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These notes cover Chronic Lymphoid Leukaemia (CLL), including its cell appearance, locations, function, and other chronic lymphoid leukemias. It also details Sickle Cell Disease, its cause, genetic mutation, molecular details, and consequences of sickling. Finally, it provides information about the skin and integumentary system, including layers and functions.
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**Chronic Lymphoid Leukaemia (CLL)** - **CLL** is a type of leukaemia originating from **B-cells**. - The CLL cells lie between the **B-lymphoblast** and **B-lymphocyte** stages, meaning they share characteristics of both immature and mature B-cells. - **Cell appearance**: -...
**Chronic Lymphoid Leukaemia (CLL)** - **CLL** is a type of leukaemia originating from **B-cells**. - The CLL cells lie between the **B-lymphoblast** and **B-lymphocyte** stages, meaning they share characteristics of both immature and mature B-cells. - **Cell appearance**: - CLL cells resemble mature B-cells. - They are **fragile** and can rupture easily during lab procedures, forming **smudge cells**, which can help diagnose CLL. **CLL Cell Locations** - Like normal B-cells, CLL cells travel to the **lymph nodes, liver, and spleen**. - This leads to the enlargement of these organs, especially the **lymph nodes**, causing **generalized lymphadenopathy**. **CLL in Lymph Nodes** - Enlarged lymph nodes filled with CLL cells are referred to as **small lymphocytic lymphomas**. - CLL cells in the lymph nodes can acquire mutations, leading to the formation of true masses (tumors), which can progress to **diffuse large B-cell lymphoma (Richter transformation)**. - If one lymph node becomes significantly larger than others, it may indicate this transformation. **CLL Function and Antibody Production** - CLL cells poorly produce antibodies, leading to **hypogammaglobulinemia** (reduced antibodies in the blood). - This immune deficiency makes CLL patients more vulnerable to infections. - CLL cells may produce faulty antibodies, causing **autoimmune hemolytic anemia** where the immune system attacks red blood cells. **Other Chronic Lymphoid Leukemias** - Besides CLL, other chronic lymphoid leukemias include: - **Hairy cell leukemia** (a B-cell leukemia) - **Adult T-cell leukemia** - **Mycosis fungoides** (a T-cell leukemia) In summary, **CLL** is a B-cell leukemia that primarily affects the lymph nodes, liver, and spleen, causes immune deficiencies, and can progress to a more aggressive form of lymphoma. **Overview of Sickle Cell Disease (Sickle Cell Anemia):** - **Sickle cell disease (SCD)** is also called **sickle cell anemia** or simply \"sickle cell.\" - It's a **genetic disease** where **red blood cells (RBCs)** can take a **crescent (sickle)** shape. - This change in shape leads to: - **Easier destruction** of RBCs, causing **anemia**. - Other health complications. **Cause of Sickle Cell Disease:** - Sickle cell disease is caused by defective **hemoglobin** (the oxygen-carrying protein in RBCs). - **Hemoglobin Structure:** - Made of **four peptide chains**, each bound to a **heme group**. - The most affected hemoglobin in sickle cell is **Hemoglobin A (HbA)**, which consists of: - **Two α-globin chains**. - **Two β-globin chains**. - In sickle cell, the **β-globin chains** are misshapen due to a mutation. **Genetic Mutation in Sickle Cell Disease:** - The mutation occurs in the **beta-globin gene (HBB gene)**. - **Sickle cell disease** is an **autosomal recessive disease**, meaning: - Both copies of the **HBB gene** must be mutated for the person to have the disease. - **Sickle cell carriers** (sickle trait) have one mutated and one normal copy of the gene. **Sickle Cell Trait (Carriers):** - Carriers usually **don't have health problems** unless exposed to extreme conditions (e.g., **high altitude** or **dehydration**), where symptoms similar to sickle cell disease can appear. - **Heterozygote advantage**: Sickle trait offers protection against **Plasmodium falciparum malaria**. - This gives an **evolutionary advantage** in regions with high malaria prevalence (e.g., Africa, southern Asia). - However, it results in a **higher rate** of sickle cell disease in these regions. **Molecular Details of the Mutation:** - The sickle cell mutation is a **nonconservative missense mutation**. - The 6th amino acid in the β-globin chain changes from **glutamic acid (hydrophilic)** to **valine (hydrophobic)**. - This results in the production of **sickle hemoglobin (HbS)**. **Sickling Process:** - **HbS** functions normally when oxygenated but **changes shape when deoxygenated**, leading to: - **Aggregation** of HbS proteins. - Formation of **long polymers** that distort RBCs into the sickle shape, known as **sickling**. - Factors that promote sickling: - **Acidosis** (low pH), reducing hemoglobin's oxygen affinity. - **Low-flow vessels** where RBCs lose oxygen. **Consequences of Sickling:** 1. **Intravascular Haemolysis:** - **Repeated sickling damages RBC membranes**. - Leads to **premature RBC destruction** in the bloodstream (**intravascular hemolysis**). - Causes **anemia** (low RBCs/hemoglobin levels). - **Free hemoglobin** in plasma is bound by **haptoglobin**, which recycles it. - **Low haptoglobin levels** indicate intravascular hemolysis. - Heme group recycling produces **unconjugated bilirubin**, which can lead to: - **Jaundice** (yellowing of the skin/eyes). - **Bilirubin gallstones**. 2. **Bone Marrow Compensation:** - The bone marrow produces more **reticulocytes** (immature RBCs) to counteract anemia. - This can cause: - **New bone formation**. - Expansion of skull medullary cavities, resulting in: - **Enlarged cheeks**. - **'Hair-on-end' appearance** on skull X-rays. - **Extramedullary hematopoiesis** (RBC production outside the bone marrow), commonly in the **liver**, causing **hepatomegaly**. 3. **Vaso-occlusion (Blockage of Blood Flow):** - Sickled RBCs clog small capillaries, leading to **vaso-occlusion**. - In **infancy**, they can block blood flow in bones of the hands and feet, causing **dactylitis** (pain/swelling of digits). - In older patients, they block other bones, causing: - **Sickle cell pain crises**. - **Avascular necrosis** of bones. - Blockages in the **spleen** lead to: - **Splenic infarcts** (tissue death). - **Splenic sequestration** (blood pooling in the spleen, a life-threatening condition). - **Auto-splenectomy**: Repeated infarcts cause the spleen to shrink and scar down to nothing. 4. **Impaired Immune Function (Due to Splenic Damage):** - **Loss of spleen function** leads to vulnerability to **encapsulated bacteria** (e.g., Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Salmonella). - Also leads to the presence of **Howell-Jolly bodies** (nuclear remnants in RBCs) visible on a blood smear. 5. **Cerebral and Organ Damage:** - **Cerebral vaso-occlusion** can cause: - **Strokes**. - **Moya-moya disease**: Damage to cerebral vessels leads to development of collateral vessels, giving a \"puff-of-smoke\" appearance on imaging. - **Lung vaso-occlusion** can cause: - **Acute chest syndrome** (a dangerous complication). - Hypoxia worsens vaso-occlusion due to the lung's natural **hypoxic vasoconstriction**. - **Kidney damage**: Clogging in the renal papillae can lead to: - **Necrosis**. - **Hematuria** (blood in urine) and **proteinuria** (protein in urine). - **Priapism**: In men, blockage of penile vasculature can cause **painful, prolonged erection**. **Diagnosis of Sickle Cell Disease:** - **Newborn screening** includes testing for sickle cell. - Can be identified by: - Blood smear showing **sickled cells**. - **Protein electrophoresis** to detect HbS. **Treatment of Sickle Cell Disease:** 1. **Management of Sickling Factors**: - **Oxygen** and **fluids** help improve hypoxia and dehydration, which are factors that promote sickling. 2. **Pain Management**: - **Opioids** for managing **pain crises**. 3. **Antibiotics**: - Treat infections causing **acute chest syndrome**. 4. **Blood Transfusions**: - Used occasionally but can lead to: - **Iron overload**. - Development of **new antibodies** against future transfusions. 5. **Preventive Measures**: - **Prophylaxis with penicillin** in children. - **Polysaccharide vaccine** against **Streptococcus pneumoniae** to prevent sepsis and meningitis from encapsulated bacteria. 6. **Hydroxyurea**: - Increases **gamma globin** and **fetal hemoglobin (HbF)** production. - HbF doesn't have the mutated β-globin, which prevents sickling by inhibiting HbS polymerization. - Explains why sickle cell symptoms don't appear until a few months after birth (when adult hemoglobin replaces fetal hemoglobin). 7. **Bone Marrow Transplants**: - Rare but possible treatment for some patients. 8. **Gene Therapy**: - Research into gene therapy is ongoing, as sickle cell involves a single point mutation. **Summary of Sickle Cell Disease:** - **Autosomal recessive genetic disease** affecting the **β-globin subunit** of hemoglobin. - RBCs become sickled when deoxygenated, leading to their **premature destruction** and **vaso-occlusion**. - This results in **multiorgan damage** and a **shortened life span**. **Overview of the Skin and Integumentary System** - **Skin** is the largest organ, making up 16% of body weight. - The **integumentary system** consists of skin and accessory structures like oil and sweat glands. - Functions: - Protects against infections - Regulates body temperature - Contains nerve receptors for pain, sensation, and pressure. **Layers of the Skin** 1. **Epidermis** (outermost layer) - Thin outer layer made of multiple layers of keratinocytes (flat cells filled with **keratin**, a protective fibrous protein). - Keratinocytes produce **glycolipids** that prevent water loss. - **Stratum basale**: deepest layer containing **stem cells** and **melanocytes**. - **Melanocytes** produce **melanin**, a pigment that protects against UV damage and determines skin color. - **Keratinization process**: - Cells migrate from the **stratum basale** to the upper layers, flatten, produce keratin, and die. - Layers of the epidermis include: - **Stratum spinosum**: 8-10 cell layers, contains **dendritic cells** (immune cells). - **Stratum granulosum**: 3-5 layers; keratinization begins. - **Stratum lucidum**: present in **thick skin** (palms/soles), 2-3 layers of dead cells. - **Stratum corneum**: thick outer layer of dead, keratinized cells forming the **skin barrier**. 2. **Dermis** (middle layer) - Contains blood vessels, nerves, and sensory receptors. - Divided into two layers: - **Papillary layer** (thin, superficial): - Contains **fibroblasts** that produce **collagen**. - Contains **free nerve endings** (detect pain). - Responsible for **fingerprints**. - **Reticular layer** (thick, deep): - Contains tightly packed collagen and **elastin** (gives skin flexibility). - Houses sweat/oil glands, hair follicles - Regulates **temperature** through blood vessel dilation (heat loss) and constriction (heat conservation). 