Lecture 1: The Nature of Health and Disease

Definition of Health and Disease

Health is not merely the absence of disease. According to the World Health Organization (WHO), it is defined as "a state of
complete physical, mental, and social well-being and not merely the absence of disease and infirmity." It reflects adequate
functioning under specific genetic and environmental conditions.
Disease is characterized by a pattern of responses to insult or injury, leading to disturbed function and/or structural changes. It
is the result of failed homeostasis, which is the body's equilibrium.
Concepts of Normality

It indicates the frequency of a specific condition in a defined population.

Normal distribution involves examining the distribution of health indicators, defining cutoff points as abnormal above or below.
Examples include hemoglobin (Hb) and cholesterol levels, and reference ranges may change over time.
Causes of Disease

Multiple agents and stimuli contribute to the etiology of human disease.

Often, it's challenging to pinpoint a single causative agent.
Factors affecting disease causation include the status of the host's immune system, the size of the infective dose, and more.
Aetiological Factors

Endogenous factors originate from within the body, such as chromosome abnormalities.
Exogenous factors come from outside the body, such as microorganisms.
Overlap can occur, such as parental exposure to environmental mutagens leading to genetic mutations in offspring.
Classification of Disease

Based on outward signs (manifestations) produced by the disease.

Some diseases may share a common etiological agent but present differently in different individuals.
Classification helps assign patients to specific groups for treatment.
Identifying Disease

Diagnosing disease involves clinical history, signs, symptoms, and various lab and clinical tests.
Predisposing factors like genetic disorders, lifestyle, psychological factors, environmental factors, and the presence of other
diseases are considered.
Differential diagnoses are suggested, and a final diagnosis is chosen based on available evidence.
Treatment and Prognosis

Treatment aims at relieving symptoms (palliative therapy) or curing the underlying cause (curative).
Patients may be cured, experience remission (symptom-free period), or relapse (symptoms return).
Research focuses on understanding disease development and progression to improve prevention and treatment.
Psychological and Social Aspects of Disease

Biological Psychiatry integrates psychiatry with the biology of the brain.

It studies the relationship between mind and brain through systematic research and experimental methods.
The second wave of biological psychiatry emphasized genetics and the discovery of effective medications.
The third wave focuses on neural systems' dysfunction as the basis for mental disorders.
Psychological and Social Aspects of Disease (Continued)

Mental disorders include affective disorders (e.g., depression and bipolar disorder), schizophrenia, and dementia.
Biological changes in affective disorders involve neurotransmitter abnormalities, hormonal imbalances, and neurological factors.
Schizophrenia has genetic components, season of birth correlations, and CNS abnormalities, especially in dopamine receptors
and glutamate neurotransmission.
Dementia is linked to degenerative changes, genetics, infections, cerebral artery atherosclerosis, and more.
Other Physical Illnesses Contributing to Mental Illness

Confusional states can result from inflammation, infection, drugs, and anemia.
Hypothyroidism can cause depression, while hyperthyroidism can lead to anxiety.
Psychological and social factors like poverty, unemployment, and poor housing can influence mental health.
Principles of Epidemiology
Epidemiology studies the distribution of health and disease in populations.
Morbidity (illness) rates are expressed as incidence and prevalence rates.
Mortality rates should be standardized to account for demographic differences.
Epidemiological studies include descriptive, observational, and experimental approaches.
Randomized controlled trials are experimental studies used to evaluate interventions.
Confounding variables and overdiagnosis are important considerations in epidemiology.
Key Points

Measuring disease and health rates aids in comparisons, trend identification, decision-making, healthcare distribution,
etiological investigations, and health promotion.

Learning Outcome 2
Part 1: Molecular basis of cell reproduction, senescence and death

Cell Cycle:
Divided into 4 phases: S (synthetic), M (mitotic), G1 (first gap), G2 (second gap), and G0 (denotes cells which have left the cell
cycle).
Stimulus for cell growth: Extracellular growth factors activate receptors and initiate cell division.
Molecular control of cell cycle:
Controlled by three groups of regulatory proteins: Cyclins, Cyclin-dependent kinases (CDKs), and Cyclin-dependent kinase
inhibitors (CDKIs).
CDKs phosphorylate proteins to allow cell progression.
CDKs are activated by cyclins; CDKIs regulate their activity.
CDKI (Cyclin-dependent kinase inhibitors):
Two families: P21 family (p21, p27, p57) and INK4 (inhibitors of CDK4).
Regulate cell cycle progression at specific checkpoints.
Cell Senescence:
Cells no longer divide, often due to telomere shortening.
Telomeres are repeated sequences of DNA at chromosome ends.
Telomerase maintains telomere length in some cells, like stem cells and cancer cells.
Cell Death:
Two types: Apoptosis (programmed) and Necrosis (usually due to injury).
Apoptosis is controlled by a complex series of biochemical events.
Involves Bcl-2 gene family, including prosurvival and proapoptotic proteins.
Caspases are cysteine proteases involved in apoptosis.
Part 2: The Inflammatory Response

