Pathogenesis How, when and why do body systems fail?
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Transcript of Pathogenesis How, when and why do body systems fail?
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PathogenesisHow, when and why do body
systems fail?
Nancy Long Sieber, Ph.D.September 10, 2012
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Factors that Contribute to Disease Genes
Genetic diseases Genetic risk factors Gene – environment interactions
Epigenetic changes – altered expression of genes due to environment during development
Nutrition Injury and Toxicity Infection Immune Dysfunction Neoplasia (cancer)
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Genetics
Will analyzing your genotype foretell your
future?
http://wildcat.arizona.edu/papers/98/135/01_7_1.jpg
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http://cellbio.utmb.edu/cellbio/DNA-RNA.jpg
Recall the “Central Dogma”
Shape of proteins gives
rise to function.
Small errors can result in dysfunctional
proteins
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In any given cell type, physiologic or environmental challenges cause changes in
gene expression.Example: When you have an infection,
the genes for proteins that help you fight the infection are turned on.
This allows you to adapt to changing conditions inside and outside the body.
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What can go wrong?
MutationA mutation is an error in the genetic
code, causing you to make an incorrect form of the protein
This gives rise to genetic diseases, such as cystic fibrosis and sickle cell anemia.
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Sickle Cell Disease
http://www.sciencemuseum.org.uk/exhibitions/genes/images/1-3-5-1-4-2-1-3-1-0-0.jpg
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The change of a single base-pair causes one change in the amino acid sequence
of the hemoglobin molecule
http://www.wasdarwinright.com/images/sickle%20cell%20DNA.gif
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http://evolution.berkeley.edu/evolibrary/images/evo/hemoglobin.gif
Normal vs. Sickle Cell Hemoglobin
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What else can go wrong?
Certain genes increase risk of diseaseEg: breast cancer Some people are at high genetic risk for
breast cancer. Environment and lifestyle may not make much difference in these cases.
However, most cases occur in people with no strong family history.
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Genes influence breast cancer riskbut other factors are also involved
http://www.dnadirect.com/img/content_images/tests/breast_cancer/percentage_breast_cancer.gif
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http://en.wikipedia.org/wiki/Image:BRCA_Genes-location_of_BRCA1_and_BRCA2_on_chromosomes_13_and_17.gif from http://press2.nci.nih.gov/sciencebehind/cioc/survival/49.1.htm
Breast Cancer Genes
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Type of Cancer
General Population That Will Develop Disease
Women With BRCA1 or BRCA2 Mutation Who Will Develop Disease
Breast 13.2% 36-85%
Ovarian 1.7% 16-60%
Source: National Cancer Institute (http://www.cancer.gov)
BRCA2 is also associated with increased risk of prostate cancer,male breast cancer, and pancreatic cancer.
BRCA genes and increased cancer risk
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What else can go wrong?
Gene-environment interactions Some genes promote disease, but only
under certain environmental conditions.
This is probably the most common scenario for disease – nature and nurture.
Eg: Obesity and type II diabetes
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Insulin is necessary to transport glucose from the blood into cells
http://www.humanillnesses.com/original/images/hdc_0001_0001_0_img0082.jpg
Type 1 diabeticslack insulin
Type 2 diabeticsare insulinresistant
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Certain ethnic groups are at greater risk of type II
diabetes.Eg: Pima Indians of North
America
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“Thrifty genes” plus Western eating habits increase the risk of obesity and
diabetes among Pima Indians
Luis Morago, a noted scout for the U.S. Army in 1872 (Smithsonian Institution)
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Pima Indians appear to have genes that favor obesity, but only become
obese in certain environmentsAmong Pima Indians living in the US
75% of Adult Pima Indians are obese 50% have type II diabetes, a common
consequence of obesity.Among Pima Indians living a more
traditional lifestyle in Mexico Most are not obese About 10% have diabetes
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Long-term Changes in Gene Expression:Epigenetics
Altered expression of genes based on environment during critical periods of development.
Can explain discrepancy between genotype (what genes you have) and phenotype (what characteristics you express).
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.
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DNA Methylation One mechanism of epigenetic
change
https://www.hgu.mrc.ac.uk/Research/Meehan/images/4.jpg
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The Dutch Famine of 1944
During the Dutch Famine, the average caloric intake for an adultwas about 400 – 800 calories, compared to 1800 calories before the famine.
http://www.beeldbank.leidenuniv.nl/ImageDisplay.php?uid=FT083778&thumbed=5
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Studies of people who were in early gestation during the Dutch Famine showed ahigher risk of obesityhigher levels of lipids in the bloodstream3-fold higher risk of cardiovascular
disease than people who were not exposed to the famine.
Also: higher risk of schizophrenia and addictions.
