Tropical Medicine publications 2006

Larson BA, Amin AA, Noor AM, Zurovac D, Snow RW. 2006. The cost of uncomplicated childhood fevers to Kenyan households: implications for reaching international access targets. BMC Public Health, 6 (1), pp. 314. | Citations: 11 (Scopus) | Show Abstract | Read more

BACKGROUND: Fever is the clinical hallmark of malaria disease. The Roll Back Malaria (RBM) movement promotes prompt, effective treatment of childhood fevers as a key component to achieving its optimistic mortality reduction goals by 2010. A neglected concern is how communities will access these new medicines promptly and the costs to poor households when they are located in rural areas distant to health services. METHODS: We assemble data developed between 2001 and 2002 in Kenya to describe treatment choices made by rural households to treat a child's fever and the related costs to households. Using a cost-of-illness approach, we estimate the expected cost of a childhood fever to Kenyan households in 2002. We develop two scenarios to explore how expected costs to households would change if more children were treated at a health care facility with an effective antimalarial within 48 hours of fever onset. RESULTS: 30% of uncomplicated fevers were managed at home with modern medicines, 38% were taken to a health care facility (HCF), and 32% were managed at home without the use of modern medicines. Direct household cash expenditures were estimated at $0.44 per fever, while the total expected cost to households (cash and time) of an uncomplicated childhood fever is estimated to be $1.91. An estimated mean of 1.42 days of caretaker time devoted to each fever accounts for the majority of household costs of managing fevers. The aggregate cost to Kenyan households of managing uncomplicated childhood fevers was at least $96 million in 2002, equivalent to 1.00% of the Kenyan GDP. Fewer than 8% of all fevers were treated with an antimalarial drug within 24 hours of fever onset, while 17.5% were treated within 48 hours at a HCF. To achieve an increase from 17.5% to 33% of fevers treated with an antimalarial drug within 48 hours at a HCF (Scenario 1), children already being taken to a HCF would need to be taken earlier. Under this scenario, direct cash expenditures would not change, and total household costs would fall slightly to $1.86 because caretakers also save time with prompt treatment if the child has malaria. CONCLUSION: The management of uncomplicated childhood fevers imposes substantial costs on Kenyan households. Achieving substantial improvements in the numbers of fevers treated within 48 hours at a HCF with an effective antimalarial drug (Scenario 1) will not impose additional costs on households. Achieving additional improvements in fevers treated promptly at a HCF (Scenario 2) will impose additional costs on some households roughly equal to average cash expenses for transportation to a HCF. Additional financing mechanisms that further reduce the costs of accessing care at a HCF and/or that make artemisinin-based combination therapies (ACTs) accessible for home management need to be developed and evaluated as a top priority.

Vera J, Hensiek A, Woodrow C, Crawley F, Krishna S. 2006. Ophthalmoplegia and Slurred Speech in an Intravenous Drug User PLoS Medicine, 3 (12), pp. e453-e453. | Read more

Stepniewska K, White NJ. 2006. Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria. Malar J, 5 pp. 127. | Citations: 45 (Scopus) | Show Abstract | Read more

BACKGROUND: Treatments for uncomplicated falciparum malaria should have high cure rates. The World Health Organization has recently set a target cure rate of 95% assessed at 28 days. The use of more effective drugs, with longer periods of patient follow-up, and parasite genotyping to distinguish recrudescence from reinfection raise issues related to the design and interpretation of antimalarial treatment trials in uncomplicated falciparum malaria which are discussed here. METHODS: The importance of adequate follow-up is presented and the advantages and disadvantages of non-inferiority trials are discussed. The different methods of interpreting trial results are described, and the difficulties created by loss to follow-up and missing or indeterminate genotyping results are reviewed. CONCLUSION: To characterize cure rates adequately assessment of antimalarial drug efficacy in uncomplicated malaria requires a minimum of 28 days and as much as 63 days follow-up after starting treatment. The longer the duration of follow-up in community-based assessments, the greater is the risk that this will be incomplete, and in endemic areas, the greater is the probability of reinfection. Recrudescence can be distinguished from reinfection using PCR genotyping but there are commonly missing or indeterminate results. There is no consensus on how these data should be analysed, and so a variety of approaches have been employed. It is argued that the correct approach to analysing antimalarial drug efficacy assessments is survival analysis, and patients with missing or indeterminate PCR results should either be censored from the analysis, or if there are sufficient data, results should be adjusted based on the identified ratio of new infections to recrudescences at the time of recurrent parasitaemia. Where the estimated cure rates with currently recommended treatments exceed 95%, individual comparisons with new regimens should generally be designed as non-inferiority trials with sample sizes sufficient to determine adequate precision of cure rate estimates (such that the lower 95% confidence interval bound exceeds 90%).

