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Malaria continues to be important Tropical diseases effecting millions of humans ,A basic understanding of the disease can reduce the incidence of morbidity and mortality

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Malaria l.jpg

MALARIA

Dr.T.V.Rao, MD

Professor of Microbiology


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Ancient History of Malaria

  • Malaria parasites have been with us since the dawn of time. They probably originated in Africa (along with mankind), and fossils of mosquitoes up to 30 million years old, show that the malaria vector, the malaria mosquito, was present well before the earliest history.



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Hippocrates and Malaria

  • Hippocrates, a physician born in ancient Greece, today regarded as the "Father of Medicine", was the first to describe the manifestations of the disease, and relate them to the time of year and to where the patients lived.


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Malaria

  • Name is derived from Italian

    Mal’ aria or bad air

    Malaria continues to be most important cause of fever and morbidity in the Tropical world

    Malaria has been eradicated from Europe, Most of North America, USA South America Korea and Japan,


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History – Events on Malaria

  • 1880 - Charles Louis Alphose Lavern discovered malarial parasite in wet mount

  • 1883 - Methylene blue stain - Marchafava

  • 1891 - Polychrome stain- Romanowsky

  • 1898 - Roland Ross - Life cycle of parasite transmission, wins Nobel Prize in 1902

  • 1948 - Site of Exoerythrocytic development in Liver by Shortt and Garnham


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Major Developments in 20th Century

  • 1955 - WHO starts world wide malaria eradication programme using DDT

  • 1970 – Mosquitos develop resistance to DDT Programme fails

  • 1976 – Trager and Jensen in vitro cultivation of parasite

  • 1948 - Site of E1948 - Site of Exoerythrocytic dev in Liver by Shortt and Garnham

  • xoerythrocytic dev in Liver by Shortt and Garnham


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Lavern and Ronald RossPioneered the Events on Malaria



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Nobel Prizes in Malaria

  • The discovery of this parasite in mosquitoes earned the British scientist Ronald Ross the Nobel Prize in Physiology or Medicine in 1902. In 1907, Alphonse Lavern received the Nobel prize for his findings that the parasite was present in human blood.


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Introduction

  • Malaria is probably one of the oldest diseases known to mankind that has had profound impact on our history.

  • It is a huge social, economical and health problem, particularly in the tropical countries.

  • Malaria is a vector-borne infectious disease caused by single-celled protozoan parasites of the genus Plasmodium.

  • Malaria is transmitted from person to person by the bite of female mosquitoes.




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What causes Malaria

  • Malaria is caused by a parasite called Plasmodium, which is transmitted via the bites of infected mosquitoes. In the human body, the parasites multiply in the liver, and then infect red blood cells.

  • Transmission of Malaria do not occur <160c and >330c

  • Do not occur > 2000 meters altitude.


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Parasites Cause of Malaria

  • Malaria is caused by an infection by one of four single celled Plasmodia species, they are: falciparum, vivax,malariae, and ovale. The most dangerous of the four is.P.falciparum


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Falciparum most Dangerous

  • Falciparum accounts for 90% of deaths due to malaria and vivax is the most widely spread species because it exists in both temperate and tropical climates (Encarta). The malaria life cycle is a complex system with both sexual and asexual aspects .


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Why it is important in Medicine

  • Malaria remains the world's most devastating human parasitic infection. Malaria affects over 40% of the world's population. WHO, estimates that there are 350 - 500 million cases of malaria worldwide, of which 270 - 400 million are Falciparum malaria, the most severe form of the disease.


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Malaria Kills more people than AIDS

  • Malaria kills in one year what AIDS kills in 15 years. For every death due to HIV/AIDS there are about 50 deaths due to malaria. To add to the problem is the increasing drug resistance to the established drug.


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Etiology of Malaria

  • Four Species known to infect Man

  • 1 Plasmodium vivax – Benign Tertian, Tertian Malaria

  • 2 P.ovale - Ovale tertian Malaria

  • 3 P.malariae – Quartan malaria

  • 4 P.falciparum – Falciparum malaria or Malignant Tertian malaria.



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Events in Humans start with Bite of Mosquito

  • Man – Intermediate host.

