like:

  • Chronic kidney disease
  • Cancer
  • Heart failure
  • Diabetes

• These conditions promote inflammation, oxidative stress, and catabolism of muscle tissue

5. Inflammation

• Elevated inflammatory markers like TNF-α and IL-6 promote muscle protein breakdown.
• Common in chronic disease and frailty

6. Hormonal Changes

• ↓ Testosterone, estrogen, growth hormone, and IGF-1 = ↓ muscle protein synthesis
• ↑ Cortisol (chronic stress hormone) can worsen muscle breakdown

7. Neuromuscular Decline

• Loss of alpha motor neurons
• Leads to fewer and smaller motor units → less effective muscle contraction

---

Summary Table

Cause	Mechanism
Ageing	↓ protein synthesis, hormonal decline
Inactivity	Muscle disuse atrophy
Malnutrition	Inadequate protein and calorie intake
Chronic illness	Catabolic stress, inflammation
Inflammation	↑ Cytokines = ↑ muscle breakdown
Hormonal decline	↓ Testosterone, GH, IGF-1
Neural degeneration	Loss of motor neurons and impaired muscle firing

---

2. Describe changes found in sarcopenia

In short:

• Muscle mass: Reduced myofiber size and number
• Muscle fiber type shift: From slow-twitch (Type I) to fast-twitch (Type II) fibers
• Satellite cell depletion: Reduced regenerative potential
• Fat infiltration: Loss of lean muscle mass leads to intramuscular fat accumulation
• Leads to decreased strength, slower gait, and functional impairment

---

Structural and Functional Changes in Sarcopenia

Sarcopenia involves both quantitative (loss of mass) and qualitative (loss of function) changes in skeletal muscle. These changes affect muscle fibres, neuromuscular control, and metabolic function.

---

Reduction in Muscle Mass

• Progressive loss of skeletal muscle tissue, particularly in the limbs.
• Mainly affects type II (fast-twitch) fibers, which are responsible for quick and powerful movements.
• Leads to smaller muscle cross-sectional area and reduced lean body mass.

---

Alteration in Muscle Fiber Composition

• Selective atrophy of type II fibers, while type I (slow-twitch) fibers are relatively preserved.
• Some type II fibers may convert to type I, reducing overall power output.
• Infiltration of fat and connective tissue into muscle (myosteatosis), which impairs contractility.

---

Impaired Muscle Strength and Power

• Decline in maximum voluntary contraction strength.
• Muscle power (force × velocity) decreases more rapidly than strength.
• Reduced ability to perform daily tasks such as rising from a chair or climbing stairs.

---

Changes in Neuromuscular Function

• Loss of motor neurons and motor units (a motor neuron plus the muscle fibers it innervates).
• Leads to denervation of muscle fibers and incomplete or weak muscle activation.
• Decreased neuromuscular junction integrity, which compromises signal transmission from nerve to muscle.

---

Impaired Regeneration and Repair

• Reduction in satellite cells (muscle stem cells), which are responsible for muscle repair and regeneration.
• Slower or incomplete recovery after injury or periods of disuse.

---

Decreased Anabolic Signaling

• Blunted response to anabolic stimuli such as:

  • Dietary protein
  • Resistance exercise
  • Hormones like insulin, growth hormone, and IGF-1

• Increased inflammatory cytokines (e.g., TNF-α, IL-6) promote catabolism over synthesis.

---

Summary of Sarcopenia-Related Changes

• Loss of muscle mass and fiber number (especially type II)
• Infiltration of fat and connective tissue into muscle
• Decreased muscle strength and functional capacity
• Reduced motor unit recruitment and neuromuscular efficiency
• Impaired muscle regeneration and anabolic response

---

3. Impact in hormone-deprived populations

• Postmenopausal women: Loss of estrogen → reduced muscle strength
• Androgen-deprived men (e.g., prostate cancer treatment): Muscle atrophy, fat gain, impaired gait and balance
• Hormones regulate muscle protein synthesis, mitochondrial health, and neuromuscular coordination

📘 Cheung et al., J Cachexia Sarcopenia Muscle (2017)

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Sarcopenia in Hormone-Deprived Populations

Hormones play a key role in maintaining muscle mass and strength. In populations with reduced levels of anabolic hormones—such as postmenopausal women, older men with low testosterone, or patients undergoing hormone suppression therapy—sarcopenia is more common and often more severe.

---

Estrogen Deprivation (Postmenopausal Women)

• Estrogen helps preserve muscle protein synthesis and supports satellite cell activity (muscle regeneration).

• After menopause, estrogen levels decline sharply, leading to:

  • Accelerated muscle mass loss
  • Greater fat infiltration in muscle
  • Decline in muscle strength and function

• Combined with concurrent bone loss, this increases frailty, fall risk, and fracture risk.

---

Testosterone Deprivation (Aging Men and Prostate Cancer Patients)

• Testosterone supports muscle fiber hypertrophy, particularly of type II fibers, and enhances protein synthesis.

• Aging men experience gradual andropause, with declining testosterone levels, contributing to sarcopenia.

• Men undergoing androgen deprivation therapy (ADT) for prostate cancer show:

  • Rapid reduction in muscle mass
  • Decreased physical performance
  • Increased fat mass and risk of metabolic syndrome

---

Combined Effect with Other Factors

• In both sexes, hormone deprivation often coexists with:

  • Reduced physical activity
  • Nutritional deficiencies
  • Comorbidities (e.g. diabetes, cancer)

• These factors synergize with hormonal deficits, accelerating muscle atrophy and functional decline.

---

Clinical Consequences

• Increased frailty and loss of independence
• Higher rates of falls, fractures, and hospitalizations
• Reduced ability to recover from illness, surgery, or injury
• Negative impacts on metabolic health, including insulin resistance

---

Summary

Hormone deprivation impairs the body’s ability to maintain and repair skeletal muscle. In such populations, sarcopenia develops more rapidly, leads to worse outcomes, and requires targeted interventions including resistance training, nutritional support, and in some cases, hormone replacement therapy under medical supervision.

---

🧱 BONE FRACTURES

1. Causes of bone fractures

• Trauma (most common)

• Pathological conditions:

  • Osteoporosis
  • Bone metastases
  • Chronic diseases (CKD, IBD)
  • Nutrient deficiencies (e.g., Vitamin D)
  • Sarcopenia, neurological conditions (e.g., Parkinson’s)

---

2. Process of fracture healing

Source: L7.3 pg 5

1. Hematoma and inflammation
2. Soft callus (cartilaginous) forms
3. Hard callus: Cartilage is ossified into woven bone
4. Remodelling: Osteoclasts and osteoblasts reshape bone to pre-injury state

🧠 Reference: McDonald MM et al.

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Phases of Fracture Healing

Fracture healing is a dynamic and highly regulated biological process that restores the structure and function of broken bone. It occurs in three overlapping phases: inflammatory, reparative, and remodelling.

---

Inflammatory Phase (Days 1–7)

• Immediately after the fracture, blood vessels are torn, leading to a hematoma (blood clot) at the fracture site.

• The hematoma forms a temporary scaffold and releases cytokines and growth factors (e.g., IL-1, TNF-α, PDGF, TGF-β).

• These signals:

  • Recruit inflammatory cells (macrophages, neutrophils)
  • Stimulate mesenchymal stem cell recruitment –> will differentiate into cartilage cells
  • Promote angiogenesis (new blood vessel formation)
  • Granulation tissue

This sets the stage for tissue repair.

---

Reparative Phase (Days 7–21)

• Soft Callus Formation:

  • blood clot and granuloma tissue is replaced by cartilage

  • Fibroblasts and chondroblasts produce a fibrocartilaginous callus bridging the fracture.

  • This stabilizes the fracture site but is not yet mineralized.

• Hard Callus Formation:

  • Chondrocytes in the soft callus undergo endochondral ossification.

  • Osteoblasts begin to lay down woven bone, converting the soft callus to a hard (bony) callus.

This phase restores mechanical strength but not the original architecture.

---

Remodelling Phase (Weeks to Months)

• The hard callus is gradually replaced by lamellar bone, restoring the bone’s original structure and alignment.

• Osteoclasts resorb excess bone and shape the callus.

• Osteoblasts deposit new bone in response to mechanical load, realigning the bone according to Wolff’s Law.

• Eventually, the medullary cavity is restored, and the bone returns to its pre-fracture state (if healing is successful).

---

Key Cells and Signals in Fracture Healing

• Osteoblasts: Build new bone
• Osteoclasts: Resorb bone
• Chondrocytes: Form cartilage scaffold during soft callus phase
• Mesenchymal stem cells: Differentiate into osteoblasts and chondrocytes
• Growth factors: BMPs, VEGF, TGF-β play critical roles in coordination

---

Summary

Phase	Time Frame	Key Events
Inflammatory	0–7 days	Hematoma, immune activation, MSC recruitment
Reparative	1–3 weeks	Soft callus → hard callus, bone formation
Remodelling	Weeks–months	Woven bone → lamellar bone, restoration of shape

---

3. Compare healthy vs compromised healing

Healthy: Timely callus formation, vascularization, remodelling Compromised:

• Local: Poor blood supply, instability, infection
• Systemic: Malnutrition, smoking, diabetes, corticosteroids Results in delayed union, non-union, or malunion

🔗 Nature Rev Disease Primers – Non-union fractures

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Healthy vs Compromised Fracture Healing

Fracture healing normally proceeds through coordinated biological phases that result in complete bone repair. However, in some cases, healing is delayed or fails due to intrinsic or extrinsic factors. This section compares the processes and outcomes of healthy and compromised fracture healing.

---

Healing Timeline

• Healthy Healing:

  • Follows the standard sequence: inflammatory → reparative → remodelling.
  • Healing typically occurs within 6–12 weeks, depending on fracture type and patient age.

• Compromised Healing:

  • Delayed union: Healing takes longer than expected.
  • Non-union: Healing does not occur without intervention.
  • May become malunion: Bone heals in the wrong position.

---

Callus Formation and Bone Bridging

• Healthy Healing:

  • Robust formation of hematoma, soft callus, and eventual hard callus.
  • Proper alignment and vascular supply enable callus to ossify and bridge the fracture.

• Compromised Healing:

  • Insufficient callus formation or incomplete ossification.
  • Poor mechanical stability or poor blood flow impairs tissue bridging.
  • In atrophic non-union, no callus forms; in hypertrophic non-union, callus forms but fails to bridge.

---

Vascularization

• Healthy Healing:

  • Angiogenesis (formation of new blood vessels) supplies oxygen and nutrients to regenerating tissue.
  • Critical for osteoblast function and callus mineralization.

• Compromised Healing:

  • Poor perfusion from injury, smoking, diabetes, or infection can delay or prevent healing.
  • Hypoxia reduces osteoblast activity and enhances osteoclast-mediated resorption.

---

Cellular and Molecular Regulation

• Healthy Healing:

  • Coordinated activity of osteoblasts, osteoclasts, chondrocytes, and inflammatory cells.
  • Proper release of growth factors like BMPs, VEGF, and TGF-β.

• Compromised Healing:

  • Impaired cell recruitment or differentiation.
  • Imbalance in signaling pathways (e.g., excess inflammation or insufficient BMP signaling).
  • Chronic inflammation can impair regeneration.

---

Influencing Factors

Category	Healthy Healing	Compromised Healing
Nutrition	Adequate calcium, vitamin D, protein	Malnutrition, vitamin D deficiency
Systemic Health	Normal endocrine and metabolic function	Diabetes, renal disease, osteoporosis
Medications	No interference	Corticosteroids, NSAIDs, chemotherapy
Lifestyle	Non-smoker, active lifestyle	Smoking, alcohol use, immobilization
Mechanical Stability	Well-aligned, stabilized fracture	Instability, infection, poor surgical fixation

---

Summary

• Healthy fracture healing is a well-regulated biological repair process resulting in full restoration of bone structure and strength.
• Compromised healing occurs when one or more critical processes are disrupted, often requiring clinical intervention (e.g., bone grafting, electrical stimulation, or revision surgery).

---

4. Consequences and community impact

• Individual: Chronic pain, disability, reduced independence, increased mortality (20% 1-year mortality post-hip fracture)

• Community:

  • High economic burden (projected to reach $8.3 billion/year in Australia by 2033)

  • Increased healthcare usage, rehabilitation, long-term care

📘 Source: Nature Reviews Rheumatology (2009)

---

OSTEOARTHRITIS (OA)

1. Societal and personal burden

• 500+ million people worldwide affected

• Leading cause of chronic pain and disability

• In Australia:

  • ~$3.75 billion in direct healthcare costs
  • $25 billion projected by 2030

• OA increases risk of cardiovascular disease and mental health issues

---

2. Mechanobiology and joint function

Certainly. Here’s a clear explanation of how mechanobiology supports normal synovial joint function, using only ##### as the highest level of subheading for R Markdown formatting:

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Mechanobiology and Synovial Joint Function

Mechanobiology is the study of how mechanical forces influence biological processes. In synovial joints, mechanical loading is critical for maintaining the structure and function of cartilage, subchondral bone, synovium, and supporting tissues.