Newton PN, Barnes KI, Smith PJ, Evans AC, Chierakul W, Ruangveerayuth R, White NJ. 2006. The pharmacokinetics of intravenous artesunate in adults with severe falciparum malaria. Eur J Clin Pharmacol, 62 (12), pp. 1003-1009. | Citations: 27 (Scopus) | Show Abstract | Read more

OBJECTIVE: Intravenous artesunate is commonly used in the emergency treatment of patients with severe falciparum malaria in Asia. The choice of doses used has been empirical. To inform dosage recommendations we assessed the pharmacokinetics of intravenous artesunate after the first dose. METHODS: As part of a clinical trial of artesunate in adults with severe falciparum malaria in western Thailand, we assayed plasma concentrations of artesunate and the principal biologically active metabolite dihydroartemisinin (DHA) in 17 patients given an initial dose of 2.4 mg/kg body weight of intravenous artesunate. Drug levels were measured using high performance liquid chromatography with mass spectroscopy-electrospray ionisation detection. RESULTS: Median (range) observed DHA Cmax was 2128 (513-5789) nmol/L, elimination half-life was 0.34 (0.14-0.87) h, and the time to the last detectable DHA was 2 h. CONCLUSION: The large inter-individual variability (10 fold) in DHA Cmax and AUC in patients with potentially lethal, severe malaria, suggests that 2.4 mg/kg should be the minimum daily dose in severe malaria.

Sayasone S, Odermatt P, Vongphrachanh P, Keoluangkot V, Dupouy-Camet J, Newton PN, Strobel M. 2006. A trichinellosis outbreak in Borikhamxay Province, Lao PDR. Trans R Soc Trop Med Hyg, 100 (12), pp. 1126-1129. | Citations: 19 (Scopus) | Show Abstract | Read more

Trichinellosis is documented in Southeast Asia, particularly in Thailand and China. Data from Lao PDR are lacking. An outbreak investigation was conducted in Borikhamxay Province after three patients with suspected trichinellosis consulted the Mahosot Hospital, Vientiane. In total, 22 trichinellosis cases were identified; 21 cases could be confirmed by Western blot. High fever (100%), muscle pain (91%), upper eyelid oedema (86%) and diarrhoea (59%) were observed. Among the 22 patients, 86% had consumed pork meat from the same source. This is the first report of an outbreak investigation in Lao PDR since 1975. It shows that the incidence of trichinellosis is much higher than currently thought.

Lindegårdh N, Giorgi F, Galletti B, Di Mattia M, Quaglia M, Carnevale D, White NJ, Mazzanti A, Day NPJ. 2006. Identification of an isomer impurity in piperaquine drug substance. J Chromatogr A, 1135 (2), pp. 166-169. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

A significant contaminant of the antimalarial drug piperaquine (1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]propane) has been identified using liquid chromatography-mass spectrometry (LC-MS) and 2D NMR spectroscopy (1H-1H COSY, 1H-13C HSQC, 1H-13C HMBC). The impurity was identified as the positional isomer 1-[(5-chloroquinolin-4)-piperazinyl]-3-[(7-chloroquinolin-4)-piperazinyl]propane. The impurity is formed because of contamination of batches of 4,7-dichloroquinoline (a precursor in the synthesis of piperaquine) with 4,5-dichloroquinoline. The amount of impurity (peak area impurity/peak area piperaquine using LC-UV at 347 nm) in old batches of piperaquine and in Artekin (the combination of dihydroartemisinin-piperaquine) ranged from 1.5 to 5%.

