Malaria and Methylene Blue

Methylene blue is both a dye and a medicine. Methylene blue is a thiazine dye and was first prepared in 1876 by Heinrich Caro, a German chemist. It is mainly used to treat methemoglobinemia, a condition caused by elevated levels of methemoglobin in the blood. Methemoglobin is a form of hemoglobin that contains the ferric [Fe3+] form of iron.
Methylene blue has a similar mode of action as chloroquine and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase[1].

The mature gametocytes of Plasmodium are solely responsible for parasite transmission from the mammalian host to the mosquito. They are therefore a logical target for transmission-blocking antimalarial interventions, which aim to break the cycle of reinfection and reduce the prevalence of malaria cases[2].

Now, research had shown that methylene blue was found to target these gametocytes[3]. It is proposed to be used as a gametocytocidal adjunct with artemisinin-based combination therapy. Further exploration of methylene blue in clinical studies, including G6PD deficient patients, is recommended.

Common side effects of ingesting methylene blue include headache, vomiting, confusion, shortness of breath, and high blood pressure. Other side effects include serotonin syndrome, red blood cell breakdown and allergic reactions. Its use often turns the urine, sweat and stool blue to green in colour.

[1] Meissner et al: Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine in Malaria Journal – 2006. See here.
[2] Delves et al: Male and Female Plasmodium falciparum Mature Gametocytes Show Different Responses to Antimalarial Drugs in Antimicrobial Agents and Chemotherapy – 2013. See here.
[3] Wadi et al: Methylene blue induced morphological deformations in Plasmodium falciparum gametocytes: implications for transmission-blocking in Malaria Journal - 2018

New Plasmodium species found in Bonobos

If malaria parasites are widespread among wild chimpanzees and gorillas, but not found in bonobos, closely related to chimpanzees, what would you conclude from that factoid? You could argue that bonobos have developed some resistance to Plasmodium, the causal agent of malaria. But what really happened was that scientists only searched for known species of the Plasmodium parasite. Which means they didn't detect a new species, because they weren't looking for it.
A more extensive survey, increasing both the number and places they sampled wild bonobo populations. Wild bonobos are found in the forests of central Africa, south of the Congo River in the Democratic Republic of Congo (DRC). “Not finding any evidence of malaria in wild bonobos just didn’t make sense, given that captive bonobos are susceptible to this infection,” professor Beatrice Hahn said.

Hahn’s team found that bonobos are, in fact, susceptible to a wide variety of Plasmodium malaria parasites, including a previously unknown Laverania species that is specific to bonobos. Laverania parasites can be considered part of the Plasmodium genus[1].

Until recently, there were six known ape Laverania species that exhibited strict host specificity (association with a single host species) in wild populations: three in chimpanzees and three in western gorillas. In 2010, Hahn and her colleagues discovered that gorillas were the origin of the human malaria parasite Plasmodium falciparum, the most prevalent and lethal of the malaria parasites that infect people[2]. Later the same team proved that Plasmodium vivax originated in Africa[3][4].
One surprising finding from the current study was that bonobos harbour Plasmodium gaboni, which was previously only found in chimpanzees, as well as a new Laverania species, termed Plamodium lomamiensis, in recognition of the recently established Lomami National Park.

As scientists consider how malaria can be eliminated from the human population, Hahn notes that it is possible that these newly discovered parasites could (again) jump from primates into humans.

[1] Liu et al: Wild bonobos host geographically restricted malaria parasites including a putative new Laverania species in Nature Communications - 2017
[2] Liu et al: Liu, W. et al. Origin of the human malaria parasite Plasmodium falciparum in gorillas in Nature - 2010
[3] Liu et al: Liu, W. et al. African origin of the malaria parasite Plasmodium vivax in Nature Communications - 2014 
[4] Loy et al: Out of Africa: origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax in International Journal for Parasitology - 2017

Quinine-containing sodas may induce G6PD in breastfed children

Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is the most common human enzyme defect. To date there are a total of nine different forms known with some 140 different genotypes, all found on the long arm of the X chromosome on band Xq28.
One form is known as favism as a result of consuming fava beans. It is defined as an X-linked recessive inborn error of metabolism that predisposes to hemolysis (spontaneous destruction of red blood cells) and resultant jaundice in response to a number of triggers, such as certain foods, illness, or medication. There is no specific treatment, other than avoiding known triggers.

One of these triggers is, of course, the fava bean (or broad bean). The second one is stress from a viral or bacterial infection. Some drugs may also trigger acute hemolysis in people with G6PD deficiency.

There is a known link between G6PD deficiency and malaria. People with G6PD deficiency are more protected against malaria[1]. So, while G6PD deficiency may result in a potentially fatal acute hemolysis, the same deficiency offers protection against malaria. It's simply a trade-off between two ills.
But antimalarial drugs can also trigger acute hemolysis in people with G6PD deficiency. If you are breastfeeding your child with (an as yet unknown) G6PD deficiency, please remember that maternal consumption of a tonic soft drink which contains (just a bit of) quinine, may induce a G6PD crises[2]. It is recommended that consumption of quinine-containing sodas should be avoided during breastfeeding in populations with a high prevalence of G6PD deficiency.

[1] Huheey, Martin: Malaria, favism and glucose-6-phosphate dehydrogenase deficiency in Experimentia – 1975
[2] Bichali et al: Maternal consumption of quinine-containing sodas may induce G6PD crises in breastfed children in European Journal of Pediatrics - 2017

The rise of the giant lizards

What happens if you destroy a tropical rain forest and replant it with a monotonous monoculture of palms for the production of palm oil? We turn our attention to the northern part of Borneo, which is part of Malaysia. Rain forests have been cut down, turning some 20 percent of the land into plantations.

Not many animals can survive on these giant plantations, except scavengers, like snakes, rats, mice and lizards. They provide vital services including the removal of carrion, which is a crucial step in recycling nutrients and preventing disease.
Scientists captured 118 individual animals, with the most abundant being the South-east Asian water monitor (Varanus salvator macromaculatus), a large lizard and the Malay civet cat (Viverra tangalunga)[1]. There was a consistent trend: the more disturbed the land, the more lizards they found and the less civet cats they found.

Water monitors are primarily adapted for life in and around water. These 'dragons' have a phenomenal ability to eat almost anything that can fit inside their stomachs. Their diet includes small invertebrates, crustaceans and amphibians through to larger mammals, birds and their eggs. They’ll even eat other monitors.

This unfussy eating is what enables lizards to survive in the wasteland of oil palm. In the natural forests that surround the plantations, they face competition from mammal scavengers and predators such as sun bears, otters, civets and mongoose. There, water monitors are found only in relatively low numbers and at significantly smaller sizes.

But those mammals struggle to survive in the plantations, where a lack of shade boosts the temperature and lower plant diversity filters up through the food chain. Lizards can handle the heat and the presence of extra food from human refuse means water monitors appear to thrive there, reaching large sizes (in excess of two meters) and high numbers.

This 'survival of the toughest' is what drove the males of the species to reach such formidable sizes. But it is also one of the reasons why degraded habitats such as oil palm may be an ecological trap. The easy availability of food from human garbage sites or domestic animals draws in extra male monitors, resulting in increased competition for prime spots in the plantations then means they use up lots of energy, and risk serious injury just holding onto their territory and fighting off other males.

So, what we have is a monoculture of palms and a monoculture of lizards. This cannot be a positive issue, but it's even worse. This type of habitat is also a prime breeding ground for mosquitoes. On Borneo they carry the parasite Plasmodium knowlesi, which has recently been found to be a major cause of human malaria in Malaysian Borneo[2].