  • Mosquito – Definitive host

    – Sporozoites are infective forms

  • Present in the salivary gland of female anopheles mosquito

  • After bite of infected mosquito sporozoites are introduced into blood circulation.


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Human cycle

1 Pre erythrocytic schizogony

2 Erythrocytic Schizogony

3 Gametogony

4 Exoerythrocytic schizogony


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Pre erythrocytic cycle

  • Sprozoites undergo developemtnal phase in the liver cell

  • Sprozoites are elongated and spindle shaped become rounded inside the liver parenchyma

  • Multiple nuclear divisions develop to Schozonts

  • A Schizont contains 20,000 – 50,000 merozoites.



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Period of Pre erythrocytic cycle

  • 1 P.vivax 8 days

  • 2 P.falciparum – 6 days

  • 3 P.malariae - 13 – 16 days,

  • 4 P.ovale 9 days

    On maturation Liver cells ruputure

    Liberate Merozoites into blood stream


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Affinity of Parasite to Erythrocytes

  • P.vivax

  • P.malariaeInfectes only young or

  • P.ovale Old Erythocytes

  • P.falciparum Infects all age groups

    Also adhere to the endothelial lining of Blood vessesl

    Causes the obstruction, Thrombosis and Local Ischemias


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Erythrocytic Schizogony

  • Liberated Merozoites penetrate RBC

  • Three stages occur

    1 Trophozoites

    2 Schizont

    3 Merozoite


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Erythrocytic cycle

  • Ruptured red cells release Merozoites which attack new red cells

  • Continue with Schizogony

  • Repeated cycles will continue

  • In P.falciparum - infected erythrocytes with Schizonts aggregate in the capillaries of brain and other internal organs

  • Only ring forms are seen in the blood smears


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Trophozoites

  • After invasion grow and feed on hemoglobin

  • Blue cytoplasm and red nucleus, Called as Signet ring appearance

  • Hence called ring form


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Schizont

  • When the Trophozoite is fully developed becomes compact.

  • Malarial pigments are scattered through the cytoplasm

  • The Nucleus is large and lies at the periphery starts dividing.

  • Becomes Schizont


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Exo Erythrocytic Schizogony

  • Some Sprozoites do not undergo sporogony in the first instance

  • But go into resting stage called as Hypnozoites,( hibernation )

  • Within 2 years reactivate to form Schizonts release Merozoites and attack red cell and produce relapses

  • Absent in P falciparum


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Gametogony

  • Merozoites differentiate into Male and female gametocytes

  • Macrogametocytes also called female gametocytes

  • Microgametocyte also called as male gametocytes

  • They develop in the red cells

  • Found in the peripheral blood smears

  • Microgametocyte of all species are similar in size

  • Macro gametocytes are larger in size.


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Mosquito cycleA definitive Host – Mosquito


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Mosquito cycleSexual cycle

  • Sexual cycle will be initiated in the Humans by the formation of Gametocytes

  • Develop further in the female Anopheles Mosquito

  • Only mature sexual forms are capable of further development in Mosquito

  • In midgut one Microgametocyte develops into 4-8 thread like filamentous structures named Micro gametes

  • From one macrogametocyte only one macrogamete is formed


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Events in Mosquitos

  • Fertilization occurs when a Microgametocyte penetrate into Macrogametocyte

  • Fertilized macrogametocyte is known as ZYGOTE

  • ZYGOTE matures into OOKINETE

  • OOKINETE to OOCYST


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Formation of Sporozoites in Mosquitos.

  • OOCYST matures with large number of Sporozoites ( A few hundred to thousands.)

  • OOCYST ruptures and release SPOROZOITES in the body cavity of Mosquito

  • There is a specific predilection for salivary glands

  • Now capable to transmit the infection to new Host


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Pathology and Pathogenesis

  • Sporozoites result from sexaul and sporogenic cycle of development in mosquitoes and injected into human blood serum.

  • Events start with bite of Infected Anopheles Mosquitoes

  • Sporoozoites enter liver, in 1 hour infect the parenchymal cell.


