Malaria Journal published its 2500th article today. The article by Rolling et al., comparing Artesunate and quinine for treating severe imported malaria shows how we are tackling this ancient disease today, but what did our ancestors make of the disease? At this important milestone for the journal, we look back at how human perceptions of the disease has changed over time with a review by Hempelman & Krafts published in the journal recently.
Emergence and spread of insecticide resistance
Vector management is a common strategy for controlling mosquito-borne diseases. Such measures are almost entirely dependent on the use of insecticides. The emergence and spread of insecticide resistance coupled with the meagre number of alternative insecticides poses a huge threat to malaria control programs in particular.
Insecticide resistance is driven by misuse of insecticides, leading to exposure to sub-optimal and tolerable concentrations of insecticide. This can be through poor spraying technique, counterfeit insecticide treated bednets (ITNs) and the use of insecticides as pesticides at varying concentrations.
Furthermore, the insecticides used are generally all single-insecticide formulations e.g the use of pyrethroids on bednets. Although this keeps manufacturing costs down, it drives selection for resistant mosquitoes. Cross-resistance to several classes of insecticide is also an emerging problem in Africa, particularly worrying as there are very few alternative approved insecticides and even fewer in development. Consequently, insecticide resistance is now widespread across Africa.
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Vector control is heavily reliant on insecticide efficacy[/caption]
Mechanisms of Resistance
There are three broadly classified mechanisms of resistance: behavioural, molecular and mechanical resistance. Molecular resistances including target-site mutations and increased metabolism of insecticides are the most studied forms, and so we have a better understanding of the genetics of this kind of resistance. Behavioural resistance is often difficult to measure, as it is heavily influenced by environmental factors. Finally, mechanical resistance describes physiological changes such as thickening of the cuticular layer that reduce the penetration of the insecticide, resulting in suboptimal dosing. The evidence for this form of resistance in mosquitoes is sparse, although some studies have confirmed this mechanism in Drosophila and a few agricultural pests.
Cuticle thickening and reduced uptake
The cuticle structure comprises two main layers, the epicuticle and the procuticle. Below these layers lies the epidermis and a layer of specialised oenocytes. Until now it was not known which part of the cuticle was reinforced to result in insecticide resistance. In a recent study by Vasileia Balabanidoua and colleagues, Transmission Electron Microscopy (TEM) showed that the outer epicuticle was much thicker in resistant mosquitoes compared to susceptible mosquitoes. This was also associated with reduced uptake and internalization of radiolabeled deltamethrin insecticides. Similar findings had been previously demonstrated in Triatoma infestans. Furthermore, resistance was reduced in response to acetone-based insecticides which circumvent lipid barriers in the cuticle, indicating a critical role of lipid components. These researchers go on to investigate the underlying molecular mechanism of cuticular-based resistance.
Role of Cuticular Hydrocarbons
Oenocytes synthesise cuticular hydrocarbons (CHCs) from long-chain fatty acids which prevent desiccation of the insect. Previously, P450 enzymes such as those in the CYP4G subfamily have been shown to catalyse CHC synthesis. Since orthologues of these proteins are commonly overexpressed in resistant Anopheles mosquitoes, the role of CHC synthesis was investigated further.
CHC profile
As suspected, Gas Chromatography (GC) analysis by both GC-flame ionization detector (FID) and GC-MS Gas chromatography (GC) revealed a ~29% increase of CHC’s in resistant female mosquitoes compared to susceptible phenotypes. No difference was found in the molecular forms or distribution of CHCs.
[caption id="attachment_2881" align="alignleft" width="300"]
Mosquitoes boost their body armour[/caption]
CYP4G proteins function and cellular localisation
Immunofluorescence staining using high-magnification confocal microscopy revealed the high abundance and dispersion of CYP4G17 proteins throughout the oenocyte cytoplasm. CYP4G16, whilst also abundant, was found to localise at the periphery of the cell, most likely associated with the plasma membrane- a unique location for P450 enzymes. Finally, the function of CYP4G16 was confirmed as a functional oxidative decarbonylase that produces hydrocarbons similarly to its orthologue CYP4G1/2 in Drosophila.
