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Anders Björkman

Publications and source records attributed to Anders Björkman.

At least 19 recordsLinked to original sources
PubMed2007

Independent evolution of pyrimethamine resistance in Plasmodium falciparum isolates in Melanesia.

Pyrimethamine resistance in Plasmodium falciparum has previously been shown to have emerged once in Southeast Asia, from where it spread to Africa. Pyrimethamine resistance in this parasite is known to be conferred by mutations in the gene encoding dihydrofolate reductase (dhfr). We have analyzed polymorphisms in dhfr as well as microsatellite haplotypes flanking this gene in a total of 285 isolates from different regions of Melanesia (Papua New Guinea, Vanuatu, and the Solomon Islands) and Southeast Asia (Thailand and Cambodia). Nearly all isolates (92%) in Melanesia were shown to carry a dhfr double mutation (CNRNI [underlining indicates the mutation]) at positions 50, 51, 59, 108, and 164, whereas 98% of Southeast Asian isolates were either triple (CIRNI) or quadruple (CIRNL) mutants. Microsatellite analysis revealed two distinct lineages of dhfr double mutants in Melanesia. One lineage had the same microsatellite haplotype as that previously reported for Southeast Asia and Africa, suggesting the spread of this allele to Melanesia from Southeast Asia. The other lineage had a unique, previously undescribed microsatellite haplotype, indicative of the de novo emergence of pyrimethamine resistance in Melanesia.

Animals↗
PubMed2007

False-reactive microbiologic screening test results in Swedish blood donors-how big is the problem? A survey among blood centers and deferred donors.

BACKGROUND: Screening of blood donors for markers of transfusion-transmissible infectious agents leads to a varying number of false-reactive test results and sometimes thereby temporary or permanent deferral of donors and also to loss of collected units. STUDY DESIGN AND METHODS: Data on false-reactive screening test results in 2002 and 2003 were collected from 19 blood centers in Sweden. A questionnaire was sent to donors deferred because of false-reactive screening test results to investigate their perception of the information and their reaction to the deferral. RESULTS: Testing of 21,189 samples from new donors and 423,543 donations from regular and/or repeat donors produced 1,059 false-reactive test results, mostly from hepatitis C virus antibody testing, and 299 deferrals. Six different human immunodeficiency virus tests led to between 0.02 and 0.2 percent false-reactive results. The deferral rate varied considerably between different counties. Of 204 deferred donors contacted, 180 (88%) answered the questionnaire. More than 80 percent were worried about their test results and worry was more common among those who did not feel sufficiently informed. CONCLUSION: The results imply that there is a need for a more standardized approach to the screening of blood donors and donations with the aim of minimizing the number of false-reactive screening test results. They also emphasize the importance of appropriate information and support to deferred donors.

Adult↗
PubMed2006

Relationship between antipyretic effects and cytokine levels in uncomplicated falciparum malaria during different treatment regimes.

We have previously shown that both chloroquine and paracetamol (acetaminophen) have antipyretic activity during treatment of acute uncomplicated Plasmodium falciparum malaria in children 1-4 years old. Here, we studied if this effect was accompanied by changes in plasma cytokine levels. The 104 children were treated with either chloroquine or sulfadoxine/pyrimethamine (SP) alone, SP+chloroquine or SP+paracetamol for 4 days. Cytokine levels were determined days 0, 2 and 3, body temperature every sixth hour until 72h and parasitemia once daily for 4 days. At admission, body temperature correlated with levels of IL-10, IFN-gamma and IL-6, and parasitemia correlated with IL-10 and IL-6. Except for TNF-alpha and IL-1beta, where no significant effect was found, all cytokine levels (IL-10, IFN-gamma, IL-6, IL-12, IL-13, IL-18 and IL-4) decreased up to day 2 (p<0.05). IL-6 levels continued to fall from days 2 to 3 (p<0.05), whereas increased levels were found for several cytokines (IL-12, IL-13, IL-18 and IL-1beta) (p<0.05). The antipyretic effects of chloroquine and paracetamol could not be related to any specific changes in the evaluated cytokine production or in Th1/Th2 or inflammatory/anti-inflammatory cytokine ratios. Alternative mechanisms for antipyretic effects and associations between fever and cytokine levels during uncomplicated P. falciparum malaria are therefore discussed.