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Pathogenesis in Pre Erythrocyte cycle

  • Numerous asexual progeny – Merozoites ruputure and leave from liver cells

  • Enter the Blood and invade Erythrocytes

  • Erythrocytic cycle starts – Multiply in species specific fashion

  • Broods of Merozoites appearing at 48 hour interval in P.ovale, P.vivax , P.falciparum

  • P.malariae appear in 72 hour cycles,


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Erythrocyte cycle

  • Merozoites released invade red cells

  • P.vivax infects young erythrocytes

  • P.malariae Infects old erythrocytes

  • P.falciparum infects RBC of all ages

  • The Merozoites are pear shaped 1-5 microns in length

  • The receptors for Merozoites are on red cells in the glycoprotein


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Chooses to enter the RBC

  • Specific for each species

  • They pit on red cells

  • By endocytosis enters the RBC

  • Becomes a Trophozoites


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What happens in RBC

  • Size of Trophozoites is 1/3 of the RBC except in P.falciparum which is 1/5 of RBC

  • Feed on Hemoglobin but donot totally metabolize and forms the Malarial pigment


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Schizont

  • When the Trophozoite is fully developed becomes compact.

  • Malarial pigments are scattered through the cytoplasm

  • The Nucleus is large and lies at the periphery starts dividing.

  • Becomes Schizont


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Schizont

  • Schizont’s are 9 -10 microns

  • Divide and produce 8-32 Merozoites

  • Arranged in Rossets in two rows.

  • Mature schizonts rupture and release Merozoites

  • Causes the paroxysms of fever.

  • Merozoites invade fresh RBC \ Cycles repeats


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Cycles differs in Different species

Cycle repeats every 48 hours in

1 P.falciparum

2 P.ovale

3 P.vivax

Repeats every 72 hours In

P.malariae


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Incubation period varies according to species

  • Which includes Exo eythrocytic cycle time and one or two erythocytic cycles,

  • P.vivax and P.falciparum 10 – 15 days (can vary from weeks to months)

  • P.malariae infection can start after 28 days.




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What are the characteristics of a malaria attack relation to RBC

  • Fever and shivering. The attack begins with fever, with the temperature rising as high as 40ºC and falling again over a period of several hours.

  • A poor general condition, feeling unwell and having headaches like influenza.

  • Diarrhea, nausea and vomiting often occur as well.


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Clinical events relation to RBC

  • The symptoms often associated with malaria are due to bursting red blood cells and clogged capillaries of major organs. Infection occurs when an infected anopheles mosquito feeds on an individual releasing sporozites into the blood stream. Mosquitos can carry more than one species and thus can infect peoples with more than one species


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Broad clinical manifestations of Malaria relation to RBC

  • Fever

  • Sweating

  • Anemia

  • Splenomagaly (enlarged spleen)

  • Irratability

  • Coma, Retinal Hemorrages 

  • Algid Malaria ( a shocklike syndrome)

  • Respiratory distress syndrome


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Cerebral Malaria relation to RBC

Malignant malaria can affect the brain and the rest of the central nervous system. It is characterized by changes in the level of consciousness, convulsions and paralysis.


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Cerebral Malaria relation to RBC

  • Present with Hyperpyrexia

  • Can lead to Coma

  • Paralysis and other complications.

  • Brain appears congested


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Black water fever relation to RBC

In malignant malaria a large number of the red blood corpuscles are destroyed. Hemoglobin from the blood corpuscles is excreted in the urine, which therefore is dark and almost the color of cola.


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How long Malaria infection can lost in Man relation to RBC

  • Without treatment P.falciparum will terminate in less than 1 year.

  • But in P.vivax and P.ovale persist as hypnozoites after the parasites have disppeared from blood.

  • Can prodce periodic relapses upto 5 years

  • In P.malariae may last for 40 years

    ( Called as recrudescence X relapse )

    Parasites survive in erythrocytes Liver ?


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Why Falciparum Infections are Dangerous relation to RBC

  • Can produce fatal complications,

    1.Cerebral malaria

    2.Malarial hyperpyrexia

    3.Gastrointestinal disorders.