---

Load-Responsive Tissue Adaptation

• Chondrocytes, the primary cells in articular cartilage, are mechanosensitive.

• When joints are used (e.g., walking), the cyclic compression and shear:

  • Stimulate matrix synthesis (collagen type II and proteoglycans)
  • Maintain hydration and elasticity of the cartilage

• Proper mechanical loading ensures that cartilage remains strong, smooth, and resilient.

---

Maintenance of Extracellular Matrix (ECM)

• ECM provides the cartilage with tensile strength and compressive resistance.

• Mechanical stimuli help:

  • Regulate ECM turnover
  • Prevent catabolic degradation of the cartilage

• Balanced loading encourages anabolic responses, while underuse or overuse can cause ECM breakdown.

---

Joint Lubrication and Synovial Fluid

• Movement promotes the circulation of synovial fluid, which:

  • Lubricates the joint surfaces
  • Delivers nutrients and removes waste from the avascular cartilage

• Without regular loading, nutrient supply to cartilage diminishes, leading to degeneration.

---

Bone Remodeling at the Joint Interface

• Subchondral bone responds to joint loading via osteoblast and osteoclast activity.

• Mechanical cues regulate:

  • Bone thickness
  • Trabecular alignment

• This ensures proper load distribution across the joint to minimize focal stress and microdamage.

---

Synovial Tissue Health

• Synovial membrane cells also respond to mechanical signals.
• Regular motion prevents fibrosis or thickening of the synovium and helps modulate inflammatory mediators.

---

Consequences of Altered Mechanobiology

Condition	Mechanobiological Impact
Immobilization	Reduced ECM synthesis, cartilage atrophy
Overloading (injury)	Microtrauma, inflammation, ECM breakdown
Osteoarthritis (OA)	Disrupted mechanosensing → catabolic signaling

---

Summary

Mechanobiology is essential for joint homeostasis. It helps maintain cartilage integrity, bone strength, and synovial fluid circulation. Regular, moderate joint loading promotes healthy joint function, while disuse or overloading contributes to joint degeneration and disease.

---

3. Pathophysiology of OA

OA is a disease of the whole joint organ:

• Cartilage loss: Breakdown of aggrecan and collagen by MMPs/ADAMTS
• Subchondral bone sclerosis: Increased turnover, altered mechanics
• Synovial inflammation: Releases cytokines (e.g., IL-6, TNF-α), causing more degradation
• Meniscus, ligament degeneration → instability and pain
• Osteophytes form at joint margins

📘 Chris Little – OA is an active, inflammatory disease, not just “wear and tear”

Certainly. Below is a structured explanation of the basic pathophysiology of osteoarthritis and the concept of disease phenotypes, formatted for R Markdown using only ##### as the highest-level subheading:

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Basic Pathophysiology of Osteoarthritis

Osteoarthritis (OA) is a chronic, progressive joint disease characterised by the degeneration of articular cartilage, changes in subchondral bone, and joint inflammation. It is driven by both mechanical and biochemical factors.

---

Articular Cartilage Breakdown

• Healthy cartilage provides a low-friction, load-bearing surface.

• In OA:

  • Chondrocytes become dysregulated.
  • There is a loss of proteoglycans and collagen II in the extracellular matrix (ECM).
  • Cartilage becomes soft, fibrillated, and eroded, eventually leading to exposed subchondral bone.

---

Subchondral Bone Changes

• Increased bone turnover and sclerosis (thickening of the subchondral plate).
• Formation of osteophytes (bony outgrowths) at joint margins.
• Bone marrow lesions may develop, associated with pain and inflammation.

---

Synovial Inflammation

• Although OA is not a classic inflammatory arthritis, low-grade synovitis is common.
• The inflamed synovial membrane releases cytokines (e.g., IL-1β, TNF-α) and matrix-degrading enzymes (MMPs, ADAMTS).
• This further promotes cartilage breakdown and joint degradation.

---

Impaired Mechanobiology

• Normal mechanical loading is required for cartilage maintenance.
• In OA, either overloading (e.g., obesity, joint malalignment) or underloading (e.g., immobilisation) disrupts cartilage homeostasis.
• This leads to abnormal joint stress and mechanotransduction failure.

---

Pain and Functional Decline

• Pain results from:

  • Bone marrow lesions
  • Synovitis
  • Activation of nociceptors in bone and synovium

• Functional decline is due to joint stiffness, instability, and reduced range of motion.

---

4. Disease phenotypes

• OA varies in presentation: metabolic, mechanical, inflammatory, post-traumatic

• Disease stage, joint affected, pain drivers differ

• Targeted therapies may need to address:

  • Phenotype (e.g., inflammation-dominant vs cartilage-only)
  • Endotype: Molecular signature of disease
  • Use of biomarkers to guide personalized treatment

🔬 OA phenotyping: Kolling Institute Research

In osteoarthritis, not all patients present or respond to treatment in the same way. The term “disease phenotypes” refers to distinct subgroups of disease based on underlying mechanisms, symptoms, or risk factors.

---

Examples of OA Phenotypes

Phenotype	Key Features
Mechanical phenotype	Driven by trauma, joint loading, or malalignment
Inflammatory phenotype	Prominent synovial inflammation and cytokine activity
Metabolic phenotype	Associated with obesity, metabolic syndrome
Pain-dominant phenotype	Severe pain disproportionate to joint damage
Ageing phenotype	Age-related cartilage degeneration and cellular senescence

Why Phenotypes Matter

• Help explain variability in symptoms and disease progression.
• Enable development of personalised treatments (e.g., anti-inflammatory drugs for inflammatory phenotype).
• May influence decisions about exercise, pharmacological therapy, and surgery.

---

CARDIOVASCULAR DISEASE

🔴 Hypertension

• What is blood pressure?

Blood pressure (BP) is the force exerted by blood on arterial walls. It has two components:

• Systolic BP: Pressure during heart contraction

• Diastolic BP: Pressure during relaxation

🩺 BP = Cardiac Output × Peripheral Resistance

---

• Primary vs Secondary Hypertension

Primary (Essential) Hypertension:

• No identifiable cause (90% of cases)

• Clinically silent

• Risk factors:

  • Age, male sex, family history

  • Smoking, high sodium diet, alcohol, obesity, stress, sedentary lifestyle

Secondary Hypertension:

• Has a specific cause (10% of cases):

  • Renal artery stenosis
  • Hyperaldosteronism
  • Pheochromocytoma
  • Coarctation of the aorta
  • RAAS overactivity

🧬 RAAS promotes vasoconstriction and water retention via aldosterone and vasopressin

It’s to do with either low renal blood flow. We’ll come back to renal perfusion in a couple of lecturets time.

or if there’s a problem with the adrenal gland now, there can be 2 reasons that the adrenal gland might be causing secondary hypertension.

The 1st is something known as primary Aldosteronism. This is a disease where it’s something other than a tumour which makes the adrenal gland produce way too much Aldosterone.

The last one is, if there is a tumor of the adrenal gland or a tumor which is regarded as a neuroendocrine tumour which secretes extra secreting factors to promote much more production of Aldosterone from the adrenal gland. So it’s an upstream effect.

So how is it that the kidney and the adrenal gland has a role to play in regulating hypertension? This is all because of the Renin-angiotensin-aldosterone system.

In short, this system has a role to play in regulating blood volume and vasoconstriction. 2 things that we spoke about as having a big impact on blood pressure.

if the amount of blood supply to the kidney drops, the kidneys will release an enzyme known as Renin. Now Renin has, when it comes in contact with a protein known as angiotensinogen.

Angiotensinogen comes from the liver. That enzyme turns angiotensinogen into angiotensin 1. –> angiotensin one in the presence of angiotensin converting enzyme is converted into Angiotensin 2. And it’s Angiotensin 2 that has these devastating effects.

Angiotensin 2, specifically, is a potent vasoconstrictor and it does this by constricting the muscular walls of small arteries, making them constrict, which increases our peripheral resistance and our blood pressure.

Okay, the second thing that angiotensin 2 specifically does is, it targets 2 things, it targets aldosterone and vasopressin release. Both of these hormones have the capacity to influence the kidney and increase and change how it holds sodium and potassium, and it changes its clearance.

So there’s less salt clearance, more salt retention. By doing this it increases water retention, drawing water out of the cells of the body, bringing it into the bloodstream. This obviously increases blood volume to increase blood pressure.

So this is why the Renin Angiotensin Aldosterone system has a big role to play in hypertension, and it will help you understand why the treatment approaches target this system quite extensively.

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• Hypertension-mediated organ damage

Chronic high BP causes:

• Vascular fibrosis and loss of compliance –> reduces elasticity

• Endothelial damage → atherosclerosis, thrombosis

• Target organ damage:

  • Heart: LV hypertrophy, heart failure

  • Brain: Stroke

  • Kidneys: CKD

  • Eyes: Retinopathy

🧠 Long-term consequence: major contributor to cardiovascular morbidity and mortality

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🟠 Atherosclerosis

• Classifying lesions

A type of arteriosclerosis involving plaque buildup in large and medium-sized arteries. Fatty streak → fibrous plaque → complicated lesion (necrotic core, rupture)

Atherosclerosis: Classification of Lesions (AHA Types I–VI)

Type I: Initial Lesion

• Features: Isolated macrophage foam cells (lipid-laden macrophages) in the intima
• Clinical significance: Earliest detectable change; not visible macroscopically
• Reversible

Type II: Fatty Streak

• Features: Accumulation of intracellular lipid in foam cells and some smooth muscle cells
• May contain: Some extracellular lipid
• Common in youth; still asymptomatic and reversible

Type III: Intermediate Lesion

• Features: More extracellular lipid accumulation between cells
• Represents a transition from fatty streak to plaque
• Often remains clinically silent

Type IV: Atheroma

• Features: Core of extracellular lipid, especially cholesterol
• Begins forming a lipid-rich necrotic core
• Macroscopically visible; forms the basis of a plaque

Type V: Fibroatheroma

• Features: Lipid core + fibrous cap made of collagen and smooth muscle
• Cap provides mechanical stability
• May begin to calcify

Subtypes of Type V:

• V(a): Predominantly fibrous
• V(b): With calcification
• V(c): With lipid pools

Type VI: Complicated Lesion

• Features: Plaque rupture, hemorrhage, or thrombosis
• May result in acute cardiovascular events like myocardial infarction or stroke
• Highly clinically significant

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Summary Table

Type	Name	Key Features	Reversibility
I	Initial	Isolated foam cells	Yes
II	Fatty Streak	Intracellular lipid in foam cells	Yes
III	Intermediate	Beginning of extracellular lipid accumulation	Partially
IV	Atheroma	Core of extracellular lipid	No
V	Fibroatheroma	Lipid core + fibrous cap, possibly calcified	No
VI	Complicated lesion	Rupture, thrombosis, hemorrhage	No

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• Risk factors

Modifiable: Smoking, hypertension, hyperlipidaemia, diabetes, inactivity

Non-modifiable: Age, male sex, genetics 🛡️ Estrogen is protective pre-menopause

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Non-Modifiable Risk Factors

These are factors that cannot be changed but significantly influence an individual’s baseline risk:

• Age: Risk increases with age, especially >45 in men and >55 in women.
• Sex: Males are at higher risk earlier in life; post-menopausal women’s risk increases due to estrogen loss.
• Family history: A history of premature cardiovascular disease in a first-degree relative (e.g., MI before age 55 in men or 65 in women).
• Genetic disorders: Such as familial hypercholesterolemia.

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Modifiable Risk Factors

These can be controlled or treated to reduce risk:

• Dyslipidaemia:

  • High LDL cholesterol promotes plaque formation.
  • Low HDL cholesterol reduces cholesterol clearance.

• Hypertension:

  • Damages endothelium and promotes plaque development.

• Smoking:

  • Enhances oxidative stress, inflammation, and endothelial dysfunction.

• Diabetes mellitus / Insulin resistance:

  • Increases endothelial dysfunction and pro-inflammatory state.

• Obesity (especially visceral fat):

  • Linked with insulin resistance, hypertension, and abnormal lipid profiles.

• Physical inactivity:

  • Associated with poor cardiovascular fitness and increased atherogenic risk.

• Unhealthy diet:

  • Diets high in saturated fat, trans fats, and added sugars promote lipid abnormalities and inflammation.

• Alcohol overuse:

  • Excessive intake contributes to hypertension and liver-related dyslipidaemia.

