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PATHOLOGY LECTURE

SERIES
Butch Dumdum

Outline
Day 1 (General Pathology)
Introduction, Cellular Adaptation,Tissue Injury
Inflammation (Acute and Chronic)
Hemostasis,Thrombosis, and Infarct
Neoplasia

Day 2 (Systemic Pathology)


Common systemic diseases (Pathological
basis of disease)
Radiologic Correlation (Diagnostic Radiology)

Introduction, Cell & Tissue


Damage

Pathology
Definition
Pathology is the study (logos) of
suffering/diseases (pathos)
Involves basic medical sciences and
clinical practice to investigates of the
causes (etiology) of the diseases and
the mechanism (pathogenesis)

Basic terminology in
Pathology

Disease
Etiology
Pathogenesis
Diagnosis
Clinical manifestation - Signs and
symptoms
Prognosis
Epidemiology
5

Disease / dis-ease
Disease is a condition in which the presence of
an abnormality of the body causes a loss of
normal health
Idiopathic no identifiable causes
Iatrogenic occur as a result from medical
treatment
Congenital disease existing at birth or before
birth, involves in the development of fetus
Acquired - develops post fetally
Nosocomial due to being in a hospital
environments
6

Etiology
Refers to the study of the cause of
the disease
General categories of etiological
agents; genetic abnormalities,
infective agents, chemical, radiation,
mechanical trauma, malnutrition

Pathogenesis
Is a mechanism of the disease which
etiology operates to produce the
pathological and clinical
manifestation
For examples inflammation,
degeneration, immune response

Diagnosis
Refers to the process of attempting to
determine or identify a possible disease
or disorder.

Prognosis
Refers to the expected outcome of a
disease.
9

Complication and sequalae


Complication is the onset of the
disease in a person who is already
coping with another existing disease.
Sequalae unwanted outcomes of
having disease or are the result of
trauma

10

Clinical Manifestation
Are the signs and symptoms or
evidence of disease
Signs objective alteration that can
be observe or measured by another
person; pulse rate, blood pressure,
Temperature etc
Symptoms subjective experiences
reported by the person, complains
such as pain, nausea, vomiting etc
11

Epidemiology
Is the study of tracking patters of
disease occurrence and transmission
among populations and by
geographic areas.
Incidence of a disease is the number
of new cases occurring in specific
time of period
Prevalence of a disease is the
number of existing cases within a
populations during the specific time

12

Prefixes and Suffixes and


Roots
Root- the foundation of the word
Prefix place before the root to modify its
meaning
Suffix places after root to modify and give
essential meaning to the root
1. Hyperlipoproteinemia
Prefix : hyper (higher)
Roots : lipoprotein
Suffix : -emia (blood condition)
13

2. Hepatosplenomegaly
Root : hepato (hepar), spleno (spleen)
Suffix : -megaly (enlargement)
3. Meningitis
Root : mening (meninges)
Suffix : - itis (inflammation)
4. Tachycardia
Root : cardia (heart)
Prefix : tachy (fast/rapid)
14

Relationship between Cell Adaptation,


Cells degeneration, Cell Death
CELLS ADAPTATION
Injuries

NORMAL
CELLS

Injurie
s

CELLS
DEGENERATION

Injuries
CELLS DEATH
(NECROSIS/APOPTOSI
S
15

Cellular Adaptation
Under normal conditions, cells must
constantly adapt to changes is their
environment (physiological,
pathological).
Atrophy
Hypertrophy
Hyperplasia
Dysplasia
Metaplasia
16

Atrophy

Shrinkage of the size of the


cells by the lost of the cells
substance.
The entire tissue or organs
diminishes in size and
function
May be due to decrease in
workload, lost of nerve
innervations, Lack of blood
supply, inadequate
nutrition, lost of endocrine
stimulation and aging
process.