[1] Twining et all: Increasing land-use intensity reverses the relative occupancy of two quadrupedal scavengers in PLoS One - 2017
[2] William et al: Severe Plasmodium knowlesi Malaria in a Tertiary Care Hospital, Sabah, Malaysia in Emerging Infectious Diseases - 2011

Oil of Lemon Eucalyptus (OLE)

Lemon Eucalyptus is not – I repeat NOT – the same as Lemon-Eucalyptus or Lemon & Eucalyptus. The Lemon Eucalyptus (Corymbia citriodora) is a tall tree that grows up to 35 meters tall and is endemic in temperate and tropical north eastern Australia. The species is now cultivated in many warm places around the world.
The narrow leaves smells strongly of lemons. The lemon eucalyptus is closely relatied to the eucalyptus (Eucalyptus globulus), but lacks the specific smell of that genus. The essential oil of the tree consists mainly of citronelal (80%). This compound does have insect repellent properties and research shows high repellent effectiveness against mosquitoes[1].

But it is the remaining 20% that is highly interesting: it is chemically known as p-Menthane-3,8-diol, para-menthane-3,8-diol, menthoglycol or PMD. When refined to increase its PMD, it is known in the United States as oil of lemon eucalyptus (OLE) or by the tradenames Citrepel and Citriodiol. Refined OLE contains approximately up to 70% PMD (a mixture of the cis and trans isomers of p-menthane-3,8-diol).

OLE is an active ingredient used in insect repellents. It smells similar to menthol and has a cooling feel. OLE is in all likelyhood a more potent mosquito repellant than DEET[2]. Did I already mention that mosquitoes are increasingly 'insensitive' to DEET[3]?

[1] Kim et al: Evaluation of Repellency Effect of Two Natural Aroma Mosquito Repellent Compounds, Citronella and Citronellal in Entomological Research – 2005 
[2] Carroll, Loye: PMD, a Registered Botanical Mosquito Repellent with Deet-Like Efficacy in Journal of the American Mosquito Control Association - 2006
[3] Stanczyk et al: Behavioral insensitivity to DEET in Aedes aegypti is a genetically determined trait residing in changes in sensillum function in PNAS - 2010.

Malaria in Roman times

Even today, Malaria is one of the greatest medical challenges worldwide, still killing hundreds of thousands of people every year. In the past, people have adapted to the threat of malaria in various ways. One of these are genetic adaptations that evolved as survival mechanisms.
Malaria was not eradicated on the Italian island of Sardinia until the 1950s[1]. Until now, it has been assumed that the disease was only endemic on the island since the Middle Ages (500-1500 CE).

However, researchers have now studied the history of malaria on Sardinia in far greater depth[2]. Since antique DNA (aDNA) of malaria is very difficult to extract, they studied thalassemia and other genetic adaptations instead. Thalassemias are genetic diseases that interrupt the development of red blood cells. These diseases, however, have the advantage that many people affected lead a relatively healthy life and are bad hosts for malaria parasites. They are therefore partially immune against infections with malaria. Even today, such thalassemias occur relatively frequently in former malaria regions, such as the Mediterranean.

The researchers studied a thalassemia allele called cod39 β-thalassemia, which is dominant on Sardinia. They were therefore able to prove that, contrary to what has been known until now, malaria was probably already endemic on Sardinia in the Roman period, long before the Middle Ages.

The decisive evidence of this supposition has been provided by the 2,000 year old (circa 300 BC to 100 AD) remains of a Roman, in which the cod39 allele could be proven. “This is the very first documented case of the genetic adaptation to malaria on Sardinia,” Claudia Vigano, lead-researcher, says. “We also discovered that the person was genetically a Sardinian in all probability and not an immigrant from another area.”

[1] Eugenia Tognotti: Program to Eradicate Malaria in Sardinia, 1946–1950 in Emerging Infectious Diseases - 2009. See here.
[2] Viganó et al: 2,000 Year old β-thalassemia case in Sardinia suggests malaria was endemic by the Roman period in American Journal of Physical Anthropology - 2017

Malaria: Mosquito vs. Fungus

In several regions of sub-Saharan Africa where malaria is endemic, mosquitoes have become increasingly resistant to traditional chemical pestisides. Several species of Plasmodium, the parasitic protozoans that cause malaria are also becoming increasingly resistent to the medication we use to treat patients. What we have here is a potential perfect storm.
Researchers needed to think of new ways to combat the mosquito and the disease causing organism. Enter a fungus with the scientific name Metarhizium pingshaense[1]. The wild-type Metarhizium pingshaense strain has a narrow host range: just two disease-carrying mosquito species Anopheles gambiae and Aedes aegypti. It penetrates the mosquito’s exoskeleton and gradually killing it from the inside out.

Normally, high doses of spores and long periods of time are required for regular Metarhizium pingshaense to kill the mosquito. The researchers therefore decided to give the fungus a genetic makeover, pasting in several new genes expressing neurotoxins derived from both spider and scorpion venom. These toxins act by blocking ion channels integral to the transmission of nerve impulses, thereby effectively paralysing their victims.

“Unlike chemical insecticides that target only sodium channels, many spider and scorpion toxins hit the nervous system’s calcium and potassium ion channels, so insects have no pre-existing resistance,” explains senior author Professor Raymond St. Leger.
The team concluded the most effective strain should contain two toxins – one derived from the North African desert scorpion (Androctonus australis) and the other from the Australian Blue Mountains funnel-web spider (Hadronyche versuta).

The researchers also took care to ensure their anti-malarial 'spiderman' would not become an environmental problem. To keep the potent toxins from disseminating into the broader environment, the team attached a highly specific promotor sequence of DNA to the toxin genes, acting as a genetic 'switch' to ensure the expression of the toxins was only triggered once in the blood of an insect.

The next step is to expand testing from custom-built greenhouse-like enclosures in Burkina Faso to deploying the spores in field tests, and eventually to use on wild mosquito populations.

[1] Bilgo et al: Improved efficacy of an arthropod toxin expressing fungus against insecticide-resistant malaria-vector mosquitoes in Scientific Reports – 2017. See here.

Malaria and Deforestation

Nearly 130 million hectares of forest—an area almost equivalent in size to South Africa—have been lost since 1990[1]. A new study of 67 less-developed, malaria-endemic nations finds a link between deforestation and increasing malaria rates across developing nations[2].
Malaria is an infectious disease tied to environmental conditions, as mosquitoes are the disease vector. Deforestation, lead-author Kelly Austin notes, is not a natural phenomenon, but rather results predominantly from human activitie.

The study builds on evidence that patterns in climate change, deforestation, and other human-induced changes to the natural environment are amplifying malaria transmission. "Human-induced changes to the natural environment can have a powerful impact on malaria rates," she says. Deforestation can impact malaria prevalence by several mechanisms, including increased amounts of sunlight and standing water in some areas. Those factors are favourable for most species of Anopheles mosquitoes which are the key vector of malaria transmission[3].

Results of the study suggest that rural population growth and specialization in agriculture are two key influences on forest loss in developing nations. Deforestation from agriculture comes in part from food that is exported to more-developed countries, Austin notes. "In this way, consumption habits in countries like the U.S. can be linked to malaria rates in developing nations."

Austin thinks that leaving some trees and practicing more shade and mixed cultivation, rather than plantation agriculture which involves clear-cutting forests, could help to mitigate some of the harmful impacts.

[1] Food and Agriculture Organization (FAO): Global Forest Resources Assessment 2015, 2015. See here.
[2] Austin et al: Anthropogenic forest loss and malaria prevalence: a comparative examination of the causes and disease consequences of deforestation in developing nations in AIMS Environmental Science - 2017
[3] Vittor et al: Linking deforestation to malaria in the Amazon: characterization of the breeding habitat of the principal malaria vector, Anopheles darlingi in American Journal of Tropical Medicine and Hygiene - 2009 

Monkey malaria

Monkey malaria is caused by a malaria parasite, the Plasmodium knowlesi. The parasite is endemic in Southeast Asia and causes primarily malaria in long-tailed macaques (Macaca fascicularis) and pig-tailed macaques (Macaca nemestrina), but increasingly infects humans. It is largely the result of continued massive deforestation, mostly for palm oil plantations.
Plasmodium knowlesi is one of the six species of malaria parasite that infect humans, the others being: Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum, Plasmodium ovale curtisi and Plasmodium ovale wallikeri. Plasmidium ovale has recently been shown to consist of two subspecies[1]. Plasmodium knowlesi appears to occur in regions that are reportedly free of the other types of human malaria.