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Emerging or Contributing Risk Factors

These are being increasingly recognised for their role in atherogenesis:

• Chronic inflammation (e.g., elevated CRP)
• Psychosocial stress and depression
• Sleep disorders (e.g., obstructive sleep apnoea)
• Air pollution
• Chronic infections or autoimmune diseases

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• Arterial wall anatomy

source: L8.2 pg 9 - diagram here

Tunica Intima (Inner Layer)

• Location: Directly lines the lumen (inside space of the vessel)

• Structure:

  • Endothelium: A single layer of flattened endothelial cells
  • Basement membrane
  • Subendothelial connective tissue

• Function:

  • Maintains a non-thrombogenic surface
  • Regulates vascular tone and permeability
  • Responds to inflammatory and metabolic signals

• Clinical Relevance: Site of initial lipid deposition and foam cell accumulation in atherosclerosis

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Tunica Media (Middle Layer)

• Location: Between intima and adventitia

• Structure:

  • Mainly composed of smooth muscle cells
  • Contains elastic fibers, collagen, and ground substance
  • In elastic arteries (like the aorta), contains prominent elastic lamellae

• Function:

  • Provides mechanical strength and elasticity
  • Regulates vascular diameter via contraction and relaxation of smooth muscle

• Clinical Relevance: Important in blood pressure regulation; medial calcification can occur with ageing

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Tunica Adventitia (Outer Layer)

• Structure:

  • Made of collagen-rich loose connective tissue
  • Contains fibroblasts, nerve fibers, and in larger arteries, vasa vasorum (small blood vessels that supply the outer wall)

• Function:

  • Anchors the vessel to surrounding tissue
  • Protects and supports the vessel

• Clinical Relevance: Involved in vascular remodelling and inflammation during disease progression

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Summary Table

Layer	Key Components	Function
Intima	Endothelium, basal lamina, subendothelium	Barrier, regulation of vascular tone
Media	Smooth muscle, elastic fibers	Contraction, structural integrity
Adventitia	Collagen, fibroblasts, vasa vasorum	Support, nutrient supply to vessel wall

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• Atherogenesis

Source: L8.2 pg 10, 11

Preclinical Phase of Atherogenesis

This is the silent phase where atherosclerotic changes begin, but the individual has no symptoms. It may last decades, starting as early as childhood or adolescence.

Key Features:

1. Endothelial Dysfunction:

   • Triggered by risk factors such as hypertension, smoking, high LDL, and diabetes.
   • Leads to increased permeability and reduced nitric oxide production.

2. Lipoprotein Entry and Modification:

   • LDL cholesterol enters the intima and becomes oxidised (oxLDL), a key atherogenic trigger.

3. Monocyte Recruitment and Foam Cell Formation:

   • OxLDL attracts monocytes, which differentiate into macrophages.
   • These macrophages engulf oxLDL and become foam cells, forming a fatty streak.

4. Smooth Muscle Cell (SMC) Migration and Proliferation:

   • SMCs migrate from the media into the intima and begin producing extracellular matrix.
   • This leads to development of a fibrous cap over a lipid-rich necrotic core.

5. Plaque Maturation:

   • Over time, the plaque enlarges, with accumulation of lipids, calcium, and fibrous tissue.
   • Inflammation persists, contributing to further damage and growth of the lesion.

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Clinical Phase of Atherogenesis

In this phase, the atherosclerotic plaque becomes symptomatic, often due to complications like narrowing or rupture. This is when cardiovascular disease (CVD) becomes evident.

Key Features:

1. Luminal Narrowing (Stenosis):

   • Progressive growth of the plaque may narrow the artery, reducing blood flow.
   • This can lead to angina, claudication, or other symptoms of ischemia.

2. Plaque Rupture or Erosion:

   • If the fibrous cap is thin and unstable, it may rupture, exposing the lipid core to blood.
   • This triggers thrombus (clot) formation.

3. Thromboembolic Events:

   • A clot may block the artery locally (e.g., leading to myocardial infarction or stroke).
   • Or it may embolise and cause blockage elsewhere.

4. Clinical Presentations:

   • Stable angina (predictable chest pain with exertion)
   • Acute coronary syndromes (unstable angina, MI)
   • Stroke
   • Peripheral arterial disease

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Summary

Phase	Key Events	Symptoms
Preclinical	Endothelial dysfunction, lipid accumulation, inflammation	No symptoms (silent)
Clinical	Plaque rupture, thrombosis, lumen narrowing	Yes (e.g., angina, MI, stroke)

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• Atherosclerotic cardiovascular disease (ASCVD)

Atherosclerotic Cardiovascular Disease (ASCVD) refers to a group of conditions caused by the build-up of atherosclerotic plaques in arterial walls, which restrict blood flow and can lead to serious or fatal events.

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Definition

ASCVD is the clinical manifestation of atherosclerosis — a progressive disease where lipid-rich plaques form in medium and large arteries, leading to reduced or obstructed blood flow. Over time, these plaques may rupture, triggering thrombosis (clot formation) and acute events like myocardial infarction or stroke.

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Pathogenesis

1. Initiation:

   • Triggered by endothelial dysfunction due to risk factors like hypertension, smoking, high LDL, and diabetes.
   • LDL cholesterol infiltrates the vessel wall, becomes oxidised, and attracts immune cells.

2. Plaque Development:

   • Foam cells, smooth muscle cells, and extracellular matrix accumulate to form plaques.
   • Over time, the plaque grows and may calcify, form a fibrous cap, or become unstable.

3. Clinical Event:

   • If the fibrous cap ruptures, a thrombus may form, blocking the artery.
   • This can lead to ischemia (oxygen deprivation), infarction (tissue death), or organ dysfunction.

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Major Clinical Forms of ASCVD

• Coronary Artery Disease (CAD):

  • Affects coronary arteries.

  • May present as:

    • Stable angina
    • Acute coronary syndrome (ACS)
    • Myocardial infarction (heart attack)

• Cerebrovascular Disease:

  • Affects cerebral arteries.

  • May lead to:

    • Transient ischemic attack (TIA)
    • Ischemic stroke

• Peripheral Artery Disease (PAD):

  • Affects arteries in the limbs (commonly legs).
  • Symptoms include claudication, poor wound healing, or critical limb ischemia.

• Aortic Atherosclerosis:

  • Can lead to aneurysm formation or aortic dissection, especially if plaque weakens the vessel wall.

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❤️ Myocardial Infarction (MI) and Stroke

• What is CVD?

Cardiovascular disease encompasses:

• Coronary artery disease (myocardial infarction)

• Stroke

• Heart failure

• Peripheral artery disease

• Arrhythmias

• cardiomyopathy

• atrial fibrilation

• rheumatic heart disease

• congenital heart disease

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• Ischemia vs Infarction

Definition

• Ischemia: A reversible condition where tissue receives insufficient blood supply, usually due to partial obstruction of an artery. This leads to reduced oxygen and nutrient delivery.

• Infarction: A condition where prolonged or severe ischemia leads to tissue death (necrosis). This is typically irreversible and results from complete or critical obstruction of blood flow.

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Causes

• Ischemia:

  • Atherosclerotic plaque narrowing
  • Vasospasm
  • Thrombus with partial blockage
  • Embolism with incomplete occlusion

• Infarction:

  • Thrombotic or embolic complete arterial occlusion
  • Plaque rupture with thrombus formation
  • Severe and sustained vasospasm

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Reversibility

• Ischemia: Reversible if blood flow is restored in time
• Infarction: Irreversible tissue damage due to prolonged ischemia

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Clinical Examples

Condition	Type
Stable angina	Ischemia
Transient ischemic attack	Ischemia
Myocardial infarction (MI)	Infarction
Ischemic stroke	Infarction

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Diagnostic Clues

• Ischemia:

  • ECG: ST depression or T-wave inversion
  • Symptoms: Chest pain or neurological deficits that resolve
  • Biomarkers: Usually normal

• Infarction:

  • ECG: ST elevation, Q-waves (in MI)
  • Symptoms: Persistent pain or deficit
  • Biomarkers: Elevated troponin or CK-MB (in MI)

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Summary Table

Feature	Ischemia	Infarction
Blood flow	Reduced	Severely reduced or stopped
Tissue damage	None or reversible	Irreversible cell death (necrosis)
Duration	Short-term	Prolonged
Reversibility	Yes (if treated early)	No
Example	Angina, TIA	MI, Ischemic stroke

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• Types of stroke

There are two main types of stroke, classified based on their cause: ischemic and hemorrhagic. A third, related condition is a transient ischemic attack (TIA), often referred to as a “mini-stroke.”

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1. Ischemic Stroke

• Definition: Caused by blockage of blood flow to part of the brain, leading to ischemia and tissue damage.
• Accounts for approximately 85% of all strokes.

Subtypes:

• Thrombotic stroke:

  • Caused by a local blood clot (thrombus) forming in an artery supplying the brain, usually over atherosclerotic plaque.

• Embolic stroke:

  • Caused by a clot or debris that travels (emboli) from elsewhere (often the heart, e.g., in atrial fibrillation) and lodges in cerebral arteries.

• Lacunar stroke:

  • Caused by occlusion of a small penetrating artery, leading to small, deep brain infarcts (commonly in basal ganglia, thalamus, internal capsule).

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2. Hemorrhagic Stroke

• Definition: Caused by rupture of a blood vessel, leading to bleeding into or around the brain.
• More severe than ischemic strokes, but less common (~15%).

Subtypes:

• Intracerebral hemorrhage:

  • Bleeding directly into the brain tissue.
  • Often caused by hypertension, trauma, or anticoagulant use.

• Subarachnoid hemorrhage:

  • Bleeding into the subarachnoid space (between the brain and skull).
  • Usually due to ruptured aneurysms or arteriovenous malformations (AVMs).

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3. Transient Ischemic Attack (TIA)

• Definition: A brief episode of neurological dysfunction caused by temporary ischemia, without permanent brain damage.
• Symptoms resolve within 24 hours, usually within minutes.
• Often a warning sign of impending full ischemic stroke.

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Summary Table

Stroke Type	Cause	Key Features
Ischemic	Arterial blockage	Sudden focal deficit; most common type
Hemorrhagic	Vessel rupture and bleeding	Severe headache, vomiting, decreased consciousness
TIA	Temporary blockage (no damage)	Symptoms resolve fully within 24 hrs

Why diagnosis is important?

It is critically important to confirm the type of stroke before initiating treatment because ischemic and hemorrhagic strokes require completely different — and often opposing — management strategies. Treating the wrong type can cause severe harm or even death.

Key Reasons:

1. Opposite Treatments for Ischemic vs Hemorrhagic Stroke

• Ischemic stroke (caused by a blood clot):

  • Often treated with thrombolytic (clot-busting) drugs like tPA (tissue plasminogen activator) or mechanical thrombectomy.
  • Goal: Re-establish blood flow to the brain.

• Hemorrhagic stroke (caused by bleeding):

  • Thrombolytics would worsen bleeding and could be fatal.

  • Treatment involves:

    • Controlling bleeding
    • Lowering blood pressure
    • Surgical intervention if needed

▶ Misidentifying a hemorrhagic stroke as ischemic and giving tPA could lead to massive brain hemorrhage.

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• Types of MI

1. Type 1: Plaque rupture and thrombus (classic MI)
2. Type 2: Oxygen mismatch (e.g., anaemia, tachycardia)
3. Type 3: Sudden death without biomarker confirmation
4. Type 4: Post-stent insertion
5. Type 5: Post-CABG (coronary artery bypass graft) surgery

Summary

Type	Description	Key Feature
Type 1	Spontaneous, due to atherosclerotic plaque	Plaque rupture + thrombosis
Type 2	Oxygen supply-demand imbalance	No thrombosis, secondary cause (e.g., anemia)
Type 3	Cardiac death before confirmation	Suspected MI, no biomarkers
Type 4	PCI-related MI	MI due to intervention or stent complication
Type 5	CABG-related MI	Post-bypass, large enzyme rise

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• Clinical manifestations

• MI: Chest pain (crushing), jaw/arm pain, pallor, fatigue
• Stroke: Weakness, speech issues, visual changes, confusion

🔬 Diagnostic tools:

• ECG
• Cardiac biomarkers: Troponin I, CK-MB
• CT/MRI brain imaging for stroke

Here’s a breakdown of the clinical manifestations and diagnostic approaches for myocardial infarction (MI) and stroke, which are both acute and potentially life-threatening consequences of cardiovascular disease:

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Myocardial Infarction (MI)

Clinical Manifestations

• Chest pain:

  • Classically central or left-sided, described as pressure, squeezing, or tightness.
  • May radiate to the left arm, jaw, neck, or back.

• Shortness of breath

• Sweating (diaphoresis)

• Nausea or vomiting

• Light-headedness or syncope

• Silent MI:

  • Especially common in diabetics or elderly; may present only with fatigue or shortness of breath.