17

Hypertrophy
Increase the size of the
cells and consequently
the size of the organs
Increased the synthesis
of structural protein and
organelles
Can be physiologic
(ex;increase workload
during exercise, uterine
myometrium during
pregnancy) and
pathologic (hypertrophy
of myocardium
hypertension/aortic
valve disease)

18

Hyperplasia
Increase the number of
cells in an organ or tissue.
(increase rate of cellular
division)
Hypertrophy and
hyperplasia are closely
related (exp : gravid
uterus)
Can be compensatory
hyperplasia (exp: liver),
hormonal hyperplasia
(exp: uterus, breast) and
pathological (exp:
endometrium)
19

Metaplasia
Is a reversible change in which one adult cell type
is replaced by another cell type.
Adaptation of cells that sensitive to particular
stress to cell types better able to withstand the
adverse of environment

20

21

Dysplasia
Not a true cellular
adaptation
Atypical hyperplasia
Abnormal change in the
size, shape and
organization of mature
cells
Strongly associated with
common neoplastic
growth
Exp: CIN cervical
intraepithelial neoplasia,
hip dysplasia
22

23

Cell Injury
Nonlethal injury - cell degeneration
Lethal injury necrosis

24

Cell Degeneration (Nonlethal Injury)


Nonlethal injury may produce cell
degeneration
Manifested as a abnormality of
biochemical function, structural
changes or combination.
Its reversible but may become
irreversible (necrosis/apoptosis)
May produce clinical disease.
25

Necrosis (Lethal Injury)


Definition unprogrammed cell
death and living tissues. (opposite to
apoptosis)
Irreversible
Accompanied with by biochemical
and morphological changes
Due to hypoxia, chemical
substances, free radical,
immunologic response, infections etc
26

Stages of Necrosis
Early changes : morphologically normal
Nuclear changes : pyknosis chromatin
clumps into coarse strands, nucleus
become shrunken
Cytoplasmic changes : denaturation of
cytoplasmic protein and lost of
ribosomes, swelling of mitochondria and
disruption of organelle membranes and
autolysis occur via lysosomes
27

Type of Necrosis
Different cells shows different
morphologic changes after they undergo
necrosis. Base on that necrosis can be
classified into:
1. Coagulative necrosis
2. Liquefactive necrosis
3. Caseous / gummatous necrosis
4. Fat necrosis
5. Gangrenous Necrosis
29

Coagulative Necrosis
Typically occur in solid organ; heart, kidney, adrenal
glands
Due to hypoxia (maybe from severe ischemia or
chemical)
Normally, this necrotic cells retains its cellular outline.
Denaturation of protein albumin causes coagulation.

30

Liquefactive Necrosis
Normally occurs in CNS
which affects neuron
and neuroglia cells
Associated with focal
bacterial and fungus
infections
The affected cells
completely digest by
hydrolytic enzymes thus
changes the tissue into
liquid viscous mass.
31

Caseous Necrosis
Caseous cheese
like appearance
Associated with
tuberculous
pulmonary (TB)
infection, esp by
Mycobacterium
Tuberculosis
32

Fat Necrosis
Occur in pancreas, breast and other abdominal structures
Caused by lipases enzymes which break down
triglycerides (lipid) into fatty acids and glycerol
Fatty acids and glycerol then combine with Ca, Mg, Na to
form Calcium Soaps (Saponification)
The necrotic tissue appears opaque and chalk white.

33

Gangrenous Necrosis (gangrene)


Extensive tissue necrosis
Divide into two; dry and wet
Dry occurs in extremities as
a results of ischemic
coagulative necrosis due to
arterial obstruction
Wet occurs in extremities
and internal organ as a
results of liquefactive
necrosis due to bacterial
infection.
Gas necrotic tissue infected
by clostridium perfringes
34

Causes of Cell Injury

Oxygen deprivation
Chemical agents
Infectious agents
Immunologic reactions
Genetic defects
Nutritional imbalances
Physical agents
Aging
35

Oxygen deprivation
Hypoxia oxygen deficiency
Due to ischemia lost/lack of blood
supply (due to arterial blockage or
reduce venous drainage)
Hypoxia also can occurs via:
Lack of oxygen inside blood
Reduction in oxygen carrying capacity in
RBC (anemia)
Carbon monoxide poisoning
36

Chemical agents
Most of the chemical substances can
cause cell injury
For example : poisons, air pollutants,
insecticides, CO, asbestos, ethanol,
therapeutics drugs etc
This agents can cause cell death by:
Altering membrane permeability
Altering osmotic homeostasis
Altering integrity of an enzyme
37

Infectious agent
Viruses, bacteria, fungi, parasites,
helminths

38

Immunologic Reactions
Autoimmune disease immunity
against its own tissues . For
examples SLE, Rheumatoid Arthritis
etc

