Pathophysiology (Exam 4) Flashcards
1
Q
what are the mechanisms that cells respond to injury
A
- homeostasis
- adaptation
- cell injury
- cell death
2
Q
what is homeostasis?
A
Cells maintain their intracellular environment within a narrow range of physiological parameters
3
Q
what is adaptation
A
As cells encounter physiological stresses or pathological stimuli, they can undergo adaptation, achieving new steady state and preserving viability and function by changing their size, number, and form
1. this involves the 5 forms
4
Q
what is cell injury
A
Occurs when cells are stressed to the point that they are unable to adapt
5
Q
what is cell death
A
Is one of the most crucial events in the evolution of disease in any tissue or organ
Can lead to necrosis or apoptosis
6
Q
what are the 5 major cellular adaptations in response to injury or stimuli
A
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
dysplasia
7
Q
what is hypertrophy
A
An increase in the size of cells resulting in increase in the size of an organ
8
Q
where does hypertrophy only occur (and example)
A
- in cells capable of dividing
–> Striated muscle cells in both skeletal muscle and heart
9
Q
hypertrophy is commonly caused by increased workload which includes _____?
A
- Physiological stimuli
- Estrogen-induced uterus enlargement during pregnancy - Pathological conditions
- Hypertension
- Aortic valve
10
Q
what is hypertrophy characterized by and examples
A
- increased protein synthesis
–>Mechanical triggers such as stretching
–> Hormonal triggers like adrenergic hormones
11
Q
what is hyperplasia
A
- Increase in the number of cells
–> Not cell size - Can be pathological or physiological
12
Q
what are examples of physiologic hormonal hyperplasia
A
Proliferation of the female mammary epithelium during puberty
13
Q
what is an example of physiologic compensatory hyperplasia
A
Regeneration of partially resected liver by the remaining hepatocytes or liver cells
14
Q
what are examples of pathologic hyperplasia
A
- Typically the result of excessive hormonal or growth factor stimulation
- Hyperplastic tissue may eventually become malignant
15
Q
hyperplasia has a specific example of proliferation. what is it?
A
proliferation of connective tissue cells during wound healing
16
Q
what is atrophy
A
- Shrinkage in the cell size of the cell by the loss of cell substance
–> No decrease in cell number
–> Decrease in size of tissue or organ
17
Q
what is atrophy frequently caused by:
A
- Decreased workload
- Loss of innervation
- Reduced blood supply
- Inadequate nutrition
- Aging
–> Senile atrophy
18
Q
what is the decreased in cell size in atrophy caused by:
A
- Increased protein degradation
- Reduced protein synthesis
19
Q
what is metaplasia
A
- Reversible change in which one adult cell is replaced by another adult cell
- Often is a response to chronic inflammation and irritation that makes cells better able to withstand stress
20
Q
what are examples of metaplasia
A
- Barretts esophagus
- Ciliated columnar epithelial cells of the trachea and bronchi help clear foreign materials and mucous
- In smokers, they may be replaced by squamous epithelial cells, which are more rugged but not ciliated
- This leads to coughing and increase in infections
21
Q
why is metaplasia a precursor to malignancy
A
May be caused by reprogramming of stem cells rather than by transdifferentiation of mature cells
22
Q
what is dysplasia
A
Characterized by deranged cellular growth of a specific tissue that results in cells that vary in size, shape, organization, and number
1. Adaptive in that it is potentially reversible after irritating cause has been removed
23
Q
what is dysplasia associated with
A
chronic irritation and inflammation
24
Q
when does dysplasia often occur
A
in metaplastic squamous epithelium in respiratory tract and uterine cervix
25
dysplasia is a strong precursor of malignancy; what is a cancer example?
Pap smears (cervical cancer)
-- every 3 years from age 21
-- 3-5 years hav test for ages 30-65
26
what two cellular adaptations can cause cancer
1. metaplasia
2. dysplasia
27
what are the 8 causes of cell injury
1. oxygen deprivation
2. chemical agents
3. infectious agents
4. immunological reactions
5. genetic defects
6. physical agents
7. nutritional imbalances
8. aging
28
what are examples for oxygen deprivation
1. Hypoxia- oxygen deficiency
--> Inadequate oxygenation of the blood- pneumonia
--> Reduction in oxygen-carrying capacity of the blood- blood loss anemia or carbon monoxide poisoning in which forms a stable complex with hemoglobin that prevents oxygen binding
2. Ischemia- loss of oxygenated blood supply to tissues
29
what are examples of chemical agents
Poisons, air pollutants, CO, asbestos
30
what are examples of infectious agents
Viruses, bacteria, fungi, parasites
31
what are examples of immunological reactions
Autoimmune diseases
32
what are examples of genetic diseases
Sickle cell anemia, familial hypercholesterolemia
33
what are examples for physical agents
Trauma, heat, cold, electric shock
34
what are examples for aging
- Accumulation of damage by ROS
