Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases

HIV undergoes rapid genetic variation; this variation is caused primarily by the enormous number of viruses produced daily in an infected individual. Because of this variation, HIV presents a moving target for drug and vaccine development. The variation within individuals has led to the generation of diverse HIV-1 subtypes, which further complicates the development of effective drugs and vaccines. In general, it is more difficult to hit a moving target than a stationary target. Two broad strategies for hitting a moving target (in this case, HIV replication) are to understand the movement and to aim at the portions that move the least. In the case of anti-HIV drug development, the first option can be addressed by understanding the mechanism(s) of drug resistance and developing drugs that effectively inhibit mutant viruses. The second can be addressed by designing drugs that interact with portions of the viral machinery that are evolutionarily conserved, such as enzyme active sites.     

Severity of imported falciparum malaria: effect of taking antimalarial prophylaxis.

OBJECTIVE--To investigate the effects of antimalarial chemoprophylaxis and other variables on the severity of falciparum malaria. DESIGN--Review of consecutive malaria cases between 1987 and 1991. SETTING--The Hospital for Tropical Diseases, London. SUBJECTS--250 consecutive cases of mild and 51 consecutive cases of severe falciparum malaria. RESULTS--Prophylaxis was taken in 52.4% (131/250) of the cases of mild malaria and 21.6% (11/51) of cases of severe malaria. Severe malaria was more common in white patients than in those of African origin and was also seen more commonly in people returning from central, southern, and east Africa than in those returning from west Africa. Patients with severe malaria presented sooner than patients with mild malaria. CONCLUSIONS--Prior chemoprophylaxis led to a reduction in the severity of falciparum malaria. Ethnic origin, time to presentation, and sex were also associated with the severity of malaria.     

Evolution: constantly avoiding mutation.

The genomic mutation rate of the archaeon Sulfolobus acidocaldarius, which inhabits a harsh and potentially mutagenic environment, surprisingly agrees well with the previously observed constancy of genomic mutation rates in microbes. The evolutionary explanation for this constancy of genomic mutation rates remains obscure.     

Malaria prophylaxis: postal questionnaire survey of general practitioners in south east Wales.

Postal questionnaires were sent to 494 general practitioners in south east Wales asking about their experience and understanding of antimalarial prophylaxis; 293 were returned, giving a response rate of 59%. Forty eight (16%) of the respondents reported being consulted by immigrants returning home for advice about malaria prophylaxis, of whom 13 (27%) overestimated the time for which their protective immunity might last after leaving the malarious area. Two hundred and eighty respondents (96%) considered that they were responsible for advising travellers and 195 (67%) would always consult a publication before giving chemoprophylactic advice (magazines were particularly popular), but only 18 (6%) would always consult a specialist centre--the Ross Institute in eight cases (3%), a local centre in 39 (13%). Only about half of the doctors were aware of chloroquine resistance in Kenya and Thailand. Over half would withhold chloroquine in pregnancy, and many chose pyrimethamine alone or sulfadoxine-pyrimethamine as suitable chemoprophylactic drugs, though neither is still recommended by the World Health Organisation. One hundred and ninety two respondents (66%) would give advice about protective measures other than chemoprophylaxis. More must be done to encourage general practitioners to contact specialist centres and to educate them in the use of antimalarial chemoprophylactic drugs.     

Malaria prophylaxis: survey of the response of British travellers to prophylactic advice.

A cohort study was conducted to determine the compliance of travellers with chemoprophylactic advice given over the telephone by the malaria reference advisory service. Travellers who visited their general practitioner first for advice about malaria prophylaxis were often advised to consult a specialist service themselves. Compliance fell in travellers who were given complicated information and those who received conflicting advice when they contacted other advisory services. After returning to Britain 48% of the travellers reported that they were fully compliant with prophylactic advice; over a third of the travellers studied did not maintain prophylaxis on their return.     

Malaria elimination: moving forward with spatial decision support systems

Operational challenges facing contemporary malaria elimination have distinct geospatial elements including the need for high-resolution location-based surveillance, targeted prevention and response interventions, and effective delivery of essential services at optimum levels of coverage. Although mapping and geographical reconnaissance (GR) has traditionally played an important role in supporting malaria control and eradication, its full potential as an applied health systems tool has not yet been fully realised. As accessibility to global positioning system (GPS), geographic information system (GIS) and mobile computing technology increases, the role of an integrated spatial decision support system (SDSS) framework for supporting the increased operational demands of malaria elimination requires further exploration, validation and application; particularly in the context of resource-poor settings.     

Crop proteomics: aim at sustainable agriculture of tomorrow

The advent of proteomics has made it possible to identify a broad spectrum of proteins in living systems. This capability is especially useful for crops as it may give clues not only about nutritional value, but also about yield and how these factors are affected by adverse conditions. In this review, we describe the recent progress in crop proteomics and highlight the achievements made in understanding the proteomes of major crops. The major emphasis will be on crop responses to abiotic stresses. Rigorous genetic testing of the role of possibly important proteins can be conducted. The increasing ease with the DNA, mRNA and protein levels can be conducted and connected suggests that proteomics data will not be difficult to apply to practical crop breeding.     

Malaria: a peek at the var variorum

Geneticists encountering the diversity of the malaria parasite's var gene family for the first time often complain that its complexity is a nightmare. A new article by Barry et al. presents the latest and most systematic attempt to date to decipher the var variorum. This important work, combined with other recent articles on var global variation such as that by Kraemer et al., suggests that only the tip of the var diversity iceberg is currently in view. In this article, we discuss these recent results and provide an overview of current understanding of var diversity.     

Separate colour-opponent mechanisms underlie the detection and discrimination of moving chromatic targets.

Current opinion holds that human colour vision is mediated primarily via a colour-opponent pathway that carries information about both wavelength and luminance contrast (type I). However, some authors argue that chromatic sensitivity may be limited by a different geniculostriate pathway, which carries information about wavelength alone (type II). We provide psychophysical evidence that both pathways may contribute to the perception of moving, chromatic targets in humans, depending on the nature of the visual discrimination. In experiment 1, we show that adaptation to drifting, red-green stimuli causes reductions in contrast sensitivity for both the detection and direction discrimination of moving chromatic targets. Importantly, the effects of adaptation are not directionally specific. In experiment 2, we show that adaptation to luminance gratings results in reduced sensitivity for the direction discrimination, but not the detection of moving chromatic targets. We suggest that sensitivity for the direction discrimination of chromatic targets is limited by a colour-opponent pathway that also conveys luminance-contrast information, whereas the detection of such targets is limited by a pathway with access to colour information alone. The properties of these pathways are consistent with the known properties of type-I and type-II neurons of the primate parvocellular lateral geniculate nucleus and their cortical projections. These findings may explain the known differences between detection and direction discrimination thresholds for chromatic targets moving at low to moderate velocities.