Monkey malaria is an emerging infection that was reported for the first time in humans in 1965[2]. These days it accounts for up to 70% of malaria cases in certain areas in Southeast Asia, particularly in Borneo, Cambodia, Malaysia, Myanmar, Philippines, Singapore, Thailand and neighboring areas.

The parasite is transmitted by the bite of several species Anopheles mosquitoes. These Mosquitoes are typically found in forested areas in Southeast Asia, but it is entirely possible that the mosquito might be able to adapt to environments with less trees.
The Plasmodium knowlesi parasite replicates and completes its blood stage cycle in 24-hour cycles[3]. This results in fairly high loads of parasite densities in a very short period of time. This makes it a potentially very severe disease if it remains untreated. The associated fever also occurs at 24-hour cycles. This is called a quotidian fever.

[1] Sutherland et al: Two nonrecombining sympatric forms of the human malaria parasite Plasmodium ovale occur globally in Journal of Infectious Diseases – 2010
[2] Chin et al: A naturally acquired quotidian-type malaria in man transferable to monkeys in Science – 1965
[3] Cox-Singh et al: Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening in Clinical Infectious Diseases – 2008

Experimental vaccine protects (some) monkeys from malaria

Researchers modified an experimental malaria vaccine and showed that it completely protected four out of eight monkeys who received it against the virulent Plasmodium falciparum malaria parasite[1]. In three of the remaining four monkeys, the vaccine delayed when parasites first appeared in the blood by more than 25 days. 

[Plasmodium falciparum in blood]
Malaria symptoms occur when parasites replicate inside red blood cells and cause them to burst. To enter blood cells, the parasite first secretes its own receptor protein, called RON2, onto the cell’s surface. Another parasite surface protein, called AMA1, then binds to a specific portion of RON2, called RON2L, and the resulting complex initiates attachment to the outer membrane of the red blood cell.

Several experimental malaria vaccines previously tested in people were designed to elicit antibodies against AMA1 and thus prevent parasites from entering blood cells. Although AMA1 vaccines did generate high levels of antibodies in humans, they have shown limited efficacy in field trials in malaria-endemic settings.

To improve vaccine efficacy, the scientists modified an AMA1-vaccine to include RON2L so that it more closely mimics the protein complex used by the parasite.
Monkeys were vaccinated with either AMA1 alone or with the AMA1-RON2L complex vaccine. Although the overall levels of antibodies generated did not differ between the two groups, animals vaccinated with the complex vaccine produced much more neutralizing antibody, indicating a better quality antibody response with AMA1-RON2L vaccination. Moreover, antibodies taken from AMA1-RON2L-vaccinated monkeys neutralized parasite strains that differed from those used to create the vaccine.

This suggests, the authors note, that an AMA1-RON2L complex vaccine could protect against multiple parasite strains. Taken together, the data from this animal study justify progression of this next-generation AMA1 vaccine toward possible human trials, they conclude.

[1] Srinivasan et al: A malaria vaccine protects Aotus monkeys against virulent Plasmodium falciparum infection in Nature – 2017

Malaria, Fava Beans and Favism

[Additional material by Valentina Caracuta, Laboratory of Archaeobotany and Palaeoecology, University of Salento, Italy]

Malaria is a debilitating disease and humans have been adapting and mutating constantly to overcome the disease or mitigating its effects. Today there are three known mutations[1]. The first are (multiple) sickle-cell anemias[2], the second is thalassaemia[3] and the third is glucose-6-phosfate-dehydrogenase deficiency (or G6PD deficiency)[4].
The fava bean (Vivia faba) is a broad flat bean that is a dietary staple in malaria-endemic areas along the Mediterranean coasts. Glucose-6-phosfate-dehydrogenase (or G6PD) is an enzyme that serves to reduce one specific sugar, glucose-6-phosfate, to another sugar. During the process it releases an energy-rich molecule.

Several forms of glucose-6-phosfate-dehydrogenase deficiency exist in human populations. The pattern of deficiency has been thought to correspond to the distribution of malaria caused by the malaria parasite(Plasmodium falciparum) Although this hypothesis is still in dispute, many scientists support it.
The malaria parasite lives in the red blood cells and 'feeds' off energy-rich molecules. Individuals with a mutation in the G6PD-gene, the so-called glucose-6-phosfate-dehydrogenase deficiency, produce energy via an alternative pathway that doesn't involve this specific enzyme. The malaria parasite cannot use this alternative molecule. Furthermore, G6PD deficient blood cells seem to turn over more quickly, thus allowing less time for the parasite to grow and multiply.

With G6PD deficiency, fava bean consumption leads to a hemolytic crisis ('breaking of red blood cells') and a series of chemical reactions that release free radicals and hydrogen peroxide into the blood stream. This condition is known as favism. Favism is characterized most often by four signs and symptoms: weakness or fatigue, pallor, jaundice and haemoglobinuria.
The question is therefore: is glucose-6-phosfate-dehydrogenase deficiency really a survival mechanism to mitigate the effects of malaria or are they simply two problems occurring in the same geological area? While one rogue study supported the assertion that patients with G6PD-deficient red blood cells had no protection against a Plasmodium falciparum infection[5], most studies do prove that G6PD deficiency is protective against malaria [6],[7],[8],[9].

[1] Choremies et al: Three inherited red-cell abnormalities in a district of Greece. Thalassaemia, sickling, and glucose-6-phosphate-dehydrogenase deficiency in Lancet – 1963
[2] Luzzatto: Sickle Cell Anaemia and Malaria in Mediterranean Journal of Hematology and Infectious Diseases - 2012
[3] Wambua et al: The Effect of α+-Thalassaemia on the Incidence of Malaria and Other Diseases in Children Living on the Coast of Kenya in Plos Med – 2006
[4] Hendrick: Population genetics of malaria resistance in humans in Heredity - 2011
[5] Kotepui et al: Prevalence and hematological indicators of G6PD deficiency in malaria-infected patients in Infectious Diseases of Poverty - 2016
[6] Bienzle et al: Glucose-6-phosfate dehydrogenase and malaria: Greater resistance of females heterzygous for enzyme deficiency and of males with non-deficient variant in Lancet - 1972 

[7] Ruwende et al: Natural selection of hemi and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria in Letters to Nature - 1995 
[8] Guindo et al: X-Linked G6PD Deficiency Protects Hemizygous Males but Not Heterozygous Females against Severe Malaria in PLoS Medicine - 2007
[9] Lesly et al: The Impact of Phenotypic and Genotypic G6PD Deficiency on Risk of Plasmodium vivax Infection: A Case-Control Study amongst Afghan Refugees in Pakistan in PLoS Medicine - 2010

The end of malaria (or the end of artemisinins)?

From 2010-2015 new malaria cases and malaria deaths in the world fell by circa 20% and circa 30% respectively. Yet a substantial global burden remains, with almost 440,000 deaths and some 214 million new cases reported over 2016[1]. Presently drugs are the path to treat malaria infection and reduce the parasite burden and disease in patients.
In particular, artemisinin combination therapies (ACTs) have played a central role against Plasmodium falciparum (the most deadly of human malaria parasites). Artemisinins are 'harvested' from sweet wormwood (Astemisia annua). Unfortunately, resistance to these artemisinins has emerged and spread throughout Southeast Asia, casting a grim specter of losing on gains in malaria control and elimination[2].