39

Genetic Defects
Abnormalities to the genomes mutation
This chromosome anomaly is
associated with missing, or
irregularities or extra in portion of
chromosomal DNA
Syndrome Down, Alzheimer's
Disease, Huntingtons Disease etc
40

Nutritional Imbalance
Cause by directly or indirectly lack of
essential nutrients (malnutrition)
Or it maybe related to excessive of
food intake (Diabetic Mellitus)
For example protein deficiency
Kwashiorkor, Marasmus
Calcium deficiency osteoporosis
Vitamin C - Scurvy
41

Physical Agents
Trauma, extremes of temperature,
radiation, electrical shock all have
wide ranging effects on cells.

42

Aging
Aged cells become larger, less able
to divide and multiply
Lose their ability to functions, or
function abnormally.

43

Inflammation
Acute vs Chronic

SEQUENCE OF EVENTS
NORMAL HISTOLOGY
VASODILATATION
INCREASED VASCULAR PERMEABILITY
LEAKAGE OF EXUDATE
MARGINATION, ROLLING, ADHESION
TRANSMIGRATION (DIAPEDESIS)
CHEMOTAXIS
PMN ACTIVATION
PHAGOCYTOSIS: Recognition, Attachment,
Engulfment, Killing (degradation or
digestion)
TERMINATION
100% RESOLUTION, SCAR, or CHRONIC
INFLAMMATION are the three possible

ACUTE
INFLAMMATION
PROTECTIVE
RESPONSE

NON-specific

ACUTE
INFLAMMATION

VASCULAR EVENTS
CELLULAR EVENTS (PMN
or PolyMorphonuclear
Neutrophil, Leukocyte?,
POLY, Neutrophil,
Granulocyte, Neutrophilic
Granulocyte

ACUTE
INFLAMMATION
Neutrophil
Polymorphonuclear
Leukocyte, PMN, PML
Leukocyte
Granulocyte,
Neutrophilic
granulocyte
Poly-

HISTORICAL
HIGHLIGHTS
(Egypt, 3000 BC)

Rubor
Calor
Tumor
Dolor
5th (functio
laesa)

STIMULI
for acute inflammation

INFECTIOUS
PHYSICAL
CHEMICAL
Tissue Necrosis
Foreign Bodies (FBs)
Immune responses, or
complexes

Vascular Changes
Changes in Vascular
Flow and Caliber
Increased Vascular
Permeability

INCREASED
PERMEABILITY

DILATATION
Endothelial gaps
Direct Injury
Leukocyte Injury
Transocytosis
(endo/exo)

LEAKAGE OF
PROTEINACEOUS
FLUID (

EXUDATE,

NOT TRANSUDATE)

EXTRAVASATION of
PMNs

MARGINATION
(PMNs go
toward wall)
ROLLING
(tumbling and
HEAPING)
ADHESION
TRANSMIGRATIO
N (DIAPEDESIS)

ADHESION MOLECULES
(glycoproteins) affecting
ADHESION and TRANSMIGRATION

SECRETINS (from
endothelial cells)
INTEGRINS (from many
cells)

CHEMOTAXIS
PMNs going to the site of
injury
AFTER transmigration

LEUKOCYTE
ACTIVATION
triggered by the offending stimuli for
PMNs to:
1) Produce eicosanoids
(arachidonic acid derivatives)
Prostaglandin (and thromboxanes)
Leukotrienes
Lipoxins

2) Undergo DEGRANULATION

PHAGOCYTOSIS
RECOGNITION
ENGULFMENT
KILLING
(DEGRADATION
/DIGESTION)

CHEMICAL
MEDIATORS

From plasma or cells


Have triggering
stimuli
Usually have specific
targets
Can cause a

CLASSIC MEDIATORS

HISTAMINE
SEROTONIN
COMPLEMENT
KININS
CLOTTING
FACTORS
EICOSANOIDS
NITRIC OXIDE

PLATELET
ACTIVATING
FACTOR (PAF)
CYTOKINES
/CHEMOKINES
LYSOSOME
CONSTITUENTS
FREE RADICALS
NEUROPEPTIDES

HISTAMINE
Mast Cells,
basophils
POWERFUL
Vasodilator
Vasoactive
amine
IgE on mast
cell