Diagnostic Tools

• Electrocardiogram (ECG):

  • ST-elevation = STEMI
  • ST-depression/T-wave inversion = NSTEMI or ischemia

• Cardiac biomarkers:

  • Troponin I/T: Most specific and sensitive; elevated within 3–12 hours
  • CK-MB: Less specific; may help detect reinfarction

• Coronary angiography:

  • Identifies occluded coronary arteries

• Echocardiography:

  • Assesses wall motion abnormalities and ejection fraction

• Chest X-ray:

  • Rules out other causes of chest pain (e.g., aortic dissection, pulmonary edema)

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Stroke

Clinical Manifestations

• Sudden onset of:

  • Hemiparesis or weakness on one side
  • Facial droop
  • Aphasia (difficulty speaking or understanding language)
  • Vision loss or double vision
  • Coordination or balance problems
  • Severe headache (more common in hemorrhagic stroke)
  • Altered level of consciousness (e.g., confusion, coma)

🧠 Use the FAST acronym for quick recognition:

• Face drooping
• Arm weakness
• Speech difficulty
• Time to call emergency services

Diagnostic Tools

• Non-contrast CT scan (first-line):

  • Rapidly differentiates ischemic vs hemorrhagic stroke

• MRI brain:

  • More sensitive for early ischemic changes

• CT or MR angiography:

  • Visualises arterial occlusions or aneurysms

• Carotid Doppler ultrasound:

  • Detects stenosis of carotid arteries

• ECG and echocardiography:

  • Rules out cardioembolic sources (e.g., atrial fibrillation, ventricular thrombus)

• Blood tests:

  • Glucose, coagulation profile, cholesterol levels

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Summary Comparison

Feature	Myocardial Infarction (MI)	Stroke
Key symptom	Chest pain, SOB	Sudden neurological deficit
Onset	Usually sudden	Sudden
Common cause	Coronary artery blockage	Cerebral artery blockage or hemorrhage
Primary diagnostic test	ECG + troponin	CT brain (non-contrast)
Confirmatory imaging	Angiography	MRI or CT angiography
Time-critical treatment	PCI, thrombolysis	Thrombolysis, thrombectomy (if ischemic)

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• Complications

MI:

• Arrhythmias
• Ventricular aneurysm
• Pericarditis
• Heart failure
• Myocardial rupture

Stroke:

• Persistent deficits
• Seizures
• Hydrocephalus
• Death

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🟣 Heart Failure (HF)

• What is Heart Failure?

Inability of the heart to meet metabolic demands because ↓ cardiac output

• End-stage of many CVDs

• Can be systolic (contractility issue) or diastolic (filling issue)

• Functional failure: inability to contract

• structural failure: not enough blood circulating to be pumped out

Heart failure is a condition where the heart can’t pump blood well enough to meet the body’s needs. It doesn’t mean the heart has stopped — it means the heart is weakened or stiff and can’t pump or fill efficiently.

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Main Problem in Heart Failure

• The heart either:

  • Can’t pump blood out properly (reduced ejection)
  • Can’t relax and fill properly (stiff chambers)

This leads to less oxygen and nutrients reaching the body and fluid build-up in the lungs, legs, or abdomen.

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Common Symptoms

• Shortness of breath (especially during activity or when lying down)
• Fatigue or tiredness
• Swollen ankles, legs, or abdomen
• Weight gain from fluid retention
• Cough or wheezing (from fluid in lungs)

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Common Causes

• Heart attack (damaged heart muscle)
• Long-standing high blood pressure
• Heart valve disease
• Cardiomyopathy (disease of the heart muscle)
• Arrhythmias (irregular heartbeats)

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Why It Matters

Heart failure is a chronic, progressive condition that can severely affect quality of life. Early diagnosis and treatment (e.g., medication, lifestyle changes, sometimes surgery) can improve symptoms and prevent worsening.

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V2

What Is Heart Failure?

Heart failure (HF) is a complex clinical syndrome where the heart is unable to pump blood efficiently enough to meet the body’s metabolic demands. This can result from structural or functional abnormalities that impair the filling or ejection of blood from the heart.

Importantly, heart failure is not a disease in itself — it is the final common pathway of many forms of cardiovascular disease, particularly hypertension, myocardial infarction, and valvular disease.

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How Does Heart Failure Happen?

At the root of heart failure is a decrease in cardiac output — the volume of blood ejected by the heart per minute. This may happen due to:

• Reduced contractility (e.g. myocardial infarction causes loss of functional muscle)
• Increased afterload (e.g. hypertension makes it harder for the heart to pump)
• Impaired filling (e.g. stiff ventricular walls prevent adequate filling)

The heart initially tries to compensate using mechanisms such as:

• Frank-Starling mechanism: Increased preload stretches the myocardium to increase stroke volume.
• Neurohormonal activation: Activation of the RAAS, sympathetic nervous system, and ADH increases blood volume and peripheral resistance.

But over time, these adaptations become maladaptive:

• RAAS activation leads to fluid overload, worsening congestion.
• Sympathetic activation increases heart rate and afterload, worsening myocardial oxygen demand.
• Myocyte hypertrophy and fibrosis occur, reducing compliance and efficiency.

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Types of Heart Failure – Based on Affected Side

Left-Sided Heart Failure

• Most common type
• Blood backs up into the lungs, causing pulmonary congestion.
• Caused by conditions like hypertension, aortic stenosis, or ischemic heart disease.

Key Symptoms:

• Dyspnoea (breathlessness) – first on exertion, then at rest
• Orthopnoea – difficulty breathing when lying flat
• Paroxysmal nocturnal dyspnoea – waking up at night gasping for air
• Fatigue (due to poor perfusion of muscles)
• Fine crackles in lungs on auscultation

Right-Sided Heart Failure

• Often occurs secondary to left-sided failure, but can also be caused by pulmonary hypertension or right-sided valve disease.
• Blood backs up into the systemic circulation.

Key Symptoms:

• Peripheral oedema (pitting in lower limbs)
• Ascites (fluid in the abdomen)
• Hepatomegaly and splenomegaly
• Jugular venous distension
• Anorexia, nausea (due to gut congestion)

Biventricular Heart Failure

• Failure of both ventricles, often in advanced stages.
• Features a combination of pulmonary and systemic symptoms.

Congestive Heart Failure

• Often used to refer to heart failure with fluid accumulation.
• May refer to left, right, or both types, but always involves congestion due to elevated pressures.

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Types Based on Ejection Fraction

HFrEF (Heart Failure with Reduced Ejection Fraction)

• Ejection fraction < 40%
• Also called systolic heart failure
• The left ventricle is dilated and contractility is reduced

Causes:

• Myocardial infarction (scarred myocardium)
• Dilated cardiomyopathy
• Chronic hypertension
• Valvular insufficiency (e.g. mitral regurgitation)

Pathophysiology:

• Fewer functioning cardiomyocytes
• Ventricular dilatation
• Decreased stroke volume and cardiac output

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HFpEF (Heart Failure with Preserved Ejection Fraction)

• Ejection fraction ≥ 50%
• Also called diastolic heart failure
• The heart contracts normally, but the ventricle is stiff and does not fill properly

Causes:

• Longstanding hypertension → LV hypertrophy
• Aortic stenosis
• Age-related stiffening of the myocardium
• Obesity and metabolic syndrome

Pathophysiology:

• Impaired relaxation → decreased preload
• Normal ejection fraction, but less blood is ejected because less enters the ventricle

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HFmrEF (Heart Failure with Mid-Range EF)

• Ejection fraction 41–49%
• Features overlap between HFrEF and HFpEF
• Clinical and therapeutic significance still under study

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Stages of Heart Failure (ACC/AHA)

Stage	Description
A	At risk of HF but no structural heart disease or symptoms (e.g., hypertensive, diabetic)
B	Structural heart disease present (e.g., LV hypertrophy), but no symptoms yet
C	Structural heart disease + symptoms (e.g., dyspnoea, fatigue, oedema)
D	Advanced heart failure; symptoms at rest despite maximal therapy

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Symptoms and Clinical Signs

• Fatigue: due to poor oxygen delivery to muscles
• Shortness of breath: due to pulmonary congestion
• Swelling (edema): from fluid retention
• Weight gain: from fluid accumulation
• Orthopnoea / PND: classic signs of pulmonary congestion
• Cough with frothy sputum: pulmonary oedema
• Hepatomegaly / JVD: right-sided failure

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Key Risk Factors

Modifiable:

• Hypertension (leads to LV hypertrophy and stiffness)
• Coronary artery disease / MI
• Obesity
• Diabetes
• Smoking, alcohol
• Poor sleep hygiene (e.g., sleep apnoea)

Non-modifiable:

• Ageing (stiff myocardium, reduced compliance)
• Genetic predisposition
• Ethnicity

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Complications

• Pulmonary edema: fluid in alveoli impairs gas exchange
• Renal dysfunction: due to poor perfusion + RAAS activation
• Liver congestion and dysfunction: due to systemic venous congestion
• Arrhythmias: due to chamber dilation and scarring
• Thromboembolism: from stagnant blood in dilated chambers
• Malabsorption: due to gut oedema (leading to weight loss and anorexia)
• Multi-organ failure: in severe, end-stage HF

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Hemodynamic Mechanisms

• Cardiac output = stroke volume × heart rate

• Factors influencing stroke volume:

  • Preload (Frank-Starling law)
  • Afterload (resistance the ventricle pumps against)
  • Contractility

• As CO falls, body compensates with:

  • RAAS activation → vasoconstriction + fluid retention
  • Sympathetic stimulation → increased HR and contractility
  • ADH release → water retention

These mechanisms become pathological, worsening oedema and promoting hypertrophy and fibrosis.

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THERAPEUTIC STRATEGIES: DRUGS, BIOLOGICS, ANTIBODIES, NON-DRUG TREATMENTS

Drugs

1. Define the term “drug”

A drug is defined as:

A substance of known structure that produces a biological effect in a living system. It is exogenous, meaning it is introduced into the body and is not produced by internal physiological mechanisms.

Drugs can be:

• Small molecules (chemicals) – e.g. statins, antidepressants, antibiotics.
• Biologicals – e.g. antibodies, enzymes, growth factors (covered in other lectures).

Key features:

• Drugs do not create new effects; they modify existing biological activity.

• They are classified by names:

  • Chemical name – based on structure, e.g. 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride.
  • Generic name – commonly used, e.g. sertraline.
  • Brand/trade name – e.g. Zoloft.
  • International variations – e.g. paracetamol (AU/UK) = acetaminophen (USA).

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2. Describe how a drug can bind to a target

Drug–target binding relies on molecular complementarity in:

• Shape (3D fit)
• Size
• Charge distribution

This is often described using a lock-and-key model:

• The drug (key) fits precisely into its target (lock).
• Functional groups and charge interactions help orient and stabilise the interaction.

Types of bonds involved:

• Ionic bonds: strong attraction between opposite charges.
• Hydrogen bonds, dipole-dipole, ion-dipole: help in close proximity.
• Van der Waals (induced dipole): weak, but relevant at very close distances.
• Covalent bonds: rare and usually irreversible (e.g. enzyme inhibitors).
• Cation–pi interactions: specific cases of charged molecules interacting with aromatic rings.

Drugs typically bind to:

• Proteins (e.g. enzymes, receptors)
• Nucleic acids (e.g. DNA, RNA)
• Other macromolecular components of cells.

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3. Describe drug affinity and drug selectivity

Affinity:

• Refers to the strength of binding between a drug and its target.
• High-affinity drugs require lower concentrations to achieve binding.
• Determined by how well the drug’s shape, charge, and functional groups match the target.

Selectivity:

• A drug is selective if it binds preferentially to one target over others.
• Even though a drug might bind to multiple targets, its therapeutic dose is chosen to target only the desired molecule.
• Higher selectivity → fewer side effects and better clinical efficacy.

Analogy: Affinity = how strongly a key fits a lock. Selectivity = how many different locks that key can open (ideally, only one).

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4. Give examples of drug targets

The main drug targets include:

A. Receptors

• G-protein coupled receptors (GPCRs)
• Ligand-gated ion channels
• Kinase-linked receptors
• Nuclear receptors

Drugs can act as agonists (activators) or antagonists (blockers).

B. Ion Channels

• Voltage-gated and ligand-gated

• Drugs can:

  • Block ion flow
  • Modulate (enhance or reduce opening probability)

C. Enzymes

• Drugs can:

  • Inhibit synthesis or breakdown of endogenous molecules
  • Act as substrates (e.g. prodrugs like codeine → morphine)

D. Transporter Proteins

• Move ions or molecules across membranes

• Drugs can:

  • Block transport
  • Compete as substitutes

E. Other targets

• DNA, RNA, ribosomes (e.g. antibiotics)
• Physical-chemical processes (e.g. antacids neutralise stomach acid)
• Some drugs have unknown mechanisms despite widespread use (e.g. early metformin use).

