Quinine and Leg Cramps

Muscle cramp or leg cramp is a recurrent and painful condition and a common complaint among the elderly. It is commonly nocturnal and can disturb a good night's sleep. No specific cause can be identified and therapy is mostly symptomatic.
Quinine sulfate (200-300 mg at bedtime) is widely used as an effective therapy for idiopathic nocturnal leg cramps[1]. Several studies have questioned the effectiveness of quinine in leg cramps, whereas other studies have shown significantly more benefit with use of quinine in reducing the frequency and severity of cramps compared with placebo or vitamin E.

However, the mechanism of this effect is obscure. Quinine appears to decrease the excitability of the motor end plate, thereby reducing the muscle contractility.

New research has found that long term use of quinine, prescribed off label for leg cramps, muscle cramps or restless leg syndrome, is associated with increased mortality[2]. Therefore, it is not recommended for routine treatment and is advised only when cramps are very painful or frequent.

[1] Mandal et al: Is quinine effective and safe in leg cramps? In Journal of Clinical Pharmacology – 1995
[2] Wise: Long term quinine for muscle cramps may increase death risk in British Medical Journal - 2017

Malaria and Dubonnet Rouge

Most brands record their history and that's that, but some need to be economical with the truth to be able to create a distinct niche for themselves. The Dubonnet family had no need for an invented history for their famous a sweet, aromatised wine-based aperitif containing 14.8% alcohol.

The French Foreign Legion (Legion Étrangère) fought their wars in some parts of the world where malaria was rife. To treat malaria the men needed to be treated with quinine, which was for some sometimes simply too bitter to swallow.
To combat this problem, the French government started a competition in order to find a solution that made quinine more palatable for soldiers battling their way trough northern Africa. They could have looked to the other side of the English Channel to discover gin and tonic (the famous G&T), but as could be expected, they went their own French way.

Dubonnet Rouge was created in 1846 as a response to that competition by Parisian chemist annex wine merchant Joseph Dubonnet.

Dubonnet Rouge is a mix of fortified red wine, a proprietary blend of herbs, spices and peels, cane sugar plus medicinal quinine. The taste is described as "cherry, mint and walnut aromas, with notes of lemon zest, cardamom and toffee" or as "flavors of orange, nuts, chocolate and coffee; finishes fairly sweet, with lemon and herb notes." Observe that nobody mentions the bitter quinine? Mission accomplished.

The brand ownership was taken over by Pernod Ricard in 1976. Although Dubonnet Rouge is still the best selling product, there are now two new varieties: Dubonnet Blanc (based on white fortified wine) and Gold (with vanilla and orange).

Nosocomial malaria

A nocosomial malaria infection is an infection with a Plasmodium parasite that has been acquired in a hospital or other healthcare facility. It's hardly a surprise that, in a hospital where patients with all sorts of ailments are living as a group, infections might spread from one patient to the other.
[Plasmodium from the saliva of a female mosquito moving across a mosquito cell]
Infections are spread to any susceptible patient in the clinical setting by a variety of means. According to the scientific literature, the following modes of transmission should be taken into account in the investigation of hospital-acquired malaria: [1] Parenteral introduction of blood that contains parasite-infected erythrocytes from one infectious individual to another patient during healthcare procedures, [2] Blood transfusion, or bone marrow or organ transplant from a malaria-infected patient or [3] Accidental contact of blood containing parasite-infected erythrocytes with an open wound.

Between Januari 2016 and April 2018 a total of six patients with nosocomial malaria have been reported in Germany, Greece, Italy and Spain[1]. Five patients were infected with Plasmodium falciparum, while one had a co-infection with Plasmodium malariae en Plasmodium ovale.

Investigations into the source of these infections revealed that in all six cases the cause was probably a parenteral transmission of blood, infected with Plasmodium spp from malaria patients that where admitted at the same time in the same ward.

Well, only six cases in Europa in more than two years, that isn't a big deal, you might think. It is when you're thinking of making sub-Saharan Africa as your holiday destination. If you do, don't get hurt, because aAs research has shown, prevalence of malaria parasites in blood for transfusion ranged from 6.5 per cent to 74.1 per cent in different study sites[2].

[1] European Centre for Disease Prevention and Control: Rapid risk assessment: Hospital-acquired malaria infections in the European Union – 30 April 2018. See here.
[2] Talia Frenkel Blood transfusions a ‘hidden’ malaria risk on SciDevNet - 26 April 2018. See here.