SEROTONIN
(5HT,

5-

HydroxyTryptamine)
Platelets and
EnteroChromaffin
Cells
Also vasodilatation,
but more indirect
Evokes N.O.
synthetase (a

COMPLEMENT
SYSTEM
>20
component
s, in
circulating
plasma
Multiple
sites of
action, but
LYSIS is
the

KININ SYSTEM
BRADYKININ is KEY component, 9
aas
ALSO from circulating plasma
ACTIONS
Increased permeability
Smooth muscle contraction, NON
vascular

PAIN

CLOTTING
FACTORS
Also from circulating plasma
Coagulation, i.e., production
of fibrin
Fibrinolysis

EICOSANOIDS
(ARACHIDONIC ACID DERIVATIVES)

Part of cell
membranes
1) Prostaglandins
(incl.
Thromboxanes)
2)
Leukotrienes
MULTIPLE
ACTIONS AT MANY

Prostaglandins
(thromboxanes included)

Pain
Fever
Clotting

Leukotrienes
Chemotaxis
Vasoconstriction
Increased
Permeability

Lipoxins
INHIBIT chemotaxis
Vasodilatation
Counteract actions
of leukotrienes

Platelet-Activating Factor
(PAF)
Phospholipid
From MANY cells,
like eicosanoids
ACTIVATE
PLATELETS,
powerfully

CYTOKINES/CHEMOKIN
ES
CYTOKINES are PROTEINS produced
by MANY cells, but usually
LYMPHOCYTES and MACROPHAGES,
numerous roles in acute and chronic
inflammation

TNF, IL-1, by
macrophages

CHEMOKINES are small proteins


which are attractants for PMNs
(>40)

NITRIC OXIDE
Potent vasodilator
Produced from the
action of nitric oxide
synthetase from
arginine

LYSOSOMAL
SECONDARY
CONSTITUENTS
PRIMARY
Also called
AZUROPHILIC,
or NONspecific
Myeloperoxida
se
Lysozyme
(Bact.)
Acid
Hydrolases

Also called
SPECIFIC

Lactoferrin
Lysozyme
Alkaline
Phosphatase
Collagenase

FREE RADICALS
O2 (SUPEROXIDE)

H2O2 (PEROXIDE)
OH- (HYDROXYL RADICAL)

VERY VERY
DESTRUCTIVE

NEUROPEPTIDES
Produced in CNS
(neurons)
SUBSTANCE P
NEUROKININ A

OUTCOMES OF
ACUTE INFLAMMATION
1) 100% complete
RESOLUTION
2) SCAR
3)CHRONIC inflammation

Morphologic PATTERNS
of Acute INFLAMMATION
(EXUDATE)

Serous (watery)
Fibrinous

(hemorrhagic, rich in
FIBRIN)

Suppurative (PUS)

BLISTER, Watery, i.e.,

FIBRINOUS

PUS
=
PURULEN
T
ABSCESS
=
POCKET
OF
PUS

PURULENT, FIBRINOPURULENT

ULCERATIVE

SEQUENCE OF EVENTS
NORMAL HISTOLOGY
VASODILATATION
INCREASED VASCULAR PERMEABILITY
LEAKAGE OF EXUDATE
MARGINATION, ROLLING, ADHESION
TRANSMIGRATION (DIAPEDESIS)
CHEMOTAXIS
PMN ACTIVATION
PHAGOCYTOSIS: Recognition, Attachment,
Engulfment, Killing (degradation or
digestion)
TERMINATION
100% RESOLUTION, SCAR, or CHRONIC
inflammation

CHRONIC INFLAMMATION

(MONOS)

LYMPHOCYT

MONOCYTE
MACROPHAGE
HISTIOCYTE

CAUSES of
CHRONIC INFLAMMATION

1) PERSISTENCE of
Infection
2) PROLONGED
EXPOSURE to insult
3) AUTO-IMMUNITY

Cellular Players
LYMPHOCYTES
MACROPHAGES
(aka,
HISTIOCYTES)
PLASMA CELLS
EOSINOPHILS
MAST CELLS

MORPHOLOGY
INFILTRATION
TISSUE
DESTRUCTION
HEALING

GRANULOMAS
GRANULOMATOUS INFLAMMATION
4
COMPONENTS

FIBROBLAST
S
LYMPHS

HISTIO
S

GRANULOMAS
GRANULOMATOUS INFLAMMATION

CASEATING (TB)
NON-CASEATING

LYMPHATIC
DRAINAGE
SITE REGIONAL LYMPH
NODES

SYSTEMIC MANIFESTATIONS
(NON-SPECIFIC)
FEVER, CHILLS
C-Reactive Protein (CRP)