Chierakul W, Wangboonskul J, Singtoroj T, Pongtavornpinyo W, Short JM, Maharjan B, Wuthiekanun V, Dance DAB, Teparrukkul P, Lindegardh N et al. 2006. Pharmacokinetic and pharmacodynamic assessment of co-amoxiclav in the treatment of melioidosis. J Antimicrob Chemother, 58 (6), pp. 1215-1220. | Citations: 12 (Scopus) | Show Abstract | Read more

OBJECTIVES: We conducted a prospective pharmacokinetic study of oral co-amoxiclav in patients with melioidosis to determine the optimal dosage and dosing interval in this potentially fatal infection. PATIENTS AND METHODS: Serial plasma concentrations were measured after administration of two 1 g tablets of Augmentin (1750 mg of amoxicillin and 250 mg of clavulanate) to 14 adult patients with melioidosis. Monte Carlo simulation was used to predict the concentration of each drug following multiple doses of co-amoxiclav at different dosages and dose intervals. The proportion of the dose-interval above MIC (T > MIC) was calculated from 10,000 simulated subject plasma concentration profiles together with chequerboard MIC data from 46 clinical isolates and four reference strains of Burkholderia pseudomallei. RESULTS: The median (range) observed maximum plasma concentrations of amoxicillin and clavulanate were 11.5 (3.3-40.2) mg/L and 5.1 (0.8-12.1) mg/L, respectively. The median (range) elimination half-lives were 94 (73-215) and 89 (57-140) min, respectively. Simulation indicated that co-amoxiclav 1750/250 mg given at 4, 6, 8 or 12 hourly dosing intervals would be associated with a T > MIC of < or = 50% in 0.7%, 2.8%, 8.6% and 33.2% of patients, respectively. Corresponding proportions for T > MIC of > or = 90% were 95.8%, 78.6%, 50.2% and 10.8%, respectively. CONCLUSIONS: The dosing interval for co-amoxiclav (750/250 mg) in melioidosis should not be greater than 6 h.

Ashley E, McGready R, Singhasivanon P, Nosten F, Carrara V, Price R. 2006. In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Trop Med Int Health, 11 (12), pp. 1898-1899. | Read more

Sonthayanon P, Chierakul W, Wuthiekanun V, Blacksell SD, Pimda K, Suputtamongkol Y, Pukrittayakamee S, White NJ, Day NP, Peacock SJ. 2006. Rapid diagnosis of scrub typhus in rural Thailand using polymerase chain reaction. Am J Trop Med Hyg, 75 (6), pp. 1099-1102. | Citations: 32 (Scopus) | Show Abstract

The aim of this study was to evaluate the use of polymerase chain reaction (PCR) amplification of the O. tsutsugamushi 16S rRNA gene for the diagnosis of scrub typhus in rural Thailand. A prospective study of acute febrile illness in Udon Thani, northeast Thailand, identified 183 patients as having scrub typhus on the basis of immunofluorescent antibody testing (IFA) of paired sera. A further 366 febrile patients admitted concurrently with a range of other diagnoses acted as negative controls. Diagnostic sensitivity and specificity of 16S rRNA PCR was 44.8% and 99.7%, respectively, compared with IFA. PCR positivity was related to duration of symptoms and presence of eschar (P < 0.001, both cases). PCR using primers to amplify a fragment of the 56-kd gene had a sensitivity and specificity of 29.0% and 99.2%, respectively. PCR has a high specificity but low sensitivity for the rapid diagnosis of scrub typhus in this endemic setting.