    4.Algid malaria

    5 Black water fever can lead to death


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Complication of P.malariae relation to RBC

  • Can produce Nephrotic syndrome

  • Affects mainly children of years age


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Pernicious Malaria relation to RBCCarries a High Mortality

  • On few occasions life threading complications can occur.

  • Occurs in infections with P.falciparum

  • Associated with Heavy parasitaztion

  • Grouped into three types

    1. Cerebral Malaria

    2 Algid malaria

    3 Black water fever


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How Malaria present Clinically relation to RBC

  • Stage 1

  • Chills for 15 mt to 1 hour

  • Caused due to rupture from the host red cells escape into Blood

  • Preset with nausea, vomitting,headache

    • Stage 2

  • Fever may reach upto 400c may last for several hours starts invading newer red cells.


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Clinical Malaria relation to RBC

  • Stage 3

    patent starts sweating, concludes the episode

    Cycles are frequently Asynchronous

    Paroxysms occur every 48 – 72 hours

    In P.malariae pyrexia may lost for 8 hours or more and temperature my exceed 410c


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Systemic Manifestations relation to RBC

  • Hepatomegaly

  • Splenomegaly

  • A.normocytic anemia devlops due repeated ruputure of RBC’s



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Laboratory Diagnosis relation to RBC

  • Laboratory diagnosis of malaria can be made through microscopic examination of thick and thin blood smears. Thick blood smears are more sensitive in detecting malaria parasites because the blood is more concentrated allowing for a greatervolume of blood to be examined; however, thick smears are more difficult to read



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Making of Thick smear relation to RBC


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How a thick smear looks relation to RBC


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Appearance of Thick and Thin relation to RBCSmears


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Microscopy relation to RBC

  • Malaria parasites can be identified by examining under the microscope a drop of the patient's blood, spread out as a "blood smear" on a microscope slide. Prior to examination, the specimen is stained (most often with the Giemsa stain) to give to the parasites a distinctive appearance. This technique remains the gold standard for laboratory confirmation of malaria


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Microscopic demonstration still the Gold standard in Diagnosis

Blood smear stained with Giemsa’s stain


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QBC system has evolved as rapid and precise method in Diagnosis

  • The QBC Malaria method is the simplest and most sensitive method for diagnosing the following diseases.

    • Malaria

    • Babesiosis

    • Trypanosomiasis (Chagas disease, Sleeping Sickness)

    • Filariasis (Elephantiasis, Loa-Loa)

    • Relapsing Fever (Borreliosis)




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Antigen Detection Methods are Rapid and Precise Diagnosis

  • Antigen Detection

  • Various test kits are available to detect antigens derived from malaria parasites. Such immunologic ("immunochromatographic") tests most often use a dipstick or cassette format, and provide results in 2-15 minutes. These "Rapid Diagnostic Tests" (RDTs) offer a useful alternative to microscopy in situations where reliable microscopic diagnosis is not available. Malaria RDTs are currently used in some clinical settings


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Serology Diagnosis

  • Serology detects antibodies against malaria parasites, using either indirect immunofluorescence (IFA) or enzyme-linked immunosorbent assay (ELISA). Serology does not detect current infection but rather measures past experience.


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Newer Diagnostic methods Diagnosis

Molecular Diagnosis

  • Parasite nucleic acids are detected using polymerase chain reaction (PCR). This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory (even though technical advances will likely result in field-operated PCR machines).


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Other Laboratory Findings Diagnosis

  • Normocytic anemia of variable severity.

  • Liver function tests may be abnormal

  • Presence of protein and casts in the Urine of children with P.malariae is suggestive of Quartan nephrosis.

  • In severe Falciparum malaria with renal damage may cause oliguria and appearance of casts, protein, and red cells in the Urine


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Treatment Diagnosis

  • Still the Choroquine continues to be Drug of choice in all forms of susceptible in all forms of Acute Malaria

  • 1.5 grams of Chloroquine ( Base ) in over 3 days peroid in adults

  • 1.8 grams of Chloroquine in over 4 days.

  • In children dose to be calculated according to weight

  • In cases of P.falcipqrum leading to coma need to be treated with Quinidine gluconate till the oral treatment is feasible.


