Green synthesized nanoparticles in the fight against mosquito-borne diseases and cancer-a brief review.

Nanobiomedicine and parasitology are facing a number of key challenges, which mostly deal with the paucity of effective preventive and curative tools against mosquito-borne diseases and cancer. In this scenario, the employ of botanical and invertebrate extracts as reducing, stabilizing and capping agents for the synthesis of nanoparticles is advantageous over chemical and physical methods, since it is one-pot, cheap, and does not require high pressure, energy, temperature, or the use of highly toxic chemicals. Considering the overlooked connection between mosquito vector activity and the spread of cancer in USA, this review focused on the current knowledge available about green synthesized nanoparticles with efficacy against mosquito-borne diseases and cancer. Green fabricated metal nanoparticles showed antiplasmodial activity that often encompasses the efficacy of currently marked drugs for malaria treatment. They have been also reported as growth inhibitors against dengue virus (serotype DEN-2), with moderate cytotoxicity on mammalian cells. However, this feature is strongly dependent to the botanical agents employed during nanosynthesis. In addition, green nanoparticles have been successfully used to reduce mosquito young instar populations in the field. The final section focuses on some issues for future research, with special reference to the chemical standardization of the botanical extracts used for nanosynthesis and the potential effects on green fabricated nanoparticles on non-target organisms.

Acceptability--a neglected dimension of access to health care: findings from a study on childhood convulsions in rural Tanzania.

BACKGROUND: Acceptability is a poorly conceptualized dimension of access to health care. Using a study on childhood convulsion in rural Tanzania, we examined social acceptability from a user perspective. The study design is based on the premise that a match between health providers' and clients' understanding of disease is an important dimension of social acceptability, especially in trans-cultural communication, for example if childhood convulsions are not linked with malaria and local treatment practices are mostly preferred. The study was linked to health interventions with the objective of bridging the gap between local and biomedical understanding of convulsions. METHODS: The study combined classical ethnography with the cultural epidemiology approach using EMIC (Explanatory Model Interview Catalogue) tool. EMIC interviews were conducted in a 2007/08 convulsion study (n = 88) and results were compared with those of an earlier 2004/06 convulsion study (n = 135). Earlier studies on convulsion in the area were also examined to explore longer-term changes in treatment practices. RESULTS: The match between local and biomedical understanding of convulsions was already high in the 2004/06 study. Specific improvements were noted in form of (1) 46% point increase among those who reported use of mosquito nets to prevent convulsion (2) 13% point decrease among caregivers who associated convulsion with 'evil eye and sorcery', 3) 14% point increase in prompt use of health facility and 4)16% point decrease among those who did not use health facility at all. Such changes can be partly attributed to interventions which explicitly aimed at increasing the match between local and biomedical understanding of malaria. Caregivers, mostly mothers, did not seek advice on where to take an ill child. This indicates that treatment at health facility has become socially acceptable for severe febrile with convulsion. CONCLUSION: As an important dimension of access to health care 'social acceptability' seems relevant in studying illnesses that are perceived not to belong to the biomedical field, specifically in trans-cultural societies. Understanding the match between local and biomedical understanding of disease is fundamental to ensure acceptability of health care services, successful control and management of health problems. Our study noted some positive changes in community knowledge and management of convulsion episodes, changes which might be accredited to extensive health education campaigns in the study area. On the other hand it is difficult to make inference out of the findings as a result of small sample size involved. In return, it is clear that well ingrained traditional beliefs can be modified with communication campaigns, provided that this change resonates with the beneficiaries.

Malaria evolution in South Asia: knowledge for control and elimination.

The study of malaria parasites on the Indian subcontinent should help us understand unexpected disease outbreaks and unpredictable disease presentations from Plasmodium falciparum and Plasmodium vivax infections. The Malaria Evolution in South Asia (MESA) research program is one of ten International Centers of Excellence for Malaria Research (ICEMR) sponsored by the US National Institutes of Health. In this second of two reviews, we describe why population structures of Plasmodia in India will be characterized and how we will determine their consequences on disease presentation, outcome and patterns. Specific projects will determine if genetic diversity, possibly driven by parasites with higher genetic plasticity, plays a role in changing epidemiology, pathogenesis, vector competence of parasite populations and whether innate human genetic traits protect Indians from malaria today. Deep local clinical knowledge of malaria in India will be supplemented by basic scientists who bring new research tools. Such tools will include whole genome sequencing and analysis methods; in vitro assays to measure genome plasticity, RBC cytoadhesion, invasion, and deformability; mosquito infectivity assays to evaluate changing parasite-vector compatibilities; and host genetics to understand protective traits in Indian populations. The MESA-ICEMR study sites span diagonally across India and include a mixture of very urban and rural hospitals, each with very different disease patterns and patient populations. Research partnerships include government-associated research institutes, private medical schools, city and state government hospitals, and hospitals with industry ties. Between 2012 and 2017, in addition to developing clinical research and basic science infrastructure at new clinical sites, our training workshops will engage new scientists and clinicians throughout South Asia in the malaria research field.