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Further studies have shown a greater risk of disease in adults who were low birth weight babies, including:
High Blood Pressure Coronary Artery Disease Type II Diabetes Stroke Dyslipidemia (high cholesterol, fatty acids in
blood) Elevated clotting factors (increasing risk of
stroke and heart attack)
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Fig. 1 Standardized mortality ratios for coronary heart disease in England and Wales during 1968–79 and neonatal mortality during 1921–25 (♦ London boroughs; county boroughs; ○ urban districts; □ rural districts)
From: DJP Barker, “The Origins of the Developmental Origins Theory. Journal of Internal Medicine. 2007; 261: 412-417.
People born in areas with high infant mortality (most often due to low birth weight) are at high
risk of death from heart disease as adults
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Why do these particular epigenetic changes occur in response to
insufficient nutrition? Some may help the fetus survive in utero.
Some may be adaptations to what appears to be a world without sufficient calories – thus the “thrifty phenotype” .
Some changes may result from having insufficient nutrients to develop properly – brain and heart are prioritized, other organs suffer.
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What can compromise fetal nutrition in the US today?
Eating disordersAssociated with a doubled risk of
having a low birth weight baby, even if the mother was treated before becoming pregnant
Maternal smoking Associated with smaller babies who are
at greater risk of obesity as teens Nutrient-deficient diets, even if calorically
sufficient, may also impede growth.
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What do we mean by malnutrition?
A diet deficient in essential nutrients.
A diet too low or too high in calories.
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Malnutrition is most common in Africa and South East Asia
http://www.bread.org/learn/global-hunger-issues/maps/malnutrition-hotspots_small.jpg
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Malnutrition weakens defenses against many kinds of diseases.
http://www.usaid.gov/our_work/global_health/nut/images/malnutrition_chart.gif
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http://www.biologymad.com/Immunology/inflammation.jpg
Inflammation
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Signs of InflammationRubor (redness)Tumor (swelling)Calor (heat)Dolor (pain)
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These changes result from Increased blood flow to affected area Increased capillary permeabilityMovement of phagocytic cells into
site of injury
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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
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Normal Cell or Tissue
Injury
Adaptive Changes
Maladaptive Changes(generally reversible)
Irreversible Damage(cell death by
necrosis)
How do Cells and Tissues Respond to Stress?
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http://www.angelfire.com/ab7/mystro157/year/arnold3.jpg
Adaptive Changes: An increase in muscle mass in response to exercise
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Adaptive Changes:Weight-bearing exercise increases bone density
http://www.x-trainers.com/images/bicep%20pull.jpg
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Adaptive Changes: Calluses on your feet
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Cilia on the respiratory epithelium
When exposed to cigarette smoke, this tissue adapts by producing epithelial cells that lack cilia.
The cells are more likely to survive smoke exposure, but the person loses function.
Some adaptive changes come at a cost
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Scarring is generally an adaptive response, but can interfere
with organ function
http://www.shands.org/health/graphics/images/en/10296.jpg
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How Cells Die
Necrosis vs. Apoptosis
http://www.nature.com/labinvest/journal/v83/n4/images/3780641f1.jpg
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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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Developing human hand before web apoptosis
http://www.i-am-pregnant.com/img/day48-hand.gif
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Developing hand after web apoptosis
http://www.grg.org/breakingnews2001.htm
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Ischemic Stroke
http://strokecenter.stanford.edu/guide/images/thrombotic.jpg
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Modified from: http://www.chrononhotonthologos.com/inactive/strokedr/hbothera.htm
.
.Area of necrotic (dead) tissue
Cells in the surrounding area are commonly irreversibly damaged.
Cells in this region often undergo apoptosis in the hours after the stroke.
Damage Control Apoptosis of Irreversible Injured Cells
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http://www.wirednewyork.com/hotels/marriott_marquis/images/marriott_marquis_elevators.jpg
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http://www.gkivdo.com/gkii/wire_3.jpg
Elevator cable for passenger elevators has a safety factor of about 11
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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
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http://www.biologymad.com/Immunology/inflammation.jpg
Inflammation
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http://www.easterncarolinaent.com/Allergy-Triggers-copy.jpg
Common Allergens
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http://www.euromeds.co.uk/allergy-treatment-information.htm
Allergen binds to IgE, which links to mast cells, triggering release of histamine.
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Autoimmune Diseases
http://www.theintellectualdevotional.com/blog/2010/01/25/autoimmune-diseases-basically-an-epic-body-fail/
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Mechanisms of Autoimmunity Modification of a molecule on the host cell Molecular mimicry Exposure of a sequestered antigen to the
immune system Inappropriate activation of lymphocytes that
should be “tolerant Imbalance of suppressor T cells, which
inhibit the immune response, and helper T cells, which promote it.
Genetic factors – the risk of autoimmune disease runs in families.
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http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/cancergrowth.gif
The Development of Cancer
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http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/cancer.html
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http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/cancer.html
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http://www.medicinenet.com/images/illustrations/butterfly_rash.jpg
Lupus
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http://www.naturosante.ch/B.L.-lupus-evolution-1.jpg