- Loss of telomerase function
35
what are examples of nutritional imbalances
- Typically indirect cause of injury
1. Nutrition; deficiencies
--> Caloric or vitamin
2. Excess nutrition
3. Diabetes
--> Can be caused by obesity
-------- Excess blood sugar can damage cells
4. Atherosclerosis
--> Can be caused by diet rich in fats
-------- Can result of blockage of coronary arteries
36
what are the characteristics of reversible injury
cellular swelling and fatty change
37
explain cellular swelling
Result of failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis
38
examples fatty change
Occurs in hypoxic injury and various forms of toxic or metabolic injury, and is manifested by the appearance of small or large lipid vacuoles in the cytoplasm. Mainly occurs in cells involved in metabolism such as hepatocytes and myocardial cells
39
explain irreversible injury
1. Inability to reverse mitochondrial dysfunction
--> Lack of oxidative phosphorylation and ATP generation
2. Profound disturbances in membrane function
--> Membrane dysfunction
40
what is apoptosis
phagocytosis of apoptotic cells and fragments
41
what is necrosis
enzymatic digestion and leakage of cellular contents
42
what are the physiological causes of the apoptotic pathways
1. Programmed destruction of cells during embryogenesis: many
2. Involution of hormone-dependent tissues upon hormone deprivation: endometrial cell breakdown during menstrual cycle
3. Cell loss in proliferating cell populations: intestinal crypt epithelia
4. Elimination of potentially harmful self-reactive lymphocytes: before or after maturation
5. Cell death induced by cytotoxic T lymphocytes
43
what are the pathological causes of the apoptotic pathways
DNA damage; accumulation of misfolded proteins; cell injury in certain infection (viral infections); pathological atrophy in parenchymal organs after duct obstruction (pancreas, kidney, and parotid gland)
44
what is the intrinsic pathway
1. Mitochondrial (intrinsic) pathway
- Cell injury
GF withdrawal
--> DNA damage (radiation, toxins, free radicals)
--> Protein misfolding (ER stress)
45
what is the extrinsic pathway
2. Death receptor (extrinsic) pathway
- Receptor-ligand interactions
--> Fas
--> TNF receptor
46
what are the two apoptotic pathways
intrinsic and extrinsic
47
what is the role of BCL-2 in apoptosis
- Bax, Bak, and Bad proteins can increase mitochondrial membrane permeability by forming a dimer and inserting into the mitochondrial membrane. So this is called pro-apoptotic proteins
- Bcl-2 and Bcl-x can bind Bax family proteins and inhibit their function so this is called anti- apoptotic proteins
1. central players
48
what is the role of Cytochrome C in apoptosis
- Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases)
- released from mitochondria can activate caspase-9 to initiate caspase cascade
49
what is the role of the 2 types of caspases in apoptosis
Initiators and executioner (caspase-3 and 7)
50
what is the role of activated caspases
1. activate other proteases
--> Degradation of cytoskeletal proteins
2. can activate endonucleases
--> Cleavage of DNA leading to DNA fragmentation (DNA ladder)
51
what is the role of blebs formation
Dying cells collapse into cytoplasmic buds and apoptotic bodies
52
what is the role of phagocytosis in apoptosis
- bodies of macrophages
- Dead cells are cleared before they can release their cytoplasmic contents
- Prevents triggering an inflammatory response
- Nothing remains of dead cell
53
what mechanisms of cell injury are there
1. ATP depletion
2. mitochondria damage
3. membrane damage
4. increased ROS
5. calcium influx
54
what is the cell size of necrosis vs. apoptosis
necrosis: enlarged
Apoptosis: reduced
55
what is the nucleus of necrosis and apoptosis
necrosis: Pyknosis → karyolysis
Apoptosis: Fragmentation into nucleosome sized fragments
56
what is the plasma membrane for necrosis and apoptosis
necrosis: disrupted
apoptosis: Intact, but altered structure
57
what is the cellular contents of necrosis and apoptosis
necrosis: enzymatic digestion, leakage
apoptosis: Intact, in apoptotic bodies
58
what is the inflammation in necrosis and apoptosis
necrosis: frequent
apoptosis: none
59
does necrosis or apoptosis deal with physiologic or pathologic roles
necrosis: Invariably pathologic
apoptosis: Often physiologic; may be pathologic
60
what are the characteristics of acute inflammation
1. Rapid in onset and short duration
--> Minutes to days
2. Accumulation of fluid and plasma proteins
--> Exudation
3. Accumulation of neutrophils
4. Tumor necrosis factor (TNF), interleukin-1 (IL-1), chemokines
61
what are the characteristics of chronic inflammation
1. Insidious and of longer duration (months to years)
2. Tissue destruction by inflammatory cells
3. Vascular proliferation and fibrosis
--> Scarring
4. Influx of lymphocytes and macrophages
5. Interferon- y (IFN-y) by T cells and interleukin-I2 (IL-I2) by macrophages
--> Synergistic stimulation
62
what are some characteristics of inflammation
- Occurs upon infections or noxious stimuli
--> Injuries, burns, foreign bodies, etc.