Malaria in South Asia: prevalence and control.

The "Malaria Evolution in South Asia" (MESA) program project is an International Center of Excellence for Malaria Research (ICEMR) sponsored by the US National Institutes of Health. This US-India collaborative program will study the origin of genetic diversity of malaria parasites and their selection on the Indian subcontinent. This knowledge should contribute to a better understanding of unexpected disease outbreaks and unpredictable disease presentations from Plasmodium falciparum and Plasmodium vivax infections. In this first of two reviews, we highlight malaria prevalence in India. In particular, we draw attention to variations in distribution of different human-parasites and different vectors, variation in drug resistance traits, and multiple forms of clinical presentations. Uneven malaria severity in India is often attributed to large discrepancies in health care accessibility as well as human migrations within the country and across neighboring borders. Poor access to health care goes hand in hand with poor reporting from some of the same areas, combining to possibly distort disease prevalence and death from malaria in some parts of India. Corrections are underway in the form of increased resources for disease control, greater engagement of village-level health workers for early diagnosis and treatment, and possibly new public-private partnerships activities accompanying traditional national malaria control programs in the most severely affected areas. A second accompanying review raises the possibility that, beyond uneven health care, evolutionary pressures may alter malaria parasites in ways that contribute to severe disease in India, particularly in the NE corridor of India bordering Myanmar Narayanasamy et al., 2012.

Sahel, savana, riverine and urban malaria in West Africa: Similar control policies with different outcomes.

The study sites for the West African ICEMR are in three countries (The Gambia, Senegal, Mali) and are located within 750 km of each other. In addition, the National Malaria Control Programmes of these countries have virtually identical policies: (1) Artemisinin Combination Therapies (ACTs) for the treatment of symptomatic Plasmodium falciparum infection, (2) Long-Lasting Insecticide-treated bed Nets (LLINs) to reduce the Entomololgic Inoculation Rate (EIR), and (3) sulfadoxine-pyrimethamine for the Intermittent Preventive Treatment of malaria during pregnancy (IPTp). However, the prevalence of P. falciparum malaria and the status of malaria control vary markedly across the four sites with differences in the duration of the transmission season (from 4-5 to 10-11 months), the intensity of transmission (with EIRs from unmeasurably low to 4-5 per person per month), multiplicity of infection (from a mean of 1.0 to means of 2-5) and the status of malaria control (from areas which have virtually no control to areas that are at the threshold of malaria elimination). The most important priority is the need to obtain comparable data on the population-based prevalence, incidence and transmission of malaria before new candidate interventions or combinations of interventions are introduced for malaria control.

An ethnobotanical survey of mosquito repellent plants in uMkhanyakude district, KwaZulu-Natal province, South Africa.

ETHNOPHARMACOLOGICAL RELEVANCE: The aim of the study was to document plants traditionally used to repel mosquitoes in the uMkhanyakude district, KwaZulu-Natal, South Africa. The specific objectives of the study were to: (1) identify plant species and their parts being used; (2) determine the condition of plant material used and the method of application. MATERIALS AND METHODS: Data was collected from 60 respondents in five villages in the district using standardised and pre-tested questionnaires. RESULTS: Thirteen plant species are used in the study area to repel mosquitoes. These species belong to 11 genera from 9 families. Meliaceae and Anacardiaceae were the most represented families with two species each. The most frequently recorded species were Lippia javanica (91.67%), followed by Aloe ferox (11.67%), Sclerocarya birrea (5%), Melia azedarach (3%), Balanite maughamii (3%) and Mangifera indica (3%). Leaves were the most (38%) common plant part used. The majority (82%) of the plant parts were used in a dry state. Burning of plant materials to make smoke was the most (92%) common method of application. Nine plant species, namely: A. ferox, Calausena anista, Croton menyharthii, S. birrea, B. maughamii, Olax dissitiflora, Trichilia emetic, M. indica, and Atalaya alata are documented for the first time as mosquito repellents. CONCLUSION: This documentation provides the basis for further studies in developing new, effective, safe and affordable plant-derived mosquito repellents especially for Africa where malaria is highly prevalent. The study also plays a part in documenting and conserving traditional knowledge of mosquito repellent plants for future use.

