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Phylum Apicomplexa – Chapters 8 & 9
Phylum Apicomplexa consists of 4 groups of protozoan parasites:

1.

2.

3.

4.

We will examine the first 3 groups, as they contain many parasites
of medical and veterinary importance.

We will omit the gregarines as they are parasites of invertebrates
and are not important.

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Characteristics of the Phylum Apicomplexa
1. ______________________________________________________________

2. Possess _______________________________________________________
- these organelles are concentrated at _______________________________
- function? ____________________________________
- see diagram in text p. 124

3. _______________________________________

4. _______________________________________
- alternation of _____________________________
- hosts?


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Plasmodium and Malaria – Chapter 9
Malaria is one of the most important diseases of mankind.
It has played an important part in the rise and fall of nations and
has killed untold millions of persons.
Today, __________________________are infected with malaria
1.5 billion people (2/3 of the world's population) live in endemic
areas and are potential hosts.
Malaria kills _____________________ people each year.
In areas of Africa with high malaria transmission, an estimated
________________ people die of malaria each year – over 2700
deaths per day, or 2 deaths per minute.


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Plasmodium and Malaria – Chapter 9
In areas of Africa with high malaria transmission, an estimated
________________people die of malaria each year – over 2700
deaths per day or 1 death every 30 seconds.
• Uganda – 12 million infections/population 31 million
• Tanzania – 11 million infections/population 40 million
• Ethiopia – 9 million infections/population 78 million
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Species of Plasmodium
The genus Plasmodium contains 127 species in lizards, birds,
and mammals.
• life cycle worked out in a bird species (Plasmodium relictum)
• rodent species (P. berghei) important in research (we will do an
experimental infection of this parasite in lab)
• several species in monkeys and apes are similar to human
species - important in drug studies
• four species infect humans – they are:
P. vivax, P. falciparum, P. malariae, P. ovale

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Species of Plasmodium
VECTOR – ____________________________________________
• several species can serve as vectors
• ___________________feed on blood and vector malaria

RESERVOIR HOSTS – __________________________________

SURVIVAL OF MALARIA is dependent upon:
1. Many infected humans
2. Many Anopheles mosquitoes
3. Good contact between these 2 hosts

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Life Cycle of Plasmodium
The life cycle is complex, so we will go through it step by step to understand it.
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Life Cycle of Plasmodium – Human Cycle
1. An infected Anopheles mosquito bites a
human and
_______________________________
into the bloodstream
2. Within 30 minutes, the sporozoites
enter _________________________
and begin the PRE-
ERYTHROCYTIC INCUBATION
(lasts for about a week).
3. Within the liver cell, the sporozoite
becomes a trophozoite
• divides by schizogony to form a
multinucleate form called a
____________________________
• individual nuclei will form
____________________________

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Life Cycle of Plasmodium – Human Cycle
4. Liver cell ruptures to release the merozoites
• In 2 species of malaria, some of these
merozoites will re-invade liver cells to
begin a new cycle in the liver - called the
EXO-ERYTHROCYTIC CYCLE.
• Cryptozoites in these liver cells become
dormant and are called
_________________________________
• Merozoites may break out of hypnozoites
years later and enter rbc's causing a
_________________________________
• In all species, most or all of the
merozoites leave the liver and enter the
bloodstream

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Life Cycle of Plasmodium – Human Cycle



5. In the ERYTHROCYTIC CYCLE, a
merozoite penetrates a rbc and
transforms into a uninucleate
_______________________________
6. Trophozoite undergoes schizogony and
becomes a multinucleate
______________________________
7. Schizont ruptures rbc to release
______________________________
- This coincides with the onset of a
fever followed by a period of chills.
- Length of time of fever/chill cycle
varies by species
8. Merozoites re-invade erythrocytes
initiating a new erythrocytic cycle. This
process is repeated over and over again
resulting in the destruction of rbc's.

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Life Cycle of Plasmodium – Human Cycle



9. Not all the merozoites re-entering
rbc's become trophozoites - some
transform into gametocytes.
_____________________________
are female
_____________________________
are male.
10. Rbc's containing gametocytes are
infective to an Anopheles mosquito
when she bites and takes another
blood meal.