It is especially concerning that de novo emergence of resistance (rather than spread) has now also been reported in an area of high endemicity in Africa[3].
Novel drugs are needed to target Plasmodium vivax, a second, widespread parasite species with a latent liver stage infection that is not blocked by ACTs. Given that, as malaria burdens decrease, antimalarial drugs have to eliminate malaria in the absence of blood stage immunity, there is also the need to reduce transmission by the mosquito vector, a critical focus of prevention strategies.

Since 2010, seven countries have been certified to have eliminated malaria (by achieving three consecutive years of zero locally-acquired malaria): United Arab Emirates (2007), Morocco (2010), Turkmenistan (2010), Armenia (2011), Maldives (2015), Sri Lanka (2016) and Kyrgyzstan (2016). Malaria elimination campaigns in India and Bangladesh are expected to be particularly important to stem the global spread of artemisinin and multi-drug resistant strains from Southeast Asia to the rest of the world.

Don't hold your breath. The parasite is even smarter than we give it credit for.

[1] WHO: Fact Sheet: World Malaria Report 2015
[2] Hanboonkunupakarn: The threat of artemisinin resistant malaria in Southeast Asia in Travel Medicine and Infectious Diseases – 2016. See here.
[3] Lu et al: Emergence of Indigenous Artemisinin-Resistant Plasmodium falciparum in Africa in New England Journal of Medicine – 2017

Chloroquine triggers Burkitt lymphoma

Burkitt lymphoma is is a form of non-Hodgkin's lymphoma in which cancer starts in immune cells called B-cells. The disease characteristically involves the jaw or other facial bone, distal ileum, cecum, ovaries, kidney, or breast. Recognized as the fastest growing human tumor, Burkitt lymphoma is associated with impaired immunity and is rapidly fatal if left untreated.

Burkitt lymphoma was first identified in 1956 among children in Africa. Since a couple of variants exist, the endemic variant is also called the African variant. Burkitt lymphoma is common in young children who also have malaria and Epstein-Barr, the virus that causes infectious glandular fever (mononucleosis).
One possible mechanism may be that malaria weakens the immune system's response to Epstein-Barr, allowing it to change infected B-cells into cancerous cells. About 98% of African cases are associated with Epstein-Barr infection. But suppose it's the other way around: it is entirely possible that drugs to treat or prevent malaria could be the culprit.

A protozoan parasite, Plasmodium falciparum, is just one of the species of Plasmodium that cause malaria in humans. It is transmitted by a female Anopheles mosquito. The parasite is resistant to chloroquine treatment except in Haiti, the Dominican Republic, parts of Central America and parts of the Middle East. But in some regions Plasmodium falciparum regained susceptibility to chloroquine.
Trials to reintroduce chloroquine into parts of Africa are underway. However, because there are concerns about whether chloroquine increases replication of the Epstein-Barr virus, thereby contributing to the development of endemic Burkitt lymphoma[1].

It is therefore of the utmost importance to research if that connection really exists. Novel research found that chloroquine indeed drives Epstein-Barr virus replication and in turn might trigger Burkitt lymphoma[2].

But if there's one, there might be more. Research also shows that chloroquine may be involved in the enhancement of replication of other viruses. A study demonstrated that chloroquine indeed enhances Semliki Forest virus and encephalomyocarditis virus replication in mice[3].

[1] Karmali et al: Chloroquine enhances Epstein-Barr virus expression in Nature – 1978
[2] Li et al: Chloroquine triggers Epstein-Barr virus replication through phosphorylation of KAP1/TRIM28 in Burkitt lymphoma cells in Plos Pathogens – 2017. See here.
[3] Maheshwari et al: Chloroquine enhances replication of Semliki Forest virus and encephalomyocarditis virus in mice in Journal of Virology – 1991

Mosquitoes like blood from people infected with malaria

Malaria mosquitoes (Anopheles gambiae) prefer to feed - and feed (and feast) more - on blood from people infected with malaria. Researchers have now discovered why[1].
The malaria parasite Plasmodium falciparum produces a molecule, HMBPP, which stimulates the human red blood cells to release more carbon dioxide and volatile compounds, such as monoterpenes[2]. Together they produce an irresistible smell to malaria mosquitoes. The mosquitoes also eat more blood. Ingrid Faye and her colleagues discovered that most malaria mosquitoes were attracted by HMBPP-blood, even at very low concentrations. The mosquitoes are also attracted more quickly and drink more blood.

Moreover, these mosquitoes acquire a more severe malaria infection, which means that higher numbers of parasites are produced. This indicates that the extra nutrients from the larger meal of blood are used to produce more parasites, researchers believe. Neither humans nor mosquitoes use HMBPP themselves, but the parasite needs the substance to be able to grow."HMBPP is a way for the malaria parasite to hail a cab, a mosquito, and successfully transfer to the next host", Noushin Emami explains. She has worked over three years in the project.
"This seems to be a well-functioning system, that evolved over millions of years, which means that the malaria parasite can survive and spread to more people without killing the hosts", says Faye.

These results may be useful in combatting malaria. Today the most efficient way is to use mosquito nets and insecticides to prevent people from being bitten. Increasing resistance against the insecticides require new control methods to be developed to tackle the mosquitoes. In addition, medicines become progressively inefficient when the parasite becomes resistant to them and new drugs must be developed constantly.

A vaccine seems far away. Faye thinks that a major step forward in the fight against malaria would be to create a trap that uses the parasite's own system for attracting malaria mosquitoes.

[1] Noushin Emami et al: A key malaria metabolite modulates vector blood seeking, feeding, and susceptibility to infection in Science – 2017
[2] Lindberg et al: Immunogenic and Antioxidant Effects of a Pathogen-Associated Prenyl Pyrophosphate in Anopheles gambiae in PloS One – 2013

Malaria in historic times

Analysis of 2,000-year-old human remains from several regions across the Italian peninsula has confirmed the presence of malaria during the Roman Empire, addressing a riddle about its pervasiveness in this ancient civilization[1].
Research managed to extract mitochondrial genomic evidence of malaria, coaxed from the pulp of teeth of bodies buried in three Italian cemeteries, dating back to the 1st to 3rd centuries Common Era. The genomic data is important, because it serves as a key reference point for when and where the parasite existed in humans and provides more information about the evolution of human disease.

“Malaria was likely a significant historical pathogen that caused widespread death in ancient Rome,” says evolutionary geneticist Hendrik Poinar. Even now malaria is a serious and sometimes fatal infectious disease that is spread by infected mosquitoes. It is responsible for nearly 450,000 deaths every year, the majority of them children under the age of five.

“There is extensive written evidence describing fevers that sound like malaria in ancient Greece and Rome, but the specific malaria species responsible is unknown,” says lead author Stephanie Marciniak. “Our data confirm that the species was likely Plasmodium falciparum, and that it affected people in different ecological and cultural environments.
Marciniak sampled teeth taken from 58 adults and 10 children interred at three Imperial period Italian cemeteries: Isola Sacra, Velia and Vagnari. Located on the coast, Velia and Isola Sacra were known as important port cities and trading centres. Vagnari is located further inland and believed to be the burial site of labourers who would have worked on a Roman rural estate.

They were able to extract, purify and enrich specifically for the Plasmodium species that is still known to infect humans. Extracting usable DNA was difficult, because the parasites primarily dwell within the bloodstream and organs, including the spleen and liver, which decompose and break down over the course of two millennia. In the end, the scientists managed to recover more than half of the Plasmodium falciparum mitochondrial genome from two individuals from Velia and Vagnari.
Literary evidence of malarial infection dates back to the early Greek period, when Hippocrates described the typical undulating fever highly suggestive of plasmodial infection[2]. Recent immunological and molecular analyses describe the unambiguous identification of malarial infections in several ancient Egyptian mummies[3].