"Wonders unconceived": reflections on the birth of medical entomology.

Prior to Patrick Manson's discovery in 1877 that the mosquito Culex fatigans was the intermediate host of filariasis, the association of insects with disease and the nature of disease transmission was almost entirely speculation. Manson's work was incomplete, however, because it showed the manner in which the mosquito acquired the infection from humans, but failed to show the way in which the mosquito passed the infection to humans. That pathogens were transmitted by the bite of an infected female mosquito was later proven experimentally with bird malaria by Manson's protégé, Ronald Ross. In 1898 Ross demonstrated that the infective stage of the malarial parasite was injected into the host when the mosquito released saliva into the wound prior to injesting blood. Insects were suspected as carriers of disease for centuries, yet it was not until the late 1870s that the uncritical acceptance of folk beliefs was supplanted by research-based scientific medicine. Why did it take so long? The answer lies in the fact that early medicine itself was imprecise and could not have pursued the subject with any hope of useful results until the last quarter of the 19th century. A better understanding of the nature of the disease process (germ theory of disease) and improved technology (microscopes and oil-immersion lenses with greater resolving power, and synthetic tissue stains) were indispensable for revealing the nexus between those partners in crime: insects and parasites.

Diurnally subperiodic filariasis in India-prospects of elimination: precept to action?

The elimination of lymphatic filariasis in the Andaman and Nicobar Islands provides unique opportunities and challenges at the same time. Since these islands are remote, are sparsely populated, and have poor transport networks, mass drug administration programs are likely to be difficult to implement. Diurnally subperiodic Wuchereria bancrofti vectored by Downsiomyia nivea was considered for the scope of vector control options. Considering the bioecology of this mosquito, vector control including personal protection measures may not be feasible. However, since these islands are covered by separate administrative machinery which also plays an important role in regulating the food supply, the use of diethylcarbamazine (DEC)-fortified salt as a tool for the interruption of transmission is appealing. DEC-fortified salt has been successfully pilot tested in India and elsewhere, operationally used by China for eliminating lymphatic filariasis. Administration of DEC-fortified salt though simple, rapid, safe, and cost-effective, challenges are to be tackled for translating this precept into action by evolving operationally feasible strategy. Although the use of DEC-fortified salt is conceptually simple, it requires commitment of all sections of the society, an elaborate distribution mechanism that ensures the use of DEC-fortified salt only in the endemic communities, and a vigorous monitoring mechanism. Here, we examine the inbuilt administrative mechanisms to serve the tribal people, health infrastructure, and public distribution system and discuss the prospects of putting in place an operationally feasible strategy for its elimination.

Application of pharmacogenomics to malaria: a holistic approach for successful chemotherapy.

Drug resistance in malaria jeopardizes the most elementary objectives of malaria control--reducing suffering and eliminating mortality. An important, and so far the only known, mechanism of drug resistance appears to be polymorphisms in the malaria parasite genes. Efforts to circumvent antimalarial drug resistance now range from the use of combination therapies with existing agents to genomics-based studies directed toward discovering novel targets and agents. However, the potential contribution of host genetic/molecular factors, particularly those associated with antimalarial drug metabolism, remains largely unexplored. Our knowledge concerning the basic mechanisms involved in the pharmacokinetics of antimalarial drugs is fragmentary. In addition, the link between antimalarial drug pharmacokinetics and treatment outcomes is generally unclear. The purpose of this article is to provide general background information on antimalarial drug resistance and associated parasite genetic factors, and subsequently highlight the aforementioned unexplored and unclear areas, with a view to stimulate much needed further research.

Assessment of knowledge and usage custom of traditional insect/mosquito repellent plants in Addis Zemen Town, South Gonder, North Western Ethiopia.