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Life Cycle of Plasmodium – Mosquito Cycle




11. In the mosquito stomach:
• macrogametocyte undergoes
meiosis to become a
__________________________
• microgametocyte undergoes
meiosis to form 6 - 8 elongate
___________________________
in a process called
___________________________
12. The microgametes detach. Each
swims to find a macrogamete,
penetrates it, and syngamy occurs
to form a ____________________
13. Zygote elongates to form an
___________________________
which penetrates the stomach wall
and comes to lie on the outside of
the stomach.



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Life Cycle of Plasmodium – Mosquito Cycle




14. Ookinete rounds up to form the
_________________________
15. Within the oocyst, sporogony
(a type of asexual multiple
fission) occurs, resulting in an
enlarged oocyst containing
thousands of
__________________________
16. Oocyst bursts releasing the
sporozoites into the body cavity.
17. Sporozoites migrate to the
__________________________
__________________________
and are injected into the human
bloodstream with the next blood
meal.

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Life Cycle of Plasmodium – Review of Human Cycle
from text page 150




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Life Cycle of Plasmodium – Review of Mosquito Cycle
from text page 150




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Some Stages of Malaria in Anopheles
Feeding female Anopheles
Exflagellation showing microgametes
Oocysts on outside of mosquito stomach
Sporozoites from salivary gland
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Some Stages of Malaria in the human
Cryptozoite in liver cell – it
will burst releasing merozoites
Schizont – multinucleate form in rbc
Trophozoite – uninucleate form in rbc Gametocyte – uninucleate form in rbc
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Plasmodium vivax
Disease is ________________________________________________________
• "tertian" indicates that the parasite undergoes a ____________
erythrocytic cycle in human rbc's (parasites invade rbc's every third day,
hence tertian)
• "benign" indicates that the species is ____________________________
Has an exo-erythrocytic cycle resulting in ____________________________
occurring every 2-3 years up to 8 years.
Was once the most common and widely distributed species - occurred throughout
tropical and temperate regions of the world.
• once occurred in Wisconsin
Habitat now -
____________________________________
___________________________________
This species is responsible for ____________
of malaria in the world.


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Plasmodium
falciparum
distribution
(2005)
Plasmodium
vivax
distribution
(2005)
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Plasmodium vivax – stages in human blood
Ring-stage Trophozoite
1.

2.


Mature Trophozoite
1.

2.

3.
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Plasmodium vivax – stages in human blood
Schizont
1.
2.
3.
4.

Gametocyte (we will not distinguish
between macro- and microgametocytes)
1.
2.
3.
4.
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Plasmodium ovale
Disease is _____________________________________________________
• produces mild disease
• 48 hour erythrocytic cycle
_______________________________________ - occurs in scattered areas of
western Africa, India, and islands of the western Pacific (Philippines, New
Guinea)
Nearly identical to P. vivax and is difficult to differentiate from this species
from P. vivax
• we will not distinguish between P. vivax and P. ovale in human blood
smears examined in lab
Is responsible for ___________________ % of world malaria.

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Plasmodium ovale – stages in human blood
Ring-stage Trophozoite
1.

2.



Mature Trophozoite
1.

2.

3.
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Plasmodium ovale – stages in human blood
Schizont
1.
2.
3.
4.

Gametocyte
1.
2.
3.
4.
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Plasmodium malariae
Causes _________________________________
- quartan indicates a ______________________ erythrocytic cycle
Occurs throughout the tropics but has a discontinuous distribution
Also occurs in chimpanzees but is not considered a zoonosis as wild chimps
and humans do not live together in nature for disease transmission to occur
between them
Relapse? ______________________________________________________
A human can be infected for many years with no apparent symptoms, and the
parasite can suddenly become pathogenic. This phenomenon is called
__________________________________. Fatalities are not uncommon.
Is responsible for ___________% of world's malaria.


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Plasmodium malariae – stages in human blood
Ring-stage Trophozoite
1.

2.



Mature Trophozoite
1.

2.

3.


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Plasmodium malariae – stages in human blood
Schizont
1.
2.
3.
4.