3. **Hypodermis** (subcutaneous layer) - Composed of **fat cells (adipocytes)**, **fibroblasts**, and connective tissue. - Functions: - Insulates the body - Provides padding - Anchors skin to underlying muscle. **Key Functions of the Skin** - **Protection**: Epidermis protects against pathogens and UV radiation. - **Temperature regulation**: Dermis controls sweating and blood flow to manage body temperature. - **Sensation**: Nerves in the dermis detect touch, pain, and pressure. - **Vitamin D production**: Epidermal cells use UVB light to produce Vitamin D. **Overview of Wound Healing** - **Wound healing** is the body's process of repairing damaged tissue. - Types of wounds: - **Acute wounds** (heal quickly in days/weeks). - **Chronic wounds** (e.g., bedsores, ulcers, infections) may last months. - **Tissue regenerative capacity**: - **Labile tissues** (e.g., skin, connective tissue, intestines): Heal well due to stem cells. - **Stable tissues** (e.g., liver): Heal through mature cell division (hyperplasia). - **Permanent tissues** (e.g., muscle, neurons, cartilage): Limited regeneration, often replaced by scar tissue. **Types of Wound Healing** 1. **Primary intention**: Wound edges are brought together (e.g., sutured wounds). Minimal scarring as stem cells regenerate tissue. 2. **Secondary intention**: Edges are far apart (e.g., large tissue loss, burns). Heals from the base upwards with connective tissue, leading to more scarring. 3. **Tertiary intention**: Wounds are left open to prevent infection (e.g., dog bites) and are closed later. **Steps in Wound Healing** 1. **Hemostasis** (blood clotting): - Blood vessels constrict, and **platelets** form a plug. - Platelet plug is reinforced by **fibrin**, creating a blood clot. 2. **Inflammation**: - Damaged cells release **cytokines** and **chemokines** that recruit immune cells (e.g., **macrophages** and **neutrophils**). - Blood vessels dilate and immune cells clean up debris, dead cells, and microbes. - Formation of a **scab**. 3. **Epithelialization**: - **Basal cells** in the epidermis proliferate to replace lost cells. - This occurs within 48 hours, forming a new, weak epidermal layer. 4. **Fibroplasia** (strengthening): - **Fibroblasts** in the dermis produce **collagen** that forms strong extracellular scaffolding. - Collagen also stimulates **angiogenesis** (new blood vessels). - **Granulation tissue** forms beneath the scab. 5. **Maturation** (final strengthening): - **Collagen crosslinking**: Collagen bonds form, increasing tensile strength. - **Collagen remodeling**: Old collagen is replaced. - **Contraction**: **Myofibroblasts** contract, pulling wound edges together. - **Repigmentation**: **Melanocytes** restore skin color. **Factors That Impair Healing** - **Reduced blood flow** (e.g., diabetes, atherosclerosis, prolonged compression): - Limits oxygen/nutrients and immune cells, leading to **necrosis**. - **Infection**: Pathogens compete for oxygen and prolong inflammation. - **Swelling (edema)**: Disrupts fibroblast activity and collagen formation. **Bone Fractures and Healing** **Bone Fractures Overview:** - **Causes:** Trauma, vitamin A deficiency, low bone density, and aging can all lead to bone fractures. - **Complications:** Fractures can cause tears in blood vessels, leading to disrupted nutrient supply. **Classification of Bone Fractures:** 1. **Position of Bone Ends:** - **Non-displaced:** Bone ends remain aligned. - **Displaced:** Bone ends are misaligned after the fracture. 2. **Completeness of the Break:** - **Complete:** Bone is completely broken. - **Incomplete:** Bone is only partially broken. 3. **Orientation of the Break:** - **Linear:** Fracture is along the bone\'s vertical axis. - **Transverse:** Fracture is along the bone's horizontal axis. 4. **Skin Penetration:** - **Compound (Open):** Bone penetrates the skin. - **Simple (Closed):** Bone does not penetrate the skin. **Bone Healing Process** 1. **Hematoma Formation (Stage 1):** - Occurs immediately after the fracture. - Blood accumulates at the fracture site, forming a **hematoma**. - Results in swelling, pain, and cell death due to blood vessel damage. 2. **Fibrocartilaginous Callus Formation (Stage 2):** - Starts after a few days. - New blood vessels form, and **granulation tissue** fills the gap between fractured bone ends. - A **soft callus** forms around the fracture to stabilize it. 3. **Bony Callus Formation (Stage 3):** - Occurs after a few weeks. - The soft callus hardens into a **bony callus**. - New bone begins to replace the soft tissue. 4. **Bone Remodeling (Stage 4):** - Occurs over several months. - **Compact bone** is laid down, and **osteoblasts** (bone-forming cells) remodel the bony callus into stronger bone. - Healing is complete once the bone is fully restored. **Osteomyelitis (Bone Infection)** - **Definition:** Infection of the bone, often caused by **Staphylococcus aureus**. - **Causes:** Can occur during a fracture or via bloodstream infection. - **Symptoms:** Severe pain, swelling, and pus formation. - **Complications:** - Necrosis (death) of bone cells, especially at the ends of long bones. - If untreated, osteomyelitis can become chronic and lead to further bone damage. - New bone formation may occur in response to infection, but the bone becomes weaker overall. **Summary:** - Bone fractures can be classified by the position of the bone ends, the completeness and orientation of the break, and whether or not the fracture penetrates the skin. - Bone healing involves four stages: hematoma formation, soft callus formation, bony callus formation, and bone remodeling. - **Osteomyelitis** is a serious infection of the bone that can lead to bone death and chronic complications if not treated promptly Haven't made notes on: make them if I have time or not just read them **Kids\' Bone Growth and Development** 1. **Long Bones in Children:** - Long bones (arms, legs) undergo rapid growth from childhood to adolescence. - Growth occurs at the **growth plate (Physis)**, located at the ends of long bones. - Growth plates are made of cartilage and determine future bone length and shape. 2. **Growth Rate:** - Doctors can assess growth rate by plotting age and height on a **growth chart**. - A steeper line on the chart indicates a faster growth rate. - Growth rates vary between different long bones; for example: - **Knee region (thighbone/femur)** grows around **10 mm/year**. - **Ankle** grows around **4 mm/year**. 3. **Growth Spurts:** - Growth rates increase during **growth spurts**, especially in preteens or early teens. - Growth slows as children approach **skeletal maturity**: - Around age **14 for girls** and **16 for boys**. - Growth rates on either side of the body should match. - Growth spurts and rates vary depending on factors like **age, sex, family history,** and **maturity**. **Limb Deformities** 1. **Limb Length Discrepancy (LLD):** - Occurs when one limb is longer than the other. - Causes include: - Naturally differing growth rates between limbs. - **Congenital conditions** (e.g., **Hemimelia**) where bones don't develop properly. - **Injury or infection** affecting the growth plate. 2. **Angular Deformities:** - **Angular deformities** happen when bones grow at the wrong angle, leading to a tilted limb. - Causes: - Can be **congenital** (present from birth) or due to diseases like **Rickets**. - Injuries to the bone or growth plate can also cause angular deformities. - Like two cars at different speeds, small differences in bone angle or length can worsen over time. **Impact and Treatment** - **Limb length discrepancies** and **angular deformities** can impact **mobility** and cause **joint problems** or **arthritis** if left untreated. - **Surgical interventions** can help correct these deformities and protect joints. - Specialized care and innovative techniques are available for growing children at **Children's Hospital Colorado Orthopedics Institute**. **Gene Activation and Deactivation in Epigenetics** - **Overview of DNA and Chromatin:** - Each skin cell contains approximately **2 meters of DNA** packed into a small space. - DNA combines with proteins called **histones** to form a complex known as **chromatin**. - DNA is wrapped around histones in units called **nucleosomes**, which resemble **beads on a string**. - Chromatin is further condensed into **chromosomes**; humans have **46 chromosomes**. - The core of a nucleosome consists of DNA wrapped around an **octamer of histones** (H2A, H2B, H3, H4). - **Gene Expression in Different Cells:** - All cells in the body (e.g., skin, muscle, liver) contain the **same DNA sequence**, but express different sets of genes. - This differential gene expression allows cells to have **different functions and structures**. - Epigenetic modifications regulate which genes are turned on or off in each cell type. - **Epigenetic Modifications:** - **Epigenetics** refers to changes **above the DNA** (without altering the DNA sequence) that affect gene expression. - These changes are **long-lasting** and play a role in turning genes on or off. **Three Key Epigenetic Processes** 1. **DNA Methylation:** - **Methylation** involves the addition of a **methyl group** directly to a **cytosine** base in a **CpG sequence** (cytosine-phosphate-guanine). - **Methylation of CpG sites** in **promoter regions** (areas before the start of a gene) leads to **gene silencing** (deactivation). - This process prevents certain genes from being expressed. 2. **Histone Modification:** - Chemical groups, such as **acetyl** or **methyl** groups, are added to **histone tails** (proteins around which DNA is wrapped). - These modifications can either activate or repress gene expression: - **Histone H3K9 acetylation** is linked to **gene activation** (transcription). - **Histone H3K27 trimethylation** is linked to **gene repression** (transcription silencing). 3. **RNA Changes:** - Epigenetic changes can also involve **RNA**, although this wasn't discussed in detail in the transcript. RNA can regulate gene expression by modifying how DNA is transcribed into proteins. **Epigenetic Patterns and Disease:** - Epigenetic modifications are established during **early development** and are maintained through **cell division**. - In diseases like **cancer**, these epigenetic patterns are often **disrupted**, leading to abnormal gene expression. **Overview of Inflammation** - **Inflammation** is the body\'s response to **infectious or harmful stimuli**, aiming to: - **Recruit defense cells** (immune cells). - **Inactivate or destroy pathogens** (e.g., bacteria, viruses). - Begin **tissue repair** in the damaged area. - **Inflammation** is often indicated by the suffix **\"-itis\"** (e.g., **dermatitis** = skin inflammation, **arthritis** = joint inflammation). **Structure of Tissues Involved in Inflammation** - **Layers of tissue** include the **surface skin** and the underlying **submucosa**. - Beneath the submucosa are **blood vessels** and **lymphatic vessels**. - **Blood vessels** carry immune cells and proteins to the site of injury or infection. - **Lymphatic vessels** carry immune cells (like **lymphocytes**, **B cells**, and **T cells**) to **lymph nodes** or organs like the **spleen**. **Key Immune Cells and Mediators in the Blood** - The blood contains: - **Erythrocytes** (red blood cells). - **Monocytes** (which become macrophages in tissues). - **Neutrophils** (phagocytic cells). - **Inflammatory mediators**, which are substances that promote inflammation. These include: - **Plasma-derived mediators** like **complement proteins** and **kinins**, which are made in the **liver** and circulate in the blood. - **Cell-derived mediators**, like **cytokines** and **histamine**, are released directly from immune cells (e.g., **mast cells**, **macrophages**). **Immune Cells Present in Tissues** - **Mast cells** in tissues contain **histamine** granules, crucial for promoting inflammation. - **Phagocytic cells** like **tissue macrophages** and **dendritic cells** (called **Langerhans cells** in the skin) are also present. These cells engulf pathogens and present antigens to other immune cells. **The Inflammatory Process** 1. **Injury and Pathogen Entry**: - When tissue is damaged, **pathogens** may infiltrate the tissue. - These pathogens express surface molecules called **PAMPs** (pathogen-associated molecular patterns), which are recognized by immune cells like **mast cells** and **macrophages**. 