AIM OF THE STUDY: A cross-sectional descriptive study was carried out to assess the knowledge and usage custom of traditional insect/mosquitoes repellent plants among the inhabitants in Addis Zemen Town, Ethiopia. MATERIALS AND METHODS: Stratified, systematic random sampling was used for selection of 393 households from the total of 5161 households. One adult from each household was interviewed. The ethnobotonical survey was carried out during the period February 2007 to March 2007. Data analysis was carried out using SPSS, version 9.0. Range and mean were analysed and appropriate tables, graphs and percentage were displayed. Level of significance also determined by using 95% of confidence intervals and p-value. RESULTS: Overall, 97.2% of the respondents had ample knowledge and usage custom concerning traditional insect/mosquito repellent plants. Application of smoke (91.55%) was one of the most commonly well-known methods amongst local community by burning the plant parts such as leaves, stems and roots. Leaves were used by 90.2% for the application smoke. Knowledge and usage custom of traditional insect/mosquito repellent plants had significantly associated with sex (p=0.013) and lower income of respondents (p=0.002). In spite of this, knowledge and usage custom had no significant association with age and educational status. Furthermore, the survey also indicated that most commonly known traditional insect/mosquito repellent plants were Woira*(1) (Olea europaea) 44%, Tinjut* (Ostostegia integrifolia) 39%, Neem* (Azadirachta indica) 14.1%, Wogert* (Silene macroserene) 1.4%, and Kebercho* (Echinops sp.) 1.1%. CONCLUSIONS: Indigenous traditional insect/mosquito repellent plants have been used by local hamlet since ancient times for various medicinal purposes. Besides, they are not toxic like existing modern synthetic chemical repellents. Therefore, the traditional use of repellent plants should be encouraged and promoted among the local community.

Climate change and mosquito-borne disease: knowing the horse before hitching the cart.

Speculations on the potential impacts of climate change on human health often focus on the mosquito-borne diseases but ignore the complex interplay of the multitude of factors that are generally dominant in the dynamics of their transmission. A holistic view of this complexity - particularly the ecology and behaviour of the host and the ecology and behaviour of the vector - is the only valid starting point for assessing the significance of climate in the prevalence and incidence of these diseases.

Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite.

Transmission of malaria parasites to mosquitoes is initiated by the obligatory sexual reproduction of the parasite within the mosquito bloodmeal. Differentiation of specialized transmission stages, the gametocytes, into male and female gametes is induced by a small mosquito molecule, xanthurenic acid (XA). Using a Plasmodium berghei strain expressing a bioluminescent calcium sensor, we show that XA triggers a rapid rise in cytosolic calcium specifically in gametocytes that is essential for their differentiation into gametes. A member of a family of plant-like calcium dependent protein kinases, CDPK4, is identified as the molecular switch that translates the XA-induced calcium signal into a cellular response by regulating cell cycle progression in the male gametocyte. CDPK4 is shown to be essential for the sexual reproduction and mosquito transmission of P. berghei. This study reveals an unexpected function for a plant-like signaling pathway in cell cycle regulation and life cycle progression of a malaria parasite.

Immunomodulator tuftsin augments antifilarial activity of diethylcarbamazine against experimental brugian filariasis.

In the present study, we evaluated the potential of an immunomodulator tuftsin in increasing the efficacy of liposomised diethylcarbamazine (DEC) against experimental filarial infection of Brugia malayi. The liposomised form of DEC, when used at sub-optimal dose of 25 mg/kg body weight, successfully eliminated filarial parasite from systemic circulation in animals inflicted with B. malayi infection. However, the formulation was effective upto 60 days post infection only, followed by recurrence of the infection. In contrast, the co-administration of liposomal formulation of DEC along with an immunomodulator tuftsin was found to be competent enough to suppress microfilarial stage of parasite till 90 days post treatment. Interestingly, tuftsin bearing DEC liposomes were found to be effective against adult parasite as well.

Molecular cloning, characterization and tissue expression of prophenoloxidase cDNA from the mosquito Armigeres subalbatus inoculated with Dirofilaria immitis microfilariae.

A cDNA encoding mosquito Armigeres subalbatus prophenol oxidase (As-pro-PO) was obtained by rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR) after Dirofilaria immitis inoculation. The 2205 bp As-pro-PO cDNA contains a 32 bp 5'-noncoding region, a 2055 bp open reading frame (685 amino acids), and a 118 bp 3'-noncoding region. Hydrophobic signal peptide for the endoplasmic reticulum targeting is not found in the NH2-terminal region. Two potential copper-binding domains, amino acids 197-245 and 345-412, are highly homologous to those of the other insect pro-POs. A 2.2 kb As-pro-PO transcript was identified by Northern blot analysis using D. immitis microfilariae-inoculated A. subalbatus. Both in situ hybridization and Northern blot analysis demonstrated that As-pro-PO mRNA was synthesized in mosquito haemocytes but not in other tissues, i.e. fat bodies, midguts and ovaries, etc.