Urban BC, Cordery D, Shafi MJ, Bull PC, Newbold CI, Williams TN, Marsh K. 2006. The frequency of BDCA3-positive dendritic cells is increased in the peripheral circulation of Kenyan children with severe malaria. Infect Immun, 74 (12), pp. 6700-6706. | Citations: 45 (Web of Science Lite) | Show Abstract | Read more

The ability of Plasmodium falciparum-infected erythrocytes to adhere to host endothelial cells via receptor molecules such as ICAM-1 and CD36 is considered a hallmark for the development of severe malaria syndromes. These molecules are also expressed on leukocytes such as dendritic cells. Dendritic cells are antigen-presenting cells that are crucial for the initiation of adaptive immune responses. In many human diseases, their frequency and function is perturbed. We analyzed the frequency of peripheral blood dendritic cell subsets and the plasma concentrations of interleukin-10 (IL-10) and IL-12 in Kenyan children with severe malaria and during convalescence and related these parameters to the adhesion phenotype of the acute parasite isolates. The frequency of CD1c(+) dendritic cells in children with acute malaria was comparable to that in healthy controls, but the frequency of BDCA3(+) dendritic cells was significantly increased. Analysis of the adhesion phenotypes of parasite isolates revealed that adhesion to ICAM-1 was associated with the frequency of peripheral blood CD1c(+) dendritic cells, whereas the adhesion of infected erythrocytes to CD36 correlated with high concentrations of IL-10 and low concentrations of IL-12 in plasma.

Tarning J, Bergqvist Y, Day NP, Bergquist J, Arvidsson B, White NJ, Ashton M, Lindegårdh N. 2006. Characterization of human urinary metabolites of the antimalarial piperaquine. Drug Metab Dispos, 34 (12), pp. 2011-2019. | Citations: 25 (Scopus) | Show Abstract | Read more

Five metabolites of the antimalarial piperaquine (PQ) (1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane) have been identified and their molecular structures characterized. After a p.o. dose of dihydroartemisinin-piperaquine, urine collected over 16 h from two healthy subjects was analyzed using liquid chromatography (LC)/UV, LC/tandem mass spectrometry (MS/MS), Fourier transform ion cyclotron resonance (FTICR)/MS, and H NMR. Five different peaks were recognized as possible metabolites [M1, 320 m/z; M2, M3, and M4, 551 m/z (PQ + 16 m/z); and M5, 567 m/z (PQ + 32 m/z)] using LC/MS/MS with gradient elution. The proposed carboxylic M1 has a theoretical monoisotopic molecular mass of 320.1166 m/z, which is in accordance with the FTICR/MS (320.1168 m/z) findings. The LC/MS/MS results also showed a 551 m/z metabolite (M2) with a distinct difference both in polarity and fragmentation pattern compared with PQ, 7-hydroxypiperaquine, and the other 551 m/z metabolites. We suggest that this is caused by N-oxidation of PQ. The results showed two metabolites (M3 and M4) with a molecular ion at 551 m/z and similar fragmentation pattern as both PQ and 7-hydroxypiperaquine; therefore, they are likely to be hydroxylated PQ metabolites. The molecular structures of M1 and M2 were also confirmed using H NMR. Urinary excretion rate in one subject suggested a terminal elimination half-life of about 53 days for M1. Assuming formation rate-limiting kinetics, this would support recent findings that the terminal elimination half-life of PQ has been underestimated previously.

McGready R, Stepniewska K, Lindegardh N, Ashley EA, La Y, Singhasivanon P, White NJ, Nosten F. 2006. The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria. Eur J Clin Pharmacol, 62 (12), pp. 1021-1031. | Citations: 84 (Scopus) | Show Abstract | Read more

OBJECTIVE: To determine the pharmacokinetic properties of artemether and lumefantrine (AL) in pregnant women with recrudescent uncomplicated multi-drug resistant falciparum malaria. METHODS: Pregnant women who had recurrence of parasitaemia following 7 days supervised quinine treatment were treated with AL. Serial blood samples were taken over a 7-day period, and pharmacokinetic parameters were estimated. For lumefantrine, these data were compared in a population pharmacokinetic model with data from non-pregnant, mainly male adults with acute malaria. RESULTS: The pregnant women (five in the second trimester and eight in the third trimester) had lower concentrations of artemether, dihydroartemisinin and lumefantrine, and the elimination of lumefantrine in pregnant women was more rapid than reported previously in non-pregnant adults. CONCLUSION: Pregnancy is associated with reduced plasma concentrations of both artemether and lumefantrine. This is likely to be of therapeutic significance as plasma concentrations of lumefantrine, after elimination of artemether, are an important determinant of cure. Further studies are needed to determine the optimum dose regimen of artemether-lumefantrine in pregnancy.

