The document discusses various biological agents that could potentially be used for terrorism purposes. It covers microbial bioterrorism, categories of biological weapons including category A, B and C agents. It then provides more detailed information about specific biological agents like anthrax, plague, smallpox, botulism toxin, tularemia and viral hemorrhagic fevers including their transmission, clinical features, diagnosis and treatment.

1. Terrorism & Clinical
Medicine
Presented by : Slc Namal Ulluvisheva
Maj Wagma
Sqn Ldr Kapil Gupta
Moderator : Col.Sanjeewan Sharma
1

2. Referrences
• Harrisons’s Text book of medicine (19th Ed.)
• Oxford Text book of Medicine (6th Ed.)
• Goldfrank’s Toxicologic Emergencies ( 10th Ed.)
2

3. Terrrorism & Clinical Medicine
• Microbial bioterrorism
• Chemical terrorism
• Radiation terrorism
3

4. Medical Bioterrorism
Slc Namal Ulluvisheva
4

5. Categories of weapons used by
terrorists
• Conventional
• Biologic
• Chemical
• Nuclear
• Cyber
5

6. 6

7. Chemical vs Biological weapons
Similarities
• Delivery system frequently similar
• Xenobiotics most frequently effectively
dispered in aerosol/vapour forms
• Movement of xenobiotics highly subject to
wind and weather conditions
• Appropriate PEP prevent illness
7

8. Chemical vs Biological weapons
8
Chemical Weapons Biological Weapons
Rate at which attack result
in illness
Rapid
Usually min - Hours
Delayed
Days - weeks
Identification of release
substances
Easier :
Rapid clinical effects
Possible chemical odour
Harder :
Delayed clinical effects
Lack of colour,odour or
taste
Xenobiotics persistance Variable
Liquids – Semi persistant to
persistant
Gases – Non persistant
Generally non persistant
Most BWs xenobiotics
Degraded by sun light,Heat
or Desiccation (Exception :
Anthrax spores)
Victim distribution Near and downwind from
release point
Victim may be widely
dispersed by the time
disease is apparent
Decontamination Critically important Not required in delayed
presentation
Less important for acute
exposures

9. Chemical vs Biological weapons
9
Chemical Weapons Biological Weapons
Medical Rx Chemical Antidotes
Supportive care
Vaccine ,Antibiotics and
supportive care
Patient Isolation Unnecessary after
adequate decontamination
Important for easily
communicable diseases
First responders EMTs,Hazard material
teams,Law enforcement
officers
Emergency medical
teams/Infectious disease
physicians
Epidimiologist
PHO

10. Bio terrorism
• Deliberate use of biological agents to cause
illness, death & fear for ideological or personal
purposes
• Most potential bioterrorism agents occur
naturally as known pathogens
10

11. History of biological warfare
• 1346 Siege of Kaffa; plague
• 1763 French and Indian War; smallpox
• WW I German program; anthrax, glanders
• 1925 Geneva protocol bans biological
weapons
• WW II Japanese program; anthrax, plague,
cholera, shigella
• 1941 George W. Merck named U.S. civilian
head of chemical war fare service later
changed to war research service
11

12. History of biological warfare
• 1946 U.S. announces its involvement in
bio weapons research
• 1969 Nixon eliminates offensive biological
warfare program
• 1972 Biological Weapons Convention
• 1979 Accidental release of B. anthracis
spores at bioweapons research
center, Sverdlovsk, U.S.S.R
• 1989-92 Scientists from the former
U.S.S.R. involved in biological
weapons research defect to the West
12

13. Domestic biological terrorism
• 1984 - Rajneeshee cult members contaminate
salad bar with Salmonella typhimurium in
Oregon
• 1992 - Ricin attack planned by Minnesota militia
• 2001 - Anthrax releases in USA(FL,DC,NY,NJ)
13

14. Bio terrorism
Features of biological agents as weapon
• Inexpensive
• Available
• Easily transported/Concealed and dispersed
• Incubation period “Hides Tracks” of
perpetrator
• Modifiable (Resistance,Virulence )
14

15. Key features of biological agents used as bio
weapons
• High morbidity and mortality rates
• Potential for person-to-person spread
• Low infective dose and highly infectious by aerosol
• Lack of rapid diagnostic capability
• Lack of universally available effective vaccine
• Potential to cause anxiety
• Availability of pathogen and feasibility of production
• Environmental stability
• Data base of prior research and development
• Potential to be "weaponized"
15