Blackwater fever

Blackwater fever (also knownn as malarial hemoglobinuria) is a rare but one of the most dangerous complications of malaria. It occurs almost exclusively with infections from the malaria parasite Plasmodium falciparum.
The symptoms of blackwater fever include a rapid pulse, high fever and chills, extreme prostration, a rapidly developing anemia and the passage of urine that is black or dark red in colour, hence the name of the disease. Acute kidney failure is common[1].

The distinctive colour of the urine is due to the presence of large amounts of hemoglobin, released during the extensive destruction of the patient’s red blood cells by malarial parasites. Patients frequently develop anemia because of the low numbers of red blood cells.

The presence of blood pigments in the blood serum usually produces jaundice early in the course of the disease.

Blackwater fever is most prevalent in Africa and Southeast Asia. Individuals with increased susceptibility, such as non-immune immigrants or individuals who are chronically exposed to malaria, are classic sufferers from the complication. Blackwater fever seldom appears until a person has had at least four attacks of malaria and has been in an endemic area for at least six months.
Historical epidemiological observations from the 20th century demonstrated variable patterns in prisoners in Andaman Islands (in the Indian Ocean), refugees in Macedonia, canal workers in Panama, expatriates in Rhodesia and Second World War soldiers (in Burma)[2].

Treatment for blackwater fever includes antimalarial drugs, whole-blood transfusions and complete bed rest, but even with these measures the mortality remains between 25 and 50 percent.

[1] Bodi et al: Black water fever associated with acute renal failure among Congolese children in Kinshasa in Saudi Journal of Kidney Diseases and Transplantation – 2014
[2] Shanks: The Multifactorial Epidemiology of Blackwater Fever in American Journal of Tropical Medicine and Hygiene – 2017

Malaria and Green-Blooded Lizards

When scientists discovered six species of lizard on Papua New Guinea that evolved to have toxic, lime green blood, they were puzzled. The lizards' blood appears green as a result of extremely large doses of a green bile biliverdin[1]. These high concentrations of biliverdin in the blood overwhelms the crimson colour of red blood cells resulting in a lime-green coloration of the muscles, bones, and even their tongue.
After mapping the evolutionary family tree of New Guinea lizards the scientists found that green blood developed at four different points in history.

'These green-blooded lizards are not each other's closest relatives, and they all likely evolved from a different ancestor that had red blood', explains said evolutionary biologist Zachary Rodriguez. 'This means that green blood likely emerged independently in different lizards, suggesting that green blood has beneficial properties.'

The green blood probably gives the lizards an evolutionary advantage of some kind, said Christopher Austin of Louisiana State University[2].

Dr Austin thinks this could be why lizards evolved to be green-blooded, as malaria is an issue for lizards in New Guinea. It is possible the threat posed by malaria was so severe to past lizards that evolution heavily favoured animals with high levels of this toxic compound, which meant green blood became common in the animals.

Michael Oellermann, a researcher at the University of Tasmania in Australia, wondered what the evolutionary cost of having green blood may be. He believes there must be a price to pay, otherwise more critters would bleed green.

In humans, having elevated levels of biliverdin has been linked to reducing the growth of malaria parasites[3].

[1] Rodriguez et al: Multiple origins of green blood in New Guinea lizards in Science Advances – 2018 
[2] Austin, Perkins: Parasites in a biodiversity hotspot: a survey of hematozoa and a molecular phylogenetic analysis of Plasmodium in New Guinea skinks in Journal of Parasitology – 2006 
[3] Alves et al: Biliverdin targets enolase and eukaryotic initiation factor 2 (eIF2α) to reduce the growth of intraerythrocytic development of the malaria parasite Plasmodium falciparum in Science Reports – 2016

Malaria and Wali kambing

The wali kambing (Sarcolobus spanoghei) is a twining shrub that is native to tropical regions of Asia, including India, China, Thailand, Malaysia, Burma, the Philippines and Indonesia. In India the plant is found in the mangrove forests and the Andaman and Nicobar Islands that are situated in the Indian Ocean.
The plant is a twining shrub with stout glabrous branches. It has rather simple ovate or oblong leaves. The flowers are small, starry and purplish. The wali kambing produces many poisonous seeds.

The wali kambing is listed by the U.S. Food and Drug Administration (FDA) as poisonous plant. The seeds are known to be highly toxic to mammals. Native people of Asia widely use it to kill stray dogs, pigs and wild animals. It was demonstrated that it effectively killed cats.

The local traditional name, wali kambing, can be reconstructed into English as 'guardian of the goats'.