Khan AM, Miotto O, Heiny AT, Salmon J, Srinivasan KN, Nascimento EJM, Marques ETA, Brusic V, Tan TW, August JT. 2006. A systematic bioinformatics approach for selection of epitope-based vaccine targets. Cell Immunol, 244 (2), pp. 141-147. | Citations: 53 (Scopus) | Show Abstract | Read more

Epitope-based vaccines provide a new strategy for prophylactic and therapeutic application of pathogen-specific immunity. A critical requirement of this strategy is the identification and selection of T-cell epitopes that act as vaccine targets. This study describes current methodologies for the selection process, with dengue virus as a model system. A combination of publicly available bioinformatics algorithms and computational tools are used to screen and select antigen sequences as potential T-cell epitopes of supertype human leukocyte antigen (HLA) alleles. The selected sequences are tested for biological function by their activation of T-cells of HLA transgenic mice and of pathogen infected subjects. This approach provides an experimental basis for the design of pathogen specific, T-cell epitope-based vaccines that are targeted to majority of the genetic variants of the pathogen, and are effective for a broad range of differences in human leukocyte antigens among the global human population.

Hay SI, Snow RW. 2006. The malaria Atlas Project: developing global maps of malaria risk. PLoS Med, 3 (12), pp. e473. | Citations: 143 (Scopus) | Read more

Barnes KI, Little F, Smith PJ, Evans A, Watkins WM, White NJ. 2006. Sulfadoxine-pyrimethamine pharmacokinetics in malaria: pediatric dosing implications. Clin Pharmacol Ther, 80 (6), pp. 582-596. | Citations: 80 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: Our objective was to characterize the pharmacokinetic properties of sulfadoxine-pyrimethamine in African adults and children with acute falciparum malaria. Despite decades of widespread use, there are few data to inform dose recommendations. METHODS: In a prospective multicenter pharmacokinetic study in 307 patients with acute falciparum malaria, capillary blood concentrations of sulfadoxine and pyrimethamine were determined at 9 visits over a period of 42 days by mass spectrometry. RESULTS: After adjustment for dose, the area under the concentration-time curves (AUCs) of sulfadoxine and pyrimethamine in children aged 2 to 5 years were half of those in adults (median AUC, 410 microg/mL x d [interquartile range (IQR), 126-705 microg/mL x d] versus 816 microg/mL x d [IQR, 536-1150 microg/mL x d] [P = .0001] for sulfadoxine and 620 ng/mL x d [IQR, 229-1399 ng/mL x d] versus 1518 ng/mL x d [IQR, 1117-2013 ng/mL x d] for pyrimethamine). The effect of age on the AUC of sulfadoxine and pyrimethamine reflected higher clearance rates and larger apparent volumes of distribution in children aged 2 to 5 years when compared with adults (median clearance, 64.5 mL x kg(-1) x d(-1) [IQR, 46.2-132.6 mL x kg(-1) x d(-1)] versus 32.7 mL x kg(-1) x d(-1) [IQR, 22.3-52.2 mL x kg(-1) x d(-1)] for sulfadoxine [P = .0001] and 1.77 L x kg(-1) x d(-1) [IQR, 1.0-3.0 L x kg(-1) x d(-1)] versus 0.85 L x kg(-1) x d(-1) [IQR, 0.62-1.21 L x kg(-1) x d(-1)] for pyrimethamine [P = .0001]; median volume of distribution, 413 mL/kg [IQR, 299-711 mL/kg] versus 372 mL/kg [IQR, 267-488 mL/kg] for sulfadoxine [P = .0021] and 6.28 L/kg [IQR, 3.83-11.24 L/kg] versus 3.83 L/kg [IQR, 2.73-5.11 L/kg] for pyrimethamine [P = .0001]). Day 7 concentrations of both sulfadoxine and pyrimethamine provided good surrogate measures (R(2) >or= 0.72) of their respective AUCs. CONCLUSIONS: Pharmacokinetic factors may contribute to the increased risk of sulfadoxine-pyrimethamine antimalarial treatment failure in young children. The current dose recommendations need revision. We predict that children aged 2 to 5 years should be treated with 1 g sulfadoxine/50 mg pyrimethamine to achieve drug concentrations equivalent to those in adults.