Real-world examples:

• Statins → enzyme target (HMG-CoA reductase)

  • e.g. rosuvastatin used to lower cholesterol

• SSRIs (sertraline) → transporter inhibition (serotonin reuptake)

  • antidepressant aka Zoloft

• Amoxicillin → bacterial enzyme inhibition

• Metformin → multiple targets; action still being studied

  • used for T2D

TOP 10 PBS DRUGS

Drug Name	Indication Category	Drug Class / Notes	Target Type
Rosuvastatin	Cardiovascular Disease	Statin	Enzyme
Atorvastatin	Cardiovascular Disease	Statin	Enzyme
Amlodipine	Cardiovascular Disease	Calcium Channel Blocker	Ion Channel
Perindopril	Cardiovascular Disease	ACE Inhibitor	Enzyme
Candesartan	Cardiovascular Disease	Angiotensin II Receptor Blocker	Receptor
Telmisartan	Cardiovascular Disease	Angiotensin II Receptor Blocker	Receptor
Irbesartan	Cardiovascular Disease	Angiotensin II Receptor Blocker	Receptor
Sertraline	Depression and Anxiety	SSRI	Transporter Protein
Escitalopram	Depression and Anxiety	SSRI	Transporter Protein
Metformin	Type 2 Diabetes	Biguanide	Multiple Targets

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5. Describe the different ways in which drugs can modify function

Once a drug binds its target, it can modify biological function in different ways:

1. Activating – stimulates function:

• Agonists at receptors (e.g. salbutamol for β2-adrenergic receptor)

2. Enhancing – boosts an existing response:

• Allosteric enhancers (e.g. benzodiazepines enhance GABA-A receptor response)

3. Attenuating – weakens a biological response:

• Partial antagonists, channel modulators

4. Interfering – blocks or disrupts a process:

• Enzyme inhibitors (e.g. ACE inhibitors)
• Receptor blockers (e.g. beta-blockers)
• Transporter blockers (e.g. SSRIs)

Some drugs produce a temporary effect, others irreversibly alter a function (e.g. aspirin’s covalent inhibition of COX enzyme in platelets).

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🧬 Biologics

1. Describe the differences between biologics and conventional small-molecule drugs

Biologics are large, complex therapeutic agents derived from living organisms (humans, animals, microorganisms), or produced through biotechnology. In contrast, small-molecule drugs are chemically synthesised, relatively simple compounds.

Key differences:

Feature	Small-Molecule Drugs	Biologics
Size	Small (<1 kDa); e.g. aspirin (180 Da)	Large (4–150 kDa+); e.g. IgG1 antibody (150 kDa)
Structure	Simple, defined chemical structure	Complex tertiary and quaternary protein structures
Source	Chemically synthesised	Derived from natural/living sources
Manufacturing	Predictable and scalable	Complex; requires living cells or bioprocesses
Administration	Oral (tablets, capsules)	Injectable (IV, subcutaneous); oral is unstable
Stability	Stable under varied conditions	Sensitive; must be refrigerated or frozen
Examples	Aspirin, sertraline, statins	Vaccines, insulin, antibodies, GLP-1 agonists

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2. Describe the different types of biologics

Biologics span a wide range of therapeutic categories:

A. Nucleic Acid-Based Therapies

• Antisense oligonucleotides (ASOs) – Single-stranded DNA or RNA that binds mRNA to block or alter protein synthesis.
• RNA interference (RNAi) – siRNAs degrade target mRNA using the RISC complex.
• mRNA therapy – Synthetic mRNA instructs cells to produce therapeutic proteins (e.g., Pfizer/Moderna COVID-19 vaccines).

B. Protein-Based Therapies

• Peptide hormones – e.g., GLP-1 receptor agonists (e.g., Ozempic) regulate insulin, appetite, and blood pressure.
• Enzymes – Replace dysfunctional enzymes in metabolic diseases (mentioned briefly).
• Antibodies – Covered in a separate lecture.

C. Cell-Based Therapies

• CAR-T cells – Genetically engineered T cells to target cancer.

  • Autologous: Patient’s own T cells.
  • Allogeneic: Donor-derived T cells (experimental).

• Stem cells – Donor-derived hematopoietic cells used after chemo/radiation to regenerate blood-forming tissues.

• Microbiome therapies – e.g., faecal microbiota transplant for C. difficile infection; emerging uses in IBD and cancer.

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3. Describe the mechanisms of action for different biologics

Each class of biologics acts at different biological levels:

Nucleic Acids:

• ASOs: Bind to mRNA and recruit RNase H to degrade it, block ribosome binding, or modulate splicing.
• RNAi: siRNA is loaded into RISC, which cleaves target mRNA.
• mRNA therapy: Delivers synthetic mRNA → translation of therapeutic protein inside cells.

Proteins:

• GLP-1 receptor agonists (e.g., Ozempic):

  • Pancreas: Increase insulin secretion.
  • Brain: Suppress appetite.
  • Blood vessels: Lower blood pressure.
  • Stomach: Delay gastric emptying.

Cells:

• CAR-T cells: Recognise tumour antigens and kill cancer cells by lysis.
• Stem cells: Regenerate blood-forming tissues after myeloablation.
• Microbiota therapy: Restore healthy gut flora to outcompete pathogens like C. difficile.

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4. Describe the challenges associated with different biologics

Common challenges across biologics:

Type	Challenges
Nucleic Acids	Large/charged molecules; poor cell entry → need lipid nanoparticles or local injection
Proteins/Peptides	Poor oral availability, rapid degradation, difficulty crossing membranes, need for injection
CAR-T Cells	Costly, slow to manufacture, immune rejection (GVHD or host attack), no FDA-approved allogeneic
Stem Cells	Requires donor matching, immune suppression, infection risks
Microbiome Therapy	Lack of standardisation, infection risk, regulatory hurdles

Additionally, biologics require special handling and cold-chain logistics, as seen during the COVID-19 vaccine rollout.

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5. Correlate drug suffixes with their respective drug classes and therapeutic uses

Suffixes in drug names often reveal their mechanism, class, or biologic origin:

Suffix	Class / Mechanism	Example Drugs
–rsen	Antisense oligonucleotides (ASOs)	Eteplirsen, Golodirsen
–siran	RNAi-based siRNA therapies	Patisiran, Lumasiran
–meran	mRNA vaccines	Tozinameran (Pfizer), Elasomeran (Moderna)
–tide	Peptide-based biologics	Semaglutide (Ozempic), Liraglutide

These suffixes are part of INN (International Nonproprietary Naming) standards and often help clinicians quickly identify drug types and actions.

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Antibody Therapies

1. Describe the structure of a typical antibody molecule

Antibodies (also called immunoglobulins) are Y-shaped glycoproteins produced by B cells in response to antigens such as viruses, bacteria, toxins, or tumour cells.

Key Structural Components:

• Four polypeptide chains:

  • 2 heavy chains
  • 2 light chains

• Fab region (Fragment antigen-binding):

  • Located at the arms of the Y
  • Contains the variable region, which is responsible for binding to specific antigens
  • The variability in amino acid sequence allows different antibodies to recognize an enormous diversity of antigens

• Fc region (Fragment crystallizable):

  • The stem of the Y
  • Constant region, more conserved across antibodies
  • Interacts with immune effector cells such as natural killer (NK) cells, macrophages, and complement proteins
  • Essential for triggering downstream immune responses such as cytotoxicity and phagocytosis

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2. Describe the different formats of therapeutic antibodies

Therapeutic antibodies come in multiple formats based on their specificity, structure, and functional additions:

1. Monospecific Antibodies

• Bind to a single epitope on one antigen

• Examples:

  • Trastuzumab: Binds HER2 receptor in HER2+ breast cancer

2. Bispecific Antibodies

• Bind to two different antigens or two epitopes (on the same or different antigens)

• Types:

  • T-cell engagers: e.g., Mosunetuzumab (binds CD3 on T cells and CD20 on tumour cells)
  • Dual tumour-targeting antibodies: e.g., Amivantamab (targets MET and EGFR)

3. Antibody–Drug Conjugates (ADCs)

• Antibody is conjugated to a cytotoxic drug, toxin, or radioisotope

• Examples:

  • Brentuximab (antibody binds CD30, internalises and delivers a cytotoxic payload)
  • Moxetumomab (an immunotoxin targeting CD22)
  • Ibritumomab (linked to a radioisotope; delivers radiation directly to tumour cells)

4. Polyclonal vs Monoclonal vs Recombinant Antibodies

• Polyclonal: A mix of antibodies produced by different B cell clones in response to one antigen (recognize multiple epitopes)
• Monoclonal: Identical antibodies from a single hybridoma clone (recognize one epitope)
• Recombinant: Genetically engineered in vitro using plasmids and mammalian cells

5. Multispecific Antibodies

• Trispecific or even multi-specific antibodies that can bind multiple targets
• Increase tumour specificity, T-cell activation, and reduce escape mutations

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3. Describe the mechanisms of action of different types of therapeutic antibodies

Therapeutic antibodies can eliminate cells or block signaling through multiple mechanisms:

A. Neutralization

• Antibodies bind directly to pathogens or toxins and prevent them from interacting with their targets
• E.g., preventing virus entry into cells

B. Antibody-Dependent Cellular Cytotoxicity (ADCC)

• Fc region of antibody binds Fcγ receptors on NK cells
• NK cells release perforin (forms pores) and granzymes (induce apoptosis)

C. Antibody-Dependent Cellular Phagocytosis (ADCP)

• Fc region engages macrophage Fc receptors
• Macrophages engulf the antibody-tagged cells → degraded in lysosomes

D. Complement-Dependent Cytotoxicity (CDC)

• Fc region binds complement proteins

• Leads to:

  • Opsonisation (coating pathogen for phagocytosis)
  • Membrane Attack Complex (MAC) formation → cell lysis

E. Immune Checkpoint Inhibition

• Antibodies such as anti-PD-1 and anti-PD-L1 block inhibitory signals that suppress T-cell activity
• Restores T-cell-mediated tumour killing

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4. Describe challenges associated with developing therapeutic antibodies

Therapeutic antibodies face several developmental and clinical challenges:

Category	Challenges
Immunogenicity	Antibodies may be recognized as foreign → immune reactions, anaphylaxis, cytokine release syndrome, tumor lysis syndrome
Cost & Complexity	Expensive to produce; requires bioreactors and quality control
Stability	Sensitive to heat and pH; require cold-chain storage
Delivery	Typically injectable (IV or subcutaneous); no oral route due to degradation
Resistance	Tumours can mutate antigens or develop downstream escape mechanisms

Notably, early murine antibodies had high immunogenicity. This was addressed through:

• Chimeric antibodies (part mouse, part human)
• Humanized antibodies
• Fully human antibodies (via phage display or transgenic mice)

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5. Describe ways we can build better or different therapeutic antibodies

Modern antibody engineering allows precise tailoring of antibody properties:

A. Fc Engineering

• Modify the constant region to:

  • Improve binding to Fc receptors (enhancing ADCC)
  • Increase serum half-life (less frequent dosing)
  • Change specificity for different immune cell types

B. Glycoengineering

• Alter carbohydrate groups on Fc region to enhance binding to effector cells

C. Antibody–Drug Conjugation

• Attaching cytotoxic drugs, radioisotopes, or toxins to deliver targeted cell death

D. Multispecific Formats

• Trispecific antibodies: Engage two T-cell receptors and one tumour antigen to maximize immune activation
• Multispecific tumour-targeting: Improve selectivity and reduce escape mutations

E. Combination Therapies

• Combine antibodies with chemotherapy, checkpoint inhibitors, or biologics
• Designed to overcome resistance or synergise immune effects

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Non-Pharmaceutical Interventions (NPIs)

1. Describe non-pharmacological interventions and their role in disease management

Non-pharmaceutical interventions (NPIs) refer to strategies for preventing, diagnosing, managing, or rehabilitating disease that do not involve drugs or medications. Unlike pharmaceuticals, which act by chemically altering molecular pathways, NPIs influence external factors, behaviors, or supportive systems.

Key Roles of NPIs:

• Used across all stages of disease:

  • Prevention: e.g. lifestyle changes, hygiene
  • Diagnosis: e.g. symptom tracking, screening tools
  • Treatment: e.g. ventilation, nutrition, surgery
  • Rehabilitation: e.g. exercise and cognitive support after illness

• Improve human health holistically

• Minimize side effects and may reduce long-term costs

COVID-19 as an Example:

Before vaccines or antivirals, NPIs were crucial for disease control, including:

• Social distancing
• Mask wearing
• Isolation/quarantine
• Hand hygiene
• Work-from-home and virtual learning

These interventions disrupted transmission and had broad effects on daily life and the economy (considered “side effects” of NPIs).

Additional Examples of Preventive NPIs:

• Nutrition and immunity:

  • Maintaining healthy micronutrient levels (e.g. zinc, vitamin D) may reduce disease severity.
  • Excess iron may worsen outcomes (as in COVID-19).

• Lifestyle: Regular exercise, stress reduction, and adequate sleep support general immunity.