Acetaminophen↗
PubMed2006

Role of pfmdr1 mutations on chloroquine resistance in Plasmodium falciparum isolates with pfcrt K76T from Papua New Guinea.

The N86Y mutation in pfmdr1 is reported to play an additional role for the chloroquine resistance in Plasmodium falciparum isolates. However, not much has been done to clarify whether this mutation augments the level of chloroquine resistance in the isolates harboring pfcrt K76T mutation. We compared the in vitro chloroquine efficacy between pfcrt K76T mutant parasites with or without N86Y mutation from Papua New Guinea. A total of 57 isolates (4% sensitive, 14% borderline, and 82% resistant) were successfully tested in vitro for chloroquine sensitivity. We found a slightly higher effective concentration of chloroquine needed to inhibit P. falciparum by 50% (mean EC50=107 nM) in isolates with the pfcrt K76T+pfmdr1 N86Y than that in isolates with the pfcrt K76T+pfmdr1 N86 (EC50=88 nM), but this difference was not statistically significant. A significant non-random association was observed between the pfcrt K76T and pfmdr1 N86Y alleles. Our results suggest that the pfmdr1 N86Y mutation plays a compensatory role to chloroquine-resistant isolates under a chloroquine pressure while it may also augment the level of chloroquine resistance in the K76T parasites to a small extent.

ATP-Binding Cassette Transporters↗
PubMed2006

Rapid selection of dhfr mutant allele in Plasmodium falciparum isolates after the introduction of sulfadoxine/pyrimethamine in combination with 4-aminoquinolines in Papua New Guinea.

To overcome the declining efficacy of the 4-aminoquinolines in Papua New Guinea, sulfadoxine/pyrimethamine (SP) was combined with the 4-aminoquinolines as the first line treatment for falciparum malaria since 2000. To assess how this change had affected SP resistant gene polymorphisms, we determined allele frequencies of dhfr and dhps in 113 Plasmodium falciparum isolates from Wewak, East Sepik of Papua New Guinea in 2002 and 2003. In dhfr, double mutant (ACNRNVI) was the predominant allele with a prevalence of 91%. We found a significant decrease of wild dhfr allele prevalence (7%) compared with that reported in the adjacent area of East Sepik called the Wosera region (57%), before the drug policy changed in 1990-1993. Between 2002 and 2003, the prevalence of this allele decreased from 15% to 3% (P=0.02). Two distinct microsatellite haplotypes flanking dhfr were found in isolates with dhfr double mutant, suggesting the selection of preexisting SP resistant parasites rather than a frequent occurrence of dhfr mutations. The dhfr/dhps quartet mutations (ACNRNVI in dhfr and SGEAA in dhps) were identified in six of the isolates (8%) from 2003. This genotype, which is associated with in vivo resistance to SP, has not been reported before in Papua New Guinea. These findings suggest that isolates resistant to SP were rapidly selected despite the use of the SP combination therapy, probably because of their preexisting high level of resistance to the 4-aminoquinoline partner drug.

Alleles↗
PubMed2006

Multiplex PCR-RFLP methods for pfcrt, pfmdr1 and pfdhfr mutations in Plasmodium falciparum.

Plasmodium falciparum drug resistance is a major factor for the death toll of malaria. Resistance has been associated with specific single nucleotide polymorphisms (SNPs) in the parasite genes pfmdr1 (N86Y) and pfcrt (K76T) associated with quionoline antimalarial resistance, and pfdhfr (N51I, C59R, S108N) correlated with resistance of the antifolate combination sulfadoxine-pyrimethamine. These SNPs constitute the basis for the surveillance of drug resistance through high sensitive molecular methods in malaria endemic countries. In this work, we developed a multiplex PCR-RFLP protocols for the diagnosis of these molecular markers, leading to significant decreases in reagent costs, time, number of manipulations and hence human resources.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Amodiaquine resistance is not related to rare findings of pfmdr1 gene amplifications in Kenya.

