HMB204 - lecture 6

• Human biology is studied using human samples (biological fluids, post-mortem tissue donation, imaging data from human tissue), and population research, but sometimes in the context of human disease, the tissue cannot be readily harvested during disease progression
• Translational research


  Research focused on understanding human biology, especially pertaining to disease, using the foundation set by basic science research to advance therapeutic understanding
• Basic research


  Research that focuses on understanding the general molecular underpinnings of phenomena
• PICO


  A framework for human research consisting of four components: Patient (P), Intervention (I), Comparison (C), and Outcome (O)
• Different PICO questions


  • Therapy (Treatment)
  • Prevention
  • Diagnosis
• Patient


  An individual who seeks or receives medical or healthcare services for the diagnosis, treatment, or management of a health condition, injury, or illness
• As a translational researcher, the focus is first to find a disease to tackle, and the decision is often based on personal motivation, curiosity, and the diseases that are having the greatest impact on us as a species
• Epidemiology


  The study of the patterns, causes, and effects of health and disease conditions in populations
• Common epidemiological measures


  • Incidence rate
  • Prevalence rate
  • Morbidity
  • Mortality rate
• Incidence rate


  Measure used to describe the occurrence of new cases of a specific disease or condition within a defined population during a specified time period
• Example of incidence rate

  • In a population of 10,000 individuals, 200 new cases of a respiratory infection were diagnosed during a one-year period, with a population at risk of 8,000 individuals. The incidence rate is 25 per 1,000 population at risk.
• Prevalence rate


  Measure that determines a person's likelihood of having a disease, including both new and existing cases
• Example of prevalence rate


  • In a population of 10,000 individuals, there are 500 individuals diagnosed with diabetes and 2,000 individuals currently living with the condition. The prevalence rate is 250 per 1,000 population at risk.
• Morbidity


  Also known as illness, referring to the presence of a disease or condition in an individual or population
• Mortality


  Means death, and the annual mortality rate is calculated as the total number of deaths from all causes in 1 year divided by the number of persons in the population at midyear, multiplied by 100,000

  
• Years of potential life lost (YPLL)

  A measure that subtracts the deceased person's age at death from a predetermined age, usually 75 years, to quantify the loss of potential years of life

  
• Disability-adjusted life years (DALY)

  A measure that combines the years of life lost (YPLL) and the years lived with disability (YLD) to quantify the impact of a disease on an individual or population
• Example of DALY


  • A female patient develops severe alcohol use disorder (disability weight = 0.55) at age 40 and dies at age 60. The DALY is 26 years, consisting of 11 years lived with disability and 15 years of potential life lost.
• The Global Burden of Disease (GBD) study is the most comprehensive and consistent set of estimates of mortality and morbidity, using the DALY to quantify the burden of premature mortality and disability for major diseases or disease groups

  
• WHO now regularly develops GBD estimates at regional and global levels for a set of more than 135 causes of disease and injury

  
• A GBD study aims to quantify the burden of premature mortality and disability for major diseases or disease groups

  
• Uses the DALY to combine estimates of the years of life lost and years lived with disabilities

  
• Data broken down by age, sex and region
• Non-communicable diseases are not a physical injury, not transmissible, and not infections
• The PiCO Framework consists of Patient (P), Intervention (I), Comparison (C), and Outcome (O)
• For P, we can use the highest DALY score diseases as a start

  
• For I, in order to understand how to intervene, we must understand the cellular or molecular basis of disease
• Common themes in understanding human disease are oxidative stress, inflammation, and cell death
• When in balance, these processes are naturally occurring and keep us alive, but when imbalanced they fuel each other in a pathological way
• Mitochondria

  The primary source of reactive oxygen species (ROS)
• Exercise can lead to transient ROS rises

  Which stimulates adaptive responses including improved antioxidant capacity and mitochondrial biogenesis
• During ischemia/hypoxia, reduced oxygen availability


  Impairs the electron transport chain, leading to electron leakage and the generation of superoxide radicals, contributing to mitochondrial dysfunction and exacerbating tissue damage
• Cell death


  A fundamental biological process that occurs in multicellular organisms to maintain tissue homeostasis, eliminate damaged or unwanted cells, and regulate development

  
• Types of cell death

  • Apoptosis
  • Necrosis
  • Autophagy

  
• Apoptosis (programmed cell death)


  • Cell shrinkage, chromatin condensation, nuclear fragmentation (pyknosis), formation of apoptotic bodies
  • Mediated by caspases, protease enzymes
  • Extrinsic pathway: Initiated by death ligands binding to death receptors (e.g. Fas)
  • Intrinsic pathway: Triggered by cellular stressors like DNA damage or oxidative stress, involves mitochondrial outer membrane permeabilization
  • Role: Tissue remodeling during development, Immune system regulation and elimination of damaged cells
  • Dysregulation linked to diseases like cancer, neurodegenerative disorders, and autoimmune diseases

  
• Necrosis (uncontrolled cell death)


  • Caused by injury, pathogen etc.
  • Rapid loss of membrane integrity, swelling of organelles and release of cellular contents, triggering inflammation
  • Triggers inflammation and tissue damage
  • Release of pro-inflammatory molecules and DAMPs (damage associated molecular patterning molecules – like mitochondrial DNA, heat shock proteins)
  • Activates the innate immune system

  
• Healthy Inflammation


  • Normal physiological response to injury or infection
  • Protective mechanism to remove harmful stimuli and initiate tissue repair
  • Controlled and self-limiting
  • Involves recruitment of immune cells, release of cytokines, and activation of inflammatory pathways
• Pathological Inflammation


  • Dysregulated immune response
  • Chronic inflammation can lead to tissue damage and contribute to various diseases
  • Associated with conditions like autoimmune disorders, chronic infections, and metabolic syndrome
  • Involves sustained activation of inflammatory pathways and impaired resolution mechanisms
• Healthy inflammation promotes healing and tissue repair, while pathological inflammation can result in tissue destruction and organ dysfunction
• Ischemic heart disease or coronary heart disease (CHD) belongs in a class of diseases known as atherosclerotic cardiovascular disease (CVD) which includes CHD, hypertension, and stroke