- Eliminates harmful agents and necrotic cells
--> Microbes and toxins
- Initiates the healing process
63
inflammation can cause injury but what are the different types of responses
1. Too strong response
--> Severe infection
2. Prolonged response
--> Persistent or recurrent infection
3. Inappropriate response
--> Self-antigens in autoimmune diseases
64
what are some pharmacologic approaches of inflammation
1. Glucocorticoids
2. NSAIDs
3. Antihistamines
4. Leukotriene antagonists
5. Biologics targeting cytokine signaling
65
what are the characteristics
1. Heat
-- calor
2. Redness
-- rubor
3. Swelling
-- tumor
4. Pain
-- dolor
5. Loss of function
-- Functio laesa
66
what are the events occurring during the acute inflammation response
1. Phagocytosis in tissues recognize offending agents and liberate chemical mediators of inflammation
2. Chemical mediators widen blood vessels (vasodilation) and increase their permeability in the vicinity
3. Plasma and circulating leukocytes diffuse to the location of the offending agents
--> Leukocyte recruitment
4. Activated leukocytes remove the offending agents
--> Phagocytosis
5. Leukocytes produce signaling molecules that suppress inflammation
-- Lipoxins
6. The damaged tissue is repaired
-- Cell proliferation
67
what are some vascular stages responses
1. vasodilation
2. increased lipophilicty
68
whaat are some stages of cellular acute inflammation
1. Leukocyte recruitment
2. phagocytosis
69
what results in vasodilation
1. Decrease in fluid velocity
2. Increased viscosity
--> Due to fluid loss to tissues
3. Increased leukocytes settling along the inner surface of the blood vessels
--> margination
70
what results in increased lipophilicty
1. Gaps due to endothelial contraction
--> Most common mechanism
--> Histamines, leukotrienes, bradykinin
2. Increase fluid life through endothelial cells
--> transcytosis
3. Direct endothelial traumatic injury
4. Leukocyte dependent endothelial cell damage/death due to release of toxic mediators by leukocytes
5. Leakage from new blood vessels that form at the site of injury
71
what changes can result from vascular changes
1. Transudate
--> Small holes
--> Plasma with little proteins
--> No cells
2. Exudate
--> Bigger holes
--> Protein rich fluid with numerous cells
3. Edema
--> Accumulation of fluid and swelling at site of inflammation
72
what are the secret of events in leukocyte recruitment
1. Margination
2. Loose attachment and rolling
--> Selectins
3. Adhesion
--> Integrins
4. Transmigration
5. Chemotaxis
--> Bacterial products
-----> LPS
--> Chemokines
--> Complement system
-----> C5a
--> Leukotriene B4 (LTB4)
73
what is involved in the recognition of phagocytosis
direct and indirect
74
what is the engulfment of phagocytosis
- Receptor-mediated endocytosis
- Pseudopods extend around foreign body and form a phagosome
75
what is the intracellular killing of phagocytosis
1. Fusion of the phagosome with a lysosome (phagolysosome)
2. Lysosomal degradation
--> Digestive enzymes and defensins
3. Release of toxic nitrogen and oxygen compounds (oxidative burst)
--> H2O2, hydrochloric radical, NO
76
what is involved in direct recognition
- microbes by pattern recognition receptors
--> Toll-like receptors — LPS, flagellin, etc.
--> Mannose receptors
77
what is involved in indirect recognition
- Opsonins: IgG, C3b, and collectins (carb-binding lectins)
- Coat of foreign body and dead cells
--> Opsonization
- Specific receptors recognize opsonins
--> Fc receptor; C3b receptor
78
what are the functions of histamines
- First mediator released upon acute inflammation but transient
- Binds to type 1 receptor on endothelial cells and causes vasodilation and increases vascular permeability
- H1 receptor antagonists are used as antihistamine drugs
79
what are the roles of PAF
- Generated from phospholipids by phospholipase A2
- Induces platelet aggregation
- 100-1000 times more potent than histamine in inducing inflammation reactions
80
what are the roles of eicosanoids
- Derived from polyunsaturated fatty acids such as arachidonic acid
- has COX pathway
- has lipoxygenase pathway
81
what is the cox pathway
1. Prostaglandins
- Complex inflammatory responses including fever and pain
2. Thromboxane
- Vasoconstriction, platelet aggregation
- Inhibited by NSAIDs
82
what is the lipoxygenase pathway
1. Leukotrienes
- Similar to histamine but more potent and long acting
- Significant contributors to allergic reactions
83
what are the 3 roles of plasma membranes
1. thrombin and fibrinopeptides in clotting system
2. bradykinin in the kinin system
3. C3a, C5a, C3b in the complement system
84
describe the thrombin and fibrinopeptides in clotting system
1. Thrombin activates leukocytes
2. Fibrinopeptides, produced from digestion of fibrinogen by thrombin, increase vascular permeability; chemotactic
85
describe the C3a, C5a, C3b in the complement system pathway
1. C3a and C5a increase vascular permeability and cause vasodilation (anaphylatoxins)
2. C5a activates leukocytes; chemotactic
3. C3b acts as opsonin
86
describe the bradykinin in the kinin system process
1. Formed by cleavage of kinogens by a protease kallikreins
2. Increases vascular permeability and causes vasodilation
3. Causes pain
87
what is the function of cytokines
1. Serotonin is transient and tightly regulated
2. Have pleiotropic and redundant functions
3. TNF-a and IL-1 and chemokines
88
describe TNF-a and IL-1
1. The major cytokines that mediate inflammation
2. Produced by many cells, but activated macrophages are the major source
3. Generate cellular and systemic responses
89
describe chemokines
1. Chemotactic cytokines
2. Recruit and direct the migration of immune and inflammatory cells
3. Generate a persistent chemotactic gradient
90
describe nitric oxide
1. Short lived, local acting (seconds)
2. Synthesized by inducible NO synthase (iNOS), which is induced by inflammatory cytokines and mediators
3. Relaxation of vascular smooth muscle (vasodilation)
4. Antimicrobial agent in activated macrophages
91
describe reactive oxygen species
1. Short lived
2. Synthesized by NADH oxidase pathway
3. Superoxide radical, hydrogen peroxide, and hydroxyl radical
4. Released extracellularly by neutrophils and macrophages after stimulation
5. May cause tissue injury
92
describe tissue injury by lysosomal proteases
1. Release of lysosomal constituents into the extracellular space
--> Matrix degradation
--> Destructive tissue injury
2. Antiproteases inhibit lysosomal proteases
--> A2-macroglobulin, al- antitrypsin, etc.