Inflammation:
Mechanism the body uses to deal with injury or insult.
Initiated by injury, trauma, or infections.
Aims to contain and destroy the damaging agent, initiate healing and repair.
Signs of Inflammation:
Acute inflammation (rapid response) and chronic inflammation (persists).
Acute inflammation involves preformed inflammatory mediators, plasma protein cascades, and new mediator synthesis.
Inflammatory Mediators:
Include histamine (vasodilator), serotonin (vasoconstrictor), and lysosomal enzymes.
Plasma protein cascades activate components like complement proteins.
Eicosanoids derived from membrane phospholipids (e.g., prostaglandins, leukotrienes) play a role.
Cytokines and chemokines (IL-1, TNF-α, IL-8, MCP) are also synthesized.
Recruitment of Leukocytes:
Neutrophils are essential components.
Rolling, transmigration, and locomotion are involved.
Effects of Inflammatory Mediators:
Immediate responses involve isolation, restriction, vasodilation, and increased blood flow.
Swelling, pain, redness, and heat result.
Chronic Inflammation:
Occurs when infections persist or there's a failure to resolve inflammation.
Characterized by macrophage accumulation, cytokine production, and fibroblast proliferation.
Can lead to fibrous scar tissue and granuloma formation.
These notes cover the molecular basis of cell processes, including the cell cycle, cell senescence, and cell death, as well as the
mechanisms of inflammation, acute and chronic inflammation, and the roles of inflammatory mediators.

Part 2: The Inflammatory Response

Definition of Inflammation:
Inflammation is a vital mechanism through which the body responds to injury, trauma, or infections. It initiates a complex series
of interconnected reactions at the site of tissue damage to contain and eliminate harmful agents, ultimately facilitating the
process of healing and repair.

Regulation of the Inflammatory Response:

The inflammatory response must be meticulously regulated to ensure effective immune protection. It is a dynamic network that
continuously adapts based on genetic factors, lifestyle choices, and environmental influences.

Dual Nature of Inflammation:

While inflammation is a natural part of the healing process and essential for defending against infections and environmental
threats, not all inflammation is beneficial. Prolonged or chronic inflammation can become destructive, leading to pathological
conditions. Thus, it is crucial for inflammation to be appropriately tailored to the specific stressor and resolve in a timely and
controlled manner.

Signs of Inflammation:

Redness: Increased blood flow to the affected area.

Heat: Elevated local temperature due to increased blood flow.
Swelling: Accumulation of fluid and proteins.
Pain: Pressure and release of bradykinins.
Loss of Function: Impairment of normal tissue function.
Arachidonic Acid:
Arachidonic acid (AA) is a ω-6 polyunsaturated fatty acid primarily found in cell membrane phospholipids. When cells are
stressed, AA is released from these phospholipids by enzymes like phospholipase A2 (PLA2) and phospholipase C (PLC). AA
serves as a precursor to proinflammatory mediators through three metabolic pathways.

Eicosanoids - Prostaglandins, Thromboxane & Leukotrienes:

Arachidonic acid can be metabolized into various proinflammatory mediators:

Prostaglandins: Induce vasodilation and inhibit platelet aggregation.

Thromboxane: Causes vasoconstriction and platelet aggregation.
Leukotrienes: Are chemotactic, induce smooth muscle contraction, and increase vascular permeability.
Cyclooxygenase (COX):
COX is the key enzyme responsible for converting arachidonic acid into prostaglandins and thromboxane. Two isoforms, COX-1
and COX-2, play distinct roles in inflammation. COX-2 is primarily induced in response to inflammatory stimuli and is associated
with inflammation in various tissues.

Synthesis of Inflammatory Mediators - Cytokines and Chemokines:

Activated macrophages in damaged tissues synthesize and release cytokines, including Interleukin IL-1 and Tumor Necrosis
Factor (TNF-α). These cytokines induce the expression of adhesion molecules on vascular endothelial cells, forming a barrier
between the bloodstream and damaged tissue. Additionally, cytokines act on endothelial cells and fibroblasts, stimulating the
synthesis of chemokines like IL-8 and Monocyte Chemotactic Protein (MCP). Chemokines attract specific leukocyte types,
regulate their expression of adhesion molecules, facilitate attachment to endothelial surfaces, and guide their movement
towards areas with higher chemokine concentrations.

Inflammation and Disease:

In recent years, there has been a growing recognition that inflammation is a common molecular pathway involved in various
human diseases. These diseases encompass a wide range, including infectious diseases, immune-mediated disorders,
cardiovascular conditions, diabetes, metabolic syndrome, neurodegenerative disorders, cancer, and even the aging process
itself.

Key Takeaways:

Inflammation is a complex, interconnected response to injury, trauma, or infections.

It involves the release or formation of various inflammatory mediators, including prostaglandins, thromboxane, leukotrienes,
cytokines, and chemokines.
Leukocytes are recruited to the site of inflammation, and their effector functions include phagocytosis, generation of toxic
reactive oxygen intermediates, and the release of hydrolytic enzymes.
While inflammation is essential for defense against harmful agents, chronic inflammation can lead to disease.
The regulation of the inflammatory response is critical for effective immune protection and tissue repair.