Taylor WRJ, Terlouw DJ, Olliaro PL, White NJ, Brasseur P, ter Kuile FO. 2006. Use of weight-for-age-data to optimize tablet strength and dosing regimens for a new fixed-dose artesunate-amodiaquine combination for treating falciparum malaria. Bull World Health Organ, 84 (12), pp. 956-964. | Citations: 46 (Scopus) | Show Abstract | Read more

OBJECTIVE: To test a novel methodology to define age-based dosing regimens for the treatment of malaria with a new, user-friendly, blister-packaged fixed-dose combination of artesunate and amodiaquine. METHODS: A weight-for-age reference database of 88 054 individuals from sub-Saharan Africa was compiled using data from Demographic Health Surveys, observational and intervention studies, and standardized for sex, age and malaria risk. We then determined the optimal tablet strength (milligram (mg) per tablet) and age-dose categories for the combination of artesunate and amodiaquine. The proportions of patients predicted to receive doses within newly defined therapeutic ranges for amodiaquine (7-15 mg/kg/day) and artesunate (2-10 mg/kg/day), were estimated for different age categories and mg tablet strengths using models based on the weight-for-age reference database. FINDINGS: The optimal paediatric (p) and adult (a) strength tablets contained 25/67.5 and 100/270 mg artesunate/amodiaquine, respectively. A regimen with five age categories: 0-1 months (1/2 p), 2-11 months (1 p), 1-5 years (2 p), 6-13 years (1 a), and > 14 years (2 a) had an overall dosing accuracy of 83.4% and 99.9% for amodiaquine and artesunate, respectively. CONCLUSION: The proposed method to use weight-for-age reference data from countries where malaria is endemic is a useful tool for designing age-based dosing regimens for antimalarial drugs for drug registration and field use.

Kibe LW, Mbogo CM, Keating J, Molyneux S, Githure JI, Beier JC. 2006. Community based vector control in Malindi, Kenya. Afr Health Sci, 6 (4), pp. 240-246. | Citations: 10 (Scopus) | Show Abstract | Read more

BACKGROUND: Community involvement has become an important component of the National Malaria Control Strategy in Kenya, resulting in the organization of groups charged with addressing mosquito and malaria-related concerns within the community. OBJECTIVES: The purpose of this study was to identify community groups involved with intended malaria vector control activity in Malindi, Kenya. METHODS: Information was obtained from key informant interviews, focus group discussions, and a stakeholder meeting. The objectives were to determine the roles of community groups, identify examples of past successes and obstacles to successful implementation of vector control, and assess the level of knowledge about malaria and mosquitoes among the groups. RESULTS: Nineteen of 34 community groups (56%) registered at social services reported intended malaria vector control activities such as treating ditches, making and selling insecticide-treated mosquito nets, draining stagnant water, organizing clean-ups, making and selling neem soap, and the organization of campaigns such as the "Malaria Mosquito Day". Major challenges facing these groups include volunteerism, lack of technical expertise, supervision, and maintaining control activities in the absence of funds. Most groups reported limited knowledge about malaria vectors, and thus targeted all water bodies for control activities. CONCLUSIONS: We found that community groups are willing to participate in control operations, but lack government and technical support. We highlight the importance of strengthening organizational efforts and capacity building, as well as the need to clarify government policy on malaria vector control responsibilities within the communities.

Otero R, León G, Gutiérrez JM, Rojas G, Toro MF, Barona J, Rodríguez V, Díaz A, Núñez V, Quintana JC et al. 2006. Efficacy and safety of two whole IgG polyvalent antivenoms, refined by caprylic acid fractionation with or without beta-propiolactone, in the treatment of Bothrops asper bites in Colombia. Trans R Soc Trop Med Hyg, 100 (12), pp. 1173-1182. | Citations: 50 (Web of Science Lite) | Show Abstract | Read more