[1] Marciniak et al: Plasmodium falciparum malaria in 1st–2nd century CE southern Italy in Current Biology – 2016
[2] Nerlich: Paleopathology and Paleomicrobiology of Malaria in Microbiology Spectrum – 2016
[3] Lalremruata et al: Molecular identification of falciparum malaria and human tuberculosis co-infections in mummies from the Fayum depression (Lower Egypt) in PloS One - 2013

Arsenic, Syphilis and Malaria

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum pallidum. The disease presents itself in four stages (primary, secondary, latent and tertiary), with each stage being characterized by different symptoms and levels of infectivity. The history of this disease is nowadays disputed; some still think that Columbus and his crew brought syphilis to the Old World in 1493, but others suggest that syphilis originated in the Old World, simply going unrecognized until the early 15th century or perhaps noticeably increasing in prevalence or virulence at roughly this time[1].
[Congenital syphilis before penicillin]
Malaria is a mosquito-borne infectious disease caused by parasitic protozoans (a group of single-celled microorganisms) belonging to the Plasmodiums. Malaria causes symptoms that typically include fever, fatigue, vomiting and headaches. In severe cases it can cause yellow skin, seizures, coma or death. The history of this disease is a long one: the first evidence of malaria parasites was found in mosquitoes preserved in amber from the Palaeogene Era and that are approximately 30 million years old[2]. The symptoms of malaria were described in ancient Chinese medical writings (the Nei Ching or the 'Canon of Medicine')[3].

In 1786 Thomas Fowler, a British physician, published a study on the effectiveness of his solution of 1% potassium arsenite which he called 'Liquor mineralis', for 'agues, remittent fevers, and periodical headaches'[4]. In 1809 'Liquor mineralis', known by that time as 'Fowler’s solution', was accepted into the London Pharmacopeia and became widely used as an alternative to quinine for 'agues' (malaria) and was used for 'sleeping sickness' (trypanosomiasis).
Fowler’s solution remained a treatment for many conditions well into the 20th century and was still listed along with arsenic trioxide and sodium arsenate in the 1914 edition of the 'American Medical Association’s Handbook of Useful Drugs' as treatment for skin cancer, chronic inflammatory skin disorders, malaria, syphilis and protozoal diseases[4].

[1] Armelagos et al: The Science behind Pre-Columbian Evidence of Syphilis in Europe: Research by Documentary in Evolutionary Anthropology – 2013. See here.
[2] Poinar Jr: Plasmodium dominicana n. sp. (Plasmodiidae: Haemospororida) from Tertiary Dominican amber in Systematic Parasitology – 2005
[3] Neghina et al: Malaria, a Journey in Time: In Search of the Lost Myths and Forgotten Stories in American Journal of Medical Sciences - 2010
[4] Jolliffe: A history of the use of arsenicals in man in Journal of the Royal Society of Medicine - 1993. See here.
[5] Council on Pharmacy and Chemistry, American Medical Association: A Handbook of Useful Drugs. Chicago, Press of the American Medical Association - 1914

Bloodsucking Mosquitoes

Mosquitoes live worldwide except in Iceland. Males live typically 5-7 days while females live longer up to one month. Their size varies from 2mm to 6mm and typically weigh about 5mg. Average female mosquito can have a blood meal three times its weight. They can sense human target from the carbon dioxide in human breath from a distance up to 50km away. The female needs the blood for protein and iron to help her eggs develop. It feeds through a flexible tube (proboscis) which act like a drinking straw with pin-sharp end for piercing the skin. She releases her saliva into the wound. That causes slight irritation. Once her proboscis hits a blood vessel underneath the skin she injects a cocktail of chemicals into your skin, which act as a local anaesthetic and as a anticoagulant that keeps the blood in fluid form. Her saliva also contains digestive enzymes and anti-bacterial agents to control infection in their sugar meals.
Mosquitoes have a nervous system with a rudimentary brain (ganglion). Despite it small size they still seem to be outsmarting humans in the survival of the fittest. Their ability to obtain their dinner as blood suckers while avoiding host defences like nets, various chemical and ultrasound repellents, plus many predators, such as spiders, dragonflies and bats, is one of the great feats of nature.

Most species of mosquitoes are vegetarians and do not drink blood at all. They feed on plants and nectar. Out of 3,500 species only the Anopheles, Culex and Aedes are blood sucking species. It’s not known how some species of mosquitoes have evolved as blood sucking insects. Some mosquitoes do not like the blood of mammals but prefer blood of amphibians such as snakes, or birds (avian malaria).

Malaria is an ancient disease noted for more than 3000 years. The origin of malarial parasite stretches back to prehistoric Africa, where they evolved together with their human and nonhuman hosts. They contributed to the fall of Rome. They helped to turn the tide of major battles as that of Japanese against British in Burma. The Japanese, having a chronic shortage of quinine, died in their thousands from malaria during WWII, while it killed 60,000 American soldiers in the South Pacific because of shortage of quinine.

Venezuela: Worst malaria epidemic in 75 years

In 2015, Venezuela saw a record number of malaria cases with 136,402. Since reliable records have been kept in the country, this were the most reported in 75 years. However, the situation is much worse in the South American country during the first 33 weeks of 2016.
The Sociedad Venezolana de Salud Pública Red Defendamos la Epidemiología (or the Venezuelan Society Epidemiology and Public Health) reported recently that through August 20, 2016, Venezuela has seen 143,987 cases of malaria, representing an increase of 72.2% over the previous period in 2015 (83,623). “In total, 3,635 new indigenous cases were identified in epidemiological week No. 33 of 2016, from 14 to 20 August,” says the statement of the Venezuelan Society Epidemiology and Public Health.

Of the total of indigenous cases in the country, 9.48%, or 13,758 cases were in children under 10 years old.

Bolivar, the state in eastern Venezuela, bordering Brazil and Guyana, still accounts for the majority of cases 114,963 or nearly eight out of 10 cases. Of immediate concern are reports that indicate that the antimalarial drug, artemisinin, essential for the treatment of the most pathogenic strain of malaria, Plasmodium falciparum, is running low in stock. In Bolivar, where the epidemic is most severe, drug stocks are depleted as are diagnostic supplies like Giemsa stain and immunological rapid tests.

Of the 106 countries globally with continuous malaria transmission, 102 reduced the annual incidence between 1990 and 2015 by 37 percent. Venezuela is one of four countries that has seen an increase in the incidence of malaria, in fact, the incidence increased by 356 percent in that South American country.

Mefloquine causes brain damage that mimics PTSD

As a rule, American U.S. Military service members that were deployed in regions where malaria was rife, Mefloquine (Lariam) was once the prophylactic of choice. Favored for its once-a-week dosage regimen, Mefloquine (Lariam) was designated the drug of last resort in 2013 by the Defense Department after the Food and Drug Administration slapped a boxed warning on its label, noting it can cause permanent psychiatric and neurological side effects[1].
At the peak of Mefloquine's use in 2003, nearly 50,000 prescriptions were written by military doctors. That figure dropped to 216 prescriptions in 2015 and it is prescribed only to personnel who can't tolerate other preventives.

Case reports of Mefloquine (Lariam) side effects have been published before, but now a case report has emerged in which a service member was diagnosed with post-traumatic stress disorder, but found instead to have brain damage caused by Mefloquine (Lariam)[2]. The case concerned a U.S. military member who sought treatment for uncontrolled anger, insomnia, nightmares and memory loss. Physicians diagnosed the patient with anxiety, Post-Traumatic Stress Disorder (PTSD) and a thiamine deficiency. But after months of treatment, including medication, behavioral therapy and daily doses of vitamins, little changed.
It wasn’t until physicians took a hard look at his medical history, which included vertigo that began two months after his Africa deployment, that they suspected Mefloquine (Lariam) poisoning. The medication has been linked to brain stem lesions and psychiatric symptoms before.

The case demonstrates the difficulty in distinguishing from possible Mefloquine-induced toxicity versus PTSD and raises some questions regarding possible linkages between the two diagnoses. It also raises questions about the origin of similar symptoms in others like victims of the illusive Gulf War Syndrome.