2. **Mast Cell Response**: - **Mast cells** respond by releasing **histamine** from their granules. - **Histamine** triggers: - **Vasodilation** (blood vessels widen, increasing blood flow to the area). - **Increased vascular permeability** (blood vessels become \"leaky,\" allowing immune cells and proteins to move into the tissue). 3. **Macrophage Response and Cytokine Release**: - **Macrophages**, upon recognizing the pathogen, release **cytokines** like **TNF-alpha** (tumor necrosis factor-alpha) and **interleukin-1 (IL-1)**. - **Cytokines** have both **local** and **systemic** effects: - **Local effects**: - Vasodilation and increased vascular permeability. - **Tissue repair** is promoted by stimulating **fibroblasts** to produce collagen. - **Systemic effects**: - **Fever** (raised body temperature). - **Leukocytosis** (increase in white blood cells). 4. **Recruitment of Immune Cells**: - The increase in blood flow and vascular permeability allows immune cells like **neutrophils** and **monocytes** to migrate into the inflamed tissue. - **Monocytes** become **macrophages** when they enter the tissue. - This migration process is called **diapedesis** (immune cells squeezing through blood vessel walls). **Role of Inflammatory Mediators** 1. **Cell-Derived Inflammatory Mediators**: - **Cytokines** (e.g., TNF-alpha, interleukin-1) promote inflammation and tissue repair. - **Histamine**, released by **mast cells**, causes vasodilation. - **Arachidonic acid metabolites** (products like **prostaglandins** and **leukotrienes**): - **Prostaglandins** cause **fever** and **pain**. - **Leukotrienes** increase vascular permeability and act as chemoattractant, promoting the migration of immune cells to the site. **Characteristics of Inflammation** The four classical signs of inflammation are: 1. **Redness (Rubor)** -- due to increased blood flow from vasodilation. 2. **Heat (Calor)** -- also due to increased blood flow. 3. **Swelling (Tumor)** -- caused by fluid and proteins leaking from the blood vessels into the tissue. 4. **Pain (Dolor)** -- due to sensory nerve stimulation and **prostaglandin** activity. 5. **Loss of function** may occur, especially in cases of **chronic** inflammation. **The Adaptive Immune Response** - If the pathogen persists and is not quickly cleared, the **adaptive immune system** is activated. - **Antigen-presenting cells** (e.g., **dendritic cells** or **macrophages**) engulf the pathogen and present its antigens to **B and T cells** in the lymph nodes. - **B cells** differentiate into **plasma cells** that secrete antibodies. - **T cells** differentiate into **T helper cells** or **T killer cells**. - **Antibodies** (e.g., **IgM**, **IgG**, **IgA**) contribute to the inflammatory response by helping to neutralize the pathogen and bring the immune system back to normal function. **Conclusion: The Role of Inflammatory Mediators** - A wide range of **inflammatory mediators**---plasma-derived and cell-derived---play roles in recruiting immune cells, promoting inflammation, and driving tissue repair. - The balance of **innate** and **adaptive immune responses** ensures pathogens are eliminated, and tissues are repaired, ultimately helping the body recover from injury or infection. **Key Takeaways** - **Inflammation** is a complex process involving **vasodilation**, **immune cell recruitment**, and **tissue repair**. - **Cytokines**, **complement proteins**, **histamine**, and **arachidonic acid metabolites** all play significant roles in coordinating the inflammatory response. - The **innate immune system** responds first, with the **adaptive immune system** providing a targeted response if pathogens persist. **Overview of Hypersensitivity Reactions** - **Hypersensitivity** occurs when the immune system reacts to harmless substances in a way that ends up damaging the body instead of protecting it. - There are **four types of hypersensitivity**. **Type I Hypersensitivity** - **Type I hypersensitivity** relies on **Immunoglobulin E (IgE)** antibodies. - Since **IgE** is involved, this type of reaction is referred to as **IgE-mediated hypersensitivity**. - Type I reactions are often called **immediate hypersensitivities** because they occur rapidly, usually within **minutes** of exposure. - **Most allergic reactions** (e.g., to pollen, animal dander, foods) are **IgE-mediated** and are classified as Type I hypersensitivity reactions. **What Causes Allergies?** - The word \"allergy\" means a reaction to something external to the body. - Allergens are typically substances like: - **Inhalants**: pollen, animal dander, mold. - **Ingested items**: foods, drugs, medications. - **Contact allergens**: latex, lotions, soaps, or bee stings. - Allergies occur in two phases: - **Sensitization** (first exposure to the allergen). - **Subsequent exposure**, which results in a more serious reaction. **Genetic Predisposition and Allergies** - People who develop allergic reactions usually have a **genetic predisposition**. Their immune system is more likely to overreact to harmless substances. - **T-helper cells** are key players in this reaction, and people with allergies have **T-helper cells** that are hypersensitive to certain antigens. - Allergies tend to run in families because these **T-helper cell genes** are inherited. **The Sensitization Phase** 1. **First Exposure to the Allergen**: - When someone is first exposed to an allergen (e.g., **ragweed pollen**), the antigen (pollen molecule) is picked up by **antigen-presenting cells** (APCs) in the body\'s membranes (e.g., the airway). - Examples of **APCs** include **dendritic cells** and **macrophages**. - The antigen-presenting cell carries the allergen to the **lymph nodes** to present it to **T-helper cells**. 2. **T-Helper Cell Activation**: - Initially, the **T-helper cell** hasn\'t encountered this specific antigen before. - Once the T-helper cell binds the antigen and **costimulatory molecules** it becomes **primed**. - The T-helper cell then differentiates into a **TH2 cell**, a process influenced by **interleukins** (small proteins). 3. **B Cell Activation and Class-Switching**: - The **TH2 cell** releases **interleukin 4** (IL-4), which prompts **B cells** to undergo **antibody class-switching**. - The B cell switches from producing **IgM** antibodies to producing **IgE antibodies** that are specific to the allergen (e.g., ragweed pollen). - These **IgE antibodies** have a high affinity for **Fc epsilon receptors** on **mast cells**. 4. **Mast Cells Gear Up**: - Once the **IgE antibodies** bind to the surface of **mast cells**, the mast cells are \"armed\" for action, completing the **sensitization phase**. **The Second Exposure: The Allergic Reaction** 1. **Second Exposure to the Allergen**: - When the person is exposed to the allergen again (e.g., ragweed pollen), the allergen binds to the **IgE antibodies** attached to **mast cells**. - The mast cell requires **cross-linking** of two or more IgE antibodies by antigens, which signals the mast cell to release **pro-inflammatory mediators**. 2. **Mast Cell Degranulation and Mediators**: - **Degranulation** releases **histamine** and other pro-inflammatory mediators, leading to the symptoms of an allergic reaction. - **Histamine** binds to **H1 receptors**, causing: - **Bronchoconstriction** (smooth muscle contraction around the airways), making it harder to breathe. - **Vasodilation** and **increased vascular permeability**, causing blood vessels to expand, increasing blood flow, and allowing fluid to leak into surrounding tissues, leading to **swelling** and **hives** (**urticaria**). 3. **Additional Pro-inflammatory Mediators**: - Mast cells also release mediators that activate **eosinophils** and **proteases**. These proteases break down large proteins into smaller peptides. **Phases of the Allergic Reaction** - **Early Phase Reaction**: - Occurs **within minutes** of the second exposure. - Mediators like **histamine**, **eosinophils**, and **proteases** cause the classic symptoms of an allergic reaction (e.g., difficulty breathing, swelling, hives). - **Late Phase Reaction**: - Occurs **8-12 hours** after the second exposure. - More immune cells, including **TH2 cells**, **eosinophils**, and **basophils** are recruited to the site of the allergen. - Mediators include **interleukins** (IL-4, IL-5, IL-10) and **leukotrienes**. - **Leukotrienes** (e.g., **LTB4**, **LTC4**) can cause: - **Smooth muscle contraction** and **epithelial damage** similar to histamine. - Attraction of more immune cells like **neutrophils**, **mast cells**, and **eosinophils** to the allergen site, even after the allergen is gone. **Symptoms of Type I Hypersensitivity** - **Mild symptoms** include: - **Hives** (urticaria). - **Eczema**. - **Allergic rhinitis** (inflammation of the nose). - **Asthma**. - **Severe Reactions**: - In some cases, exposure to allergens like bee stings, peanuts, or seafood can trigger a life-threatening allergic reaction called **anaphylactic shock**. - **Anaphylaxis** involves: - **Severe airway constriction**, preventing the body from getting enough oxygen. - **Increased vascular permeability**, which causes a drop in blood pressure and can result in vital organs (e.g., brain) not receiving enough oxygenated blood. **Treatment for Type I Hypersensitivity** - **Antihistamines**: Block histamine receptors (H1 receptors), reducing bronchoconstriction and vascular permeability. - **Corticosteroids**: Reduce the overall **inflammatory response**. - **Epinephrine (adrenaline)**: Used for severe reactions (e.g., anaphylaxis). Administered via **EpiPen** or **intravenous injection**. - Epinephrine constricts blood vessels, preventing anaphylactic shock. - **Medical attention** is crucial for serious Type I reactions, especially since symptoms can improve temporarily before worsening again. **Type II Hypersensitivity (Cytotoxic Hypersensitivity)** - **Definition**: Type II hypersensitivity, also called **cytotoxic hypersensitivity**, involves antibody-mediated destruction of healthy cells. - **Tissue-specific**: Antibodies typically target specific tissues or organs. - **Main antibodies involved**: **IgM** and **IgG** antibodies. **Mechanism Overview:** - The immune system usually attacks "non-self" cells due to **central tolerance**, which eliminates self-reactive immune cells during development in the thymus (T cells) and bone marrow (B cells). - In Type II hypersensitivity, self-reactive **B cells** escape destruction, producing **IgM** or **IgG** antibodies that attach to antigens on host cells. **Types of Antigens Involved:** 1. **Intrinsic antigens**: Antigens that the host cell normally produces. 