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2. Outline the interaction between non-pharmaceutical and pharmaceutical interventions

NPIs often support, enhance, or complement pharmaceutical treatments:

A. NPIs that enhance or support pharmacological treatments:

1. Maintaining baseline health:

   • Good nutrition, exercise, hydration improve overall resilience and recovery

2. Biomarkers:

   • Track disease severity or treatment response

   • Examples in COVID-19:

     • Blood glucose: diabetes monitoring
     • Lymphocyte counts: inversely related to COVID severity
     • CRP, IL-6, IL-14: markers of inflammation

   • These biomarkers help guide drug dosing and selection

3. Medical devices:

   • Ventilators (non-invasive and invasive) help patients breathe when lung function fails
   • Used across many conditions beyond COVID-19
   • Reduce lung workload, prevent secondary infections, deliver oxygen
   • ~57% survival rate in severe COVID patients using ventilators

B. NPIs as alternatives when drugs fail:

• Surgical interventions (e.g. lung transplantation) used in end-stage COVID when medication was ineffective.

• Three types: single lung, double lung, and lobe transplant.

  • Lobe transplants may come from living donors, but full lungs require deceased donors.
  • High survival rates (90% at 3 and 12 months), but long wait times (2+ years in Australia).

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3. Introduction on emerging non-pharmaceutical treatments

Emerging NPIs focus on innovation, accessibility, and integration with tech and biotech:

A. Tissue Engineering:

• Aims to create artificial organs or tissues (e.g. lungs)
• Could address organ shortage for transplantation

B. Artificial Intelligence (AI) in Health:

• Chatbots for telehealth and symptom triage

• AI-based imaging analysis:

  • Faster and more accurate pattern recognition in scans
  • Could improve diagnostic turnaround and resource use

C. Digital Rehabilitation Programs:

• Example: The Great Game program

  • 8-week online rehab for post-COVID patients
  • Combines physical and psychological support
  • Improved quality of life, helped return to work and daily life

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Additional Note: Diagnosis as an NPI

Diagnostic tools (especially in early-stage COVID) are classified as non-pharmacological because they:

• Do not modify physiological pathways
• Are critical for early intervention, reducing spread, and improving recovery

Examples:

• Symptom checkers: fast but low accuracy
• Rapid antigen test (RAT): 80% sensitivity
• RT-PCR: 90% sensitivity, 97% specificity
• CT scans: most accurate but least accessible

Understanding sensitivity and specificity is essential for interpreting diagnostic value and risk of false results.

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Summary

• Non-pharmacological interventions are essential tools for disease prevention, diagnosis, treatment, and recovery.
• They can work alongside or instead of medications, and often offer fewer side effects and greater accessibility.
• Examples range from lifestyle and nutritional strategies to cutting-edge fields like tissue engineering and AI-driven diagnostics.
• In pandemics (e.g. COVID-19), NPIs have been life-saving and societally transformative.

TREATMENTS FOR AGEING MUSCULOSKELETAL SYSTEMS

🏋️‍♂️ Resistance Exercise

1. How resistance exercise affects bone and muscle health in hormone-deprived people

Resistance exercise leads to:

• Muscle hypertrophy via mechanical loading → muscle fiber damage → repair → stronger fibers

• Bone strengthening through mechanotransduction in osteocytes:

  • Mechanical strain ↓ sclerostin (a Wnt inhibitor), ↑ osteoblast activity → more bone formation

In hormone-deprived people (e.g., postmenopausal women or men on ADT for prostate cancer):

• Resistance training improves muscle mass and strength (Correa et al., 2014; Houben et al., 2023)
• Bone density is improved in postmenopausal women but not fully preserved in men on ADT unless combined with impact exercises (Newton et al., 2019)

✅ Visual examples of exercises: Chest press, Leg extension

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2. Benefits in people with osteoarthritis (OA)

Resistance exercise helps by:

• Reducing pain and stiffness (Gur et al., 2002; Wortley et al., 2013)

• Improving joint function and mobility (Lin et al., 2009)

• Building muscle support around joints, reducing biomechanical load on cartilage

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💉 Hormone Replacement Therapy (HRT)

1. Describe factors that may influence the effects of HRT

The effects of hormone replacement therapy (HRT) are influenced by multiple individual, treatment-related, and biological factors. These determine both the efficacy and the risk profile of HRT in different populations.

A. Hormone Type and Combination

• Natural vs synthetic hormones can have different effects.

• Single hormone (e.g. estrogen only) may have different outcomes than combined hormone therapy (e.g. estrogen + progesterone).

  • Example: Conjugated equine estrogen (CEE) alone can reduce the risk of hip fracture, breast cancer, and diabetes.
  • When combined with medroxyprogesterone acetate (MPA), risk increases for cardiovascular events, breast cancer, and other complications.

B. Dose

• Higher doses can lead to greater efficacy, but also increased side effects.
• Example: In men with prostate cancer, higher doses of oral estrogen (diethylstilbestrol) were associated with lower survival due to cardiovascular complications.

C. Duration of Therapy

• Short-term vs long-term therapy has differing effects.
• Intermittent therapy (on/off cycles) may produce different outcomes from continuous therapy.

D. Route of Administration

• Oral estrogen undergoes first-pass metabolism in the liver, increasing clotting factor production and thrombotic risk.
• Transdermal (patch or gel) and intramuscular injection routes bypass the liver, reducing this risk.

E. Timing of Initiation

• Earlier initiation (within 10 years of menopause) is associated with greater benefits and lower risks.

• Initiating HRT after age 60 or >20 years post-menopause increases risk of coronary heart disease.

  • Supported by reanalysis of the Women’s Health Initiative (WHI) trial.
  • Elevated cardiovascular risk seen only in women who began HRT well after menopause.

F. Monitoring and Side Effects

• Patients on HRT must be monitored for:

  • Clotting risks
  • Breast cancer (especially with combined HRT)
  • Mood, cognitive changes
  • Bone density and muscle function

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2. Explain the benefits of HRT on bone and muscle health as well as osteoarthritis in various populations

HRT has proven benefits in some musculoskeletal contexts, particularly in bone health, with mixed or inconclusive evidence for muscle and osteoarthritis outcomes.

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A. Bone Health

i. Postmenopausal Women

• Estrogen deficiency post-menopause is linked to osteoporosis and fracture risk.

• HRT reduces this risk significantly.

• Example:

  • Study by Varies et al. (2006): Women within 3 years of menopause who received oral estrogen + progesterone had lower fracture rates (3.7% vs 6.7% in placebo).

ii. Androgen-Deprived Men (e.g. prostate cancer patients)

• Men also produce estradiol, mostly via aromatization of testosterone.

• In men undergoing androgen deprivation therapy (ADT):

  • Transdermal estradiol preserves bone mineral density (BMD).
  • Example: Langley et al. found that men on estrogen patches had increased BMD, while those on LH-RH agonists had declining BMD.
  • Fracture risk was also lower in men receiving estradiol.

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B. Muscle Health

i. Postmenopausal Women

• HRT does not increase lean muscle mass, according to meta-analysis data.

• Estrogen is not anabolic for muscle tissue.

• However, muscle strength may improve with HRT:

  • Example: 1987 study found increased back extension strength in women on oral estradiol (with or without progesterone), compared to placebo.

ii. Hypogonadal Men

• Testosterone replacement therapy improves both muscle mass and strength.

• Greater efficacy seen with intramuscular injections vs transdermal gel.

  • Example 1: In older men with low testosterone, intramuscular testosterone significantly increased lean body mass.
  • Example 2: Transdermal testosterone also increased lean mass, but to a lesser extent.
  • Example 3: Leg press strength improved more with intramuscular injections than other forms.

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C. Osteoarthritis

• Inconclusive evidence for the role of HRT in preventing or modifying osteoarthritis (OA).
• Some studies suggest increased OA risk (e.g., odds ratio of 1.49 with estrogen use).
• Others show lower OA incidence in HRT users vs non-users (16.6% vs higher rate in non-HRT group).
• Conclusion: More research needed; current data are conflicting.

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Summary Table

Effect Area	Population	Benefit of HRT	Notes
Bone Health	Postmenopausal women	↓ Fracture risk, ↑ BMD	Strong evidence
	Androgen-deprived men	↑ BMD, ↓ fracture risk	Via estradiol replacement
Muscle Mass	Postmenopausal women	No significant effect	Based on multiple studies
	Hypogonadal men	↑ Lean mass (especially IM testosterone)	Intramuscular > transdermal
Muscle Strength	Postmenopausal women	Improved back extension force	Not due to mass but possibly neuromuscular
	Hypogonadal men	↑ Strength (leg press, overall)	IM testosterone more effective
Osteoarthritis	Postmenopausal women	Inconclusive evidence	Mixed study outcomes

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💊 Pharmacological Treatment of Osteoporosis

1. Recall the cellular reasons that drive bone loss in osteoporosis

Osteoporosis is a condition marked by compromised bone structure and strength, increasing the risk of fractures. Its hallmark is a disruption in the balance of bone remodeling, which normally involves three key cell types:

A. Osteoblasts

• Bone-forming cells.
• Lay down collagen matrix which is mineralized by hydroxyapatite crystals.

B. Osteoclasts

• Bone-resorbing cells.
• Break down bone matrix, releasing minerals like calcium into the bloodstream.

C. Osteocytes

• Former osteoblasts embedded in bone.
• Serve as mechanosensors and regulators, modulating osteoblast and osteoclast activity.
• Secrete signaling proteins like RANKL and sclerostin.

Pathophysiology:

• In osteoporosis, there is an imbalance:

  • ↑ osteoclast activity
  • ↓ osteoblast activity

• This leads to net bone loss — thinning, weakening, and disruption of trabecular bone.

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2. Outline what the serum markers of bone turnover are and how they respond to treatments

Serum markers of bone turnover reflect the activity of osteoblasts and osteoclasts, allowing clinicians to monitor treatment efficacy.

A. P1NP (Procollagen Type I N-terminal Propeptide)

• Marker of bone formation
• Released during collagen production by osteoblasts
• ↑ P1NP → Increased bone formation

B. CTX (C-terminal telopeptide of type I collagen)

• Marker of bone resorption
• Generated when osteoclasts break down collagen
• ↑ CTX → Increased bone breakdown

How treatments affect markers:

• Anti-resorptives (e.g., bisphosphonates, denosumab):

  • ↓ CTX significantly
  • Minor or no change in P1NP

• Anabolic agents (e.g., PTH, romosozumab):

  • ↑ P1NP
  • Variable or delayed effect on CTX

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3. Describe the difference between anti-resorptive and bone anabolic treatments

Anti-resorptive agents	Bone anabolic agents
Aim to suppress osteoclast activity or formation	Aim to stimulate osteoblast activity
Prevent further bone loss	Promote new bone formation
Result in increased BMD by decreasing turnover	Result in increased BMD by adding new bone
Common in early or maintenance therapy	Used for severe or high-risk osteoporosis

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4. Outline the mechanism of action of the two main anti-resorptives in clinical use

A. Bisphosphonates (e.g., Alendronate, Zoledronate)

• Bind avidly to bone mineral during IV infusion or oral dosing.
• Once bound, they are ingested by osteoclasts during bone resorption.
• Inside osteoclasts, they disrupt function, causing cell death.
• Result: Suppressed bone resorption and ↓ CTX.
• Long half-life due to strong bone binding (e.g., yearly IV dosing).

B. Denosumab (anti-RANKL monoclonal antibody)

• Targets RANKL, a cytokine that promotes osteoclast differentiation.
• RANKL is secreted by osteoblasts and osteocytes.
• Denosumab binds and neutralises RANKL, preventing it from activating RANK on osteoclast precursors.
• Result: Reduced osteoclast formation, activity, and survival.
• Administered via 6-monthly subcutaneous injections.
• Also reduces CTX and improves BMD at lumbar spine and hip.

Caution with Denosumab:

• Discontinuation can cause a rebound increase in CTX and rapid BMD loss, with increased vertebral fracture risk.
• Requires careful planning for transition therapy after stopping.

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5. Outline the mechanism of action of the two main anabolic agents in clinical use

A. Teriparatide (PTH 1-34 fragment)

• A recombinant form of parathyroid hormone (PTH).

• PTH typically regulates serum calcium via bone resorption.

• Continuous PTH exposure: ↑ osteoclast-mediated bone breakdown.

• Intermittent PTH dosing (daily injection):

  • Preferentially stimulates osteoblast activity more than osteoclasts.
  • Net effect: Increased bone formation and BMD.

• Increases P1NP, indicating anabolic effect.

• Clinical data show lumbar spine BMD gains.

B. Romosozumab (Anti-sclerostin antibody)

• Sclerostin is a protein secreted by osteocytes that inhibits osteoblast activity.
• Romosozumab binds and inhibits sclerostin, releasing the “brake” on bone formation.
• Effect: ↑ osteoblast activation → ↑ bone formation
• Administered as a monthly injection.
• Increases P1NP (formation marker), but effect wanes over time.
• BMD gains at lumbar spine and total hip are significant.
• Use is time-limited due to diminishing response after repeat dosing.