16. Biological agents
• Biological agents may be disseminated
through aerosolization, food, human carriers,
infected insects or water
• Incubation periods of potential bioterrorism
agents can vary from hours to weeks
• Early symptoms mimicking many other
disorders
• Diagnosis may not be suspected unless cases
occur in clusters
16

17. Dissemination of bio weapons
• Aerosolization cause severe damage by
maximizes the no. of people exposed
• Release of contagious agents at different places
could amplify the out break
• More potential agents cause illnesses with
shorter IP & atypical clinical presentation
• Clinical effects are dose dependents
17

18. Biological weapons
• Category A :Agents have the highest priority.
They are considered the greatest risk to the
public and national security
• Caregory B : diseases that are considered an
intermediate risk to the public.Causative agents
are relatively easy to spread and the diseases
result in moderately high death rates
• Category C : Agents include emerging pathogens,
which could be engineered to spread and cause
high rates of morbidity and mortality
18

19. Biological weapons
Category A
Infectious and contagious diseases
• Smallpox (Variola major)
• Plague (Yersinia pestis)
• Viral haemorrhagic fevers
Filoviruses; Ebola, Marburg
Arenaviruses; Lassa, Machupo
Bunyaviridae ; congo,Rift valley
Infectious but not contagious diseases
• Anthrax (Bacillus anthracis)
• Tularemia (Francisella tularensis)
Toxins
• Botulism (Clostridium botulinum toxin)
19

20. Biological weapons
Category B
• Brucellosis (Brucella spp.)
• Epsilon toxin of Clostridium perfringens
• Food safety threats (Salmonella, Escherichia coli 0157, Shigella)
• Glanders (Burkholderia mallei)
• Meliodosis (Burkholderia pseudomallei)
• Psittacosis (Chlamidia psittaci)
• Q fever (Coxiella burnetii)
• Ricin from Ricinus communis (castor bean)
• Staphylococcal enterotoxin b
• Typhus fever (Rickettsia prowazekii)
• Viral Encephalitis (alphavirus, e.g. Venezuelan , eastern &
western equine encephalitis)
• Water-safety threats (e.g. Vibrio cholerae, Cryptosporidium
parvum)
20

21. Biological weapons
Category C
• Emerging infectious diseases such as
Nipah virus
Hantavirus
SARS or MERS
Corona virus
Pandemic Influenza
Source : http://www.bt.cdc.gov
21

22. Anthrax
Confirmed anthrax cases associated with bioterrorism: USA, 2001.
geographic location, clinical manifestation & outcome of the 11
cases of confirmed inhalational & 11 cases of confirmed
cutaneous anthrax
22

23. Anthrax
• Caused by Bacillus anthracis - gram-positive，
nonmotile,spore-forming rod that is found in soil
• Anthrax spores can remain viable for decades
• predominantly causes disease in herbivores such
as cattle,goats & sheep
• Transmission - contact with anthrax-infected
animals or animal products such as goat hair
in textile mills/animal skins used in making drums
23

24. Anthrax
3 major clinical forms
• Gastrointestinal : typically results from ingestion
of contaminated meat.condition is rare and
unlikely to be the result of a bioterrorism event
• Cutaneous :Fatal, typically begins as a papule
following the introduction of spores through an
opening in the skin. This papule then evolves to
painless vesicle followed by the development of a
coal-black necrotic eschar
24

25. Anthrax
• Inhalational:
inhalation of spores deposited in alveolar spaces
phagocytized by macrophages
transported to the mediastinal and
peribronchial Iymph nodes & germinate
leading to active bacterial growth & elabora
tion of the bacterial products, edema toxin and
lethal toxin
subsequent heamatogenous spread cause
Bacteremia and death
25

26. Anthrax
Inhalational Anthrax
Symptoms: Viral like prodrome with fever,malaise
abdominal and chest symptoms
not contagious and don’t require isolation
CXR : Mediastinal widening & Pleural effusion
Diagnosis : Culture,Gram stain,PCR
• Rapid diagnosis and prompt initiation of antibiotics
are key to survival
26