2. **Extrinsic antigens**: Antigens from external sources like infections or medications (e.g., penicillin binding to red blood cells). **Cytotoxic Mechanisms of Type II Hypersensitivity:** 1. **Complement System Activation**: - **IgG** or **IgM antibodies** activate the **complement system** (C1 to C9) upon binding to antigens on host cells. - **Neutrophils** are attracted by complement proteins **C3a, C4a, and C5a** and release toxic enzymes that damage cells. - Example diseases: - **Autoimmune hemolytic anemia** (antibodies destroy red blood cells). - **Thrombocytopenia** (destruction of platelets). - **Goodpasture's syndrome** (antibodies target collagen in the kidneys and lungs). 2. **Membrane Attack Complex (MAC)** Formation\*\*: - The final complement proteins (**C5b to C9**) form the **MAC**, which punches holes in the cell membrane, causing **cell lysis** (cell death due to swelling and bursting). 3. **Opsonization and Phagocytosis**: - Antibodies bound to cells are marked by **C3b** for destruction. - **Phagocytes** (like **macrophages**) recognize the antibody-coated cell, engulf it, and destroy it in the spleen. 4. **Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)**: - **Natural killer (NK) cells** recognize antibody-coated cells and release **perforins**, which form pores in the cell membrane. - They also release **granzymes** and **granulysin**, which enter the cell through the pores and induce **apoptosis** (programmed cell death without inflammation). **Non-Cytotoxic Type II Hypersensitivities (Antibody-Mediated Cellular Dysfunction):** - **Function disruption**: In some cases, antibodies bind to receptors and interfere with cell function instead of killing the cell. - Examples: - **Myasthenia gravis**: Antibodies block **acetylcholine receptors**, preventing muscle contraction and causing muscle weakness. - **Grave's disease**: Antibodies stimulate **thyroid hormone receptors**, causing overproduction of thyroid hormones (**hyperthyroidism**). **Diagnostic Tests:** - **Direct Coomb's test**: Detects antibodies attached to red blood cells (RBCs). - **Procedure**: RBCs are mixed with **Coombs reagent** (anti-human globulin). If agglutination (clumping) occurs, it indicates the presence of antibodies on RBCs. - Used to diagnose autoimmune hemolytic anemia. - **Indirect Coomb's test**: Detects antibodies in the serum (before exposure to an antigen). - **Procedure**: Patient's serum is mixed with lab RBCs, then Coombs reagent. Agglutination indicates antibodies or complement in the serum. - Used for **blood group incompatibility**, such as in blood transfusions or Rh factor mismatches during pregnancy. **Type III Hypersensitivity Reaction** - **Definition**: Type III hypersensitivity occurs when **antigen-antibody complexes** (immune complexes) deposit in **blood vessel walls**, leading to **inflammation** and **tissue damage**. - **Immune Complexes**: Made of **antigen** and **antibody** (IgG or IgM). - **Antibodies** (produced by plasma cells, i.e., mature **B cells**) bind to **soluble antigens** in the blood to form immune complexes. **Mechanism Overview:** - **Antibody Production**: - B cells initially produce **IgM**. - After **class switching**, B cells produce **IgG**. - **T helper cells** help activate B cells, leading to class switching from IgM to IgG. - **Type III Immune Complexes**: - Formed when antibodies bind to **soluble antigens** (not cell surface antigens, which is a feature of Type II hypersensitivity). **Major Distinctions between Type II and Type III Hypersensitivities:** 1. **Type II Hypersensitivity**: Antibodies bind to **cell surface antigens**. 2. **Type III Hypersensitivity**: Antibodies bind to **soluble antigens**, forming immune complexes that deposit in tissues. **Example Disease: Systemic Lupus Erythematosus (SLE)** - **Lupus**: A **type III hypersensitivity** autoimmune disease. - **Antibodies involved**: **IgG antibodies** target **DNA** and **nucleoproteins**, which are self-antigens. - Normally, the immune system avoids attacking self-antigens through **tolerance**. - In lupus, self-reactive **B cells** and **T cells** escape tolerance and attack the body\'s own DNA. - **Formation of Immune Complexes**: - DNA from damaged cells acts as an **autoantigen**. - **IgG antibodies** bind to the DNA, forming **antigen-antibody complexes**. - These small immune complexes are not easily removed from the blood, leading to their **deposition** in blood vessel walls. **Complement System Activation** - **Complement system**: A series of proteins (**C1-C9**) activated by immune complexes. - **Key Actions**: 1. **C1** binds to immune complexes, triggering the activation of **C2 to C9** proteins. 2. **C3a, C4a, C5a fragments**: - **Increase vascular permeability** (leading to **edema**). - Act as **chemokines**, attracting **neutrophils** 3. **Neutrophils**: - Attempt to **phagocytize** immune complexes but typically fail. - **Degranulate**, releasing **lysosomal enzymes** and **reactive oxygen species**, leading to **inflammation**, **tissue damage**, and **vasculitis** (inflammation of blood vessels). - **Complement consumption**: In **type III hypersensitivity**, complement proteins (**C3 and C4**) are used up rapidly. **Low complement levels** in the blood can help track disease progression. **Clinical Symptoms of Type III Hypersensitivity:** - **Affected tissues**: Symptoms depend on where the immune complexes are deposited, not where they are formed. - **Common sites**: 1. **Kidneys**: Deposition in the kidney\'s **basement membrane** causes **glomerulonephritis** (kidney inflammation). 2. **Joints**: Immune complex deposition in the joints causes **arthritis** (joint inflammation). **Example 2: Serum Sickness** - **Serum Sickness**: A reaction to foreign serum proteins (e.g., anti-venom treatment). - **Mechanism**: After receiving a serum treatment (like anti-venom), the body makes antibodies against the foreign proteins. - **Secondary exposure**: Upon a second exposure, pre-existing antibodies bind to the foreign serum proteins, forming immune complexes complexes. - **Result**: These immune complexes cause **vasculitis** and **tissue necrosis** (destruction). **Key Concepts:** - **Gases and Pressure**: Gases move from areas of **higher pressure** to areas of **lower pressure** (similar to diffusion). - **Breathing Mechanism**: Involves changes in pressure inside and outside the lungs to move air in and out. **Anatomy Involved in Breathing:** 1. **Respiratory Tract**: Includes the **nose**, **mouth**, **larynx**, **trachea**, **bronchi**, and **lungs**. 2. **Pleura**: - **Visceral pleura**: Serous membrane surrounding the lungs. - **Parietal pleura**: Outer layer, part of the same membrane as visceral pleura. - **Pleural cavity**: Space between the visceral and parietal pleura. 3. **Ribs**: Surround and protect the lungs. 4. **Intercostal muscles**: Muscles between the ribs that assist with breathing. 5. **Diaphragm**: Main muscle for breathing located below the lungs. **Pressures Involved in Breathing:** 1. **Atmospheric Pressure**: Pressure outside the body, typically **760 mm Hg**. 2. **Intrapulmonary Pressure**: Pressure within the lungs. - Changes during breathing, balances with atmospheric pressure when at rest. 3. **Intrapleural Pressure**: Pressure in the pleural cavity, helps with lung expansion but not focused on here. **Key Rule:** - **Air flows from high pressure to low pressure**. To inhale, **intrapulmonary pressure must decrease**; to exhale, it must **increase**. **Mechanism of Inspiration (Inhalation):** 1. **Muscle Activity**: - **Diaphragm contracts**, moving downward. - **Intercostal muscles contract**, lifting the ribs. 2. **Effect on Volume**: - The **intrapulmonary volume** (lung volume) **increases**. 3. **Effect on Pressure**: - As lung volume increases, **intrapulmonary pressure decreases** to **759 mm Hg** (lower than atmospheric pressure). 4. **Air Movement**: - Since intrapulmonary pressure is now lower than atmospheric pressure, air flows **into the lungs** down the pressure gradient. **Mechanism of Expiration (Exhalation):** 1. **Muscle Activity**: - **Diaphragm relaxes**, moving back up. - **Intercostal muscles relax**, causing the rib cage to lower. 2. **Effect on Volume**: - The **intrapulmonary volume decreases**. 3. **Effect on Pressure**: - As lung volume decreases, **intrapulmonary pressure increases** to **761 mm Hg** (higher than atmospheric pressure). 4. **Air Movement**: - Since intrapulmonary pressure is now higher than atmospheric pressure, air flows **out of the lungs** down the pressure gradient. **Cycle of Breathing:** - **Inspiration and expiration alternate**, driven by changes in pressure and volume. - **Inspiration** increases lung volume, decreasing pressure and drawing air in. - **Expiration** decreases lung volume, increasing pressure and pushing air out. **Thoracic Cavity and Rib Cage:** - During **inspiration**, the **rib cage expands** due to the contraction of intercostal muscles and diaphragm, increasing thoracic cavity volume. - During **expiration**, the **rib cage shrinks** as muscles relax, decreasing thoracic cavity volume. **Accessory Muscles:** - In addition to the diaphragm and intercostal muscles, **accessory muscles** like the **sternocleidomastoid** and **scalene muscles** assist in breathing, especially during **forced breathing**. **Summary:** - Breathing involves **muscular contractions** (diaphragm and intercostal muscles) that change the **volume of the thoracic cavity**, which in turn changes the **pressure in the lungs**. - **Inhalation** occurs when lung pressure is lower than atmospheric pressure, and **exhalation** occurs when lung pressure is higher than atmospheric pressure. **Control of Respiration:** 1. **Medullary Respiratory Centers**: - Located in the **medulla oblongata**, part of the brainstem. - Two main groups: - **Ventral Respiratory Group (VRG)**: - Controls **rhythmic breathing** (the automatic cycle of breaths). - Responsible for generating the basic rhythm of breathing. It is particularly active during **forceful breathing** (e.g., during exercise). - **Dorsal Respiratory Group (DRG)**: - Primarily responsible for **inspiration**. - Sends signals to the **diaphragm** and **intercostal muscles** during **normal, quiet breathing** (eupnea). - Acts as a sensory processor, receiving signals from peripheral receptors about blood gas levels (O₂, CO₂) and pH. 2. **Pontine Respiratory Center**: - Located in the **pons** (above the medulla in the brainstem). - Also called the **pontine respiratory group (PRG)**. - Provides **tonic input** to the medullary centers to **smooth the transition** between inspiration and expiration. - Works in conjunction with the medullary centers to fine-tune the breathing pattern, particularly during **speech, exercise, or emotional responses**. **Mechanism of Breathing:** 1. **Respiratory Muscles**: - The medullary and pontine centers send neural signals to the respiratory muscles: - **Diaphragm**: - The **primary muscle** for breathing. - During inspiration, it **contracts and moves downward**, increasing the volume of the thoracic cavity, which decreases pressure in the lungs and allows air to flow in. - **Intercostal Muscles** (between the ribs): - Help expand the chest during **inspiration** by raising the rib cage. - In **expiration**, the intercostal muscles relax, and the chest returns to its normal position, pushing air out of the lungs. 