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Summary Table

Treatment Type	Agent	Target Mechanism	Primary Effect
Anti-resorptive	Bisphosphonates	Ingested by osteoclasts → inhibit resorption	↓ CTX, ↑ BMD
Anti-resorptive	Denosumab	Binds RANKL → prevents osteoclast formation	↓ CTX, ↑ BMD
Anabolic	Teriparatide	Intermittent PTH → stimulates osteoblasts	↑ P1NP, ↑ BMD
Anabolic	Romosozumab	Inhibits sclerostin → enhances osteoblasts	↑ P1NP, ↑ BMD (transiently)

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🦴 Osteoarthritis Management

1. Explain how OA treatment is approached in terms of structural disease versus symptoms

Osteoarthritis (OA) is now recognised as a biologically active disease, not simply “wear and tear”. It involves complex interactions between mechanical overload and biological signals, such as inflammation and systemic metabolic dysfunction. These stimuli affect multiple joint tissues (e.g., cartilage, synovium, bone), each of which can initiate and propagate pathological signalling.

However, a key clinical problem is that symptoms (especially pain) are often not well correlated with structural changes visible on imaging. For example:

• Patients may experience severe pain despite mild radiographic changes, or vice versa.
• OA pain arises from multiple sources, including bone marrow lesions, synovitis, and neuropathic components.

Thus, OA management needs to:

• Distinguish between disease pathology (structural damage) and symptom experience (pain, disability).
• Recognise phenotypic variation: not all OA patients have the same drivers of disease or pain.
• Focus on modifying risk factors (e.g., obesity, joint overload) and targeting symptoms as no structural disease-modifying drugs are currently approved.

TLDR: Osteoarthritis is driven by both mechanical and biological factors, but symptom severity (e.g., pain) does not always match structural damage. Treatment must be personalised, focusing on symptom relief and risk factor management, not just imaging findings.

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2. Recall current therapies and their efficacy

The current approach to OA management emphasises:

1. Individualised, non-drug therapies as first-line:

   • Education and self-management
   • Weight loss
   • Exercise and physical activity tailored to the patient (e.g. strengthening if weak, CBT if mood-disordered)
   • Assistive devices (e.g., braces, walking aids)
   • Heat/cold therapy
   • Management of co-morbidities (e.g., diabetes, depression, CVD)

2. Pharmacological treatments:

   • Topical and oral NSAIDs: first-line, effective for symptom relief
   • Paracetamol: no longer recommended due to limited efficacy
   • Intra-articular corticosteroids: may be used judiciously, but not repeatedly
   • Opioids, glucosamine, hyaluronic acid injections: generally not recommended due to low efficacy or risk of harm

3. Surgical interventions:

   • High tibial osteotomy (HTO):

     • Realigns the joint
     • Most effective in younger patients with unicompartmental disease

   • Total joint replacement (arthroplasty):

     • Effective for many patients but not without risk
     • Less effective in those who are younger, morbidly obese, have early-stage disease, or depression
     • Only 1 joint is replaced, but most patients have disease in multiple joints

4. Gaps in delivery:

   • ~60% of patients do not receive guideline-based care
   • Most skip non-drug therapies and are referred to surgery prematurely
   • Overreliance on imaging instead of holistic functional assessment

TLDR: First-line OA treatment includes non-drug strategies like education, exercise, and weight loss. NSAIDs can help symptoms, while paracetamol and opioids are no longer preferred. Surgery is effective for select patients, but current care delivery is often suboptimal, with many patients not receiving appropriate early interventions.

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3. Outline the development and biological rationale of future therapeutics

Despite extensive understanding of OA pathophysiology, no disease-modifying osteoarthritis drugs (DMOADs) have been approved to date. Current efforts focus on translating preclinical insights into more targeted therapies.

Key challenges:

• OA is heterogeneous: multiple pathways (e.g., inflammation, bone remodelling, cartilage degradation) can be involved
• Preclinical successes often fail in clinical trials due to lack of patient stratification

Proposed approach:

• Identify OA phenotypes (endotypes):

  • Metabolic syndrome OA: linked to systemic inflammation, obesity; may respond to anti-inflammatory biologics
  • Inflammatory OA: local joint inflammation is prominent
  • Bone-driven OA: characterised by bone marrow lesions, osteoporosis

• Use biomarkers (e.g., CRP, imaging) to stratify patients

• Develop therapies that target active pathways in specific patient subtypes

Examples of emerging strategies:

• Targeting IL-1: effective in animal models, but only helps humans with systemic inflammation
• Personalised treatment: matching drug to active mechanism in the individual

Surgical considerations:

• Some surgeries (e.g. ACL repair) improve mechanics, but do not reduce OA risk → highlights the importance of biological drivers
• Joint replacement remains the most reliable intervention, but isn’t suitable for all patients

TLDR: Future OA treatments will rely on identifying distinct disease phenotypes and targeting the biological pathways most active in each. The “one-size-fits-all” model has failed. Better patient stratification and biomarker-guided therapy may enable effective, personalised interventions.

NEUROPHARMACOLOGY: TREATMENT & MANAGEMENT OF GENETIC DISORDERS

1. Describe how dopamine synthesis is exploited to treat Parkinson disease and common treatment side-effects

Overview of Dopaminergic Deficiency:

Parkinson’s disease is characterised by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in reduced dopamine in the basal ganglia, which impairs movement control. As dopamine cannot cross the blood–brain barrier, treatment relies on manipulating its precursors and metabolism.

A. Levodopa (L-dopa)

• Gold standard treatment.
• L-dopa is a precursor of dopamine that can cross the blood–brain barrier via amino acid transporters.
• Once inside neurons, it’s converted to dopamine by DOPA decarboxylase and stored for synaptic release.

B. Metabolic Support (Enzyme Inhibitors)

To enhance L-dopa efficacy and reduce peripheral metabolism:

• Aromatic L-amino acid decarboxylase inhibitors (AADC inhibitors):

  • e.g. Benserazide, Carbidopa
  • Prevent conversion of L-dopa to dopamine outside the brain (where it would cause side effects)
  • Allows more L-dopa to reach the brain

• COMT inhibitors (e.g. Entacapone):

  • Inhibit catechol-O-methyltransferase
  • Prevent breakdown of L-dopa in the periphery and dopamine in the CNS

• MAO-B inhibitors (e.g. Selegiline, Rasagiline):

  • Inhibit breakdown of dopamine in the synaptic cleft
  • Extend the action of endogenously and exogenously derived dopamine

C. Dopamine Receptor Agonists

• Directly stimulate dopamine receptors (mainly D2)

• Less effective than L-dopa but useful in early or adjunctive therapy

• Not suitable in patients with cognitive decline or psychiatric symptoms

• Side effects:

  • Psychiatric: hallucinations, confusion
  • Impulse control disorders: gambling, hypersexuality

D. Common Side Effects of L-dopa

• Early stage: nausea, vomiting (brainstem dopamine receptor stimulation), postural hypotension

• Chronic use:

  • Motor fluctuations: “on-off” periods
  • Dyskinesia: involuntary movements, especially at peak L-dopa levels
  • Tolerance and reduced effectiveness due to ongoing neuron loss

TLDR:

Parkinson’s disease treatments exploit dopamine synthesis by using L-dopa, a precursor that crosses the blood–brain barrier. Enzyme inhibitors are co-administered to maximise central dopamine. While L-dopa remains the most effective therapy, side effects include dyskinesia and impulse control disorders, particularly with long-term use or dopamine agonists.

2. Explain other pharmacological and surgical approaches to treatment

A. Other Pharmacological Options

1. Anticholinergics:

   • Reduce activity of cholinergic interneurons in the striatum, which become overactive in dopamine deficiency
   • Useful for tremor, especially in younger patients
   • Not suitable in elderly or cognitively impaired patients

2. Amantadine:

   • Originally an antiviral drug
   • NMDA receptor antagonist
   • Reduces glutamatergic overactivity in the subthalamic nucleus
   • Can also help manage L-dopa-induced dyskinesias

B. Surgical Treatment: Deep Brain Stimulation (DBS)

• Targets the subthalamic nucleus (STN) — part of the indirect basal ganglia pathway, which becomes overactive in Parkinson’s disease

• Surgical implantation of an electrode that sends high-frequency electrical signals to reduce neuronal activity

• Most effective for:

  • Tremor
  • Reducing dyskinesia
  • Allowing L-dopa dose reduction

• Limitations:

  • Not a cure
  • Benefits typically last ~5 years
  • Major surgery (5–7 hours), patient is awake during part of it
  • Only suitable for younger patients without significant comorbidities or cognitive decline

TLDR:

Beyond L-dopa, Parkinson’s treatment includes anticholinergics (for tremor), amantadine (for dyskinesia), and dopamine agonists. Deep brain stimulation can provide major symptom relief for tremor and dyskinesia but is only suitable for select patients and does not halt disease progression.

3. Explain the challenges of long-term management of Parkinson disease

Parkinson’s disease is progressive and chronic, making long-term management increasingly complex. Key challenges include:

A. Loss of Dopaminergic Neurons

• As Parkinson’s progresses, fewer neurons remain to convert L-dopa to dopamine

• Leads to diminished L-dopa efficacy, requiring:

  • Higher doses
  • More frequent dosing
  • Complex medication regimens

B. Side Effects and Complications

• Dyskinesia: associated with high cumulative L-dopa exposure
• Motor fluctuations: due to short L-dopa half-life and disease progression
• Impulse control disorders: more common with dopamine agonists
• Cognitive decline: may limit use of several drug classes

C. Non-Motor Symptoms

• Depression, apathy, sleep disorders, constipation
• Often not responsive to dopaminergic therapy
• Require separate pharmacological and psychological interventions

D. Lifestyle and Supportive Management

• Exercise:

  • Increases central dopamine release
  • Shown to improve motor symptoms and delay progression

• Nutrition:

  • Maintain weight and general health
  • Must time protein intake to avoid competition with L-dopa at the blood–brain barrier

• Patient education:

  • Helps manage expectations
  • Increases engagement in decision-making

• Carer support:

  • Carers face significant burden
  • Must be involved in treatment planning

TLDR:

Long-term management is challenged by progressive neuronal loss, fluctuating L-dopa effectiveness, and the emergence of motor and non-motor complications. Treatment requires regular adjustment, attention to lifestyle, and support for both patients and carers.

🧬 Nervous System Disorders

1. What are neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) are a group of conditions that arise from abnormal brain development, often beginning in early life. These disorders typically involve a disruption of tightly coordinated neurodevelopmental processes, including neuronal architecture formation, connectivity, and timing.

They are characterised by:

• Impaired cognitive, emotional, and motor development
• Inability to meet expected developmental milestones
• Onset in early childhood
• Long-lasting or lifelong challenges

They affect approximately 3% of children worldwide and represent a significant global health burden.

TLDR: NDDs are early-onset conditions involving disrupted brain development, leading to impaired cognition, behaviour, and movement. They are lifelong, multifactorial, and impact millions of children globally.

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2. Range of conditions

NDDs include a wide spectrum of disorders, often overlapping or comorbid:

• Autism Spectrum Disorder (ASD)
• Intellectual Disability (ID)
• Attention Deficit Hyperactivity Disorder (ADHD)
• Global Developmental Delay (GDD)
• Communication and Language Disorders
• Motor Disorders
• Epilepsies, especially early-onset and treatment-resistant types

Many individuals may meet criteria for more than one diagnosis.

TLDR: NDDs encompass diverse conditions like ASD, ADHD, ID, and developmental delay. These conditions often co-occur and require multi-faceted diagnostic approaches.

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3. Genetics

The genetic basis of NDDs is highly heterogeneous and may include:

• Single nucleotide variants (e.g. MECP2 in Rett syndrome)
• Trinucleotide repeat expansions (e.g. Fragile X syndrome)
• Copy number variants (deletions/duplications; e.g. Prader-Willi, Angelman syndromes)
• Chromosomal rearrangements
• Aneuploidy (e.g. Down syndrome)

These variants may be:

• Inherited
• De novo (new mutations in the child)

Next-generation sequencing (NGS), including whole genome/exome sequencing, is essential for identifying genetic causes. However, not all NDDs have identifiable genetic mutations, making diagnosis complex.

TLDR: NDDs may result from a wide array of genetic abnormalities, both inherited and spontaneous. Molecular diagnostics like genome sequencing are improving detection, but many cases remain genetically unexplained.

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4. Common symptoms

While NDDs are variable, many share overlapping features in childhood:

• Delayed speech or language development
• Difficulty socialising or interacting
• Impaired fine/gross motor skills
• Hyperactivity or inattention
• Aggression, anxiety, or mood swings
• Seizures or epilepsy
• Cognitive impairment
• Emotional regulation issues

Symptoms vary in severity and presentation between individuals, requiring tailored support and monitoring.

TLDR: Core symptoms include language delay, motor dysfunction, behaviour issues, and seizures. These can differ widely across individuals and diagnoses.