[1] Grabias et al: Adverse neuropsychiatric effects of antimalarial drugs in Expert Opinion of Drug Safety – 2016
[2] Livezey et al: Prolonged Neuropsychiatric Symptoms in a Military Service Member Exposed to Mefloquine in Drug Safety – Case Reports – 2016

Malaria and Common Boxwood

Some of the most valuable antimalarial compounds, including quinine and artemisinin, originated from plants. While these drugs have served important roles over many years for the treatment of malaria, drug resistance has become a widespread problem.

Therefore, a need exists to identify new compounds that have efficacy against drug-resistant malaria strains.
So, researchers took to the field to search for plants that potentially could replace quinine or artemisinin. What they found was a bit of a surprise because common boxwood (Buxus sempervirens), a shrub usually planted as a hedge in large parts of the world, showed considerable activity against both drug-sensitive and drug-resistant malaria strains[1]. The specific active ingredient was a lupane triterpene.

In their conclusion, the researchers express their surprise that a potential medicine for malaria can be identified from a plant species in the United States, because tropical and semitropical botanical resources from around the world are much more heavily explored.

Perhaps the outcome shouldn't be a great surprise because it was already known that lupane triterpenes, the anti-malarial active ingredient in common boxwood, only has to undergo some simple modifications before it produces highly effective agents against influenza A and herpes simplex type 1 viruses[2].

[1] Cai et al: Identification of Compounds with Efficacy against Malaria Parasites from Common North American Plants in Journal of Natural Products – 2016
[2] Baltina et al: Lupane triterpenes and derivatives with antiviral activity in Bioorganic and Medicinal Chemistry Letters – 2003

Quinine and Babesiosis

While most know that quinine is used to successfully prevent and treat malaria, it is less well known that it can also treat an emerging disease called babesiosis.

Babesiosis is a parasitic disease that is transmitted by ticks. These parasites of the genus Babesia infect red blood cells. While more than 100 species within the genus have been reported, only a few have been identified to cause human infections, including Babesia microti, Babesia divergens, Babesia duncani and an as yet unnamed strain of Babesia divergens, designated MO-1.
Half of all children and a quarter of adults appear asymptomatic when infected with a Babesia parasite. For those who do develop symptoms, they are quite similar to malaria, because both cause fever (up to 40.5 °C ) and hemolytic anemia (destruction of red blood cells, because Babesia parasites reproduce in red blood cells). Symptoms appear 1 to 4 weeks after the bite of the tick. While uncommon, decreased levels of consciousness, coma or death are possible[1].

Babesiosis is a vector-borne illness usually transmitted by Ixodes scapularis ticks. Babesia microti uses the same tick vector as Lyme disease and ehrlichiosis, and may occur in conjunction with these other diseases.
In Europe, Babesia divergens is the primary cause of infectious babesiosis and is transmitted by Ixodes ricinus. In the United States, the majority of babesiosis cases are caused by Babesia microti, and occur primarily in the Northeast and northern Midwest from May through October. In Australia, babesiosis of types Babesia duncani and Babesia microti has recently been found in symptomatic patients[2].

Quinine can certainly be prescribed to treat babesiosis. However, the treatment of choice is a combination of antibiotic, because quinine has a bit more potential side effects.

Ticks are increasingly infected with all sorts of viruses, bacteria and parasites. Which means that, even in cooler climates, people are more at risk for malaria-like diseases such as babesiosis[3].

[1] Usmani-Brown et al: Neurological manifestations of human babesiosis in Handbook of Clinical Neurology - 2013  
[2] Gelfant et al: Babesiosis: An Update on Epidemiology and Treatment in Current Infectious Disease Report – 2003
[3] Ord et al: Human Babesiosis: Pathogens, Prevalence, Diagnosis and Treatment in Current Clinical Microbiology Reports - 2015

What is Quinine?

Quinine is a cinchona alkaloid that belongs to the aryl amino alcohol group of drugs. It is an extremely basic compound and is, therefore, always presented as a salt. Various preparations exist, including the hydrochloride, dihydrochloride, sulphate, bisulphate, and gluconate salts; of these the dihydrochloride is the most widely used. Quinine has rapid schizonticidal action against intra-erythrocytic malaria parasites. It is also gametocytocidal for Plasmodium vivax and Plasmodium malariae, but not for Plasmodium falciparum. Quinine also has analgesic, but not antipyretic properties. The anti-malarial mechanism of action of quinine is unknown.

Quinine is rapidly absorbed both orally and parenterally, reaching peak concentrations within 1-3 hours. It is distributed throughout the body fluids and is highly protein bound, mainly to alpha-1 acid glycoprotein. The binding capacity in plasma is concentration dependent, but also depends on the levels of alpha-1 acid glycoprotein, which therefore makes comparisons between different studies difficult. Quinine readily crosses the placental barrier and is also found in cerebral spinal fluid. Excretion is rapid - 80% of the administered drug is eliminated by hepatic biotransformation and the remaining 20% is excreted unchanged by the kidney. The half-life of quinine ranges between 11-18 hours. Several pharmacokinetic characteristics of quinine differ according to the age of the subject and are also affected by malaria. The volume of distribution is less in young children than in adults, and the rate of elimination is slower in the elderly than in young adults. In patients with acute malaria the volume of distribution is reduced and systemic clearance is slower than in healthy subjects; these changes are proportional to the severity of the disease. As a result, plasma quinine levels are higher in patients with malaria. Protein binding of quinine is increased in patients with malaria as a result of an increased circulating concentration of alpha-1 acid glycoprotein.

Quinine has a low therapeutic index, and adverse effects with its use are substantial [16]. The side effects commonly seen at therapeutic concentrations are referred to as cinchonism, with mild forms including tinnitus, slight impairment of hearing, headache and nausea. Impairment of hearing is usually concentration dependent and reversible. More severe manifestations include vertigo, vomiting, abdominal pain, diarrhea, marked auditory loss, and visual symptoms, including loss of vision. Hypotension may occur if the drug is given too rapidly, and venous thrombosis may occur following intravenous injections. Intramuscular administration is painful and may cause sterile abscesses. Hypoglycaemia is yet another common side effect of quinine therapy [15, 18] and is a particular problem in pregnant women[19]. Hypoglycaemia has been reported to occur in up to 32% of patients receiving quinine therapy[18]. However in more recent studies, hypoglycaemia occurred in only 3% of adults and 2.8% of African children receiving quinine. Less frequent but more serious side effects of quinine therapy include skin eruptions, asthma, thrombocytopaenia, hepatic injury and psychosis.

Malaria and Plasmodium

Malaria is caused by tiny Plasmodium parasites. These parasites are spread to people through the bites of an infected female Anopheles mosquito. There are five species of parasites that are known to cause malaria in humans: Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum, Plasmodium ovale curtisi and Plasmodium ovale wallikeri and Plasmodium knowlesi.

Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae together account for nearly all human infections, with Plasmodium falciparum accounting for the overwhelming majority of malaria deaths. However, an increasing number of cases of severe malaria in Southeast Asia have recently been attributed to Plasmodium knowlesi.

But nature has always more tricks up its sleeve, because other species of Plasmodium have increasingly been isolated from humans, including Plasmodium brasilianum, Plasmodium inui, Plasmodium rhodiani, Plasmodium schweitzi, Plasmodium semiovale and Plasmodium simium.

And that's not all because the parasite is very good at adapting and mutating. Over time it has been able to counter any poison we use to combat the disease. We call that poison medicine.
Plasmodium falciparum has developed resistance to nearly all antimalarials in current use, although the geographical distribution of resistance to any single antimalarial drug varies greatly. Plasmodium vivax has been shown to be resistant to chloroquine and/or primaquine in some areas. Chloroquine-resistant Plasmodium falciparum has been described everywhere malaria is transmitted except for malarious areas of Central America (northwest of the Panama Canal), the island of Hispaniola, and limited areas of the Middle East and Central Asia. Mefloquine resistance is frequent in some areas of South-East Asia and has been reported in the Amazon region of South America and sporadically in Africa.

