Publications

Foxp3+CD4+CD25+ regulatory T (T(reg)) cells are essential for the prevention of autoimmunity. T(reg) cells have an attenuated cytokine response to T-cell receptor stimulation, and can suppress the proliferation and effector function of neighbouring T cells. The forkhead transcription factor Foxp3 (forkhead box P3) is selectively expressed in T(reg) cells, is required for T(reg) development and function, and is sufficient to induce a T(reg) phenotype in conventional CD4+CD25- T cells. Mutations in Foxp3 cause severe, multi-organ autoimmunity in both human and mouse. FOXP3 can cooperate in a DNA-binding complex with NFAT (nuclear factor of activated T cells) to regulate the transcription of several known target genes. However, the global set of genes regulated directly by Foxp3 is not known and consequently, how this transcription factor controls the gene expression programme for T(reg) function is not understood. Here we identify Foxp3 target genes and report that many of these are key modulators of T-cell activation and function. Remarkably, the predominant, although not exclusive, effect of Foxp3 occupancy is to suppress the activation of target genes on T-cell stimulation. Foxp3 suppression of its targets appears to be crucial for the normal function of T(reg) cells, because overactive variants of some target genes are known to be associated with autoimmune disease.

BACKGROUND

Presumptive treatment of malaria in febrile children is widely advocated in Africa. This may occur in the absence of diagnostic testing or even when diagnostic testing is performed but fails to detect malaria parasites. Such over-treatment of malaria has been tolerated in the era of inexpensive and safe monotherapy. However, with the introduction of new artemisinin-based combination therapy (ACT), presumptive treatment becomes economically and clinically less acceptable.

METHODS

The risks and benefits of only treating children with microscopy confirmed malaria using a prospective cohort design were investigated. A representative sample of 601 children between one and 10 years of age were recruited from a census population in Kampala, Uganda and were followed for all of their health care needs in a study clinic. Standard microscopy was performed each time a child presented with a new episode of fever and antimalarial therapy given only if the blood smear was positive.

RESULTS

Of 5,895 visits for new medical problems 40% were for febrile illnesses. Of the 2,359 episodes of new febrile illnesses, blood smears were initially reported as negative in 1,608 (68%) and no antimalarial therapy was given. Six of these initially negative smears were reported to be positive following quality control reading of all blood smears: four of these patients were subsequently diagnosed with uncomplicated malaria and two cleared their parasites without antimalarial treatment. Of the 1,602 new febrile illnesses in which the final blood smear reading was classified as negative, only 13 episodes (0.8%) were diagnosed with malaria in the subsequent 7 days. All 13 of these episodes of malaria were uncomplicated and were successfully treated.

CONCLUSION

In this urban setting, malaria was responsible for only 32% of febrile episodes. Withholding antimalarial therapy in febrile children with negative blood smears was safe and saved over 1,600 antimalarial treatments in 601 children over an 18-month period. In the era of expensive ACT, directing resources towards improving diagnostic and treatment practices may provide a cost-effective measure for promoting rational use of antimalarial therapy.

BACKGROUND

Community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) infection has become common worldwide. Some researchers have argued that empirical therapy for MRSA should be given only to patients with suspected CA S. aureus infections who have risk factors for acquisition of MRSA. However, there are no prospective data examining this approach.

METHODS

We prospectively enrolled consecutive patients who were hospitalized with S. aureus infection, administered a detailed questionnaire, and collected clinical and microbiological information.

RESULTS

Of the 280 consenting patients, 180 were adults with CA S. aureus infection. Among these subjects, 108 (60%) had MRSA infection, and 78 (40%) had methicillin-susceptible S. aureus (MSSA) infection. MRSA infection was associated with younger age (P<.0001); skin/soft-tissue infection (P=.015); snorting/smoking illegal drugs (P=.01); recent incarceration (P=.03); lower comorbidity index (P=.01); more frequent visits to bars, raves, and/or clubs (P=.03); and higher frequency of laundering clothes in hot water (P=.05). However, the sensitivity, specificity, and predictive values for these factors for discriminating CA-MRSA infection from CA-MSSA infection were relatively poor. Post-hoc modeling revealed that, even in a 10% (i.e., low) MRSA prevalence population, patients lacking the 3 strongest MRSA risk factors would still have a 7% posttest probability of MRSA. Most MRSA strains belonged to the ST-8/USA300 genotype, contained SCCmec type IV, and shared virulence factors commonly found in the ST1:USA400 clone. MSSA strains were genotypically heterogeneous.

CONCLUSIONS

We found that clinical and epidemiological risk factors in persons hospitalized for CA S. aureus infection cannot reliably distinguish between MRSA and MSSA. Our findings have important implications for the choice of empirical antibiotic therapy for suspected S. aureus infections and for infection control.