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5. Clinical management

There is no cure for most NDDs, but multidisciplinary support can greatly improve quality of life. Management includes:

• Early diagnosis through comprehensive medical, developmental, and psychological assessments

• Genetic testing to guide personalised care

• Pharmacological therapy:

  • Antiepileptic drugs (AEDs) for seizure management
  • Regular drug monitoring for side effects and dose optimisation

• Behavioural interventions:

  • Cognitive behavioural therapy
  • Social skills training

• Allied health support:

  • Speech, occupational, and physical therapy
  • Educational interventions (e.g., tailored learning plans)

• Family involvement:

  • Parents are integral to therapy success
  • Psychoeducation and support services help reduce caregiver stress

TLDR: Treatment requires early, personalised, and team-based care involving medications, therapy, education, and strong family support. There is no one-size-fits-all approach.

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6. Advances in Precision Medicine

New and experimental therapies are under development:

A. Neurostimulation:

• For refractory epilepsy (unresponsive to AEDs)

• Includes:

  • Vagus Nerve Stimulation (VNS)
  • Responsive Neurostimulation (RNS)

B. Gene Therapy:

• Promising for monogenic disorders
• Only possible when the genetic cause is known
• Not suitable for polygenic or idiopathic cases

C. Antisense Oligonucleotides (ASOs):

• Custom-designed molecules that modulate gene expression
• Can reduce harmful transcripts or correct splicing

D. N-of-1 Trials:

• Individualised trials tailored to the unique genetics and symptoms of a single patient
• Useful for ultra-rare diseases where large RCTs are not feasible
• Help guide off-label use of approved drugs based on personal response

TLDR: Precision medicine in NDDs includes neurostimulation, gene therapy, and antisense technologies. For rare disorders, N-of-1 trials are emerging as powerful tools for personalised treatment.

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7. Rett Syndrome – Exemplar

Rett Syndrome is a rare X-linked neurodevelopmental disorder, primarily affecting girls, caused by mutations in the MECP2 gene.

Clinical Features:

• Microcephaly (reduced head growth)
• Loss of hand function (e.g., stereotyped hand-wringing)
• Hyperventilation, abnormal breathing patterns
• Severe communication and motor impairment
• Social withdrawal, seizures, anxiety, and scoliosis

Diagnosis:

• Based on clinical features
• Confirmed via MECP2 gene sequencing
• Some cases show no mutation on routine tests, but can be identified via whole exome/genome sequencing

Management:

• Complex and lifelong, changing over time

• Requires:

  • Neurological monitoring
  • Respiratory and gastrointestinal support
  • Psychological care
  • Educational planning
  • Support with scoliosis, mobility, communication

Therapeutic Developments:

• First approved therapy (2023): trofinetide – a new drug shown to improve symptoms

• Other therapies under investigation:

  • Gene therapy
  • ASOs
  • CBD-based treatments

TLDR: Rett syndrome is a rare monogenic disorder caused by MECP2 mutations, mostly in females. It involves severe developmental regression and multi-system challenges. Lifelong, evolving care is required, and recent therapeutic breakthroughs offer hope for symptom relief.

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Epilepsy

1. Discuss Epilepsy Treatment Strategies

a. Understand the pharmacological treatment of epilepsy, including the mechanism of action of common antiepileptic drugs (AEDs)

Antiepileptic (anti-seizure) drugs are the mainstay of epilepsy management and control seizures in about 70% of patients. The remaining 30% have drug-resistant (refractory) epilepsy and require alternative treatments.

AEDs work by targeting the electrophysiological and chemical imbalance that underlies seizures — specifically the excessive excitatory activity (glutamate) and reduced inhibitory activity (GABA).

AED Mechanisms:

1. Sodium channel blockers (e.g. phenytoin, lamotrigine):

   • Inhibit voltage-gated sodium channels, reducing depolarisation and action potential propagation.

2. Potassium channel enhancers:

   • Enhance efflux of K⁺ ions, repolarising neurons and reducing excitability.

3. Calcium channel blockers (e.g. ethosuximide, pregabalin, gabapentin):

   • Block T-type or N-type calcium channels, reducing neurotransmitter release.

4. GABAergic drugs:

   • Enhance GABA availability or receptor activity:

     • Benzodiazepines and barbiturates enhance GABA_A receptor activation (Cl⁻ influx → hyperpolarisation).
     • Valproate increases GABA synthesis and inhibits its breakdown.
     • Vigabatrin inhibits GABA transaminase (enzyme that breaks down GABA).
     • Tiagabine inhibits GAT-1 (GABA transporter), prolonging synaptic GABA presence.

5. Glutamate receptor inhibitors:

   • Drugs like perampanel block AMPA receptors, reducing excitatory transmission.

6. “Dirty drugs”:

   • AEDs like valproate have multiple mechanisms (e.g. sodium channel blockade, GABA modulation).

Genetic Considerations:

• In genetic epilepsies, it is critical to match drug mechanism to the functional effect of a mutation:

  • Gain-of-function sodium channel mutation: Use sodium channel blockers.
  • Loss-of-function mutation: Sodium blockers are contraindicated; use downstream agents like GABA modulators instead.

TLDR: AEDs target sodium, potassium, calcium channels, and neurotransmitter systems (especially GABA). Choosing the right drug depends on seizure type, patient profile, and — increasingly — genetic context. Some AEDs have broad (“dirty”) actions and remain mainstays due to effectiveness.

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b. Discuss non-pharmacological treatments for epilepsy, including ketogenic diets, surgery, and neurostimulation (e.g., Vagus nerve stimulation)

1. Ketogenic Diet:

• High-fat, low-carb diet that induces ketosis.

• Ketones become the brain’s main energy source instead of glucose.

• May:

  • Enhance GABA activity
  • Reduce glutamate-mediated excitation

• Particularly useful in children with drug-resistant epilepsy

• About 50% of children respond; requires strict medical supervision.

2. Vagus Nerve Stimulation (VNS):

• Used in children ≥4 years with refractory epilepsy.
• Device implanted to deliver periodic stimulation to the vagus nerve.
• Enhances GABAergic inhibition and decreases seizure frequency.
• Patients can activate the device if they sense an oncoming seizure.

3. Deep Brain Stimulation (DBS):

• Implanted in brain regions like the thalamus or hippocampus.
• Sends electrical impulses to modulate abnormal neuronal firing.
• Used in adolescents and adults, not suitable for children with immature brains.

4. Surgical Resection:

• Removal of the epileptogenic brain region.
• Suitable for focal epilepsies with well-localised origin.
• Can be curative in select patients.

TLDR: Non-drug therapies for epilepsy include ketogenic diets, VNS, DBS, and surgical resection. They are crucial for patients who do not respond to medication and can significantly reduce seizure frequency, though none are true cures.

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2. Explore Advances in Epilepsy Research

a. Review current trends in epilepsy research, including advances in genetic research, novel drug development and treatments, and brain stimulation technologies

Genetic-Based Therapies:

• Many epilepsies are caused by single-gene mutations.
• Understanding whether the mutation causes a gain- or loss-of-function helps guide therapy choice.

Drug Development:

• Cannabidiol (CBD):

  • Studied in Lennox-Gastaut and Dravet syndromes.
  • Mechanism unclear; may enhance bioavailability of existing AEDs.
  • Often used with clobazam, stiripentol, and others.

• Repurposed drugs:

  • Benfotiamine: GABA_A receptor modulator; originally for dementia and stroke.
  • Phenylbutyrate: Enhances GABA receptor trafficking; under trial for GABA_A-related genetic epilepsies.

Precision Medicine:

1. Antisense Oligonucleotides (ASOs):

   • Bind RNA of mutant gene to prevent translation or alter splicing.
   • Used in Dravet syndrome (e.g., SCN1A mutations).
   • Highly specific but have delivery and cost challenges.

2. Small Interfering RNAs (siRNA):

   • Work via RNA-induced silencing complex (RISC).
   • Cleave disease-causing mRNA.
   • Limitation: short half-life, poor BBB penetration.

3. Splice Switching Oligonucleotides:

   • Modify pre-mRNA splicing to promote healthy isoforms.
   • Emerging as personalised therapies.

TLDR: Future therapies focus on genetic precision — ASOs, siRNAs, and splicing modulators aim to fix root causes of epilepsy. Drug repurposing and CBD-based therapies are also under study. Brain stimulation and personalised interventions will play increasing roles.

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TREATMENT AND MANAGEMENT OF CARDIOVASCULAR DISEASES

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Hypertension

🧬 Major Systems Involved in BP Regulation

• Vascular Endothelium: Releases NO (vasodilator) and endothelin (vasoconstrictor).

• Sympatho-adrenomedullary (SAM) System:

  • Noradrenaline & adrenaline act on α- and β-adrenoceptors.
  • Affects heart rate (HR), stroke volume (SV), and systemic vascular resistance (SVR).

• Renin-Angiotensin-Aldosterone System (RAAS):

  • Renin → Ang I → Ang II → vasoconstriction, aldosterone release → Na⁺/water retention

🖼️ Diagram: RAAS Pathway

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💊 Antihypertensive Drug Classes & Mechanisms

1. β-blockers (e.g., atenolol, propranolol)

   • Block β1 in the heart → ↓ HR, ↓ contractility → ↓ CO
   • Also ↓ renin release from kidney 🔗 Mechanism overview

2. ACE inhibitors (e.g., enalapril, perindopril)

   • Inhibit Ang I → Ang II conversion → ↓ vasoconstriction, ↓ aldosterone

3. ARBs (e.g., irbesartan, candesartan)

   • Block Ang II at AT1 receptors → ↓ vasoconstriction, aldosterone effects

4. Calcium Channel Blockers (CCBs)

   • Dihydropyridines (e.g., amlodipine): target vascular smooth muscle
   • Non-dihydropyridines (e.g., verapamil): act on cardiac muscle too

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⚠️ Side Effects, Interactions, Contraindications

Class	Key Side Effects	Cautions
β-blockers	Fatigue, bronchospasm, impotence	Avoid in asthma/COPD; don’t combine with NDHP CCBs
ACE inhibitors	Dry cough, angioedema, hyperkalaemia	Switch to ARB if cough intolerable
ARBs	Dizziness, hyperkalaemia	Avoid in pregnancy
CCBs	Ankle oedema, headache	Dihydropyridines preferred in older adults

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🫀 Atherosclerosis

💊 Pharmacological Interventions

• Anti-hypertensives: reduce endothelial stress

• Lipid-lowering agents:

  • Statins: inhibit HMG-CoA reductase → ↓ cholesterol synthesis, ↑ LDL clearance
  • Ezetimibe: ↓ cholesterol absorption from gut
  • Fibrates: ↑ lipoprotein lipase (LPL) → ↓ triglycerides
  • PCSK9 inhibitors: ↑ LDL receptor expression

📈 Statins Visual: Statin MoA diagram

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🩻 Device Interventions

Type	Details
Surgical	Bypass grafting (for diffuse/complex blockages), long recovery time
Endovascular	Balloon angioplasty or stenting (for focal lesions), quick recovery

🔗 Overview: Coronary angioplasty animation

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️ Infarction

🧬 Haemostasis Overview

• Platelet adhesion → activation (via ADP, TXA₂) → aggregation (via GPIIb/IIIa)
• Coagulation cascade → thrombin converts fibrinogen → fibrin → clot formation
• Clot formation becomes pathological in atherothrombosis or embolism

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💊 Drug Mechanisms for Infarction

Drug Class	Examples	Mechanism
Anticoagulants	Warfarin, heparin, DOACs	Inhibit thrombin or factor Xa to prevent clotting
Antiplatelets	Aspirin, clopidogrel	Inhibit platelet aggregation via COX or P2Y12
Fibrinolytics	Alteplase, streptokinase	Promote fibrin breakdown (plasminogen activators)

🚫 Thrombolytics (e.g., alteplase) contraindicated in haemorrhagic stroke

🧬 Diagram: Aspirin mechanism

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⚠️ Side Effects & Clinical Use

• Bleeding is a major risk across all drug classes
• Warfarin: narrow therapeutic index, many drug interactions
• Heparin: immediate action but must be injected, risk of thrombocytopenia
• Fibrinolytics: time-sensitive, one-time use only

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🏃‍♂️ CVD and Aerobic Exercise

🔬 Dyslipidaemia in CVD Pathophysiology

• ↑ LDL & triglycerides, ↓ HDL → lipid accumulation in vessels → plaque formation
• Endothelial dysfunction + lipid stress = initiation of atherosclerosis

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🧬 Mechanisms of Exercise in Lipid Homeostasis

• ↑ LPL activity → ↑ breakdown of VLDL and chylomicrons
• ↑ HDL, ↓ LDL
• ↑ Mitochondrial density in muscle → ↑ fatty acid oxidation
• >150 min/week of moderate aerobic exercise recommended

🎥 Visual overview: Aerobic exercise on lipid metabolism

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❤️ Exercise in CVD Prevention and Management

• ↓ Blood pressure via:

  • Improved endothelial function
  • ↓ sympathetic tone

• ↑ Cardiac output & stroke volume via mild ventricular hypertrophy

• Reduces overall cardiovascular risk and enhances recovery post-infarction

📝 Summary:

• Exercise has statin-like effects on lipids
• Also improves vascular flexibility and cardiac output