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  <head>
    <title>003-01 Foundations</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Genes, proteins, adaptation, injury, and cell death">
      <outline text="Orientation">
        <outline text="Disease begins when a cell cannot maintain itself"/>
        <outline text="Outcome depends on stress, intensity, duration, cell type"/>
        <outline text="Mild stress: adaptation"/>
        <outline text="Severe but brief stress: reversible injury"/>
        <outline text="Persistent or overwhelming injury: cell death"/>
        <outline text="Cellular events scale up to organ failure"/>
      </outline>
      <outline text="Information flow and protein function">
        <outline text="DNA stores information in nucleotide sequence"/>
        <outline text="Transcription produces RNA">
          <outline text="mRNA processed, then translated by ribosomes"/>
        </outline>
        <outline text="Gene to protein is useful but incomplete">
          <outline text="Alternative splicing yields different transcripts"/>
          <outline text="Protein cleaved, modified, folded, transported, destroyed"/>
          <outline text="Phenotype depends on regulation at many levels"/>
        </outline>
        <outline text="Expression responds to hormones, nutrients, oxygen"/>
        <outline text="Epigenetics: histone modification, DNA methylation">
          <outline text="Stable change without altering sequence"/>
        </outline>
      </outline>
      <outline text="Mutation and inheritance">
        <outline text="Substitution, insertion, deletion, copy number, rearrangement"/>
        <outline text="Synonymous change may preserve the amino acid"/>
        <outline text="Missense substitutes, nonsense adds a stop codon"/>
        <outline text="Regulatory variants change expression, not sequence"/>
        <outline text="Dominant: one altered allele influences phenotype">
          <outline text="Does not mean common, severe, or beneficial"/>
        </outline>
        <outline text="Recessive usually needs both alleles affected"/>
        <outline text="Mitochondrial DNA mainly via the oocyte">
          <outline text="Heteroplasmy gives variable severity"/>
        </outline>
        <outline text="Penetrance: proportion expressing the phenotype"/>
        <outline text="Expressivity: variation in degree or form"/>
      </outline>
      <outline text="Why an altered allele can be dominant">
        <outline text="Loss of function often behaves recessively"/>
        <outline text="Haploinsufficiency: remaining output inadequate"/>
        <outline text="Dominant negative: altered protein blocks the normal one">
          <outline text="Both enter a complex needing working subunits"/>
        </outline>
        <outline text="Gain of function: excess, misplaced, or new activity"/>
        <outline text="Same gene, different disorders by mechanism"/>
        <outline text="A pedigree does not identify the mechanism"/>
      </outline>
      <outline text="Cellular adaptation">
        <outline text="Hypertrophy: increased cell size">
          <outline text="Workload with limited capacity to divide"/>
          <outline text="Later fibrosis and impaired relaxation cause harm"/>
        </outline>
        <outline text="Hyperplasia: increased cell number">
          <outline text="Physiological in pregnancy, pathological with oestrogen"/>
          <outline text="Not cancer, but some forms raise risk"/>
        </outline>
        <outline text="Atrophy: reduced size and sometimes number">
          <outline text="Synthesis falls, degradation and autophagy rise"/>
          <outline text="Conserves resources but reduces reserve"/>
        </outline>
        <outline text="Metaplasia: reversible switch of cell program">
          <outline text="Smokers: squamous epithelium loses mucociliary function"/>
          <outline text="Persistent stress can lead to dysplasia"/>
        </outline>
      </outline>
      <outline text="Reversible cell injury">
        <outline text="Central problem: impaired ATP production">
          <outline text="Ischaemia cuts oxygen, substrate, waste removal"/>
          <outline text="Hypoxaemia lowers oxygen but may keep flow"/>
        </outline>
        <outline text="Pump failure: sodium and water in, potassium out">
          <outline text="Cells and organelles swell, calcium accumulates"/>
        </outline>
        <outline text="ER swells, ribosomes detach, synthesis falls"/>
        <outline text="Unfolded-protein response"/>
        <outline text="Restoring flow within the window rescues cells">
          <outline text="Reperfusion can add oxidant and calcium injury"/>
          <outline text="Timely reperfusion is still essential"/>
        </outline>
      </outline>
      <outline text="Irreversible injury and necrosis">
        <outline text="Mitochondrial failure and profound membrane damage"/>
        <outline text="Nuclear change: pyknosis through karyolysis"/>
        <outline text="Coagulative: outlines kept, ischaemic solid organs"/>
        <outline text="Liquefactive: brain infarction and abscesses"/>
        <outline text="Caseous: friable, classically tuberculosis"/>
        <outline text="Fat necrosis: lipase release or trauma"/>
        <outline text="Fibrinoid: immune-mediated vascular injury"/>
        <outline text="Biomarkers from released intracellular proteins">
          <outline text="Troponin shows injury, not its cause"/>
          <outline text="Aminotransferases show injury, not liver function"/>
        </outline>
      </outline>
      <outline text="Apoptosis and regulated death">
        <outline text="Removes cells with minimal leakage"/>
        <outline text="Intrinsic: mitochondrial proteins, cytochrome c"/>
        <outline text="Extrinsic: death receptors"/>
        <outline text="Both activate caspases"/>
        <outline text="Too little: cancer or autoimmunity"/>
        <outline text="Too much: neurodegeneration, immune depletion"/>
        <outline text="Necroptosis and pyroptosis add inflammation"/>
        <outline text="Autophagy recycles components via lysosomes">
          <outline text="Context, degree, timing matter more than labels"/>
        </outline>
      </outline>
      <outline text="Clinical integration">
        <outline text="Not diagnosed from one symptom or value"/>
        <outline text="Ask stress, vulnerable tissue, reversibility, reserve"/>
        <outline text="Treatment follows mechanism">
          <outline text="Restore perfusion, remove toxins, support organs"/>
        </outline>
        <outline text="Intervention itself can cause harm"/>
      </outline>
    </outline>
  </body>
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