cross-experiments between CQS and CQR parasite lines and parasite transfection studies have not supported a direct role for pfmdrl mutations in CQ resistance; rather, these studies have identified mutations in a digestive vacuole transmembrane protein, PfCRT, as causally linked to CQ resistance.
There have been suggestions that pfmdrl mutations associated with CQ resistance may also account for reduced parasite susceptibility to Q; however, this needs further confirmatory studies.[19'20]
Molecular markers for drug resistance identified to date include pfcrt polymorphisms associated with CQ drug resistance; dhfr and dhps polymorphisms associated with SP resistance; and pfmdrl polymorphisms putatively associated with modulating resistance to CQ, MQ, Q, and artemisinin.
CQ acts by disrupting heme metabolism in the digestive vacuole of P. falciparum. CQR parasites survive by preventing the accumulation of CQ within the vacuole; however, the precise mechanism by which this occurs is unknown.
Polymorphisms in two genes of the P. falciparum genome have been implicated in molecular CQ resistance studies. The pfcrt gene is located on chromosome 7 and codes for PfCRT, a vacuolar membrane transporter protein. Although a number of polymorphisms in this gene are associated with CQ resistance, the substitution of threonine for lysine at position 76 has been shown to be most closely associated with in vivo resistance.[14'15] This association comes with a caveat, namely that some chloroquine-sensitive (CQS) malaria strains also harbor this mutation, suggesting that K76 is required for CQ resistance but that other pfcrt polymorphisms must also be involved. However, in vivo outcomes are also clearly influenced by the level of underlying immunity (premu-nition) to malaria in the individual being treated, and this may limit the ability of mutations in pfcrt to predict in vivo outcome following CQ therapy.[16'17] However, the wild-type sequence does reliably predict successful treatment outcome with CQ.
The second P. falciparum gene implicated in CQ resistance, pfmdrl, is located on chromosome 5 and encodes the p-glycoprotein homologue (Pgh1). The aspartic acid-to-tyrosine point mutation at codon 86 has been associated with CQ resistance, as have a number of other polymorphisms in this gene (Asp 1042, Tyr 1246, Phe 184, and Cys 1034). However, these mutations have not consistently been associated with in vivo CQ resistance, although they may well modulate susceptibility to CQ, MQ, Q, and halofantine. Furthermore, genetic
The mechanisms of action and resistance to MQ have not been fully elucidated. The pfmdrl gene has been investigated as a molecular marker for MQ resistance, but evidence remains controversial. It was suggested that both variations in gene copy number and point mutations at positions 86, 184, 1034, 1042, and 1246 of the pfmdrl gene may confer drug resistance, but these findings have been challenged. Some investigations have reported increased sensitivity with the Tyr 86 mutation in pfmdrl, whereas others have found no effect. To date, field studies do not consistently support a direct role for these mutations in vivo treatment outcomes.
Sulfadoxine Pyrimethamine (FansidarTM)
The molecular basis of resistance for SP is perhaps the best characterized. Sulfadoxine and pyrimethamine act synergistically, with the former inhibiting dihydroptoate synthase (DHPS) and the latter inhibiting dihydrofolate reductase (DHFR), both of which are enzymes involved in folate synthesis. Point mutations at five dhps codons (Gly 437, Glu 540, Gly 581, Ala 436, and Ser 614) have been implicated in resistance to SP by decreasing the binding affinity of the enzyme. Mutations in dhfr associated with SP resistance include Ile 51, Arg 59, and Leu 164, with Asn 108 representing the key mutation for SP resistance. The degree of SP resistance increases in a stepwise fashion in response to progressive accumulation of these mutations. In recent in vivo studies in Cameroon and Kenya, the triple DHFR mutation at codons 108, 59, and 51 was associated with early treatment failure, suggesting that these could be useful markers for predicting the therapeutic effectiveness of SP in a given area.[22,23] Of interest, there may be some overlap between existing SP resistance and emergence of resistance to newer anti-folate combination drugs such as chlorproguanil dapsone (LAPDAP). Hence, screening of dhfr and dhps mutations may also provide molecular data to guide the regional implementation of LAPDAP programs.
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The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.