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Treatment (cont Diagnosis)

  • P.vivax with Chloroquine resistance is on raise But Chloroquine is preferred till drug resistance is established.

  • Early decisions on P.falciparum treatment with appropriate drug is highly essential in view of the rapid detoriation with complications.


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Radical Cure Diagnosis

  • Primaquin and 8 Aminoquilone eliminates Exoeythrocytic forms ( Relapsing forms )

  • Individuals deficient in Glucose -6 phosphate dehydrogenase with Primaquin treatment leads to hemolytic complications. Avoid use of Primaquin or give in low doses

  • People living in Eastern Mediterrian regions or Some Blacks are prone.


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Treating Drug Resistance in P.falciparum Diagnosis

  • Should be treated with

    Quinine sulphate plus single dose of Combination Drug Pyramethamine and Sulphodoxine ( Fansidar )

    Other Alternatives

    1 Quinine plus Doxycycline or Tetracycline

    2 Quinine plus Clindamycin

    Newer alternatives

    1 Mefloquine and Halofantril.


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Suppressive Prophylaxis Diagnosis

  • Popular drugs include, Chloroquine, Amodiaquine.

  • Mefloquine is drug of choice in Chloroquine resistant areas of the world

  • Prophylactic drugs are chosen on the basis of scientific studies on resistance, availaility,and individual accepatability


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CDC – on Current Recommendations Diagnosis

The current guidelance on issues related to Malaraia prevention can be searched at

http://www.cdc.gov ( travelers health )


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Epidemiology Diagnosis

  • Malaria continues to be one of the most important and devastating infectious diseases in developing areas of the world. Worldwide, over 40% of the population lives in areas where malaria transmission occurs (i.e., parts of Africa, Asia, the Middle East, Central and South America, Hispaniola, and Oceania)


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Major cause of Morbidity and Morality Diagnosis

  • 1 It is estimated that 300-500 million cases of malaria occur each year resulting in 7,50,000-2 million deaths.


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Control of Malaria Diagnosis

  • Elimination of Mosquito breeding places,

  • National improvements on health and Hygiene.

  • Use of Mosquito nets, treated with Pyrithrin

  • Clothing with sleeves, and long trousers

  • Use of Mosquito repellents


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Vaccines for Malaria Diagnosis

  • This degree of protection would be extremely difficult to achieve and might not be technically feasible with current vaccinology art and science. Many vaccine developers have therefore focused their efforts on creating a vaccine that limits the ability of the parasite to successfully infect large numbers of red blood cells. This would not prevent infection but would limit the severity of the disease and help prevent malaria deaths.…Vaccine Challenges


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Current Initiatives Diagnosis

The PATH Malaria Vaccine Initiative and partner, GlaxoSmithKline Biologicals, published recent Phase 2 trial results showing that the vaccine candidate, RTS,S, has a promising safety and tolerability profile and reduces malaria parasite infection and clinical illness due to malaria. This was the first RTS,S vaccine trial in African infants.


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Current successful Trails Diagnosis

  • The most successful candidate developed to date is the RTS,S recombinant vaccine. The RTS,S/AS02A, one of the key vaccines produced using this technique, has been used in field trials in The Gambia. Three repeat doses were administered in the 6 months leading up to the period of highest malaria transmission. The vaccine efficacy was reported at approximately 71% (with 95% confidence intervals spanning from 46 to 85%) during the first 2 months of follow-up, but falling to 0% in the last 6 weeks in 250 male volunteers.


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World Malaria Day Diagnosis

  • World Malaria Day (previously Africa Malaria Day) will now be commemorated every year on 25 April. The declaration of the 2008 1st World Malaria Day reflects the emphasis the world now attaches to the burden of this disease and its impact on the lives of those who live in malaria endemic countries, especially children under five years and pregnant women


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Bill Gates greatest contribution to Malaria eradication Diagnosis

  • The Bill & Melinda Gates Foundation announced three grants totaling $258.3 million in 2005 for advanced development of a malaria vaccine, new drugs, and innovative mosquito control methods to help defeat malaria, a disease that kills 2,000 African children every day



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Created for Universal Education on Malaria Malaria

Dr.T.V.Rao MD

Email

[email protected]


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