--> Exist in the serum and extracellular matrix
93
what are the causes of lysosomal proteases
1. Premature degranulation of lysosomes
2. Phagocytosis attempts of large, flat surfaces (frustrated phagocytosis)
3. Damage of leukocytes (ex. Urate crystals of gout)
94
what mediators are responsbile for plasma
1. Factor 7
2. Complement proteins
3. acute-phase
95
what mediaotrs are responsible for cell derived
1. performed
2. newly synthesized
96
what mediators are responsible for vasodilation
Histamine, serotonin, PAF, kinins, complement
97
what mediators are responsible for increase vascular permeability
Histamine, serotonin, leukotrienes, PAF, kinins, prostaglandins
98
what mediators are responsible for chemotaxis
Leukotrienes, prostaglandins, chemokines, complement
99
what mediators are responsible for vascular smooth muscle relaxation
nitric oxide
100
what mediators are responsible for leukocyte activation
Leukotrienes, complement
101
what mediators are responsible for local endothelial activation
Cytokines (TNF, IL-1)
102
what mediators are responsible for killing of microbes
Nitric oxide, ROS
103
Describe the mechanism of the reciprocal relationship between macrophages and lymphocytes in chronic inflammation.
1. Activated by macrophages presenting antigen fragments
2. Activated lymphocytes release mediators including IFN-y
3. IFN-y activates macrophages
4. Activated macrophages release cytokines including IL-12
5. IL-12 further activates lymphocytes
6. Macrophages and lymphocytes persistently stimulate one another until the triggering antigen is removed
7. Plasma cells, eosinophils, and mast cells are also present in chronic inflammation
104
explain the roles of macrophages
1. Derived from circulating blood monocytes
2. Activated by cytokines, bacterial products, mediators of inflammation, dead cells, etc → epithelioid macrophages
3. Release various products, may cause tissue injury
4. Macrophage accumulation persists in chronic inflammation
105
explain the role of lymphocytes
1. B Cell, T cells, Natural Killer Cells
2. A lymphocyte is a type of white blood cell in the immune system of most vertebrates
3. Main type of cell found in lymph
4. In chronic inflammation
106
what are the examples about macrophages in the release of products that may result in tissue injury
1. Proteases
2. Complement components, coagulation factors
3. ROS and NO
4. Eicosanoids
5. Cytokines
6. Growth factors → fibrosis
107
what is granulomatous inflammation
1. Distinctive form of chronic inflammation
2. Formation of granuloma
--> Small (1-2 mm) lesion of epithelioid macrophages surrounded by lymphocytes
3. Foreign body giant cells
--> Multinucleated cells formed by coalesced macrophages
--> Encapsulate and isolate the offending agents
108
what is granulomatous inflammation caused by ___
1. offending agents not easily controlled by other inflammatory mechanisms
--> Foreign bodies such as splinters, sutures, silica, and asbestos
--> Microorganisms that cause tuberculosis, syphilis, sarcoidosis, deep fungal infections, and brucellosis
109
what is tissue regeneration?
Replacement of injured tissue with cells of the same type and function
110
what is tissue repair
Occurs when extent or nature of damage cannot be reversed by regeneration alone
111
State the 4 stages of healing after tissue injury.
1. hemostasis
2. inflammation
3. proliferation
4. remodeling
112
describe hemostasis
1. Results in local vasoconstriction and activation of platelets and clotting factors to form a fibrin clot
2. Creates a scaffold for migrating cells
3. minutes
113
describe inflammation
1. hours
2. Driven by platelet-derived mediators, bacteria, and secreted chemoattractants
114
describe proliferation
1. days
2. Mediated by macrophage and fibroblast-derived growth factors
115
describe remodeling
1. weeks to months
2. Transition from type 3 and type 1 collagen, restoring tensile strength of tissue
116
State the common outcome of various signal transduction pathways of growth factors.
results in the change of gene expression
117
what are the two forms of ECM and their key components
basement membrane and interstitial matrix
118
describe the basement membrane
1. Type 4 collagen
2. Laminin
3. proteoglycan
119
describe the interstitial matrix
1. Fibrillar collagens
2. Elastin
3. Proteoglycan and hyaluronan
120
what are the determinants of regeneration vs. repair after tissue injury.
1. nature of cells injured
2. extent of injury
3. underlying disease
4. Presence or absence of ongoing inflammation
121
describe the nature of cells injured
some cells (ex: adult cardiac myocytes) have marginal renewal capacity
122
describe the extent of injury
The magnitude of injury may exceed regeneration capacity
123
describe the underlying disease determinant
May impair proliferative response or remodeling (ex: diabetes)
124
describe the Presence or absence of ongoing inflammation
Due to concurrent infection or other factors, continued release inflammatory mediators may disrupt balance toward repair
125
what are the three key growth factors that regulate fibrosis.