Sulfadoxinepyrimethamine resistance occurs frequently in South-East Asia and South America. It was initially almost 100% effective in curing malaria when introduced in 1977, but within five years was curing only 10% of cases due to drug resistance.
What's left, you might ask. Artemisinin is a drug that is produced from sweet wormwood (Artemisia annua). It possesses the most rapid action of all current drugs against Plasmodium falciparum. When used correctly in combination with other anti-malarial drugs, artemisinin is nearly 95% effective in curing malaria and the parasite is highly unlikely to become drug resistant, says the WHO hopefully[1].

Now we leave the realm of fantasy and discover that the parasite increasingly develops resistance to Artemisinin[2].

[1] WHO: WHO calls for an immediate halt to provision of single-drug artemisinin malaria pills – 2006. See here
[2] Tilley et al: Artemisinin Action and Resistance in Plasmodium falciparum in Trends in Parasitology - 2016

Malaria and Bitter-wood

Bitter-wood (Quassia amara) is a shrub that can eventually grow into a small tree of about seven meters. It has leaves that can reach 25 centimeters en blooms with bright red flowers that white on the inside. The small fruit is a drupe that colours from green to almost black. Bitter-wood is endemic in South-American countries such as Costa Rica, Nicaragua, Panama, Brasil, Peru, Venezuela, Suriname, Colombia, Argentina, French Guyana and (British) Guyana.
With a name like bitter-wood every reader shall probably understand that this shrub will be tasting rather bitter and the reader is right in thinking that. Scientists believe that bitter-wood is so extremely bitter that it is just about maximum level a human can endure.

That bitterness is the result of two substances that hide in the wood of the bitter-wood: quassin (0.09 to 0.17%) and neoquassin (0.05 to 0.11%). Extracts of the wood and the bark are used as an insecticid. Research has shown that bitter-wood offers a very good protection against a host of insects that can ravage a crop. And, most importantly, tea from bitter-wood is very effective against the development of the larvae of mosquitoes in ponds, while not damaging the fishes.
Traditionally, bitter-wood is used to treat fever and to combat flees and lice in hair. Research has shown conclusively that two substances in this species, Simalikalactone D en Simalikalactone E, are a potent cure against malaria. In French Guyana, a tea from fresh young leaves is a traditional antimalarial medicine[1][2]. Experiments showed that this tea highly inhibited the development of the malaria parasites, Plasmodium yoelii yoelii and Plasmodium falciparum. It seems that a tea from dried young leaves gets an even better results than fresh young leaves[3].

All very positive news, you might be thinking at this moment. Mosquitoes and malaria parasites are getting increasingly resistant against nearly every medication and therapy we throw at them. Bitter-wood might be a feasible alternative. But all is not well in the State of Denmark because an extract of bitter-wood greatly reduced the fertility of rats[4]. Good for a potential rat infestation, but not for us humans.

[1] Bertani et al: Simalikalactone D is responsible for the antimalarial properties of an amazonian traditional remedy made with Quassia amara L. (Simaroubaceae) in Science Direct – 2006
[2] Cachet et al: Antimalarial activity of simalikalactone E, a new quassinoid from Quassia amara L. (Simaroubaceae) in AntimicrobialAgents and Chemotherapy – 2009
[3] Bertani et al: Quassia amara L. (Simaroubaceae) leaf tea: effect of the growing stage and desiccation status on the antimalarial activity of a traditional preparation in Journal of Ethnopharmacology – 2007
[4] Raji et al: Antifertility activity of Quassia amara in male rats — In vivo study in Science Direct – 1997

Malaria and Dragon Trees

The Afromontane Dragon Tree (Dracaena afromontana) is appears as a shrub to a tree, reaching heights of 2 to 12 meters. This species of Dragon Tree grows in dense moist deciduous and evergreen rain- or bamboo forest throughout Eastern and Central Africa. Its simple leaves are whorled and may reach 30 centimeters in length. The white flowers are panicles up to 30 centimeters long. It produces fruit in the form of orange berries.
The Afromontane Dragon Tree can be found, as its name implies, in mountainous areas, mostly at altitudes over 1,500 meters. Start looking for them above altitudes of 500 meters and stop looking for them above 3200 meters.

The Afromontane Dragon Tree is used to mark field boundaries and graves. It is therefore also found in cultivated and managed habitats throughout Ethiopia and Tanzania. The roots and bark of the Afromontane Dragon Tree are still used as medicine for treating chest pains and rheumatism in Tanzania, Uganda, Burundi and Rwanda.

Other uses include liver disease and the treatment of malaria: you crush the stem or leaves, mix with some water, sieve it and drink it three times a day; you can also peel the roots, dry them, pound them to make powder and drink with water.

Some scientific research has been done regarding the effects of Dracaenas on the malarial parasite, Plasmodium falciparum. A Thai study found that an extract of a species of Dracaena 'showed high selective antimalarial activity'[1][2]. While I am not claiming that Dragon Trees could one day become a replacement for quinine, the genus certainly merits some thorough scientific research.

[1] Thiengsusuk et al: Antimalarial activities of medicinal plants and herbal formulations used in Thai traditional medicine in Parasitology Research – 2013
[2] Sumsakul et al: Inhibitory Activities of Thai Medicinal Plants with Promising Activities Against Malaria and Cholangiocarcinoma on Human Cytochrome P450 in Phytotherapy Research - 2015

Malaria vaccine protects for up to a year

According to the latest WHO estimates, released in December 2015, there were 214 million cases of malaria in 2015 and 438 000 deaths. At the moment there is no vaccine.

But now, a new study – a Phase 1 trial – by researchers at the University of Maryland School of Medicine (USA) has found that an experimental malaria vaccine protected adults from infection for more than a year[1]. The vaccine was an attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine (shortened to PfSPZ Vaccine).

"These results are really important," said Kirsten E. Lyke, a researcher at the University of Maryland School of Medicine. "Malaria has such a devastating effect on children, especially in Africa. This vaccine has the potential to help travelers, military personnel and children in malaria-endemic areas."

Lyke and her colleagues, conducted a clinical evaluation of the vaccine, which involved exposing a small number of willing healthy adults to the malaria-causing parasite Plasmodium falciparum in a controlled setting. The parasite is transmitted to humans via the bite of infected mosquitos. The PfSPZ Vaccine consists of live, but weakened (attenuated), Plasmodium falciparum, specifically, the early developmental form of the parasite.

Previous research had shown that the vaccine worked for three weeks after immunization[2]. This study analyzed its longer term effects. The trial enrolled 101 healthy adults aged 18 to 45 years, who had never had malaria. Of these, 59 participants received the vaccine, while 32 participants were not vaccinated.
Participants were exposed to the bites of mosquitoes carrying the same Plasmodium falciparum strain from which the vaccine was derived. IV administration appears to provide better protection than intramuscular injection, both in the short and long term. Overall, the study found that the vaccine provided protection for up to a year in more than half (55 percent) of subjects. In those people, it appeared to provide sterile protection, meaning the subjects not only didn't get malaria, but also could not further transmit malaria.

[1] Ishizuka et al: Protection against malaria at 1 year and immune correlates following PfSPZ vaccination in Nature Medicine – 2016
[2] Seder et al: Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine in Science – 2013

The history of malaria and quinine

Malaria is caused by a parasite that is carried by several mosquitoes of the genus Anopheles. It is transmitted to humans through the bite of a infected mosquito. The parasite enters the bloodstream and the infected human suffers from intense fever and icy shivering. The spleen becomes painfully enlarged. Once recovered, patients often suffer relapses and seldom regain their original strength. Many die, especially when the parasite reaches the brain, causing cerebral malaria.
References to its unique, periodic fevers are found throughout recorded history beginning as early as 2700 BC in China. Malaria was once the scourge of the Mediterranean and of Rome in particular. Even places as far a field as France, the Netherlands, southern England and Russia were affected by it. Originally an ‘Old World’ disease, it was carried by explorers and settlers into the Americas. Its cure – the quinine found in the bark of the cinchona tree – was discovered in the 17th century in the foothills of the Peruvian Andes, an elevated area where there had never been any malaria.