OBJECTIVES: Many countries are now adopting artemisinin-based combination therapy (ACT) for treatment of Plasmodium falciparum malaria. In multi-drug resistant areas in South East Asia amplifications of the pfmdr1 gene are frequent and tentatively associated with reduced susceptibility to the common quinoline partner drugs mefloquine and lumefantrine. In Africa where amodiaquine is one of the favoured quinoline partner drugs in ACT, studies on multi-drug resistance associated pfmdr1 gene amplifications are urgent. Our aim was to determine the current prevalence of pfmdr1 gene amplifications and a possible association between pfmdr1 gene copy number and amodiaquine treatment outcome in Kenya. METHODS: Seventy-two children with Plasmodium falciparum infection in Kenya were treated with amodiaquine monotherapy and followed for 21 days. Possible amplification of the pfmdr1 gene was assessed from blood-spotted filterpaper by TaqMan probe based real-time polymerase chain reaction. RESULTS: The recrudescent rate was 14 of 72 (19%). All children had single pfmdr1 copy infections, with the exception of one child who had an infection with two pfmdr1 copies. This child had an adequate treatment response. CONCLUSION: Pfmdr1 amplifications do exist in Kenya but at a very low frequency. Yet, the substantial number of children with recrudescent infections implies that amodiaquine resistance is not related to pfmdr1 gene amplifications in Kenya.

Amodiaquine↗
PubMed2005

Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y.

The choice of partner drug is critical for artemisinine-based combination therapy (ACT) to remain effective and amodiaquine (AQ) is one important candidate to evaluate. We treated 81 children <5 years with uncomplicated Plasmodium falciparum malaria with AQ alone and related the treatment outcome to the possible selection of pfcrt 76T, 152T, 163S, 326S, pfmdr1 86Y and pfmrp 191H, 437S in recurrent infections (recrudescenses and re-infections) and to the blood concentration of desethylamodiaquine (DEAQ). During 21 days follow-up 28 children had a recurrent infection (9 recrudescenses, 13 re-infections and 6 mixed). Neither genotyping of the polymorphisms before treatment nor DEAQ blood concentrations could predict treatment outcome. pfcrt 76T was however significantly selected for in recurrent infections (p=0.020). pfmdr1 86Y was also selected for, but only in recrudescent infections (p=0.048). The study showed high prevalence of AQ resistant parasites in vivo, which appeared to be associated to pfcrt 76T and pfmdr1 86Y.

ATP-Binding Cassette Transporters↗
PubMed2005

Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania.