Acute Phase Reactants


Erythrocyte Sedimentation
Rate (ESR) increases
Leukocytosis
Pulse, Blood Pressure
Cytokine Effects, e.g., TNF(),

Hemostasis,Thrombosis
and Infarct

Thrombosis :
Formation of solid mass in
circulation from the blood
constituents - (Thrombus)

Virchows triad
Endothelial injury.
Alteration in the Blood
flow.
Hypercoagulability of the
Blood.

Blood vessel wall


Anti thrombotic factors :
Heparin like substance ,
Thrombomodulin , Inhibitors of
platelet aggrigation ADPase,
PGI2 Tissue plasminogen
activator

Blood vessel wall

Prothrombotic factors :
Thromboplastin , von Willebird
factor , Platelet activating
factor , Inhibitor of plasminogen
activator

Role of Platelets
Adhesion
Platelet release reaction
Platelet aggrigation

Coagulation system
Plasma Fibrinogen ------ Fibrin
Intrinsic Pathway
&
Extrinsic Pathway

Hypercoagulability of the Blood

Increased coagulation factors


Increased Platelet Count and
their adhesiveness.
Decreased coagulation
inhibitots Antithrombin III

Alteration in the Blood flow


Turbulance and Stasis
Platelets near endothelial
lining.

Morphology
Sites Heart , Arteries,
Veins, Capillaries.
Arterial Thrombi Effect is
Ischemia
Venous Thrombi Effect is
Embolism

Gross Various shapes n


sizes.
Arterial thrombi White
and mural
Venous thrombi Red and
occlusive
M/E : Lines of Zahn
Arterial Vs Venous thrombi

Fates of Thrombi
Resolution
Organisation
Propagation
Embolism

Predisposing
factors
:
Genetic Deficiency of
Antithrombin, Protein C and S ,
Fibrinolysis .
Acquired Old age , Prolonged
Bed rest ,Immobilisation , oral
contraceptives , smoking , Trauma
fracture burns , Atherosclerosis ,
Varicose veins, Cancers

NEOPLASIA

Neoplasia:

Neo + Plasia New + Growth.


Tumour Swelling any swelling*
Clinically tumour = neoplasm (technically
incorrect..!)

Willis definition:
A neoplasm is an abnormal mass of tissue, the growth
of which exceeds and is uncoordinated with that of the
normal tissue and persists in the same manner after
cessation of the stimuli which evoked the change

Cell division without control


Irreversible DNA damage, resulting in
autonomous growth of abnormal cells *

Cell population / Growth Control:

Proliferation Differentiation Apoptosis *


Normal
Neoplasia
Stem cell

Benign - Malignant
Carcinogen
Initiator + Promotor
C

Inflam

Organ / Tissue

1.Proto-Oncogenes (growth
factors)
2.Growth/Tumor suppressor
genes.
3.Genes controlling Apoptosis.
4.Genes controlling DNA Repair.

RAS
Rb
MYC
p53

Apoptosis

Growth Disorders:
Non neoplastic
(Polyclonal)

Neoplastic

(Monoclonal)

Hyperplasia
Hypertrophy
Aplasia
Atrophy
Metaplasia
Dysplasia

Normal

Adaptation

Benign

Malignant

Cell division Control - Carcinogenesis*

BENIGN
Well differentiated
Slow growth
Cohesive,
expansile
Capsule
No invasion/infiltration

MALIGNANT
Poorly differentiated
Rapid growth
Non Cohesive,
No capsule
invasion/infiltration
Metastases.

Benign
-

Malignant

Necrosis

117

Oma - Tumour
Carcin-oma Hard Tumour
Sarc-oma - Soft Tumour

Neoplasms Nomenclature:
Cell of Origin
Gland. Epithelium
Lining. Epithelium
Fibroblast
Osteoblast
Chondrocyte
Lipocyte
Smooth muscle
Skeletal muscle

Benign
Adenoma Papilloma -

Malignant
Adencarcinoma
Squamous cell ca.