The plant extract causes inhibition of the neuro-muscular system. The poison acts as a barrier to muscles and nerves which makes a person unable to control coordination. Other symptoms are not able to move, shivering, enlarged pupils, rapid pulse, convulsions and coma.

The symptoms of poisoning in animals include blood urine and nephrosis. An old Indonesian remedy, if used quickly enough, included leaves of the Tembelèkan, followed by leaves of the Selegeren, It arrests the intoxication and the animal will awake[1]. I'm not entirely sure if the nephrosis or acute kidney disease will can be reversed, because that is usually not the case.

The leaves and the rhizomes of the plant have been used as an herbal medicine for treatment of rheumatism, dengue and fever. The genus is known to contain barbigerone which is known to be highly effective against the malarial parasite Plasmodium falciparum[2].

[1] Het Javaansch receptenboek afkomstig van Soerakarta - 1930
[2] Yenesew et al: Anti-plasmodial activities and X-ray crystal structures of rotenoids from Millettia usaramensis subspecies usaramensis in Phytochemistry – 2003

Removing flowers helps reduce malaria transmission

Mosquitoes obtain most of their energy needs from plant sugars taken from the nectar of flowers. So, if these mosquitoes have found a suitable plant, they tend to stay in the vicinity of these plants. If those plant are located near human habitation, you know what will happen: mosquitoes will bite humans and malaria can be transmitted.
Thus, removing the flowers of an invasive tree from mosquito-prone areas might be a simple way to help reduce malaria transmission, according to a new study[1].

The study focused on the removal of the flowers of the invasive mesquite tree (Prosopis juliflora), that is native to Central and South America, but was introduced to new areas in the late 1970's and early 1980's as an attempt to reverse deforestation. The mesquite tree is a robust plant that grows rapidly and has become one of the worst invasive plants in many parts of the world. The shrub now occupies millions of hectares on the African continent, including countries such as Mali, Chad, Niger, Ethiopia, Sudan and Kenya. It tends to encroach on villages, bringing the mosquitoes closer and closer to humans.
Removing the flowers around some villages in Mali decreased the local mosquito vector population by nearly 60%.

Dr Gunter Muller, lead-author, said: "Mosquitoes obtain most of their energy needs from plant sugars taken from the nectar of flowers so we wanted to test the effect removing the flowers of the mesquite tree an invasive shrub would have on local mosquito vector populations. Our results show that the removal reduces total population levels of mosquitoes and reduces the number of older female mosquitoes in the population, which are known to transmit malaria parasites to humans. This suggests that removal of the flowers could be a new way to shift inherently high malaria transmission areas to low transmission areas, making elimination more feasible."

[1] Muller et al: The invasive shrub Prosopis juliflora enhances the malaria parasite transmission capacity of Anopheles mosquitoes: a habitat manipulation experiment in Malaria Journal - 2017

Malaria and Ivermectin

Malaria is a mosquito-borne infection that affects more than 200 million people worldwide. The disease is transmitted when an infected mosquito bites an individual, spreading a parasite called plasmodium. In humans, the parasite can cause fever, headache, chills and even death. Malaria-carrying mosquitoes are increasingly becoming resistant to the insecticides meant to wipe them out.
Suppose, for once, we start thinking creatively. Suppose we humans could take a medicine that wouldn't kill the parasite, but one that is able to kill those pesky malaria-carrying mosquitoes if they feed on human blood. Well, such a medicine already exists and it is called ivermectin.

Ivermectin was developed in the early 1980s as a drug to fight parasites that cause river blindness and elephantiasis. Scientists now hope it can also help eradicate malaria.

One study has shown that, after a cure of just seven days, Ivermectin at a dose of 600 μg/kg was able to reduce mosquito survival for at least 28 days after treatment. Ivermectin at a dose of 300 μg/kg per day for three days provided a good balance between efficacy and tolerability[1].

"The most exciting result was the fact that even one month after [the subjects took] ivermectin, their blood was still killing mosquitoes," lead-author Menno Smit says. "That's much longer than we thought."

Even at sub-lethal concentrations, Ivermectin is significantly slowing locomotor activity of mosquitoes, resulting in decreased feeding of human blood[2].

[1] Smit et al: Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial in The Lancet Infectious Diseases – 2018
[2] Sampaio et al: What does not kill it makes it weaker: effects of sub-lethal concentrations of ivermectin on the locomotor activity of Anopheles aquasalis in Parasites and Vectors - 2017

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