Gametocyte
1.
2.
3.
4.
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Plasmodium falciparum
Disease is __________________________________________________________
• "tertian" indicates a 40-48 hr. cycle in rbc's
• "malignant" indicates it is the most virulent of the 4 human species
P. falciparum is the greatest killer of humanity in the tropics.
• it was responsible for the decline of the Greek civilization, the destruction of
the Crusades, and caused more death in the Pacific in WWII than battles.
• it is the most dangerous because more rbc's are infected and destroyed - death
occurs commonly 8-10 months after infection.
Relapse? __________________________________________________________
Occurs today throughout the tropics
and is responsible for ___________ %
of the world's malaria.




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Plasmodium falciparum – stages in human blood
Ring-stage Trophozoite
1.

2.

Mature Trophozoites and
Schizonts disappear from
peripheral blood and are not seen

Gametocyte
1.
2
3.

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Plasmodium
falciparum
distribution
(2005)
Plasmodium
vivax
distribution
(2005)
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History of Malaria
Disease has been known since antiquity - one of first reports described
fevers in 1550 BC.
Malaria was commonly found in swampy areas and was thought
to be contracted by breathing in "bad air" (= mal aria) in the
swamps.
• Much effort was directed towards finding a causative agent
in the water or air of these swamps.
• We now know that the mosquitoes that vector the disease
lived in these swamps.
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History of Malaria
First breakthrough - French
physician
_______________________
identified the parasites in the rbc's
of malaria patients in 1880.
• Laveran also witnessed an
unusual step in the life cycle
called exflagellation.

_____________________ (1885)
differentiated some species of
Plasmodium and noted changes in
the parasites associated with the
fever - chill cycle.


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History of Malaria
Next breakthrough involved the mode of
transmission.
In the 1890's a famous British scientist
___________________________________
___ theorized that mosquitoes may be
involved in malaria transmission.
• Manson had recently found that
mosquitoes could vector filarial worms
that caused elephantiasis
• So why couldn't they also vector
malaria?



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History of Malaria
Manson convinced one of his
students ________________________,
a physician on leave from the Indian
Medical Service, to test his hypothesis.
• Ross went back to India and began
dissecting mosquitoes.
• After 2 years of dissecting mosquitoes, _____________
___________________________________________________
• In 1897 ___________________________________________
__________________________________by feeding Anopheles
mosquitoes on infected birds.
• Before Ross could prove transmission to humans, he was transferred to
work on kala azar. He was awarded a Nobel Prize in Medicine in 1902.



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History of Malaria
Two Italians ____________________________________(1898)
experimentally transmitted malaria from mosquitoes to humans.

It was not until 1948 that the complete life cycle was known when the
pre-erythrocytic and exo-erythrocytic stages were found in the
liver of infected humans by ________________________________.





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History of Malaria
Last name important in the history of
malaria is that of
________________________________,
a sanitation officer (ENPH!) in the
Panama Canal Zone.
• In 1906, he used the knowledge of
mosquito transmission of malaria and
yellow fever (a viral disease) to begin
a
______________________________
_______________.
• By 1913, the number of malaria
cases had been greatly reduced and
the building of the Panama Canal was
undertaken.




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Pathology of Malaria Infections
During the pre-erythrocytic and exo-erythocytic cycles in the liver,
there is ___________________________________________.
Pathology of all 4 species occurs during the erythrocytic cycle by
the synchronous rupture of schizonts and release of
merozoites which destroy erythrocytes.
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Pathology of Malaria Infections
All 4 species show the following 3 pathological effects:
1. ____________________________________ - as the rbc's are
invaded and destroyed, there is a _______________________
_________________________________________________.
2. __________________________________________________
- shown by a low hematocrit
3. ___________________________________ - liver and spleen
are overwhelmed in the breakdown and recycling of these
destroyed rbc's
results? ___________________________________________

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Pathological Differences among the 4 species

Plasmodium vivax and Plasmodium ovale


Paroxysm lasts ________________ and represents the time
from invasion of rbc’s by merozoites until new merozoites are
produced (length of erythrocytic cycle)
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Plasmodium vivax and Plasmodium ovale pathology


These malarias cause a long-term disease because they have the
ability to ___________________________.
• Relapse involves the ability of cryptozoites in the liver cells
during the exo-erythrocytic cycle to become dormant for long
periods. The dormant cryptozoites are called
_________________________________.
• Drug treatment or the immune system will effectively
remove the erythrocytic forms, and the symptoms of malaria
disappear - often for 2-3 years.
• For some reason (we do not know why), the hypnozoites
become active and release new merozoites to invade the rbc’s
- the person has a malarial relapse.
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Plasmodium vivax and Plasmodium ovale pathology


Most individuals recover from these infections and the parasites
are __________________________.
Generally, the immune system totally eliminates the parasites after
about 8 years.