Fibroma Fibrosarcoma
Osteoma Osteosarcoma
Chondroma
Chondrosarcoma
Lipoma
Liposarcoma
Leiomyoma
Leiomyosarcoma
Rhabdomyoma
Rhabdomyosarcoma

Nomenclature:

exceptions

Teratoma Tumour of Germ cell multiple tissues.


Benign (mature) or malignant (immature)
Melanoma (Melano-carcinoma) Malignancy of
melanocytes.
Seminoma (Seminal carcinoma) carcinoma of
Testes.
Leukemia white blood Ca. of Haemopoietic stem
cells.
Lymphoma (Lymphosarcoma) Malignancy of
lymphocytes.
Mixed Tumours: Both epithelial & connective tissue
components. Pleomorphic adenoma (Salivary gland)
& Carcinosarcoma (breast/uterus)

Cancer Clinical Features

Cancer Biology

Cancer Biology:
Structure:
Parenchyma Neoplastic cells.
Stroma: Non neoplastic - normal DNA

Features:
Differentiation Maturation of cells.
Rate of Growth Mitotic rate / Ki 67
Local invasion Hemorrhage, necrosis,
destruction
Metastasis Distant Spread.

121

Normal
cell
First
mutation

Tumors are clonal (one parent)


But have different mutations
different shapes & features.
Each new mutation adds a new
feature.

Second
mutation
Third
mutation

Malignant cells
Fourth or
later
mutation

More new mutations with


time.

6 Features of Cancer cells:


Clinically each
patients cancer has a
different mix of
features depending
on quality & quantity
of mutations
& changes with
time...!

Neoplasia:

Retrograde evolution!
Cancer

Embryo
Self growth
auto regulation
Limitless potential
Angiogenesis
Evade apoptosis
Invasion & infiltration

Pathogenesis of Lung Cancer.

Irritation Carcinogens Initiation Promotion Ca.


Anaplasia
Smoke
K-Ras

C-myc
p53

125

Colon: Normal Adenoma Carcinoma

Carcinogenesis)

Colon Cancer: Common type - 80%

Stage & Grade of Cancer:

Staging: Progression or spread in the body.


Grading: Cell differentiation & Rate of growth Microscopy.

Well differentiated (low grade) Adenocarcinoma Grade


grade)

Undiff. (high

Prostate Ca : Gleason Grading:


Low Grade High Grade

128

Stage

TNM: Staging of tumor:


Lung Ca
- Features

T0 In-situ
T1 Primary site
T2 Sec. Anat. site
T3 Tertiary site
T4 Adjacent
region

T
4

N0 No LN mets.
N1 Primary LN
N2 Seondary LN

T1

N3 Tertiary LN
M
0

No metastases

M
1

Metastases +
Based on - ANATOMY & LYMPHATICS

Staging of Colon cancer:

Pre-Cancer

Cancer

Prostate Cancer Staging

131

Metastasis:

Lymphatic, Hematogenous, Direct.

Metastasis:
Pathogenesis:
1. Cell loosening
2. BM degradation
3. Invasion
4. Locomotion
5. BV adhesion
6. Intra-vasation
7. Tumour
embolus
8. Adhesion
9. Extra-vasation
10. Angiogenesis

11. Growth. E-Cadherin, -catenin

Matrix Metalloproteinases (MMP)


Collagenase (not in benign)
Actin Cytoskeleton, chemokine

133 chemical mediators are involved?


What

Cancer Diagnosis:
Cancer.

Cell of origin
Rate of growth

Low, Intermediate, high

Maturation of cells
Well Mod Poor Un diff.

Tumour Stage.. 1,2,3,4.


Distant Spread..

DIAGNOSIS: (Lung cancer)


Bronchogenic Squamous cell Carcinoma, high grade,
Stage T2, N1, M1, Liver+ LN++ (in.. patient details..).

Stage

Local Invasion
Metastasis

Bronchial Epith.
Mitotic rate grade.
Grade

Differentiation

e.g. Lung

SYSTEMIC PATHOLOGY

Atherosclerosis

Myocardial Infarction

LUNGS

Tuberculosis

ASTHMA

Lung Cancer

GIT

RENAL FAILURE

Skin

Sexually Transmitted

AIDS