2. **Neural Control of Breathing**: - Breathing is controlled by **neural impulses** from the medullary centers. - **Faster neural impulses** lead to **faster breathing** (tachypnea), while **slower impulses** result in **slower breathing** (bradypnea). - This ensures that the body can adjust breathing rates according to metabolic needs (e.g., during exercise or rest). **Factors Influencing the Respiratory Centers:** 1. **Higher Brain Centers**: - The **cerebral cortex** can exert **voluntary control** over breathing (e.g., holding your breath, deep breathing). - Other areas of the brain, like the **limbic system** (emotions) and **hypothalamus** (temperature regulation), can influence breathing patterns in response to **pain, emotions, and temperature changes**. - These higher centers can stimulate or suppress the respiratory centers based on internal and external stimuli (e.g., anxiety can increase breathing rate). 2. **Peripheral Chemoreceptors**: - Located in the **carotid bodies** (near the carotid artery) and **aortic bodies** (near the aorta). - Sensitive to **chemical changes** in the blood: - **Low oxygen (O₂)**, **high carbon dioxide (CO₂)**, and **low pH** (high H⁺ concentration) trigger these receptors. - When triggered, they send signals to the medullary centers to **increase respiratory rate**. - This increases oxygen intake and speeds up the expulsion of CO₂, helping to restore normal blood gas levels. 3. **Central Chemoreceptors**: - Located in the **medulla oblongata**. - Monitor the **pH and CO₂ levels** in the cerebrospinal fluid (CSF) around the brain. - A **rise in CO₂** (which lowers pH) triggers these receptors to stimulate the medullary respiratory centers, leading to an **increased breathing rate**. - This is important for maintaining homeostasis, particularly under conditions where CO₂ accumulates (e.g., during exercise or hypoventilation). 4. **Muscle and Joint Receptors**: - These receptors are found in **muscles** and **joints** and are stimulated during **physical activity** (e.g., exercise). - When activated, they signal the respiratory centers to **increase the breathing rate**. - This ensures that more oxygen is delivered to the muscles and that CO₂ and other metabolic waste are expelled efficiently during physical exertion. **Lung Receptors:** 1. **Irritant Receptors**: - Located in the **airways**. - Triggered by **irritants** like dust, smoke, or harmful chemicals. - When activated, they can initiate reflexes like **coughing** to clear the irritants from the airways. - They can also influence the respiratory centers to **temporarily slow down breathing** to protect the lungs from inhaling further irritants. 2. **Stretch Receptors**: - Located in the smooth muscle of the **lungs**. - Responsible for the **Hering-Breuer reflex**, which prevents **overinflation of the lungs**. - When the lungs are stretched excessively, these receptors send signals to the respiratory centers to **inhibit further inspiration**, thus preventing lung damage from overinflation. - This reflex is more active during **vigorous breathing**, such as during exercise or stress. **Pneumonia** **Pneumonia** is an infection of the lungs that causes inflammation in the lung tissue due to the presence of various microbes. This inflammation leads to an accumulation of **fluid** in the lungs, which makes breathing difficult. **Defenses Against Infection:** Your respiratory system has several defense mechanisms to protect the lungs from microbes that you inevitably inhale: - **Coughing**: A mechanical defense to expel irritants or microbes. - **Mucociliary escalator**: Mucus and cilia (tiny hairs) line the airways, trapping and moving bacteria out of the lungs. - **Alveolar macrophages**: Immune cells stationed in the alveoli, ready to destroy harmful microbes that make it that far. **How Pneumonia Develops:** When a particularly aggressive or \"nasty\" microbe breaches these defenses and colonizes the **bronchioles** or **alveoli**, it leads to **pneumonia**. These microbes multiply and invade the lung tissue, triggering an **inflammatory response**. 1. **Inflammation**: - The lung tissue becomes inflamed and starts to fill with immune cells, including **white blood cells**, proteins, fluid, and sometimes even **red blood cells** if nearby capillaries are damaged. - This fluid buildup in the air sacs and tissues impairs the normal gas exchange, making it harder to breathe. **Causes of Pneumonia:** Pneumonia can be caused by various **microbes**, including: 1. **Viruses**: - The most common viral cause in adults is the **influenza virus** (the flu). 2. **Bacteria**: - Common bacterial culprits include: - **Streptococcus pneumoniae** - **Haemophilus influenzae** - **Staphylococcus aureus** - Other unusual bacteria like **Mycoplasma pneumoniae** and **Chlamydophila pneumoniae** cause \"atypical\" or \"walking\" pneumonia, often with milder symptoms like fatigue. 3. **Fungi**: - Fungal pneumonia is rare in healthy people but more common in specific geographic regions: - **Coccidioidomycosis** in the **Southwest U.S.** (e.g., California). - **Histoplasmosis** in the **Ohio and Mississippi River valleys**. - **Blastomycosis** in the eastern U.S. - **Pneumocystis jiroveci** is a fungal infection seen in **immunocompromised** individuals, such as those with HIV. 4. **Mycobacteria**: - These are slow-growing bacteria, the most well-known being **Mycobacterium tuberculosis (TB)**. **Types of Pneumonia by Acquisition:** 1. **Community-Acquired Pneumonia (CAP)**: - This occurs when someone contracts pneumonia outside of a healthcare setting. 2. **Hospital-Acquired Pneumonia (HAP)**: - A more serious form of pneumonia that develops in patients already hospitalized for other reasons. These patients often have weakened immune systems. - Hospital environments are filled with more resistant bacteria, such as **Methicillin-resistant Staphylococcus aureus (MRSA)**, making these infections harder to treat. 3. **Ventilator-Associated Pneumonia (VAP)**: - A subtype of HAP that occurs in patients on ventilators. - Biofilms (a mix of bacteria, sugars, and proteins) can form on the ventilator tubes, allowing microbes to travel directly into the lungs. **Aspiration Pneumonia:** Pneumonia can also occur if **foreign material** (such as food, liquids, or stomach contents) is inhaled into the lungs. This is called **aspiration pneumonia**. - Normally, coughing and gag reflexes help expel material that accidentally enters the airways. - However, in cases of **impaired reflexes** (e.g., due to alcohol or drug use, brain injuries), foreign material can reach the lungs and lead to infection. - Aspiration of **gastric contents** is particularly dangerous because stomach acid can irritate the lung tissue, increasing the risk of infection. **Symptoms of Pneumonia:** 1. **Respiratory Symptoms**: - **Dyspnea** (shortness of breath) - **Chest pain** - **Productive cough** (with mucus or sometimes blood) 2. **Systemic Symptoms**: - **Fever** - **Fatigue** **Diagnosis of Pneumonia:** 1. **Physical Examination**: - **Dullness to percussion**: Tapping on the chest can indicate consolidation (fluid-filled lung tissue). - **Tactile vocal fremitus**: Feeling increased vibrations on the chest when the patient speaks due to better sound conduction through fluid. - **Crackles** and other abnormal lung sounds can be heard during a stethoscope exam. 2. **Chest X-ray**: - **Bronchopneumonia**: Patchy, spread-out areas of consolidation. - **Atypical pneumonia**: Often reticular (line-shaped) opacities concentrated around the center of the lungs (perihilar region). - **Lobar pneumonia**: Consolidation in a single lobe of the lung. **Treatment of Pneumonia:** 1. **Antibiotics**: - These are prescribed based on the likely bacterial cause. - Viral pneumonias may be treated with antiviral medications, but bacterial pneumonia is the most common and responsive to antibiotics. 2. **Symptom Relief**: - **Cough suppressants** and **pain medications** can help ease discomfort. **Asthma Overview:** - **Asthma** is a chronic condition that causes **inflammation in the airways**, making them **narrow** and hard to breathe through. - It can lead to **asthma attacks**, often triggered by environmental factors like allergens or pollution, causing further inflammation. **Airway Anatomy:** - The lungs consist of the **trachea**, which branches into the **bronchi** and then into smaller **bronchioles**. - In asthma, these airways become inflamed and obstructed. **Immune Response in Asthma:** - Asthma involves an **overreaction of Th2 immune cells** to allergens, triggering a **Type 1 hypersensitivity reaction**. - **Cytokines**, such as **IL-4** and **IL-5**, are released, leading to: - **Mast cells** releasing **histamines** and other inflammatory chemicals. - **Eosinophils** activating more immune cells, causing further damage and inflammation. **Early and Late Responses:** 1. **Early Response** (minutes after trigger): - **Smooth muscle spasms** and **mucus production** narrow the airways. - This obstructs breathing, which is why asthma is an **obstructive lung disease**. 