27. Anthrax Treatment
• Active disease
Inj.Ciprofloxacin 400 mg IV BD or
Inj.Doxycycline 100 mg IV BD Plus
Inj.Clindamycin 900 mg IV TID and/or
Inj.Rifampin 300 mg IV BD
* Switch to oral when stable – Total 60 days
• Post exposure
T.Ciprofloxacin 500 mg BD x 60 day or
T.Doxycycline 100 mg BD x 60 day or
T.Amoxicillin 500 mg TID x 60 day
( Effective in penicillin sensitive cases )
27

28. Anthrax Treatment
• Antitoxin
Raxibacumab 40 mg/kg IV over 2.5 hour
• Vaccination & prevention
Anthrax vaccine adsorbed(AVA)
# PEP – Raxibacumab can use, when alternative
therapies are not available
28

29. PLAGUE
• Ideal agent of bioterrorism due to highly contagious
nature & high mortality rate
• Caused by Yersinia pestis
• Non motile,gram negative bacillus
• 3 clinical syndromes
Bubonic plague - Flea bite
Pneumonic plague - Inhalation of bacteria( i/ii ry)
Septicemic plague – due to bacteremia
29

30. PLAGUE
Pneumonic plague
• II ry : Some patient may develop pneumonia as a
complication of bubonic/septicemic plague
• I ry : transmit the pathogens to others via
respiratory route cause primary pneumonic plague.
most common manifestation of bioterrorist
attack
• Clinically - fever,cough,hemoptysis,dyspnea & GI
symptoms (1-6 days following exposure)
• CXR - Pulmonary infiltration and consolidation
• High mortality rate ( 85%)
30

31. PLAGUE
Bubonic plague
• Inoculation of regurgitated bacteria into the skin by a
flea bite organisms travel through the lymphatics to
regional lymph nodes
• They are phagocytized but not destroyed. Inside the
cell,they multiply rapidly leading to inflammation &
painful lymphadenopathy with necrosis
Septicemic plague
• Extensive ecchymosis develop due to DIC
• gangrene of digits and/or nose can develop in
Advanced stage ( Black death)
31

32. PLAGUE
• Diagnosis : Culture, GS, Direct fluorescent
antibody, PCR
• Treatment : Duration – 10 days
Inj.Gentamicin 2.0 mg/kg IV loading then
1.7 mg/kg q8h IV or
Inj.Streptomycin 1.0 g q 12h IM/IV
Alternative: Tab.Doxycycline 100mg bid or
Chloramphenicol 500 mg x qid
• Prophylaxis : Doxycycline 100 mg po bid or
Levofloxacin 500 mg po daily x 7 days
• Vaccine : Formalin-fixed whole organism vaccine
(Not available) 32

33. SMALL POX
• Aetiology: 2 variants of ds DNA virus
Variola major & Variola minor
Member of poxviridae family.
• V. minor are generally less severe than V. major
with milder constitutional symptoms and lower
mortality rates
• V. major is considered for viable bio weapon
• Transmission occur through droplet spread,
direct contact with skin lesions or body fluids and
rarely through aerosolized material from
contaminated cloths
• IP : 7-17 days 33

34. SMALL POX
Clinical features
• Fever,malaise,headache,backache and emesis
• Maculopapular to vesicular to pustular skin
lesions : Begins on the face and extremities and
spreads to trunk (centripetal pattern)
• Patients are infectious from the time of
maculopapular rash appears on the skin and
oropharynx through the resolution and scabbing
of pustular lesions
34

35. SMALL POX
• Diagnosis : Culture,PCR
• Treatment : Supportive measures
Anti viral drug ( Cidofovir)
- Efficacy not known
Strict isolation
• Prophylaxis : Vaccinia immunization
35

36. Botulism Toxin
• Produced by gram positive,spore forming anaerobe
Clostridium botulinum
• Natural habitat is soil
• In bioterrorist attack,dispersed as an aerosol/as
contamination of food supply
• Toxin can inactivated by
Chlorination of drinking water
Heating any food to >85 C for > 5 min
• 7 antigenically distinct forms of botulinum toxin,
designated A-G.Majority of humans are affected by
types A,B and E .
Antitoxins are act against only specific sub types.
36

37. Botulism Toxin
• No transmission between person to person
• Botulism can result from growth of C.botulinum
infection in a wound/intestine, the ingestion of
contaminated food or inhalation of aerosolized
toxin
• IP – 12 to 72hours
• High morbidity and 60-100 % mortality make it
close to ideal bio weapon
37