PDGF, TFGb, & FGF-2de
126
describe PDGF
1. Platelet-derived growth factor
2. Migration and proliferation of fibroblasts, smooth muscle cells, and macrophages
127
describe TGFb
1. Transforming growth factor
2. Potent fibrogenic factor that stimulates collagen, fibronectin, and proteoglycan synthesis
3. Inhibits collagen degradation
4. Inhibits lymphocyte proliferation
5. Has anti-inflammatory effect
128
describe FGF-2
1. Fibroblast growth factor
2. Stimulates proliferation of endothelial cells
3. Promotes migration of macrophages and fibroblasts to damaged areas
129
List different classes of pathogens.
prions
Viruses
Bacteria
Fungi
parasites
130
what are viruses
1. Obligate intracellular pathogens
2. Capsid (protein coats) and genome (RNA or DNA)
3. Some are enclosed within an envelope derived from the cytoplasmic membrane of the host cells
4. Cause lysis and death of the host cell during replication
5. Some remain in a latent, nonreplicating state for long periods without causing disease
--> Varicella zoster virus
6. Some cause cancer
--> Human papillomavirus
131
what are bacteria
1. Prokaryotic
2. Microscopic shapes
- Spherical
--> Diplococci, staphylococci, streptococci
- Elongated
--> bacilli
- Helical
--> Spirilla (spirochete)
132
what is spirochetes
1. type of bacteria
2. anaerobic
3. Ex: borrelia burgdorferi (lyme disease), treponema pallidum (syphilis)
133
what is mycoplasmas
1. Much smaller than other bacteria
2. No cell wall - resistant to cell-wall inhibiting antibiotics (ex. penicillins)
3. Ex: mycoplasma pneumoniae (pneumonia)
134
what is rickettsiaceae
1. type of bacteria
2. Obligate intracellular pathogens
3. Transmitted via arthropod vectors (mites, fleas, ticks, lice)
4. Ex: rickettsia rickettsia (Rocky Mountain spotted fever)
135
what is chlamydiaceae
1. type of bacteria
2. Obligate intracellular pathogens
3. Transmitted via person-to-person contact
4. Ex: chlamydia trachomatis - sexually transmitted; cause conjunctivitis in newborns
136
what are the two types of fungi
superficial mycoses and systemic mycoses
137
what is superficial mycoses
1. dermatophytosis
2. Ringworm, athletes foot (tinea pedis), and jock itch (tinea cruris)
3. caused by dermatophytes whose infection is limited to the cooler cutaneous surfaces
138
what is systemic mycoses
1. Serious fungal infections of deep tissue (rare)
2. Candidiasis (yeast infection) - opportunistic infection of candida albican, which is commensal flora in skin, mucous membranes, and GI tract
3. aspergillosis - a lethal form of pneumonia caused by aspergillus, a common mold in people with lung diseases or immunocompromised patients
139
what is fungi
- Intact immune mechanisms and competitions for nutrients provided by the bacterial flora normally keep colonizing fungi in check
- A disease or an antibiotic therapy can upset the balance, permitting opportunistic infections
140
what are the 3 types of parasites
protozoa, helminths, and parasitic arthropods
141
what are protozoa
1. Unicellular animals
2. Ex: plasmodium (malaria) - vector-bone (mosquito)
3. Ex: entamoeba histolytica (amebic dysentery, or amoebiasis), giardia duodenalis (giardiasis) - contaminated water and food
142
what are helminths
1. Wormlike parasites
2. Ex: roundworms, tapeworms, flukes
3. Transmission primarily through ingestion of fertilized eggs (ova) or the penetration of infectious larval stages through the skin
143
what are parasitic arthropods
1. Ectoparasites - mites ( scabies ), chiggers, lice (head,body,pubic) and fleas
2. May serve as vectors of other infectious diseases, such as bubonic plague (fleas)
144
what are the different modes of transmissions from pathogens
penetrations, direct contact, indigestion, inhalation
145
describe penetrations
1. Any disruption may allow the invasion of pathogens, which normally cannot penetrate intact skin or mucous membranes
2. Ex: abrasions, burns, needles, insect, and animal bites
146
what are the two routes of direct contact
sex and congenital infections
147
describe sexually transmitted infections
1. Transmitted by the exposure of the intact skin or membrane to pathogens
2. Ex: gonorrhea, syphilis, chlamydia, and genital herpes
148
describe congenital infections
1. Infection of a child during gestation or birth from mother (vertical transmission)
2. Ex: Toxoplasmosis, Others (syphilis, varicella zoster, parvovirus B19), Rubella, Cytomegalovirus infection, and Herpes simplex virus (TORCH infection) and HIV
149
describe ingestion
1. Cholera, typhoid fever, amoebic dysentery, food poisoning, etc.
2. The low pH of the gastric acid acts as a barrier for many pathogens, but some are resistant to the low pH (ex: shigella and giardia) → differences in the infectious dose
3. The normal bacterial flora of the bowel compete with pathogens
150
describe inhalation
1. Bacterial pneumonia, meningitis, and tuberculosis
2. Viral infections such as measles, mumps, chickenpox, flu, common cold, and COVID
3. The respiratory tract is equipped with multiple-tiered defense system (mucous membrane, coughing, antibodies, and enzymes, phagocytosis, etc)
4. Smoking and diseases such as cystic fibrosis impair the defense system
151
what are the types of sources for parasites to get in
endogenous, exogenous, person, fomites, animal, vector, place
152
describe endogenous sources
Opportunistic infection acquired from the host’s own microbial flora
153
describe what the sources do
1. Location, host, object, or substance from which the infectious agent was acquired
--> Who, what, where, and when
154
describe exogenous sources
environment
-- water, food, soil, air
155
describe person sources
direct contact
156
describe fomites as sources
1. An inanimate object contaminated with infected body fluids
2. Rhinovirus through shared toys
3. HIV Hepatitis B virus by shared syringes
157
describe animals as sources
- Zoonoses - infectious diseases passed from other animal species to humans
- Ex: HIV, rabies, plague, flu, SARS, MERS, etc.