At last, evidence supporting the hypothesis of cuticular resistance to pyrethroids in mosquitoes has been provided. From here, future studies will need to correlate knockdown or overexpression of CHC synthesis pathways with phenotypic data. With the event of modern molecular techniques such as CRISPR-CAS9, these sorts of experiments are more readily within reach.
Vector control is heavily reliant on insecticide efficacy[/caption]
Mechanisms of Resistance
There are three broadly classified mechanisms of resistance: behavioural, molecular and mechanical resistance. Molecular resistances including target-site mutations and increased metabolism of insecticides are the most studied forms, and so we have a better understanding of the genetics of this kind of resistance. Behavioural resistance is often difficult to measure, as it is heavily influenced by environmental factors. Finally, mechanical resistance describes physiological changes such as thickening of the cuticular layer that reduce the penetration of the insecticide, resulting in suboptimal dosing. The evidence for this form of resistance in mosquitoes is sparse, although some studies have confirmed this mechanism in Drosophila and a few agricultural pests.
Cuticle thickening and reduced uptake
The cuticle structure comprises two main layers, the epicuticle and the procuticle. Below these layers lies the epidermis and a layer of specialised oenocytes. Until now it was not known which part of the cuticle was reinforced to result in insecticide resistance. In a recent study by Vasileia Balabanidoua and colleagues, Transmission Electron Microscopy (TEM) showed that the outer epicuticle was much thicker in resistant mosquitoes compared to susceptible mosquitoes. This was also associated with reduced uptake and internalization of radiolabeled deltamethrin insecticides. Similar findings had been previously demonstrated in Triatoma infestans. Furthermore, resistance was reduced in response to acetone-based insecticides which circumvent lipid barriers in the cuticle, indicating a critical role of lipid components. These researchers go on to investigate the underlying molecular mechanism of cuticular-based resistance.
Role of Cuticular Hydrocarbons
Oenocytes synthesise cuticular hydrocarbons (CHCs) from long-chain fatty acids which prevent desiccation of the insect. Previously, P450 enzymes such as those in the CYP4G subfamily have been shown to catalyse CHC synthesis. Since orthologues of these proteins are commonly overexpressed in resistant Anopheles mosquitoes, the role of CHC synthesis was investigated further.
CHC profile
As suspected, Gas Chromatography (GC) analysis by both GC-flame ionization detector (FID) and GC-MS Gas chromatography (GC) revealed a ~29% increase of CHC’s in resistant female mosquitoes compared to susceptible phenotypes. No difference was found in the molecular forms or distribution of CHCs.
[caption id="attachment_2881" align="alignleft" width="300"] Mosquitoes boost their body armour[/caption]
CYP4G proteins function and cellular localisation
Immunofluorescence staining using high-magnification confocal microscopy revealed the high abundance and dispersion of CYP4G17 proteins throughout the oenocyte cytoplasm. CYP4G16, whilst also abundant, was found to localise at the periphery of the cell, most likely associated with the plasma membrane- a unique location for P450 enzymes. Finally, the function of CYP4G16 was confirmed as a functional oxidative decarbonylase that produces hydrocarbons similarly to its orthologue CYP4G1/2 in Drosophila.
At last, evidence supporting the hypothesis of cuticular resistance to pyrethroids in mosquitoes has been provided. From here, future studies will need to correlate knockdown or overexpression of CHC synthesis pathways with phenotypic data. With the event of modern molecular techniques such as CRISPR-CAS9, these sorts of experiments are more readily within reach.Throughout the ages, malaria has always been viewed as a mysterious disease and there were many explanations – and names – for it. The disease was once thought to be caused by ‘bad air’. Hippocrates even included it in his treatise “On Airs, Waters, and Places.”Strangely, the name we now use for the disease is derived from this early misconception: ‘mal’ ‘aria’ is from the Italian for bad air.
Today, we use antimalarials to treat the disease, but in the third century, Quintus Serenus Sammonicus, a physician to the Roman Emperor Caracalla, advised the wearing of an amulet with the word abracadabra on it to beat the disease. If that failed, the sufferer was told to rub lion fat on themselves.
Every 3 seconds someone in the world develops dementia, the collective term for degenerative, progressive brain syndromes which affect 47 million people worldwide, and can cause changes to a person’s memory, thinking, behaviour and emotion. Alzheimer’s Disease is the most common form of dementia, accounting for between 50-75% of all cases.