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Plasmodium malariae pathology


In quartan malaria, merozoites of Plasmodium malariae primarily invade
_________________________.
There is no exo-erythrocytic cycle, so all the merozoites formed from
cryptozoites invade rbc’s after the pre-erythrocytic incubation (no relapse).
Malarial paroxysms occur every __________________ and represent the time
from merozoite invasion of rbc’s to the formation of new merozoites (length of
erythrocytic cycle).



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Plasmodium malariae pathology


This parasite produces a phenonomen called a
_____________________________________.
• Numbers of infected rbc's can become very low that a person
shows no signs of the disease. This period may last for years
and the person believes he/she is free of the disease.
• For some unknown reason, the parasites increase their
numbers, invade many new rbc’s, destroy them, and cause
severe anemia.
• Longest lasting recrudescence was 53 years.
• recent problem in __________________________________
How dangerous?____________________________________

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Plasmodium falciparum pathology



Falciparum malaria is the most serious of the 4 species, usually
resulting in a fatality.
Remember that only the ring-stage trophozoites and gametocytes
are found in peripheral blood – mature trophozoites and schizonts
are in rbc’s of the spleen and bone marrow.
There is _____________________________________, so all
merozoites from the liver enter rbc’s - ______________________


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Plasmodium falciparum pathology



The erythrocytic cycle lasts from ______________ hours.
Malarial paroxysm is unusual: ____________________________
_____________________________________________________


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Plasmodium falciparum pathology



Falciparum malaria is the most pathogenic for the following reasons:
1. Merozoites invades _______________________________ - thus,
more rbc's are infected and destroyed.
2. More destroyed rbc’s leads to serious _____________________.
3. With more destroyed rbc’s to recycle, liver and spleen enlarge -
_______________________________- and often fail.
4. Infected blood becomes viscous, often plugging capillaries in the
brain causing ______________________________________



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Plasmodium falciparum pathology



5. Massive rbc destruction results in high levels of hemoglobin
removed by the kidneys. Urine often becomes dark.
Result? _________________________________________
6. ______________________________________ occurs
when plasma fills the lungs
7. ______________________________________occurs –
failure of many organs leads to shock

A combination of any of these pathologies leads to
death in 8-10 months.



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Sickle Cell Anemia


Presence of falciparum malaria has resulted in the maintenance
of another disease which affects black persons in Africa.
Cause:

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Sickle Cell Anemia


Persons who are
___________________________
have rbc’s that are sickle shaped,
and die of other factors by age 30.
However, if a person is
___________________________
for the sickle-cell anemia, rbc’s are
normal shaped but are protected
from invasion of merozoites of P.
falciparum; thus, the person is
protected from falciparum malaria.



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Sickle Cell Anemia cont.


Selective pressure of malaria in
Africa has led to the maintenance
of an otherwise undesirable gene
in the population.
Problem today?




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Diagnosis and Treatment of Malaria

DIAGNOSIS - identify parasites within human erythrocytes in a s
stained blood smear (this is what we are doing in lab)

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Treatment of Malaria

TREATMENT
1. _________________________
• used from 1640 – WWII;
____________________________________
from _____________________; used as
final resort now.


2. Qinqhaosu used to make new drug from SE
Asia called Artemisinin; commercially
available in SE Asia and Africa; not in North
America & Europe
• drugs from plant extracts
• work by
___________________________________
• use?
__________________________________

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3. ____________________________________________________
- synthetic drugs developed in WWII and used today

• chloroquine (=Aralen) and mefloquine (=Lariam) destroys
__________________________________________________

• primaquine destroys ________________________________

• used in mixtures of chloroquine-primaquine or mefloquine-
primaquine for P. vivax and P. ovale; chloroquine or mefloquine
used individually for P. malariae


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Treatment of Malaria

• Chloroquine and mefloquine can be taken as a preventative
- ______________________________ - by anyone travelling
into a malarious area to reduce risk of infection. See Health
Information for International Travelers from CDC or on the web
at http://www.cdc.gov/travel/

• Chloroquine is effective against
vivax, ovale, and most malariae


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Chloroquine resistant P. falciparum common

Chloroquine resistant P. malariae in _______________________
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Treatment of Malaria

• Mefloquine (Lariam) was developed
in 1993 to combat chloroquine-resistant
P. falciparum; it is effective against
all 4 species

• Recent problems:

1.