38. Botulism Toxin
• Clinical features: multiple cranial nerve palsies
followed by descending flaccid paralysis
majority presented with diplopia,ptosis,dilated
pupils, fatigue and extremity weakness
severe cases: Loss of gag reflex,complete
muscular collapse and respiratory failure
• Diagnosis : clinical + toxin immunoassay
• Treatment : Supportive meassures
Anti toxin (HBAT)
• Prophylaxis :Equine antitoxin
38

39. Tularemia
• Referred as “Rabit fever” or “Deer fly fever”
• Caused by “Francisella tularensis” – small,non
motile,gram negative cocobacillus
• Hardy bacterium and can survive for weeks in
the environment
• Transmission - Insect bites or contact with
organism in the environment
• Aerosol - mode of dissemination as a biologic
weapon
39

40. Tularemia
Clinical features
• Local tissue necrosis at the site of entry
• Oropharyngeal symptoms due to drinking of
contaminted water
Pharyngitis with cervical or retropharyngeal
lymphadenopathy
• Inhalation of contaminated aerosol cause
pharyngitis,pleuritis and broncho pneumonia.
50 % shows pulmonary infiltrates on CXR.
• Acute presentation of aerosol disseminated
tularemia is highly varaible
40

41. Tularemia
• Diagnosis : Culture of infected tissue/blood
Immunohistochemistry
• Treatment
Inj.Streptomycin 1g IV x BD x 14 days or
Inj. Gentamycin 5 mg/kg/day in divided dose
( 8 hourly) x 14 d or
Inj. Doxycycline 100 mg IV x BD x 14d or
Inj. Ciprofloxacin 400 mg IV x BD x 14d
• Prophylaxis: T. Doxycycline or T. Ciprofloxacin x 14d
No vaccine 41

42. Viral hemorrhagic fevers
• Group of illnesses caused by following viruses
Arena viruses:Lassa,New World (Machupo,Junin,
guana rito and Sabia
Bunyaviridae: Crimean-Congo,Rift Valley
Filoviridae: Ebola,Marburg
• Viruses are enveloped,ss-RNA viruses that depend on a
host reservoir for long-term survival.
• Transmission: Person to person transmission through
direct contact with virus-containing body fluids
• Highly infectious by aerosol route and mortality rate
high as 90%
• excellent candidate agents of bioterrorism 42

43. Viral hemorrhagic fever
• The clinical features depending on the particular agent.
Initial signs and symptoms typically include; fever,
myalgia , prostration and DIC with thrombocytopenia
and capillary H’age.
• Diagnosis should be suspected in anyone with
temperature >38.3 C for <3 weeks who also exhibits at
least two of the following
- hemorrhagic/purpuric rash, epistaxis, hematemesis，
hemoptysis,hematochezia in the absence of other
identifiable cause
• Ix : Serology testing for Ag/Ab, RT-PCR
• Rx: Supportive measurement + Anti viral (Ribavirin)
43

44. CHEMICAL TERRORISM
Sqn Ldr Kapil
D

45. Introduction
• Intentional use of chemicals as weapons to cause
significant social and economic disruption as well
as damage to human health and to the
environment
• Chemical weapons use the toxic properties of
chemical substances to cause physical and
psychological harm to the enemy.
• Chemical Weapons use the toxic properties of
chemical substances to cause physical or
psychological harm to an enemy

46. Chemical weapons on the Battlefield
• World War I use :
chlorine and mustard gas
• World War II developments:
Tabun , Sarin and Soman by Germany
VX by Great Britain
Rocket delivery
Worldwide outcry for chemical weapon treaties.

47. Causes of Increased probability of
Chemical Terrorism
• „Greater access
• Ease of use
• Cheaper
• Proven attack method (predictable)
• Visible acts of destruction
• Can be delivered through bombs, rockets,
artillery shells, spray tanks, and missile warheads.