BACKGROUND: This is the first clinical trial comparing the efficacy of artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL)--the major artemisinin-based combination therapy (ACT) candidates for treatment of malaria in Africa--that involved an extended, 42-day follow-up period, polymerase chain reaction-adjusted parasitological cure rates (PCR APCRs), and systematic analyses of genetic markers related to quinoline resistance. METHODS. A total of 408 children with uncomplicated Plasmodium falciparum malaria in Zanzibar, Tanzania, were enrolled. Children who were 6-8 months of age and/or who weighed 6-8 kg were assigned to receive ASAQ for 3 days. Children who were 9-59 months of age and who weighted > or =9 kg were randomly assigned to receive either ASAQ or AL for 3 days in standard doses. Intention-to-treat analyses were performed. RESULTS: Age- and weight-adjusted PCR-APCRs by follow-up day 42 were 91% (188 of 206 patients) in the ASAQ group and 94% (185 of 197 patients) in the AL group (odds ratio [OR] for the likelihood of cure, 2.07; 95% confidence interval [CI], 0.84-5.10; P=.115). A total of 5 and 7 recrudescences occurred after day 28 in the ASAQ and AL groups, respectively. On the assumption that 10 malaria episodes with uncertain PCR results were recrudescences, PCR-APCRs decreased to 88% in the ASAQ group and to 92% in the AL group. Unadjusted cure rates by day 42 were 56% (116 of 206 patients) in the ASAQ group versus 77% (151 of 197 patients) in the AL group (OR, 2.55; 95% CI, 1.66-3.91; P<.001). Rates of reinfection by day 42 were 36% (65 of 181 patients) in the ASAQ arm versus 17% (31 of 182 patients) in the AL arm (OR, 0.37; 95% CI, 0.22-0.60; P<.001). A significant selection of P. falciparum multidrug resistance gene 1 allele 86N was found in isolates associated with reinfection after AL treatment, compared with isolates at baseline (2.2-fold increase; P<.001). CONCLUSIONS: Both treatments were highly efficacious, but AL provided stronger prevention against reinfection. The high proportion of recrudescences found after day 28 and the genetic selection by the long-acting partner drug underlines the importance of long follow-up periods in clinical trials. A long follow-up duration and performance of PCR genotyping should be implemented in programmatic surveillance of antimalarial drugs.

Amodiaquine↗
PubMed2005

Enhanced function in nerve-injured hands after contralateral deafferentation.

To explore whether contralateral deafferentation by tourniquet-induced anaesthesia can improve function in a nerve-injured hand, we investigated 14 patients with median or ulnar nerve injuries at wrist level. Deafferentation of the contralateral forearm and hand resulted in significantly improved tactile discrimination, threshold for perception of touch in the injured nerve area and in the area corresponding to the intact nerve in the injured hand, and significantly increased grip strength. Improvements lasted at least 15 min. The results show that hand function after peripheral nerve injury can be temporarily enhanced by manipulation of the process of brain plasticity. Our results may have practical applications in the rehabilitation of peripheral nerve-injured patients.

Adult↗
PubMed2005

In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem).

Artemisinin derivative-based combination therapy is expected to suppress the development of Plasmodium falciparum drug resistance in Africa. We have performed an artemether-lumefantrine (Coartem; Novartis) follow-up clinical trial in Zanzibar, in which pfcrt K76T and pfmdr1 N86Y frequencies were determined before drug administration and in all recurrent parasites during a follow-up period of 42 days. A significant increase in pfmdr1 86N was observed after exposure to the drug. This points to 86N as a potential marker of lumefantrine resistance in vivo, while suggesting that Coartem is not robust enough to avoid selection of resistance-associated mutations in some malarial settings.

ATP-Binding Cassette Transporters↗
PubMed2005

Public health impact of drug resistant Plasmodium falciparum malaria.

The alarming increase in Plasmodium falciparum resistance to commonly used anti-malarial drugs represents a major public health threat. The impact is however difficult to quantify. In low transmission areas, an increase in acute manifestations ("epidemic") is often quickly apparent and resistance is rapidly propagated due to high drug pressure on existing parasite populations. In high transmission areas, the clinical effects are mainly prolonged/chronic infections with increasing risk of severe anemia. Mortality estimates from public health records in Africa generally suggest significant increases (from 2- to 11-fold) in malaria-associated mortality among children when resistance develops and spreads. Hospital attendances and admissions show similar trends. Change of policy to alternative efficacious treatment with radical cure is necessary at an earlier stage (from 10% treatment failure) than previously assumed in order to prevent deaths in millions of African children. Early switch to artemisinin based combination therapy (ACT) represents such a critical and urgent strategy.

Africa↗
PubMed2005

In vitro recrudescence of Plasmodium falciparum parasites suppressed to dormant state by atovaquone alone and in combination with proguanil.