2. **Late Response** (hours after trigger): - **Eosinophils** and immune cells cause more damage to lung tissue. - Over time, repeated inflammation leads to **permanent changes** like **scarring** and **narrowing of the airways**. **Causes of Asthma:** - Asthma is caused by a mix of **genetics** and **environmental factors**. - The **hygiene hypothesis** suggests that less exposure to germs in early life might increase asthma risk by altering immune development. - Common **triggers** include **air pollution**, **dust**, **pet dander**, **mold**, and certain medications. **Symptoms of Asthma:** - **Coughing**, **chest tightness**, **difficulty breathing** (dyspnea), and **wheezing** (a whistling sound during breathing). - **Mucus plugs** (like **Curschmann spirals**) can block airways and medication from reaching the site of inflammation. - **Charcot-Leyden crystals**, formed from eosinophil breakdown, may also be found in mucus. **Asthma Severity:** Asthma is classified by the frequency of symptoms and severity of airway obstruction: - **Intermittent asthma**: Symptoms occur less frequently. - **Mild, moderate, and severe persistent asthma**: Symptoms are more frequent and severe. **Treatment of Asthma:** - **Avoiding triggers** (e.g., vacuuming, removing carpets, drying damp areas). - **Medications**: - **Bronchodilators** (short-acting beta-agonists, anticholinergics) for quick relief. - **Corticosteroids** and **long-acting beta-agonists** for more severe asthma. - In extreme cases, **IV corticosteroids**, **magnesium sulfate**, and **oxygen therapy**. **Bronchiolitis Overview:** - **Bronchiolitis** is the **inflammation of the bronchioles**, often caused by a **viral infection**, most commonly **respiratory syncytial virus (RSV)**. - It primarily affects **infants under two years old** and is usually **self-limiting**. - It can be mistaken for **asthma**, but asthma generally occurs in **older children**. **Causes:** - **Respiratory syncytial virus (RSV)** is the **main cause**. - Other viral causes include **rhinovirus** and **parainfluenza virus**. - **RSV** is a **single-stranded RNA virus** spread through airborne droplets or contact with respiratory secretions. **Respiratory Tract and Bronchioles:** - The respiratory system begins with the **nasal and oral cavities**, through which oxygen travels into the **upper respiratory tract**. - The **lower respiratory tract** starts with the **larynx**, then the **trachea**, which splits into **bronchi**, **smaller bronchi**, and **bronchioles**, eventually reaching the **alveoli** where gas exchange occurs. - **Bronchioles** have smooth muscle and are lined with mucus, produced by **goblet cells**. **Bronchiolitis Pathophysiology:** - In bronchiolitis, the airways narrow due to: 1. **Mucus hypersecretion**. 2. **Cell wall thickening**. 3. **Smooth muscle contraction**. - This narrowing causes **air trapping** (air gets trapped in the alveoli), leading to **difficulty breathing**. **RSV Infection Process:** 1. **Viral replication** starts in the **nasopharynx**, causing cold-like symptoms. 2. The infection spreads to the **bronchioles**, causing inflammation. 3. **Immune cells** infiltrate the area, leading to: - **Edema (swelling)**. - **Increased mucus production** by goblet cells. - **Necrosis** and regeneration of epithelial cells. 4. These changes cause **airway obstruction**, **air trapping**, and **increased airway resistance**, leading to breathing difficulties. **Clinical Presentation:** - **Mild to moderate bronchiolitis**: - **Tachypnea** (fast breathing). - Signs of increased work of breathing: **nasal flaring**, **tracheal tug**, **intercostal recessions**, and **abdominal breathing**. - On examination: **inspiratory crepitations** (crackles) and **wheezing**. - **Severe bronchiolitis**: - High or low respiratory rate, sometimes with **apnea** (pauses in breathing). - **Grunting**, **cyanosis** (blue skin from lack of oxygen), and **paleness**. - Difficulty feeding, taking in less than **50% of normal feeds**. - **Concerning features** include severe breathing difficulties, indicating **severe bronchiolitis**. **Risk Factors for Severe Bronchiolitis:** - **Infants less than 6 weeks old**. - **Premature birth** or **low birth weight**. - **Immunodeficiency**. - **Congenital heart disease**. - **Neurological conditions** or **chronic respiratory illness**. **Diagnosis:** - **Clinical diagnosis** is key: Infants under two years with: - Initial **upper respiratory symptoms**. - Followed by **cough**, **tachypnea**, inspiratory **crepitations**, and **wheezing**. - **No routine investigations** unless the infant is severely ill or another condition is suspected. **Management:** 1. **Mild Bronchiolitis**: - Managed at home. - Encourage **oral hydration**. - Medications like **bronchodilators** and **corticosteroids** are **not recommended** in infants with the first episode. 2. **Moderate Bronchiolitis**: - Hospital monitoring if **increased work of breathing** is present. - **Paracetamol** and **ibuprofen** for fever and symptom relief. - **Oxygen** to maintain saturation above 92%. - Encourage **oral hydration**, and if necessary, use a **nasogastric feeding tube**. 3. **Severe Bronchiolitis**: - **Oxygen therapy** via **high-flow nasal prongs** or **CPAP** (Continuous Positive Airway Pressure). - **Nasogastric tube** or **IV fluids** to maintain hydration. - Admission to **ICU** may be required for **persistent hypoxemia** (low oxygen levels). **Croup Overview:** - **self-limiting viral infection** of the upper airway. It causes **inflammation** in the **larynx** (voice box) and **trachea**, leading to **upper airway obstruction**. - **6 months to 3 years** and is more frequent in **boys** than girls. **Causes:** - **Viral infections** are the most common cause of croup, especially: - **Parainfluenza virus (types 1 and 2)** (most common) - **Respiratory syncytial virus (RSV)** (also a cause of bronchiolitis) **Pathophysiology of Croup:** - Croup begins as an **upper respiratory tract infection** with symptoms like **low-grade fever** and **coryza** (runny nose). - Over a few days, the virus (e.g., parainfluenza) infiltrates the **larynx** and **trachea**, triggering an **inflammatory response**. - **White blood cells** gather at the site, causing **pain** and **edema (swelling)**. - This swelling leads to **partial airway obstruction**, increasing the work of breathing and causing the characteristic **stridor**. - **Stridor** is heard during **inspiration** due to the collapse of the airway as pressure drops below atmospheric levels. **Clinical Presentation:** - **Croup develops gradually** over days: - Starts with an **upper respiratory tract infection** (fever, coryza). - Followed by a **barking cough** and **varying degrees of respiratory distress**. - Most symptoms resolve within **two days**, but the **barking cough** and **hoarse voice** are hallmarks of croup. **Croup Classification:** - **Mild croup**: - **Barking cough** without stridor at rest. - **Moderate croup**: - **Increased respiratory effort** with **resting stridor**. - Identified by **tracheal tugging** and **intercostal recessions** (sinking of skin between ribs during breathing). - Child remains alert and active. - **Severe croup**: - Persistent **stridor** and **severe respiratory distress**. - Child may become **apathetic** or **restless**. - Severe **tracheal tugging**, **chest wall retraction**, and **marked respiratory effort**. - **Life-threatening croup**: - Child may have **cyanosis** (bluish skin), **decreased consciousness**, and requires **immediate resuscitation**. **Treatment:** - **Mild croup**: - A **single dose of steroids** (e.g., **dexamethasone**) is recommended, even for mild cases seen in the hospital. - **Moderate croup**: - **Steroids** (dexamethasone or prednisolone) to reduce inflammation. - If steroids are not tolerated, **nebulized adrenaline** may be used. - **Severe croup**: - **Oxygen** therapy. - **Nebulized adrenaline** and **steroids** (e.g., dexamethasone) are required to open the airways. - Continuous monitoring for **signs of impending airway obstruction** (e.g., irritability, **tachycardia**, **pallor**). - **Life-threatening croup**: - Immediate intervention with **oxygen** and **nebulized adrenaline**. - **Resuscitation** if necessary. **Diagnosis:** - **Investigations** (like an **x-ray**) are rarely needed unless the diagnosis is unclear. **Pneumothorax Overview:** - **Pneumothorax** refers to the presence of **air in the chest**. - More specifically, air accumulates in the **pleural space**, which is the space between the **lungs** and the **chest wall**. - This space is located between the **parietal pleura** (attached to the chest wall) and the **visceral pleura** (attached to the lungs). - The pleural space normally contains **lubricating fluid** to reduce friction as the lungs expand and contract. **Pleural Space Dynamics:** - The pressure in the pleural space is established by two opposing forces: 1. **Muscle tension** of the **diaphragm** and **chest wall**, which expands the thoracic cavity outward. 2. The **elastic recoil** of the **lungs**, which pulls the lungs inward. - These opposing forces create a **slight vacuum** in the pleural space, resulting in a pressure of **-5 cm of water** relative to the **0 cm of water** pressure in the thoracic cavity and lungs. **Pathophysiology of Pneumothorax:** - A pneumothorax occurs when the **seal of the pleural space is punctured**, allowing air to enter and equalize the pressure to **0 cm of water**. - The loss of negative pressure leads to: - **Lung collapse**, as the lungs recoil inward. - **Chest wall expansion**, as the thoracic cavity moves slightly outward. - The collapsed lung results in: - Reduced **air exchange**. - Decreased **oxygen intake** and buildup of **carbon dioxide**. **Types of Pneumothorax:** **1. Spontaneous Pneumothorax:** - Occurs **without trauma** and may result from the rupture of a **bleb** (an air pocket) on the lung surface. - Blebs form when **alveoli** (small air sacs where gas exchange occurs) develop tiny leaks, allowing air to seep into lung tissue. - If the bleb ruptures, air enters the **pleural space**, causing a pneumothorax. - **Primary spontaneous pneumothorax** occurs in people without an underlying lung disease, often in **tall, thin adolescent males** who hold their breath and create internal pressure. - **Secondary spontaneous pneumothorax** occurs in individuals with an underlying **lung disease** such as: - **Marfan syndrome** - **Cystic fibrosis** - **Emphysema** - **Lung cancer** **2. Traumatic Pneumothorax:** - Results from **chest trauma** (e.g., gunshot or stab wound) that punctures the **parietal pleura**, allowing air to enter from outside. **3. Tension Pneumothorax:** - Occurs when air enters the pleural space through a **one-way valve** mechanism, preventing air from escaping. - The flap of tissue allows air to enter but not leave, causing air to accumulate over time. - As air pressure builds, it can compress nearby structures, including the **heart** and **lungs**. - **Tension pneumothorax** can lead to: - **Tracheal deviation** (shifting of the trachea away from the affected side). - Compression of the heart, reducing **cardiac output** and impairing heart function. **Symptoms of Pneumothorax:** - **Shortness of breath** - **Chest pain** - On physical examination: - **Reduced breath sounds** on auscultation due to extra air in the pleural space. - **Hyper-resonance** on percussion (a louder sound when tapping the chest). **Diagnosis:** - **X-ray** or **CT scan** is typically used to confirm the diagnosis. - A **collapsed lung** appears with a distinct outline, showing black areas (air) in the pleural space and the lung tissue itself. - In cases of **tension pneumothorax**, imaging may show **tracheal deviation** and displacement of other chest