2.



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4. _______________________________

• used as both a preventative and a treatment
• Works by _____________________________________
• side effects include sunburning, nausea, diarrhea, and
vaginal yeast infections in women.
• Not for pregnant women and children under 8
• used as in areas of chloroquine and mefloquine resistance
to P. falciparum
• used as an alternative for travelers who cannot or choose
not to take mefloquine or Malarone.




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Treatment of Malaria
5. _______________________________ – developed in 1980 to
destroy erythrocytic forms of P. falciparum

• Causes side effects as skin rash, poor healing, excessive
bleeding, and diarrhea

• Problem -






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Treatment of Malaria

6. ________________________________– new drug that became
available in July, 2000 to combat drug resistant P. falciparum

• Has been shown to be 98% effective in treating P. falciparum

• Kills schizonts of P. falciparum

• Problem -

• Question?





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7. New drug – Fosmidomycin – reported in journal Science
in 2002

Drug shuts down enzyme in metabolic pathway of
malaria; appears to be effective against drug-resistant
malaria

Effective in mouse studies

Human trials just started – no results yet

Will it work against Plasmodium falciparum?
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Distribution of Malaria in the World
Extent of malaria in the world before any eradication programs were started.
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Distribution of Malaria in the World
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Malaria in the U.S.
About ______________cases of malaria are diagnosed in the U.S.
each year.
How were Americans infected?
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Malaria in the U.S.
Malaria was once a major problem in southern & midwestern U.S.
• Species present were ___________________________________.
• Wisconsin had both species.
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Malaria in the U.S.
By the 1950's malaria was eradicated from the U.S. due to:
1.
2.

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Malaria Eradication

Because malaria eradication was successful in the U.S., the World
Health Organization began a worldwide eradication program in
1956.
What did they have for
eradication?
1.

2.

It was thought that this was it for malaria.


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Malaria Eradication

Eradication was successful during much of the 1960's but
problems began to occur in the 1970's and continue today.
Example:
• in 1947, 7 million cases of malaria reported in India
• in 1966, 40,000 cases of malaria in India (height of control)
• in 1977, 5 million cases were diagnosed
• in 1990’s, 3 million cases

Eradication was failing. Why?


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Malaria eradication failed. Why?
1. Money was not available to combat mosquitoes or treat human
cases. (Energy crisis of 1970's took alot of money away from
malaria eradication)
2. Disease occurs in third-world countries where the disease is
poorly understood by the masses.
3. Trained medical personnel and hospitals are few in number in
these countries.
4. Resistance of P. falciparum to chloroquine, mefloquine, and
Fansidar.
5. Resistance of Anopheles mosquitoes to DDT and other
insecticides
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Malaria Prevention
1. Avoid mosquito bites – use insecticides, repellents, netting
2. Chemoprophylaxis with chloroquine, mefloquine, and
Fansidar – but this a problem in areas with P. falciparum
resistant strains
New finding:
In October, 2000, researchers at the US Institute of Allergy and Infectious
Diseases announced they found that the mutation of a single gene in
the Plasmodium parasite is responsible for the emergence of
chloroquine resistance. Formerly it was believed that a number of
mutations spread over a number of genes was likely responsible.
If this result holds up, it should make it easier to potentially alter
chloroquine in such a way as to evade the parasite's new-found
resistance and make chloroquine an effective treatment for malaria
once again.

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Malaria Prevention
3. Malaria vaccine
• a circumsporozoite vaccine (called SPf66) has been
developed, but human trials have not been promising (under
50% protection)
• A new vaccine consisting of Plasmodium genes and hepatitis
antigens that works with T lymphocytes has been developed.
Preliminary tests rated it as being 65% effective against P.
falciparum. More extensive tests are currently underway.
• Recent funding available from the
____________________________Foundation
• Several Nobel prizes in medicine await
for the development of effective malaria
vaccines.


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Despite all these advances, malaria
will likely be with us as long as there
are humans on this earth.

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Thank you

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