Post on 28-Dec-2015
PathogenesisReview
September 17, 2012
Ashkan Afshin, MD, MPHScD 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
Review Sessions
September 17, 2012 7:30-8:30pm Pathogenesis
September 24, 2012 7:30-8:30pm Neuropathophysiology
October 1, 2012 7:30-8:30pm Neuropathophysiology
Format:
• Brief review of the last lecture (20 min)• Discussing the questions received by email (10 min)• Q & A (30min)
Questions
Please send your questions or suggestions to:
Text Message: (949) 235-6137 Email: aafshin@hsph.harvard.edu
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.)
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.
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
BRCA2 belongs 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.
BRCA Genes BRCA1 and BRCA 2 are associated with increased risk of breast
cancer, and prostate cancer. BRCA2 increases the risk of pancreatic cancer.
Cancer Prevalence in
General Population Prevalence in
BRCA1 (+) or BRCA2 (+)
Breast 13.20% 36-85%
Ovarian 1.7% 16-60%
Gene-environment Interactions
Some genes promote disease, but only under certain environmental conditions.
Example?
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)
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
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.
DNA Methylation One mechanism of Epigenetic change
https://www.hgu.mrc.ac.uk/Research/Meehan/images/4.jpg
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
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
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
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
How do Cells and Tissues Respond to Stress?
Normal Cell
or Tissue
Adaptive Changes
Maladaptive Changes
(generally reversible)
Irreversible Damage
(Cell death)
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