Molecular characterization of a calcium-binding protein from the filarial parasite Dirofilaria immitis.

A full length D. immitis cDNA (nDiCal) encoding a protein with significant similarity to the calreticulin protein family was isolated from a 6-day fourth-stage larval cDNA expression library by immunoscreening, using serum from a rabbit immunized by repeated injection of small numbers of third-stage larvae. nDiCal is 1538 bp long and contains the 21 bp nematode splice leader sequence SL1 at the 5' end. nDiCal encodes for a protein (pDiCal) with a predicted molecular mass of 46 kDa. pDiCal sequence analysis revealed similarities with calreticulin, a protein that typically resides in the endoplasmic reticulum. pDiCal possesses three consensus sequences of the calreticulin family of proteins: a neutral N-terminal region with a putative signal sequence; a proline- and tryptophan-rich P region; and a highly acidic C-terminal region. A 45Ca2+-overlay assay showed that recombinant pDiCal (rDiCal) is a Ca2+-binding protein. Antibodies to rDiCal identified a 56 kDa native antigen in all developmental stages including the excretory-secretory products derived from larvae and adult worms. Localization studies demonstrated the ubiquitous presence of pDiCal with intense expression in the hypodermis and syncitial muscle cells in both male and female adult worms. Labeling was also seen in the developing embryos within the uterus of the female worms. Sera from immune as well as chronically-infected microfilaremic dogs contained antibodies that bind rDiCal. In addition, immunoblot analysis showed that serum from a rabbit immunized with L3 cuticles reacted with rDiCal.

Filariasis in the labour population of a tea estate in Upper Assam.

Preliminary random and mass blood surveys undertaken between 2000-0100 h in a tea garden of Upper Assam revealed more than 8 per cent positivity for microfilaria (mf) of Wuchereria bancrofti. The mf carriers were considerably high among males (73) as compared to females (48). Culex quinquefasciatus was incriminated as a vector with man hour density of 68.5 in human dwellings (indoors). The detection of mf in children who had never moved from the area and filaria larvae in vector mosquitoes collected from human dwellings indicate that indigenous transmission is going on in the garden and that filariasis has become a local health problem.

Current status of filariasis in Malaysia.

The Filariasis Control Program was established more than 30 years ago in the country and the disease is still a public health problem in some states. Since 1983, a total of 17 filariasis control teams were formed throughout the country to carry out filariasis control work. The teams conduct house and population censuses, nocturnal mass blood surveys and treatment of microscopically confirmed cases. Individual case follow-up is being carried out after 3-5 months while the locality is resurveyed after about 2-3 years. During the years 1988 to 1990, there appeared to be a decreasing trend in the number of filariasis cases detected countrywide. In 1991, brugian filariasis accounted for 92% of the cases detected. The microfilaria rate (MFR) also showed a decreasing trend countrywide for the years 1988 (0.57%) to 1990 (0.35%) but there was an increase in 1991 although it remained well below the 5% MFR targeted in the program objective, In 1991, the filariasis control teams and the district multi-purpose teams collected a total of 167, 151 blood slides out of which 871 were found to be positive for microfilaria. To determine the true endemicity of filariasis in the country, the malaria district multi-purpose teams are also utilized to assist in probe surveys in new areas of the district. Two species of filarial worms, namely Brugia malayi and Wuchereria bancrofti, and the mosquito vectors belonging to the Anopheles and Mansonia genera are involved in the transmission of filariasis in Malaysia. Monkeys and domestic cats are the reservoir hosts for the subperiodic strain of B. malayi.

Current status of filariasis in Indonesia.

Filariasis in Indonesia is widely distributed. Three species consisting of 5 ecologically different types have been identified infecting man. Compared to older data, infection rates are much lower, partly due to environmental change and partly as a result of control programs. Various dosage treatments have given good results. The higher dosage treatment gave severe reactions especially in brugian filariasis. Pockets of high endemicity can still be found in remote rural areas. Therefore a weekly low dosage treatment of 40 weeks through the Primary Health Care approach has been adopted. Filariasis research in Indonesia at present is concentrating on the use of biotechnological tools, especially for diagnostic and vector identification purposes, and to understand better the pathophysiology. Treatment trials with new drugs such as Ivermectin and DEC are being conducted both in man and experimental animals.