48. • Blistering / vesicant agents like Mustard (HD)/
sulfur mustard(H), Mustard gas (H), Nitrogen
mustard (HN-1, HN-2, HN-3), Lewisite (L),
Phosgene oxime (CX) cause painful burns
requiring immediate medical attention.
• Nerve agents like (Cyclohexyl sarin, (GF), Sarin
(GB),Soman (GD), Tabun (GA), VX, VR degrade the
functioning of the nervous system, causing a loss
of muscle control, respiratory failure, and
eventually death.
Types of chemical weapons

49. Many different kinds, including:
• Asphyxiant or blood agents like Arsine (SA),
Cyanogen chloride (CK), Hydrogen cyanide
(AC) cause Confusion, Nausea, Gasping for air
in some cases; similar to asphyxiation but
more abrupt onset, Seizures before death.
• Choking and pulmonary damaging agents
(like chlorine, hydrogen chloride, nitrogen
oxides and phosgene) cause respiratory
damage and asphyxiation.

50. VESICANTS: SULFUR MUSTARD
• Sulfur mustard has been a military threat since
it first appeared on the battlefield in Belgium
during WWI
• Sulfur mustard accounted for 70% of the 1.3
million chemical casualties in WWI.
• Mechanism of action:
 constitutes both a vapor and a liquid threat to
all exposed epithelial surfaces.

51. It rapidly forms cyclic ethylene sulfonium ions
that are extremely reactive with cell proteins,
cell membranes
DNA alkylation and cross-linking in rapidly
dividing cells
effects characterized as “radiomimeti”—i.e.,
similar to radiation injury.

52. Clinical features
• Erythema is the mildest and earliest form of
mustard skin injury. Begins to appear within 2 h
to 2 days after vapor exposure. Formation of
vesicles & bullae which are translucent and have
transudate fluid
• Necrosis of airway mucosa causes
“pseudomembrane” formation. These
membranes may obstruct the bronchi.
• eye injury includes progressively severe
conjunctivitis, photophobia, blepharospasm,
pain, and corneal damage

53. • Gastrointestinal tract : nausea and vomiting lasting up to 24
h. damage to mucosa
• CNS-sluggish,apathetic,lethargic
• Cause of death : sepsis and respiratory failure.
 Mechanical obstruction via pseudomembrane formation
and agent-induced laryngospasm is important in the first
24 h, but only in cases of severe exposure.
 From the third through the fifth day after exposure,
secondary pneumonia due to bacterial invasion of denuded
necrotic mucosa can be expected.
 The third wave of death is caused by agent-induced bone
marrow suppression(pancytopenia), which peaks 7–21
days after exposure and causes death via sepsis in 2 weeks
to 2 months without sequelae.

54. Treatment
• Decontamination: Immediate decontamination is essential to
minimize damage. Remove clothing immediately. Gently wash skin
with soap and water. Do not abrade skin. For eyes, flush with plenty
of water or normal saline.
• First aid: Immediately decontaminate skin. Flush eyes with water or
normal saline for 10–15 min. If breathing is difficult, give oxygen.
• Liberal use of systemic analgesics
• Maintenance of fluid and electrolyte balance
• Provision of nutrition
• Topical antibiotic and glucocorticoid ophthalmic ointments
• Administration of appropriate antibiotics
• Intubation may be necessary if laryngeal spasm or edema makes
breathing difficult or becomes life-threatening.
• Bronchodilators for bronchospasm.

55. Other Blistering agents
• Lewisite causes immediate burning pain, with
blisters developing later. Specific antidote—
British anti-lewisite— may decrease systemic
effects of lewisite.
• Phosgene oxime causes immediate pain.
Possible pulmonary edema.

56. Nerve agents
• The organophosphorus nerve agents are the
deadliest of the CWAs.
• Death ensues because of respiratory depression
and can occur within seconds to minutes.
• All the nerve agents are organophosphorus
compounds, which are liquid at standard
temperature and pressure. Their high volatility
makes a spill of any amount a serious vapour
hazard.

57. • Mechanism of action: They work by inhibition of
tissue synaptic acetylcholinesterase.
• At cholinergic synapses, acetylcholinesterase,
bound to the postsynaptic membrane, functions
as a turn-off switch to regulate cholinergic
transmission. Inhibition of acetylcholinesterases
causes the released neurotransmitter
acetylcholine, to accumulate abnormally.
• End-organ overstimulation results in cholinergic
crisis.

