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Pathogenesis Review

Pathogenesis Review . September 17, 2012. Ashkan Afshin, MD, MPH ScD Candidate, Department of Epidemiology ScD Candidate, Department of Global Health  & Population Harvard School of Public Health Kresge Building, Room 913 677 Huntington Avenue Boston, Massachusetts 02115

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Pathogenesis Review

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  1. PathogenesisReview September 17, 2012

  2. Ashkan Afshin, MD, MPH ScD Candidate, Department of Epidemiology ScD Candidate, Department of Global Health & Population Harvard School of Public Health Kresge Building, Room 913 677 Huntington Avenue Boston, Massachusetts 02115 Phone: (949) 235-6137 Email: aafshin@hsph.harvard.edu

  3. Review Sessions • Format: • Brief review of the last lecture (20 min) • Discussing the questions received by email (10 min) • Q & A (30min)

  4. Questions Please send your questions or suggestions to: • Text Message:  (949) 235-6137 • Email: aafshin@hsph.harvard.edu

  5. Factors that Contribute to Disease • Intrinsic Factors • Hereditary factors (Genetic Disorders) • Immunologic factors (Immune Dysfunction, allergies, autoimmune diseases, immunodeficiencies) • Psychological factors (depression) • Extrinsic Factors • Biological factors (Bacteria, Virus, Fungi, etc.) • Nutritional factors (Iron deficiency Anemia) • Physical factors (radiation, temperature, electricity, etc. ) • Chemical factors (dugs, carbon monoxide, acids, etc.)

  6. Mutation • A mutation is an error in the genetic code, causing you to make an incorrect form of the protein • Genetic diseases: cystic fibrosis, sickle cell anemia.

  7. BRCA Genes • BRCA1 is expressed in the cells of breast and other tissue. • Helps repair damaged DNA, or destroy cells if DNA cannot be repaired. • If BRCA1 is damaged, damaged DNA is not repaired properly and this increases risks for cancers • BRCA2belongs to the tumor suppressor gene family. • The protein encoded by BRCA2 is involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks.

  8. BRCA Genes • BRCA1 and BRCA 2are associated with increased risk of breast cancer, and prostate cancer. • BRCA2 increases the risk of pancreatic cancer.

  9. Gene-environment Interactions • Some genes promote disease, but only under certain environmental conditions. • Example?

  10. Thrifty Gene Hypothesis • Thrifty Genes: Genes which enable individuals to efficiently collect and process food to deposit fat during periods of food abundance. • Thrifty Gene Hypothesis: populations whose ancestral environments were characterized by periods of feast and famine experienced positive selection for Thrifty Genes. Under modern conditions, populations with such thrifty metabolisms are expected to have high rates of diabetes and obesity. (e.g., Pima Indians)

  11. Pima Indians • Among Pima Indians living in the US • 75% of Adult Pima Indians are obese • 50% have type II diabetes • Among Pima Indians living a more traditional lifestyle in Mexico • Most are not obese • About 10% have diabetes

  12. Epigenetics • Altered expression of genes based on environment during critical periods of development. • Can explain discrepancy between genotype and phenotype • Can be persist for generations • May also explain why adult lifestyle and genetic background alone fail to predict who is at greatest risk of heart disease and other conditions.

  13. DNA Methylation One mechanism of Epigenetic change https://www.hgu.mrc.ac.uk/Research/Meehan/images/4.jpg

  14. Injury and Toxicity • Injury can be caused by trauma or by toxic exposure • The significance of an injury depends on how much extra capacity an organ has leftover. • Safety factor: • How much beyond the expected maximal load a structure is designed to handle • Ratio of capacity to load

  15. Biological Safety Factors(ratio of capacity to load) • Human Pancreas (enzyme secretion) • About 10 • Human Kidney (plasma filtration) • About 4 • Human Mammary Gland (milk production) • About 3 • Mammalian Lungs (aerobic capacity) • About 1.25 - 2 From: Jared Diamond “Quantitative Evolutionary Design’ J. Physiol 2002, 542: 337-345

  16. Inflammation • Signs • Rubor (redness) • Tumor (swelling) • Calor (heat) • Dolor (pain) • Biologic Mechanisms • Increased blood flow to affected area • Increased capillary permeability • Movement of phagocytic cells into site of injury

  17. Is inflammation a good thing or a bad thing? • Good: • Helps with defense against infection • Helps with tissue repair • Bad: • Causes pain • Can damage healthy tissue • Sometimes occurs inappropriately, eg: allergy, autoimmune disease • Chronic inflammation as been implicated in atherosclerosis, which increases risk of heart attack and stroke

  18. How do Cells and Tissues Respond to Stress?

  19. Necrosis vs Apoptosis • Necrosis • Generally a pathological process • Promotes inflammation • Often leads to loss of function • Apoptosis • Often part of normal development • Can minimize the “biological backfire” associated with injury • Minimizes loss of function

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