structures. **Treatment:** - **Small spontaneous pneumothorax**: - If it is small and not causing severe symptoms, no immediate treatment may be needed. The pleura may heal on its own over time. - **Larger pneumothorax** or **tension pneumothorax**: - Requires immediate removal of air from the pleural space. - Treatment options include: - Inserting a **needle** or **chest tube** to provide an escape route for the air and allow the lung to re-expand. **1. Coronary Artery Disease (CAD)** - **Coronary Artery Disease (Ischemic Heart Disease)** is the most common type of CVD. - **Cause**: CAD occurs when there is **reduced blood flow** to the heart muscle due to blockages in the **coronary arteries**. This is typically caused by **atherosclerosis**, where **plaque** builds up in the artery walls. - **Complications**: - If blood flow is severely reduced or stopped, it can lead to an **acute myocardial infarction (heart attack)**, resulting in **necrosis** (death) of the heart tissue due to lack of oxygen. - **Angina** is a symptom of CAD, where patients experience **chest pain** due to temporary loss of blood flow to the heart. - **Stable Angina**: Chest pain triggered by exertion (e.g., exercise) due to a **stable plaque**. - **Unstable Angina**: Caused by a **hemodynamically unstable plaque** and the presence of **thrombosis** (clot), which can lead to a heart attack. - **Heart Attack**: Occurs when a coronary artery is suddenly blocked, leading to a **myocardial infarction**, which is life-threatening. **2. Heart Failure** - **Heart Failure** occurs when the heart is unable to pump blood effectively throughout the body. - **Causes**: It can result from conditions such as: - **Coronary artery disease** - **Hypertension** (high blood pressure) - **Cardiomyopathies** (heart muscle disease) - **Vasculitis** (blood vessel inflammation) - **Symptoms**: Patients with heart failure experience **chronic fatigue**, **reduced physical activity**, and **shortness of breath**. - **Types of Heart Failure**: - **Right-Sided Heart Failure**: - Caused by the failure of the right ventricle to pump blood effectively, leading to **blood backflow** into the liver and abdomen, causing **congestion**, **hepatomegaly** (enlarged liver), and **ascites** (fluid accumulation in the abdomen). - **Left-Sided Heart Failure**: - Affects the left ventricle\'s ability to pump **oxygenated blood** from the lungs to the rest of the body, leading to **pulmonary congestion** and **pulmonary edema** (fluid buildup in the lungs), causing **shortness of breath**. - **Congestive Heart Failure**: - Involves both right- and left-sided heart failure, causing congestion in the lungs, liver, and abdominal area. - **Impact**: Heart failure results in **reduced cardiac output**, leading to decreased **venous return** and further worsening of symptoms, creating a **vicious cycle** if untreated. **3. Cardiomyopathies** - **Cardiomyopathies** refer to diseases affecting the heart muscle (myocardium), resulting in **enlargement, thickening, or stiffness** of the heart, leading to heart failure. - **Types of Cardiomyopathies**: 1. **Dilated Cardiomyopathy**: - The heart\'s **ventricles enlarge** and weaken, leading to **systolic heart failure** (inability to pump blood effectively) with a significant decrease in **ejection fraction**. 2. **Hypertrophic Cardiomyopathy**: - The **ventricles thicken** and cannot relax properly, leading to **diastolic heart failure** (inability to fill with blood during relaxation). - The thickening of the **ventricular walls** and **septum** reduces the heart\'s capacity to fill with blood. 3. **Restrictive Cardiomyopathy**: - The left ventricle retains its normal size, but there is **hypertrophy (thickening)** and **dilation** of the left atrium, with the right ventricle also becoming enlarged due to blood backflow. **4. Aortic Diseases** - **Aortic Diseases** involve problems with the **aorta**, the main artery carrying blood from the heart to the body. - **Aortic Aneurysm**: - An abnormal **widening of the aorta**, particularly in the **abdominal** region, which weakens the aortic wall and may lead to **plaque formation**. - Aneurysms can cause **thrombosis** (clot formation) and **embolism** (clots breaking off and traveling to other parts of the body). - **Aortic Dissection**: - Occurs when **blood flows between the layers** of the aortic wall, due to a tear, creating a false channel. This can be life-threatening if untreated. **5. Peripheral Vascular Disease (PVD)** - **Peripheral Vascular Disease** (also called **Peripheral Arterial Disease**) affects the **arteries outside the heart**, particularly those supplying the limbs. - **Cause**: PVD is commonly caused by **atherosclerosis**, leading to **narrowing or obstruction** of large arteries. - **Complications**: This can result in serious conditions, such as **renal stenosis** (narrowing of arteries supplying the kidneys). **6. Valvular Diseases** - **Valvular Diseases** affect the heart valves, which regulate blood flow through the heart. - **Valvulitis** (inflammation of heart valves) is often caused by **rheumatic heart disease**, which results from **rheumatic fever**. - **Rheumatic Fever**: Caused by **Group A Streptococcus** (e.g., strep throat), which can damage the heart, particularly the valves, leading to **rheumatic heart disease**. - Other types of valvular diseases include: - **Aortic Stenosis** (narrowing of the aortic valve) - **Aortic and Mitral Regurgitation** (leakage of blood backward) - **Mitral Stenosis** (narrowing of the mitral valve) **7. Pericardial Diseases** - **Pericarditis**: Inflammation of the **pericardium**, the protective sac around the heart. - The pericardium has two layers (visceral and parietal), and **inflammation** causes **friction** between them, leading to pain and sometimes **fluid buildup** in the pericardial cavity. - Other conditions: - **Pericardial Effusion** (fluid accumulation) - **Cardiac Tamponade** (pressure on the heart due to fluid buildup) - **Hemopericardium** (blood in the pericardium), which is life-threatening. **8. Congenital Heart Diseases** - **Congenital Heart Diseases** are structural abnormalities present from birth and are the leading cause of death in the first year of life. - Common congenital defects: 1. **Patent Foramen Ovale**: Failure of the foramen ovale (a fetal blood flow opening) to close, causing a **left-to-right shunt**. 2. **Patent Ductus Arteriosus**: Failure of the ductus arteriosus (a fetal blood vessel) to close, also causing a **left-to-right shunt** between the aorta and pulmonary artery. 3. **Coarctation of the Aorta**: Narrowing of the aorta. 4. **Transposition of the Great Vessels**: Abnormal arrangement of the aorta and pulmonary artery. 5. **Tetralogy of Fallot**: Combination of four defects, including **right ventricular hypertrophy**, **ventricular septal defect**, **pulmonary stenosis**, and **overriding aorta**. **Overview of Heart Failure** - **Heart Failure**: Inability of the heart to pump enough blood to meet the body's needs. - **Types**: 1. **Systolic Heart Failure** (Reduced ejection fraction): - **Problem**: Heart's ventricles can't pump blood effectively. - **Causes**: Reduced contractility (e.g., after myocardial infarction, dilated cardiomyopathy). - **Key Sign**: Reduced ejection fraction. 2. **Diastolic Heart Failure** (Normal ejection fraction): - **Problem**: Ventricles can\'t fill properly due to reduced compliance. - **Causes**: Ventricular hypertrophy (thickened heart muscles). - **Key Sign**: Normal ejection fraction but elevated diastolic pressure. - **Clinical Signs**: - **Left-sided heart failure**: Blood backs up into lungs (pulmonary congestion/edema), dyspnea, orthopnea, PND, fatigue. - **Right-sided heart failure**: Blood backs up into systemic circulation, JVD, hepatomegaly, peripheral edema. **Pathophysiology** - **Cardiac Output (CO)**: The amount of blood pumped by the heart per minute, calculated as heart rate (HR) x stroke volume (SV). - **Ejection Fraction (EF)**: Percentage of blood pumped out of the ventricle during each beat. Normal EF is 50-70%. - In **systolic heart failure**, both stroke volume and EF decrease due to impaired contractility. - In **diastolic heart failure**, stroke volume decreases but EF remains normal due to reduced ventricular compliance. **Causes of Heart Failure** - **Systolic Heart Failure**: Caused by conditions that reduce heart contractility (e.g., myocardial infarction, dilated cardiomyopathy). - **Diastolic Heart Failure**: Caused by ventricular stiffening (e.g., ventricular hypertrophy). - **Right-Sided Heart Failure**: Often caused by left-sided heart failure, or by chronic lung diseases (e.g., pulmonary embolism, emphysema). **Symptoms** - **Left-sided Failure**: Pulmonary edema, dyspnea, orthopnea, crackles in lungs, S3 heart sound (ventricular gallop). - **Right-sided Failure**: JVD, hepatomegaly, pitting edema, congestive hepatopathy (nutmeg liver). **Mechanisms** - **Frank-Starling Mechanism**: Increased blood volume initially enhances heart contractility but eventually leads to fluid overload, worsening edema. - **Renin-Angiotensin-Aldosterone System (RAAS)**: Activated due to reduced kidney perfusion, causing fluid retention, worsening edema. **Treatment** - **Medications that Reduce Mortality**: - ACE inhibitors, ARBs, aldosterone antagonists (e.g., spironolactone), certain beta blockers (e.g., carvedilol, metoprolol). - Beta blockers used cautiously in decompensated heart failure due to negative inotropic effects. - **Symptom Relief**: - Diuretics (e.g., thiazides, loop diuretics) to reduce fluid retention. - Vasodilators (e.g., hydralazine combined with nitrates) to improve symptoms and survival. - Neprilysin inhibitors to promote sodium excretion and vasodilation. **1. Basic Blood Flow in the Heart:** - Blood returns to the heart from two places: - **Left atrium:** Blood returns from the lungs (oxygenated). - **Right atrium:** Blood returns from the rest of the body (deoxygenated). - Atrial contraction pushes blood into the ventricles. - Ventricular contraction then pushes blood out of the heart to the body (left side) and lungs (right side). **2. Electrocardiogram (ECG) and Cardiac Cycle Phases:** The cardiac cycle is reflected in the ECG, which shows the electrical signals responsible for heart muscle contractions. **Atrial Systole (Contraction of Atria):** - **P wave:** Depolarization of the atria (electrical signal causing contraction). - **Effect:** - Increase in atrial pressure as atria contract. - Blood is pushed into the ventricles through the atrioventricular valves (between atria and ventricles). - **Ventricular volume increases** as blood fills the ventricles. **Ventricular Systole (Contraction of Ventricles):** - **QRS complex:** Depolarization of the ventricles (stronger signal due to larger ventricular muscles). - **Effect:** - Ventricles contract, significantly increasing **ventricular pressure**. **Isovolumetric Contraction:** - **Key Phase:** Both atrioventricular and semilunar valves are closed, creating a sealed chamber in the ventricles. - **Result:** Pressure builds without a change in ventricular volume (isovolumetric means \"same volume\"). **Ejection Phase:** - **Semilunar valve opens** when ventricular pressure exceeds aortic pressure (around 80 mmHg). - **Effect:** Blood is ejected from the ventricles into the aorta (left ventricle) or pulmonary artery (right ventricle). - **Ventricular volume decreases** as blood leaves the heart. **Ventricular Diastole (Relaxation of Ventricles):** - **T wave:** Represents repolarization of the ventricles (relaxation). - **Effect:** - Ventricular pressure decreases as the ventricles relax. **Isovolumetric Relaxation:** - All valves are closed again during the relaxation phase, so no change in blood volume occurs. - As the ventricular pressure continues to drop, once it falls below atrial pressure, the atrioventricular valves open. **Passive Filling:** - Blood passively flows from the atria to the ventricles as the heart prepares for the next cycle. - This phase continues until the next **P wave** starts the process over. **3. Heart Sounds (Phonocardiogram):** - **Lub-dub sound:** - **First sound (lub):** Caused by the closure of atrioventricular valves after ventricular depolarization (QRS complex). - **Second sound (dub):** Caused by the closure of the semilunar valves after the ventricles relax (T wave). **Summary of Key Phases:** 1. **Atrial Systole:** Atria contract, pushing blood into the ventricles. 