Genetic markers of resistance to pyrimethamine and sulfonamides in Plasmodium falciparum parasites compared with the resistance patterns in isolates of Escherichia coli from the same children in Guinea-Bissau.

The antifolate drugs sulphadoxine and pyrimethamine are used for treatment of chloroquine-resistant Plasmodium falciparum in Africa. Resistance to pyrimethamine has been associated with point mutations in the dhfr-gene and resistance to sulphadoxine with mutations in the dhps-gene. There is concern that the use of the antifolates trimethoprim and sulphamethoxazole for treatment of other infectious diseases will result in the selection of malaria parasites with mutations in these genes. In Guinea-Bissau, where sulfonamide and trimethoprim-containing drugs have been used extensively, we decided to assess the prevalence of mutations in the dhfr-and dhps-gene in P. falciparum isolated from children suffering from acute malaria and to assess the resistance patterns to trimethoprim/sulphamethoxazole in Escherichia coli isolated from the same patients. A thick film and a blood sample for polymerase chain reaction (PCR) were obtained from 100 children attending the Bandim Health Centre in Bissau with symptoms compatible with malaria. Furthermore, a stool sample was collected from the same children and cultured for E. coli. Of the cultured E. coli, 67% were resistant both to sulfonamides and trimethoprim, 4% to sulfonamides alone, 3% to trimethoprim alone while 26% were fully sensitive to both drugs. PCR was successfully performed in 97 blood samples. Of these, 41% had triple mutations at the dhfr-gene (at codons 51, 59 and 108), and 15% had triple mutations plus mutation at codon 437 in the dhps-gene. Only 45% harboured the wild-type dhfr-gene. Thus both bacterial resistance and mutations in the parasitic genes were common, but not linked in the individual child. As sulphadoxine-pyrimethamine has only been used as a second line treatment for chloroquine resistant malaria in Guinea-Bissau for a few years, it is worrying to find a high prevalence of mutations in the parasitic genes coding for resistance to these drugs. Therefore, restricting the use of sulphadoxine-pyrimethamine for the treatment of chloroquine resistant malaria might not be sufficient to prevent the development of resistance in the parasites as long as antifolate drugs are used extensively

Impact of chondroitin sulphate on health utility in patients with knee osteoarthritis: towards economic analysis.

peer reviewedAbstract Objectives: The first objective was to assess the effect of the chondroitin 4 and 6 sulphate (CS) on health-related quality of life using utility values in patients with knee osteoarthritis (OA) during a 24-month treatment course. The second objective was, using these data, to conduct economic analyses. Methods: Data from the STOPP study was used. This study was a randomised, double-blind, placebo (PL) -controlled trial of 2-year duration. In the STOPP study, authors assessed quality of life using the Western Ontario and McMaster Osteoarthritis Index (WOMAC). WOMAC scores were translated into Health Utility Index (HUI) scores using a specific formula. Incremental cost effectiveness ratio (ICER) was calculated taking into account the cost of CS and its effect on HUI scores, compared to PL. Results: At baseline, the mean (SD) HUI scores were 0.59 (0.17), and 0.59 (0.18) for the PL and CS groups, respectively (p=0.31 between the two groups). The mean (SD) HUI scores changes from baseline to 6 months were 0.02 (0.02), and 0.05 (0.01) for the PL and CS groups, respectively (p=0.03). After 24 months of follow-up, HUI score increases by 0.04 (0.02) in the PL group and by 0.05 (0.02) in the CS group (p=0.37). Using the price bracket of CS in Europe, ICER assessment always resulted in a cost below euro30,000 per QALY gained, after 6, 12 and 24 months of treatment. Conclusion: CS treatment increases health utilities in patients with knee OA compared to PL over the first 6 months of treatment. Economic evaluation based on these data suggests that CS treatment could be considered as cost-effective in patients with knee OA up to a period of 24 months. A limitation in this study is the absence of direct utility assessment as well as the absence of effective treatment as comparator

Dysregulation of Frizzled 6 is a critical component of B-cell leukemogenesis in a mouse model of chronic lymphocytic leukemia

Wnt/Fzd signaling is known to play a key role in development, tissue-specific stem-cell maintenance, and tumorigenesis, particularly through the canonical pathway involving stabilization of β-catenin. We have previously shown that Fzd9−/− mice have a deficiency in pre-B cells at a stage when self-renewing division is occurring in preference to further differentiation, before light chain immunoglobulin recombination. To determine whether pathologic usurpation of this pathway plays a role in B-cell leukemogenesis, we examined the expression of Wnt/Fzd pathway genes in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia. We find that, in the course of leukemogenesis, the expression of Wnt16, Wnt10α, Fzd1, and most dramatically, Fzd6, is progressively up-regulated in the transformed CD5+ B cells of these mice, as are β-catenin protein levels. Elimination of Fzd6 expression by crossing into Fzd6−/− mice significantly delays development of chronic lymphocytic leukemia in this model. Our findings suggest that the self-renewal signals mediated by Wnt/Fzd that are enlisted during B-cell development may be pathologically reactivated in the neoplastic transformation of mature B cells