The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Malaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance of Plasmodium species to existing therapies has increased the need for new therapeutic approaches. The Plasmodium glucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population.     

Visceral leishmaniasis: current status of control,diagnosis, and treatment,and a proposed research and development agenda

Visceral leishmaniasis is common in less developed countries, with an estimated 500000 new cases each year. Because of the diversity of epidemiological situations, no single diagnosis, treatment, or control will be suitable for all. Control measures through case finding, treatment, and vector control are seldom used, even where they could be useful. There is a place for a vaccine, and new imaginative approaches are needed. HIV co-infection is changing the epidemiology and presents problems for diagnosis and case management. Field diagnosis is difficult; simpler, less invasive tests are needed. Current treatments require long courses and parenteral administration, and most are expensive. Resistance is making the mainstay of treatment, agents based on pentavalent antimony, useless in northeastern India, where disease incidence is highest. Second-line drugs (pentamidine and amphotericin B) are limited by toxicity and availability, and newer formulations of amphotericin B are not affordable. The first effective oral drug, miltefosine, has been licensed in India, but the development of other drugs in clinical phases (paromomycin and sitamaquine) is slow. No novel compound is in the pipeline. Drug combinations must be developed to prevent drug resistance. Despite these urgent needs, research and development has been neglected, because a disease that mainly affects the poor ranks as a low priority in the private sector, and the public sector currently struggles to undertake the development of drugs and diagnostics in the absence of adequate funds and infrastructure. This article reviews the current situation and perspectives for diagnosis, treatment, and control of visceral leishmaniasis, and lists some priorities for research and development.     

Construct Validity of Functional Capacity Evaluation Lifting Tests in Construction Workers on Sick Leave as a Result of Musculoskeletal Disorders

Gouttebarge V, Wind H, Kuijer PP, Sluiter JK, Frings-Dresen MH. Construct validity of functional capacity evaluation lifting tests in construction workers on sick leave as a result of musculoskeletal disorders.

Objectives

To assess the construct (discriminative and convergent) validity of 5 Ergo-Kit (EK) functional capacity evaluation (FCE) lifting tests in construction workers on sick leave as a result of musculoskeletal disorders (MSDs).

Design

Cross sectional within-subject design.

Setting

Occupational health service for the construction industry.

Participants

Male construction workers (N=72) on 6-week sick leave as a result of MSDs.

Interventions

Not applicable.

Main Outcome Measure

After being assessed on 5 EK FCE lifting tests, participants were asked to complete the Von Korff questionnaire on pain intensity and disability as a result of MSDs and the instrument for disability risk assessing the risk for work disability. Discriminative validity was evaluated by comparing the results of the EK FCE lifting test scores between the 2 groups of participants based on the instrument for disability risk scores (high risk for work disability compared with low risk for work disability). Convergent validity was evaluated by assessing the associations between the results of the EK FCE lifting tests and Von Korff questionnaire self-reported pain intensity and disability as a result of MSDs.

Results

The hypothesized differences between both instrument for disability risk groups on the 5 EK FCE lifting tests were found in the expected direction but were not statistically significant (1 test exhibited a trend). Pearson correlation coefficients showed a poor convergent validity between the scores of the Von Korff questionnaire and the EK FCE lifting tests (-.29≤r≤.05).

Conclusions

Poor construct validity of the 5 EK lifting tests was found: discriminative validity was not statistically established, and convergent validity with self-reported pain intensity and disability was poor.