Dementia commonly occurs in the later stages of life but is not a part of normal ageing. Early onset dementia also affects individuals who are under the age of 65. Symptoms of dementia vary by person, but typically share some characteristics including loss of memory, difficulty in performing previously routine tasks and personality and mood changes.
Although each person will experience dementia in their own way, those affected are eventually unable to care for themselves and need help with all aspects of daily life. There is currently no cure for most types of dementia, but treatments, advice, and support are available.
Alzheimer’s Disease International (ADI) is the umbrella organisation of Alzheimer associations around the world. We aim to help establish and strengthen Alzheimer associations and to raise global awareness about Alzheimer's disease and all other causes of dementia.
Our activities include supporting the training of healthcare workers and caregivers to people with dementia, contributing to global knowledge on dementia and advocating to improve the quality of life for people living with dementia and their families everywhere, through official consultative status with the World Health Organisation (WHO), and active collaboration with governments and policy makers worldwide.
World Alzheimer’s Month is the global awareness campaign led by Alzheimer associations around the world to raise awareness and challenge the stigma that surrounds the disease. World Alzheimer’s Day on 21 September is an opportunity each year to unite in the global call for a better quality of life and support for people with dementia. The fifth World Alzheimer’s Month was marked this year by health workers, governments and organisations in over 60 countries.
Activities held in support of the campaign educate individuals, businesses and stakeholders to recognise the early warning signs of dementia and understand the experience of those living with the disease by discussing dementia openly, challenging fear and offering support for those affected by the disease.
In some countries, people living with dementia face more pronounced exclusion, and may be seen as ‘witches’ due to lack of awareness of the confusing symptoms that may accompany the dementia.
World Alzheimer’s Month remains a time for action, by calling on policy makers and governments around the world to increase the level of support available, but also a time to remember those who are already living with the disease, their families and caregivers by extending services, training for caregivers and social activities that actively include them in the communities where they live.
This year’s theme during World Alzheimer’s Month was ‘Remember Me’. We asked people to get involved by visiting the World Alzheimer’s Month website and sharing materials designed to raise awareness of the campaign with their colleagues, friends and family. We asked individuals around the world to share a message or image of a memory of a loved one or others who were affected by the disease.
The website contained helpful advice on contacting the Alzheimer association in your country, but also on joining events held to draw attention to the disease worldwide.
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Alzheimer’s Disease International[/caption]
As the global population ages, awareness of and support for those living with dementia will become more important, and dementia is increasing being recognised by governments around the world as one of the most significant global health crises of the 21st century. Despite this, people diagnosed with dementia often receive a lower standard of care and face exclusion from everyday life, while millions more do not receive a diagnosis at all.
By 2050, the number of people affected by dementia is estimated to almost treble, to more than 131 million people. ADI will continue to do everything possible to reduce this number by advocating for risk reduction and finding new treatments. By supporting World Alzheimer’s Month in the future, you can help us maintain global momentum to support prevention, care and inclusion of those with the disease.
Alzheimer’s Disease International[/caption]
As the global population ages, awareness of and support for those living with dementia will become more important, and dementia is increasing being recognised by governments around the world as one of the most significant global health crises of the 21st century. Despite this, people diagnosed with dementia often receive a lower standard of care and face exclusion from everyday life, while millions more do not receive a diagnosis at all.
By 2050, the number of people affected by dementia is estimated to almost treble, to more than 131 million people. ADI will continue to do everything possible to reduce this number by advocating for risk reduction and finding new treatments. By supporting World Alzheimer’s Month in the future, you can help us maintain global momentum to support prevention, care and inclusion of those with the disease.Vector control has been an important step in eliminating the disease in many regions. Nets, sprays and removal of mosquito-friendly breeding grounds have all played a part in recent elimination programmes. However, back in ancient Egypt, they had their own vector control tool: garlic. Inscriptions on pyramids outline how much was spent on feeding radishes, onions and garlic to the workers constructing the pyramid.
At this milestone, the journal can look back at the outstanding articles it has published since 2002 and look forward to publishing landmark research in the future.
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