Nobody quite knows why, but it appears to have abated somewhat in the Middle Ages before flaring up again in the seventeenth and eighteenth centuries. The problem was that the Europeans had no idea what caused malaria. To them it was simply an intermittent fever that took hold of many in the summer months. They simply thought that it was some type of contagion that basically ‘hung about’ in the miasma (i.e. the 'summer mists'). In Rome, where malaria was the most rampant, one was said to catch the fever from the ‘bad air’ (the mal’aria) of the marsh mists.

Malaria causes fevers that recur at approximately three-day intervals (a quartan fever), longer than the two-day (tertian) intervals of the other malarial parasites, hence its alternate names quartan fever and quartan malaria. Malaria – once also variously known as the Roman marsh fever or the intermittent fever – was the ever-present enemy of the Roman Campagna. The Tiber frequently breached its banks in summer and left the countryside covered in stagnating pools of water. Numerous popes, cardinals and ordinary Romans were laid low or killed by malaria; six visiting cardinals died from malaria during the disastrous conclave of 1623. Wealthy citizens would desert the city during the worst of the summer heat, fleeing to the cooler climate of the surrounding hills in an effort to avoid catching the fever. Malaria was only really eradicated in the area in the 1930s when Mussolini had the Pontine marshes drained and the mosquitoes’ breeding grounds in western Italy were finally eliminated.

Malaria was most probably introduced to the New World by the early European explorers and settlers. American settlers then took the disease inland with them as they moved westward. It even found its way into Canada.
[Agostín Salumbrino]
In 1605, the Italian Jesuit Brother Agostín Salumbrino (1561–1642) arrived in Lima, which was then part of the Spanish Viceroyalty of Peru. Salumbrino witnessed how the Incas would take cinchona bark - ground into a powder and drunk in hot water - to stop from shivering when the winter cold had seeped into them. Salumbrino was well acquainted with the symptoms of Roman marsh fever, and the shivering of the locals caused him to think of the shivering phase caused by the fever back home. So he sent a small sample of cinchona bark to Rome in 1631, where it proved to be a cure for the marsh fever. While its effect in treating malaria (and hence malaria-induced shivering) was unrelated to its effect in controlling shivering from cold, it was nevertheless effective for malaria.

In a short time the Jesuits, with the aid of the local Indians, would begin to search for and strip the bark of the cinchona tree in order to send it to the Old World. The Jesuits showed the locals how to strip the bark in vertical pieces so as not to kill the tree. They would plant five new cinchona trees for every one they cut down and they would plant them in the shape of the cross in the hope that God would then bless their growth.

In 1767 the Jesuits were expelled from the Spanish Empire by Carlos III as the latter had grown fearful and jealous of their accrued power and properties. With time the local people would forget the conservational practices taught to them by the Jesuits and the cinchona trees would begin to be overharvested.
[Dutch Indies]
Soon after the discovery every ship traveling from the New World to the Old would carry a consignment of 'Peruvian bark' or Polvo de los Jesuitos ('Jesuits Powder'). Though nobody knew how it worked, its reputation as an effective cure for the intermittent fever soon began to spread throughout Catholic Europe. But the Protestants regarded it with great suspicion. The Reformation and counter-Reformation were in full swing, and many Protestants suspected the so-called remedy to be part of a Popish plot. In addition, the foul taste of the bitter bark led many to think they were being poisoned, and cinchona bark was therefore not widely accepted for a long time.

The next big problem was finding a way of producing plentiful, affordable and easily accessible quinine. The cinchona tree grew across northern South America, within the Spanish Empire. If you wanted to travel in Spanish territory, you had to obtain the permission of the King, who was determined that Spain should be the sole benefactor of the intellectual and financial rewards of the cinchona tree. Inadequate quinine supplies would hamper the efforts of explorers, missionaries, settlers, scientists and armies the world over. To be a missionary was a courageous thing – for centuries malaria felled them in their droves, in both Africa and Asia. The exploration of West Africa was only really made possible after the use of quinine as a prophylactic became common in the mid-19th century. Before that, West Africa had been known as “the white man’s grave”.

The Panama Canal was begun in 1881 by the French Compagnie Universelle du Canal Interocéanique. At that time, supplies of quinine were irregular and expensive the world over. The managers of the Compagnie thus considered it more economically viable to replace dead workers with fresh ones, rather than provide the current workers with adequate quinine doses. The incessant downpours in Panama meant that thousands were affected by malaria. Additionally, the legs of hospital beds were placed in water-filled glass bowls in order to prevent ants from reaching the patients, but in so doing those who went into hospital for reasons other than malaria were sure to contract the disease whilst there. Under French administration of the canal, which lasted eight years, more than 20,000 workers died from malaria or yellow fever.

When the Americans took over construction of the canal in 1903, thorough efforts were made to eradicate the area of malaria and adequate quinine supplies for all workers was a priority. Quinine was given as a prophylactic and those who did not take their daily dosage were punished.
In the mid-1900s the British, Dutch and French were all extremely eager to get their hands on cinchona tree seeds so they might grow their own trees. As already mentioned, the cinchona trees were far less numerous than they had once been, and so there was a sense of urgency to the matter. A German-born Dutch botanist, Justus Carl Hasskarl (1811-1894), triggered the rush to smuggle cinchona seeds out of South America when he disguised himself as a German businessman in an attempt to obtain seeds that he would then take to Bandoeng on the island of Java in the Dutch East Indies. Britain eventually managed to lay hold of some cinchona seeds, which they planted in India. But the Dutch were by far the most successful: by the 1930s their Java plantations were producing 97% of the world’s quinine supply.

It was only in the 19th century that scientists started to understand the disease. The first milestone came in 1880 when the Frenchman Charles-Alphonse Laveran, working in Algeria and using what was essentially a magnifying glass, caught sight of the parasite that causes malaria in the human bloodstream. In the last days of the 19th century, whilst working out of a shed in India, Major Ronald ‘Mosquito’ Ross discovered through his dissections that the mosquito is responsible for transmitting malaria. For his efforts he was awarded the Nobel Peace Prize in 1902.

The need to grow more cinchona trees and/or develop synthetic substitutes became painfully apparent during the Second World War. Soldiers were fighting in malarious regions in West Africa, Sicily, the eastern Mediterranean, Singapore, China and the south-west Pacific. In the Pacific countries, malaria took a bigger toll than combat. For the Allied powers, the German occupation of Holland in 1940 was disastrous, as the latter seized control of the quinine headquarters in Amsterdam, with its essential machinery and supplies. Furthermore, the Japanese then took control of Java and its plantations of cinchona. The Japanese kept the Axis powers supplied with quinine, but the Allies were left high and dry. The Americans began growing their own cinchona forests in Costa Rica, but not in time to help with the war effort. The Allies’ only supply of quinine came from the eastern Congo, where plantations had been grown from cinchona seeds that also had been smuggled out of Bolivia and brought there in 1933 by Prince Leopold. It is the Congo that today has the largest cinchona forest in the world.
Quinine frequently has undesirable side effects, such as vomiting, headaches and tinnitus. The synthetic and much-hailed alternative chloroquine eradicated these. But the malarial parasite eventually mutated and chloroquine became ineffective. Other drugs have since been placed on the market, but none of them have proved as effective as the natural quinine found in the bark of the cinchona tree, to which the parasite appears to have developed no immunity.

Malaria is today primarily a disease of the tropics. In 2015, about 3.2 billion people – almost half of the world’s population – are at risk of malaria. According to the latest estimates, there were 214 million cases of malaria in 2015 and 438,000 deaths.