- 70% of emerging viral infections
158
describe vectors as sources
1. Biting arthropod
- Ex; lyme disease, west nile virus
159
describe place as a source
1. Healthcare associated infection (nosocomial infection)
2. Community acquired
160
what are the stages of disease courses
incubation period, prodromal stage, acute stage, convalescent stage, and resolution stage
161
describe the incubation period
Active replication of a pathogen without recognizable symptoms
162
describe the prodromal stage
1. Initial appearance of symptoms
2. Mild fever, myalgia, headache, and fatigue (somewhat nonspecific)
163
describe the acute stage
1. Max impact of the infectious process
2. Inflammation and tissue damage (more specific)
164
describe the convalescent stage
Progressive elimination of the pathogen
165
describe the resolution stage
Tool elimination of a pathogen
166
describe virulence factors
1. Substances or products generated by infectious agents that enhance their ability to cause disease
167
what pathological functions of does virulence factors have?
exotoxins, endotoxins, adhesion factors, evasive factors, invasive factors
168
describe exotoxins
1. Proteins released by pathogenic bacteria
2. Inactivate key cellular constituents (ex: diphtheria toxin inhibits protein synthesis)
3. Many are superantigens inducing excessive and nonspecific inflammatory responses
--> Bind to MHC of antigen-presenting cells and t-cell receptors
--> T cells are activated regardless of the antigen presented on MHC
169
describe endotoxins
1. Lipids and polysaccharides, not released (ex: lipopolysaccharides)
2. Can induce clotting, bleeding, inflammation, hypotension, and fever (endotoxic shock)
170
describe adhesion factors (adhesion)
1. Bind to macromolecules on surface of host cells
2. Adhesion is critical for the colonization of the pathogens
3. Some pathogens form a mucous layer (slime)
171
describe evasive factors
1. Inactivate host’s immune system
2. Ex: leukocidins form pores in the cell membrane of neutrophils and macrophages
3. Some pathogens survive and reproduce within phagocytes after phagocytosis by neutralizing lysosomal contents with evasive factors
172
describe invasive factors
1. Facilitate the penetration of anatomic barriers
2. Ex; pseudomonas aeruginosa collagenase breaks skin
173
what does commensalism mean
1. colonizing bacteria acquire nutrition and host is neither benefit nor are harmed
--> Commensal bacteria in a human body (normal flora) are 10x more than human cells
174
what does mutualism mean
1. both the microorganisms and the host derive benefits from the interaction
-> Infectious disease
-> Infectious agents
175
what does incidence mean
The number of new cases of an infectious disease that occur within a defined population ( ex: per 100,000 people ) over an established period of time ( ex: monthly, quarterly, yearly)
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what does disease prevalance mean
The number of active cause at a given time in a population
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what does endemic mean
Describes relatively stable incidence and prevalence in a particular geographical region
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what does epidemic mean
Describes an abrupt and unexpected increase in the incidence of disease over endemic rates
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what does pandemic mean
Refers to the spread of disease beyond continental boundaries
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what do fomites mean
An animate object contaminated with infected body fluids
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what do zoonoses mean
Infectious diseases passed from other animal species to humans
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what do nosocomial infection mean
Healthcare associated infection
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what does congenital infection mean
Infection of child during gestation or birth from mom
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what does prodromal stage mean
Initial appearance of symptoms
185
what does acute stage mean
Max impact of infectious process
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what does convalescent stage mean
Progressive elimination of the pathogen
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what is a exotoxin
Proteins released by pathogenic bacteria
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what is a endotoxin
Can induce a lot of things (endotoxic shock)
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what is a superantigen
Induces excessive and nonspecific inflammatory responses
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State the three key elements of shock.
Shock is a life threatening condition of circulatory failure that results in inadequate oxygenation of body tissues
191
Identify the component of gram negative bacteria that mediates septic shock.
endotoxin
192
Define edema.
Accumulation of fluid in interstitial space of body tissues
193
Describe the role of adrenomedullin in modulating vascular function.
In intravascular space enhances the endothelial barrier, reducing movement of solutes out of vascular space. When it does this ADM enters the interstitial space and mediates the relaxation in vascular smooth muscle, resulting in lower BP (vasodilation)
194
State the primary drivers of the movement of fluid into and out of vascular space.
1. Hydrostatic pressure
--> Drives fluid out of vascular space
2. colloid osmotic pressure
--> Draws fluid back into vascular space
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what are common clinical causes of edema.
1. Increased capillary permeability
2. Increased capillary hydrostatic pressure
3. Decreased capillary oncotic pressure
4. Lymphatic obstruction (lymphedema)
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what is transudate
protein poor
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what is exudate
protein rich
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describe the mechanism of Increased capillary permeability
- Local causes: cellulitis
- Systemic causes: sepsis, hypersensitivity reactions
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describe the mechanism of Increased capillary hydrostatic pressure
- Local causes: compartment syndrome, chronic venous insufficiency
- Systemic causes: heart failure, renal failure, pregnancy
200
describe the mechanism of Decreased capillary oncotic pressure
- Systemic causes: protein deficient states (nephrotic syndrome cirrhosis)
201
describe the mechanism of Lymphatic obstruction (lymphedema)
- Local causes: tumor, trauma, infection (filariasis)
202
Name the 4 main types of shock and their most common causes.