58. Clinical features
• Miosis (the world going black)
• Exocrine glands in the nose, mouth, and pharynx
when exposed to the vapor causes increased
secretions, rhinorrhea, excess salivation, and
drooling(wet all over).
• Toxin then interacts with exocrine glands in the
upper airway, causing bronchorrhea, and with
bronchial smooth muscle, causing bronchospasm.
This combination of events can result in hypoxia.

59. • In gastrointestinal tract: abdominal cramping
and pain, nausea, vomiting, and diarrhea.
• Skeletal muscles: fasciculations followed by
frank twitching. If long enoughflaccid
paralysis.
• In the brain it cause rapid loss of
consciousness, seizures, and central apnea
leading to death within minutes.

60. Treatment
• Decontamination
• Respiratory support
• Antidotal therapy:
Atropine
PAM
Anticonvulsants

61. Antidote Recommendations after
Exposure to Nerve Agents
Patients age Mild/moderate
effects
Severe effects Other treatments
Infants (0-2 years) Atropine (0.05
mg/kg IM or 0.02
mg/ kg IV) and 2-
PAM Cl (15 mg/kg
IM or IV slowly)
Atropine (0.1
mg/kg IM or 0.02
mg/kg IV) and 2-
PAM chloride (25
mg/kg IM or 15
mg/kg IV slowly
Assisted ventilation
after antidotes for
severe exposure
Child ( 2-10 years) Atropine (1 mg IM
or 0.02 mg/kg IV)
and 2-PAM Cl (15
mg/kg IM or IV
slowly
Atropine (2 mg IM
or 0.02 mg/kg IV)
and 2-PAM
chloridec (25
mg/kg IM or 15
mg/kg IV slowly
Repeat atropine (2
mg IM, or 1 mg IM
for infants) at 5- to
10-min intervals
until secretions
have diminished
and breathing is
comfortable or
airway resistance
has returned to
nearly normal.

62. Patient’s Age Mild/Moderate
Effects
Severe Effects Other Treatment
Adolescent (>10
years)
Atropine (2 mg IM
or 0.02 mg/kg IV)
and 2-PAM Cl (15
mg/kg IM or IV
slowly)
Atropine (4 mg IM
or 0.02 mg/kg IV)
and 2-PAM Cl (25
mg/kg IM or 15
mg/ kg IV slowly)
Adult Atropine (2–4 mg
IM or IV) and 2-
PAM Cl (600 mg IM
or 15 mg/kg IV
slowly)
Atropine (6 mg IM)
and 2-PAM Cl (1800
mg IM or 15 mg/kg
IV slowly
Phentolamine for 2-
PAM-induced
hypertension (5 mg
IV for adults; 1 mg
IV for children)
Diazepam for
convulsions (0.2–
0.5 mg IV for infants
<5 years; 5 mg IV
for adults).
Elderly, frail Atropine (1 mg IM)
and 2-PAM Cl (10
mg/kg IM or 5–10
mg/kg IV slowly)
Atropine (2–4 mg
IM) and 2-PAM Cl
(25 mg/kg IM or 5–
10 mg/kg IV slowly)

63. Cyanide
Mechanism of action:
• Inhibits cellular respiration
– Cytochrome a-a3
• Tissues cannot utilize oxygen
• “Arterialization of venous blood”

64. Kreb’s cycle and Cyanide

65. What are the clinical effects of
cyanide?
• CNS
– Headache
– Dizziness
– Seizures
– Coma
• Cardiovascular
– Hypertension, bradycardia
– Hypotension, later in course
– Cardiovascular collapse

66. • Pulmonary
– Dyspnea
– Tachypnea
– Pulmonary edema
– Apnea
• Gastrointestinal
– Nausea, vomiting

67. Cyanide diagnosis
• Clinical picture
• Lactic acidosis
• ABG:
– metabolic acidosis

68. Treatment
• Remove from source
• Oxygen
• Cyanide antidote kit
 Amyl nitrite inhalation until IV established
 Sodium Nitrite 10–20 mL of 3% solution by slow IV
over no less than 5 min, or more slowly if hypotension
develops. Cyanide kit causes methemoglobinemia.
 Sodium thiosulfate: 50 mL of 25% solution IV over 10–
20 min.
 Cyanmethemoglobinsodium thiosulfatecyanide to
thiocynate. Eliminated harmlessly in urine.
 Alternative: 5 g of hydroxocobalamin(Vit B12a) in
reconstituted solution IV over 15 min.(orange skin).