2. **Ventricular Systole:** Ventricles contract after atrial systole. - **Isovolumetric Contraction:** No volume change but pressure builds. - **Ejection Phase:** Blood is pumped out of the ventricles. 3. **Ventricular Diastole:** Ventricles relax. - **Isovolumetric Relaxation:** No volume change as the ventricles relax. - **Passive Filling:** Ventricles passively fill with blood from the atria. Atrial diastole is the first part of the cardiac cycle. During this phase, the atria are relaxed and act as pathways for blood to flow into the ventricles. They also help pump any leftover blood into the ventricles. Here\'s what happens: - Blood enters the **right atrium** from the body through the superior and inferior vena cava, and into the **left atrium** from the lungs via the pulmonary veins. - At the start of this phase, the atrioventricular (AV) valves (between the atria and ventricles) are closed, so blood pools in the atria. - When the pressure in the atria becomes higher than the pressure in the ventricles, the AV valves open, allowing blood to flow from the atria into the ventricles. **Atrial Systole:** - The heart\'s **SA node** (natural pacemaker) sends an electrical signal that spreads across the atria. - This signal causes the atria to **contract** at the same time, pushing any leftover blood from the atria into the ventricles. - As the atria contract, the **pressure in the atria** increases, ensuring all blood is moved into the ventricles. **Ventricular Diastole:** - In the early phase of ventricular diastole, both the **AV (atrioventricular) valves** and **semilunar valves** are closed. - Although the ventricles are relaxing, there\'s no change in blood volume yet, but the **pressure inside the ventricles drops quickly**. This is called **isovolumetric relaxation**. - Eventually, the pressure in the ventricles falls below the pressure in the atria, causing the **AV valves to open**. - This allows blood to rapidly fill the ventricles from the atria, a phase known as **rapid ventricular filling**, which accounts for most of the blood in the ventricles. - A small amount of blood flows directly into the ventricles from the body's main veins. - At the end of this phase, any leftover blood in the atria is pumped into the ventricles. - The total amount of blood in the ventricles at the end of diastole is called the **end-diastolic volume** or **preload**. Bottom of Form **Ventricular Systole (Contraction Phase):** - **Ventricular systole** is the phase where the ventricles contract. - After the atria depolarize (contract), the electrical signal moves to the **AV node**. There\'s a small delay, which allows the atria to finish contracting before the ventricles start. - The electrical signal then travels from the AV node to the **bundle of His**, and down the left and right **bundle branches**, which carry the signal to both ventricles, triggering their contraction. **Isovolumetric Contraction:** - As the ventricles begin to contract, their **pressure rises** above that of the atria, causing the **AV valves (tricuspid and mitral)** to close. - However, the pressure isn\'t yet high enough to open the **semilunar valves** (leading to the aorta and pulmonary artery), so the blood volume inside the ventricles stays the same. This is called **isovolumetric contraction**. **Ejection Phase:** - Once the pressure in the ventricles becomes higher than the pressure in the aorta and pulmonary artery, the **semilunar valves open**, and blood is ejected from the ventricles. - The remaining blood in the ventricles after contraction is called the **end-systolic volume** (about 40--50 mL). - The amount of blood **ejected** during this phase is called the **stroke volume**. - The **ejection fraction** is the percentage of blood ejected compared to the total blood in the ventricles before contraction (**end-diastolic volume**), typically around 60%. **Isovolumetric Relaxation:** - After ejection, the ventricles relax, and the cycle briefly enters **isovolumetric relaxation** (no blood flows in or out), while the atria start to fill with blood again. - The process then repeats for every heartbeat. Bottom of Form Top of Form **Baroreceptors Overview** - **Baroreceptors**: Specialized nerve cells that detect changes in blood pressure by sensing the stretch in blood vessel walls. - This information is sent to the brain to help maintain balanced blood pressure. **Types of Baroreceptors** 1. **Arterial Baroreceptors**: - Found in the **aortic arch** and **carotid sinus** (a bulge in the internal carotid artery). - Aortic arch baroreceptors join the **vagus nerve** (10th cranial nerve), and carotid sinus baroreceptors join the **glossopharyngeal nerve** (9th cranial nerve). - Both nerves send signals to the **nucleus tractus solitarius** in the brainstem, which relays this information to the cardiovascular centers. 2. **Cardiopulmonary Baroreceptors**: - Located in the **right atrium**, **right ventricle**, **pulmonary artery**, and **veins**. - Mainly regulate **blood volume**, sensing the stretch caused by blood flow and fullness in these vessels. - Also known as **low-pressure or volume baroreceptors**. **Cardiovascular Centers** - Found in the **medulla oblongata** and **pons** of the brainstem, these centers control **autonomic** functions like heart rate and blood vessel diameter: 1. **Vasomotor Control Center**: Controls blood vessel diameter via the **sympathetic nervous system**, causing **vasoconstriction**. 2. **Cardiac Control Center**: Divided into: - **Cardiac Accelerator Center**: Increases heart rate and contractility (via sympathetic nerves). - **Cardiac Decelerator Center**: Slows heart rate (via parasympathetic nerves). **Baroreceptor Reflex (Baroreflex)** - **Rapid mechanism** that adjusts blood pressure within seconds to minutes. **Blood Pressure Increase (e.g., while running):** 1. Increased blood pressure stretches the arterial walls. 2. Baroreceptors fire more impulses via the vagus and glossopharyngeal nerves to the cardiovascular centers. 3. **Cardiovascular response**: - Inhibition of the **sympathetic system** and activation of the **parasympathetic system**: - **Vasodilation** (wider arteries) reduces resistance. - **Decreased venous return** leads to less preload and lower cardiac output. - Heart rate and contractility decrease, lowering blood pressure back to normal. **Blood Pressure Decrease (e.g., blood loss):** 1. Lower pressure causes less stretch in the arterial walls, reducing baroreceptor firing. 2. **Cardiovascular response**: - Stimulation of the **sympathetic system** and inhibition of the **parasympathetic system**: - **Vasoconstriction** increases total peripheral resistance. - Increased venous return boosts preload and cardiac output. - Heart rate and contractility increase, raising blood pressure back to normal. **Bainbridge Reflex (Volume Reflex)** - When blood volume increases, **cardiopulmonary baroreceptors** fire more frequently, sending signals via the vagus nerve: - **Increases heart rate** and cardiac output. - Increases **water and sodium excretion** by the kidneys through multiple mechanisms: - **Decreased vasopressin (antidiuretic hormone)** production. - Release of **atrial natriuretic peptide (ANP)**, which promotes filtration and reduces sodium/water reabsorption. Bottom of Form **Blood Pressure Homeostasis - Summary Notes:** - **Homeostasis:** Refers to maintaining balance in the body, including blood pressure regulation. - **Major Vessels Near the Heart:** - **Aorta:** Main artery leaving the heart. - **Left/Right Brachial Arteries:** Supply blood to the arms. - **Left/Right Carotid Arteries:** Supply blood to the neck. - **Carotid Sinus:** Bulging area in the carotid artery before it splits, important for sensing blood pressure. - **Aortic Arch:** Another important site for blood pressure sensing. - **Blood Pressure & Action Potentials:** - Normal blood pressure (e.g., 115/75 mmHg) results in a certain number of **action potentials** (nerve signals) per minute from baroreceptors. - The brain establishes a \"normal set point\" based on this. - **Higher blood pressure** (e.g., 140/90 mmHg) increases the number of action potentials. - **Lower blood pressure** (e.g., 90/60 mmHg) decreases the number of action potentials. - **Brain Response to Blood Pressure Changes:** - The brain receives signals from baroreceptors and responds via the **autonomic nervous system**. - **Autonomic Nervous System (ANS):** - Two branches: 1. **Sympathetic Nervous System (SNS):** - Increases **heart rate**, **stroke volume**, and causes **vasoconstriction** (narrowing of blood vessels) to raise blood pressure. 2. **Parasympathetic Nervous System (PNS):** - Decreases **heart rate**, **stroke volume**, and causes **vasodilation** (widening of blood vessels) to lower blood pressure. - **Key Equations:** - **Pressure = Flow x Resistance** - **Flow = Stroke Volume x Heart Rate** - Thus, changes in stroke volume, heart rate, or resistance affect blood pressure. - **Responses to High and Low Blood Pressure:** - **High Blood Pressure:** 1. Activates **parasympathetic** response to lower pressure. 2. Slows heart rate, reduces stroke volume, and dilates blood vessels. - **Low Blood Pressure:** 1. Activates **sympathetic** response to raise pressure. 2. Increases heart rate, stroke volume, and constricts blood vessels. - **Rapid Adjustment of Blood Pressure:** - The **baroreceptor reflex** allows the body to respond to blood pressure changes in **seconds to minutes**. - This quick response helps maintain a balanced blood pressure in real-time. **Heart development (cardiogenesis)** - **Early Development:** - The heart begins