1. distributive
2. hypovolemic
3. cariogenic
4. obstructive
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what are the causes of distributive shock
- Sepsis
- Anaphylaxis
- Neurogenic
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what are the causes of hypovolemic shock
- Hemorrhage
- Severe burns
- Severe vomiting, diarrhea
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what are the causes of cariogenic shock
- Myocardial infarction
- Ventricular arrhythmia
- Cardiomyopathy
- Valvular disease
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what are the causes of obstructive shock
- Cardiac tamponade
- Pulmonary embolism
- Pneumothorax
207
describe distributive shock
- Normal/high output SvO2
1. Symptoms:
- hypovolemia and hypotension that leads to vasodilation in the release of inflammatory response
2. Echocardiographic signs
- Normal cardiac chambers and preserved contractility
208
describe hypovolemic shock
- Low SvO2 and low venous pressure
1. Symptoms:
- leads to loss of plasma or blood volume
2. Echocardiographic signs
- Small cardiac chambers and normal or high contractility
--> Triad with hypothermia → coagulopathy → acidosis
209
describe cariogenic shock
- Low SvO2 and high venous pressure
1. Symptoms:
- deals with cardiogenic shock and everything related to your heart
2. Echocardiographic signs
- Large ventricles and poor contractility
210
describe obstructive shock
- Low SvO2 and high venous pressure
1. Symptoms:
- obstructive shock is characterized by a blockage in blood flow caused by massive (causes listed)
2. Echocardiographic signs
- Depends on the cause
211
what are single gene disorders?
recessive, dominant, autosomal, sex-linked
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what is recessive
Observed in absence of normal allele (homozygous)
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what is dominant
Observed in presence of normal allele (heterozygous)
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what is autosomal
chromsomes 1-22
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what is sex-linked
x and y chromosomes
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what are Mendelian traits
autosomal dominant, autosomal recessive, and x linked recessive
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what is autosomal dominant
1. 50% chance passing trait to child
--> Same probability for M/F
2. Unaffected relatives/siblings do not transmit disorder
3. Age of onset is delayed for some
--> Huntington's disease
--> Appear later in life for signs/symptoms
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what is autosomal recessive
1. If both parents have mutant gene
--> 25% = affected child
--> 50% = carrier child
--> 25% = noncarrier child
--> Same probability for M/F
2. Unaffected siblings may be carriers (67%)
3. All children of affected parent are carriers
4. Age is early in life for many conditions
5. Symptoms tend to be more uniform than dominant disorders
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what is x-linked recessive
1. Circle with blue dot inside = carrier female
2. 50% chance of passing gene to sons and daughters
--> Daughters unaffected
--> Males who receive gene are affected
2. Affected males
--> Do not pass to sons
--> Pass mutant gene to daughters
3. Only males are affected
--> Females can be affected if father has trait and has children with female (rare)
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what are examples of x linked diseases
1. Hemophilia A & B
2. Joint bleeding, muscle hematoma, soft tissue bleeding
--> A = factor 8
--> B = factor 9
3. Incidence
--> A - 1: 5000
--> B - 1: 30,000
4. Mutations
--> A - inversion & small deletions
--> B - missense
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what is penetrance
1. Many people who have a mutation in a specific gene show any traits associated with defects in that gene
2. Complete: 100%
3. Incomplete: <100%
4. Even if people do not have pentrance they still have the gene but just do not show it
222
what is expressivity
1. Mutations in a gene give rise to different outcomes in different people
- Number
- Identity (types)
- Extent (severity)
2. Ranges from complete to minimal
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what is expressivity affected by
1. Other genes
2. Environment
3. Age
4. Exposure to harmful chemicals/ conditions
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what are silent mutations
Replacement of a single nucleotide that results in the same amino acid still so you cannot see if there has beena mutation because the sequence does not change
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what are missense mutations
Replacement of single nucleotide
&
Incorrect amino acid, which may produce a malfunctioning protein
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what are nonsense mutations
Replacement of single nucleotide
&
Incorrect amino acid, shortening of protein
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what are insertions
Frameshift
&
Insertion of a single nucleotide
&
Incorrect sequence, will produce a malfunctioning protein
228
what are deletions
Frameshift
&
Deletion of a single nucleotide
&
Incorrect sequence, will produce a malfunctioning protein
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complete loss of function =
amorphic
230
partial loss of function =
hypomorphic
231
gain of function =
hypermorphic
232
dominant negative =
inhibits activity of unmutated protein
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Acquisition of a new property =
neomorphic
234
what is a genetic variant
a change is sequence of genes
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what does pathogenic mean
1. Responsible for causing disease
2. Well supported by research
3. Referred to as mutations
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what is likely pathogenic
1. Probably responsible for disease causing
2. Not enough research to be sure
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what is uncertain significance mean
1. Not confirmed to cause disease
2. Not enough research
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what is Likely benign
1. Probably not responsible for disease
2. Not enough research to be sure
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what is benign
1. Not responsible for disease
2. Strong research to rule out disease link
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what is an inherited variant
- Passed from parent to child
- Present throughout a person’s life in virtually every dell in the body
- Germline variants- present in the parent’s egg or sperm cells (germ cells)
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what is a non-inherited variant
1. Occur at some time during a person’s life
2. Not found in every cell in the body
3. Somatic variants- occur in somatic cell (cells other than sperm and egg cells)
4. Not passed to the next generation
5. Can be caused by environmental factors (e.g. UV radiation) or result from an error in DNA replication
242
what is a new (de novo) variant
1. Found in a child but not either parent (no family history of the disorder)
2. May occur
--> In a parent’s egg or sperm cell but is not present in any of their other cells
3. Variants acquired during development can lead mosaicism
243
what is meant by karyotype analysis and how it can be used to diagnose genetic diseases.