We studied the viability of Plasmodium falciparum parasites reappearing in long-term cultures after repetitive exposure to atovaquone and proguanil. Parasites (F32 and FCR3) exposed to 100-5000 nM atovaquone for 96 hours were reduced to <5% of initial parasitaemia but recrudesced after 9-15 days. Also, parasites exposed to 1000 nM atovaquone for 48, 72, 96 and 144 hours recrudesced after 9, 14, 21 and 23 days respectively. Immediately after removal of the drug, only 1-3 schizonts per 10000 red blood cells were found consistently, apparently unable to produce trophozoites and thus, possibly, adopting a "dormant state". Parasites (F32 and FCR3) exposed to 500 nM atovaquone for 72 hours reappeared after 14 days. These recrudescing parasites were then re-exposed and suppressed by atovaquone in three consecutive follow-up experiments. They reappeared after 12, 11 and 9 days respectively. No known point mutations in cytochrome b gene (cytb), associated with atovaquone resistance, were detected in any recrudescing parasites. Finally, parasites (F32) exposed to various concentrations of atovaquone and proguanil in combination for 72 hours reappeared after 9-17 days. The baseline susceptibilities of the parasites to individual drugs were similar before and after recrudescence in all experiments.

Animals↗
PubMed2005

Artificial sensibility of the hand based on cortical audiotactile interaction: a study using functional magnetic resonance imaging.

The capacity of the central nervous system for plastic alterations is the base for our ability to adapt to environmental needs. The crossmodal capacity of the brain makes interaction between senses possible, and deprivation of one sense leads to compensatory changes in other senses. We have recently shown how hearing can substitute for sensation in a transplanted insensitive hand by using a sensor glove equipped with small microphones that pick up the sound of friction, which is elicited by active touch. Here we have used functional magnetic resonance imaging (fMRI) in healthy people to illustrate their capacity for cortical audiotactile interaction with activation of the somatosensory cortex induced by auditory stimuli. The phenomenon occurred only in subjects trained to substitute sensibility by hearing, and no audiotactile interaction was found in untrained subjects.

Acoustic Stimulation↗
PubMed2005

Anaesthesia of the axillary plexus induces rapid improvement of sensory function in the contralateral hand: an effect of interhemispheric plasticity.

Acute improvement of sensory functions in the contralateral hand during experimental, tourniquet-induced anaesthesia has been described. Tourniquet compression over an extended time period, however, may be painful - which may influence the result. To study the effects of deafferentation of the upper extremity with the pain factor eliminated, we investigated 100 patients with anaesthetised axillary plexus for perception of touch and tactile discrimination in the contralateral (unanaesthetised) hand. Anaesthesia induced a rapid, significant, improvement in tactile discrimination in the contralateral hand, compared with before anaesthesia, measured as two-point discrimination (p=0.0001), and perception of touch, measured with Semmes-Weinstein monofilament (p=0.0005). The improvement lasted as long as the arm was anaesthetised. Understanding the mechanisms of brain plasticity, including interhemispheric plasticity, is essential for designing appropriate strategies for upregulation and downregulation of cortical reorganisational changes to promote sensory relearning after nerve injury.

Adolescent↗
PubMed2005

Multiple genotypes of the merozoite surface proteins 1 and 2 in Plasmodium falciparum infections in a hypoendemic area in Iran.

In Iran, malaria transmission mainly occurs in south-eastern regions through both Plasmodium falciparum and P. vivax. The genetic diversity of P. falciparum isolates was analysed in 108 patients attending the regional hospital in Chabahar District, using the molecular markers msp1 and msp2. Multiple genotypes were detected in 87% of patients and the mean numbers of msp1 and msp2 genotypes were 2.51 (95% CI: 2.29-2.73) and 2.61 (95% CI: 2.39-2.83) respectively. Various allelic types of msp1 and msp2 were found, with msp2 3D7/IC type detected in 94% of infections. Plasmodium falciparum infections in south-east Iran appear to have a higher genetic diversity than expected for an area of low transmission. A situation of higher transmission in this area may be emerging, possibly because of reduced efficacy of first-line treatments.

Adolescent↗