a. Tells if chromosomes are:
1. Missing
2. Duplicated
3. Broken
4. Have deletions, insertions, or inversions
b. Report:
1. Total # of chromosomes
2. Sex chromosome
3. Description of abnormality
4. Ex: 47, XY, +21 (male with trisomy 21)
244
describe the most common genetic changes that cause down syndrome and turner syndrome.
a. Down syndrome
-- Trisomy 21 type: 47, XX, +21
-- Translocation type: 46, XX, der(14;21)(q10;q10), +21
-- Mosaic type: 46, XX/47, XX, +21
b. Turner syndrome
-- Monosomy X
245
what are Cytogenetic disorders
1. Chromosomal abnormalities are frequent
--> Approx 1/200 newborn infants
1. Changes in chromosome number or structure
--> Autosomes or sex chromosomes affected
1. Disorders characterized by a change in autosome number are more severe than single gene disorders
246
what is translocation
Transfer part of one chromosome to another
247
what is an isochromosome
Centromere divides horizontally rather than vertically, resulting in 2 short arms and 2 long arms
248
what is a deletion
loss of portion of chromosome
249
what is an inversion
When there are 2 interstitial breaks in a chromosome, segment reunites but is flipped
250
what is a ring chromosome
1. Variant of deletion.
2. After loss of segments from each end of the chromosome, arms unite to form a ring
251
what are examples of recessive disorders
cystic fibrosis, loss of function, effects of mutations on drug discovery
252
describe cystic fibrosis
1. Most common lethal genetic disease that affects caucasian population (1/3200)
2. Caused by loss of function mutations in cystic fibrosis transmembrane conductance regulator (CFTR)
3. Many differ mutations
253
what is loss of function in terms of recessive
1. Unmutated copy of gene is unable to make up for loss of expression or activity from mutant gene
--> No dosage compensation
254
what is mutations effects on terms of recessive and drug discovery
a. CFTR variants have differ effects of CFTR
1. People with variants that have partial activity fare better than those with complete loss of function
2. Variants establish a dose response relationship
3. People with CFTR alleles with 10-20% have mild CF
--> Ivacaftor
------- Increase function of CFTR protein
------- Works only with specific genotype
------- Improves clinical symptoms
255
what is triple repeat disease
1. Some genes contain repeats of 3 nucleotides
2. Longer repeats are associated with disruption of gene function
3. 40 diseases associated with triplet repeats
--> All are associated with neurodegeneration
4. CAH repeats encode poly-glutamine (polyQ disorders)
5. Mostly dominant
--> Friedreich ataxia - only triplet disorder that is recessive
256
what are examples of triple repeat
familial retardation and fragile X
257
what is fragile X syndrome
Elongated face
Protruding ears
Low muscle tone
258
what is familial dysfunction
FRM1 gene on X chromosome repeat (>45x)
259
what is mitochondrial mutations
Have separate genome
Are inherited only from mother
Present in multiple copies/cells
260
what is mitochondrial mutations caused by ?
1. mutations in mitochondrial genes are rare
2. Mutations in mitochondrial genes are transmitted to progeny by daughters, but not sons
261
what Is affected from mitochondrial mutations
1. Affected organs that depend most on oxidative phosphorylation
--> Skeletal muscle, heart, brain
262
wha tare imprinting defects
1. Parent of origin transmission
2. Some regions of DNA are turned off in copy received from mother or father
3. Imprinting occurs in ovum or sperm and stably transmitted to all somatic cells derived from zygote
4. If region turned off in maternal copy it is mutated in paternal copy, genes in that region will not be expressed
263
what are examples of imprinting defects
prader- will and angel man and complex inheritance patterns
264
what are prader will and angel man similarities
1. Phenotypes are partially overlapping, but distinct
2. Similar region of chromosome 15 deleted in both
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what is prader willi
1. Deletion inherited from father
2. Mental retardation, short stature, hypotonia, obesity, small hands and feet, hypogonadism
266
what is angel man syndrome
1.Deletion inherited from mother
2. Mental retardation, ataxic gait, seizures, inappropriate laughter
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what are examples of autosomal dominant
complete loss of function, partial loss of function, and gain of function
268
what are some mutations of autosomal dominance
1. Familial hypercholesterolemia (FH)
2. Mutations in the LDL receptor (LDL-R)
269
what is complete loss of function in terms of dominance?
1. Some variants act as dominant negatives
2. Mutated proteins interferes with the function of unmutated version
3. More severe
4. Not able to make up for loss of expression or activity from mutant gene
5. Osteogenesis imperfecta
270
describe osteogenesis imperfecta
1. Caused by defects in production of collagen
--> Structure, support, strength
2. Collagen trimer
--> 2 subunits of alpha 1
--> 1 subunit of alpha 2
271
describe gain of function in autosomal dominance
Some PCSK9 mutations have gain of function and LDL-R levels are regulated by PCSK9
272
describe LDL-R levels are regulated by PCSK9
1. Binds LDL-R on cell surface
2. Internalized with LDL-R
3.Directs LDL-R to lysosome
4. LDL-R completely degraded
5. Reduces the number of LDL receptors on cell surface
273
describe how some PCSK9 mutations have gain of function
1. Increase affinity for LDL-R
2. Enhance sorting of LDL-R to lysosome