The efficacy and safety of two whole IgG polyvalent antivenoms (A and B) were compared in a randomised, blinded clinical trial in 67 patients systemically envenomed by Bothrops asper in Colombia. Both antivenoms were fractionated by caprylic acid precipitation and had similar neutralising potencies, protein concentrations and aggregate contents. Antivenom B was additionally treated with beta-propiolactone to lower its anticomplementary activity. Analysing all treatment regimens together, there were no significant differences between the two antivenoms (A=34 patients; B=33 patients) in the time taken to reverse venom-induced bleeding and coagulopathy, to restore physiological fibrinogen concentrations and to clear serum venom antigenaemia. Blood coagulability was restored within 6-24 h in 97% of patients, all of whom had normal coagulation and plasma fibrinogen levels 48 h after the start of antivenom treatment. Two patients (3.0%) had recurrent coagulopathy and eight patients suffered recurrence of antigenaemia within 72 h of treatment. None of the dosage regimens of either antivenom used guaranteed resolution of venom-induced coagulopathy within 6 h, nor did they prevent recurrences. A further dose of antivenom at 6 h also did not guarantee resolution of coagulopathy within 12-24 h in all patients. The incidence of early adverse reactions (all mild) was similar for both antivenoms (15% and 24%; P>0.05).

Warrell DA. 2006. Australian toxinology in a global context. Toxicon, 48 (7), pp. 718-725. | Citations: 5 (Web of Science Lite) | Read more

Maitland K, Berkley JA, Shebbe M, Peshu N, English M, Newton CRJC. 2006. Children with severe malnutrition: can those at highest risk of death be identified with the WHO protocol? PLoS Med, 3 (12), pp. e500. | Citations: 85 (Scopus) | Show Abstract | Read more

BACKGROUND: With strict adherence to international recommended treatment guidelines, the case fatality for severe malnutrition ought to be less than 5%. In African hospitals, fatality rates of 20% are common and are often attributed to poor training and faulty case management. Improving outcome will depend upon the identification of those at greatest risk and targeting limited health resources. We retrospectively examined the major risk factors associated with early (<48 h) and late in-hospital death in children with severe malnutrition with the aim of identifying admission features that could distinguish a high-risk group in relation to the World Health Organization (WHO) guidelines. METHODS AND FINDINGS: Of 920 children in the study, 176 (19%) died, with 59 (33%) deaths occurring within 48 h of admission. Bacteraemia complicated 27% of all deaths: 52% died before 48 h despite 85% in vitro antibiotic susceptibility of cultured organisms. The sensitivity, specificity, and likelihood ratio of the WHO-recommended "danger signs" (lethargy, hypothermia, or hypoglycaemia) to predict early mortality was 52%, 84%, and 3.4% (95% confidence interval [CI] = 2.2 to 5.1), respectively. In addition, four bedside features were associated with early case fatality: bradycardia, capillary refill time greater than 2 s, weak pulse volume, and impaired consciousness level; the presence of two or more features was associated with an odds ratio of 9.6 (95% CI = 4.8 to 19) for early fatality (p < 0.0001). Conversely, the group of children without any of these seven features, or signs of dehydration, severe acidosis, or electrolyte derangements, had a low fatality (7%). CONCLUSIONS: Formal assessment of these features as emergency signs to improve triage and to rationalize manpower resources toward the high-risk groups is required. In addition, basic clinical research is necessary to identify and test appropriate supportive treatments.

Caugant DA, Fogg C, Bajunirwe F, Piola P, Twesigye R, Mutebi F, Frøholm LO, Rosenqvist E, Batwala V, Aaberge IS et al. 2006. Pharyngeal carriage of Neisseria meningitidis in 2-19-year-old individuals in Uganda. Trans R Soc Trop Med Hyg, 100 (12), pp. 1159-1163. | Citations: 16 (Scopus) | Show Abstract | Read more

In southern Uganda, only sporadic cases of serogroup A meningococcal disease have been reported since 2000. As part of an immunogenicity study of the tetravalent meningococcal polysaccharide vaccine, nasopharyngeal swab samples were collected twice, 4 weeks apart, from 2-19-year-old healthy individuals in Mbarara, Uganda. Only 15 (2.0%) of the 750 individuals carried meningococci asymptomatically. Most of the strains were non-serogroupable and none were serogroup A. However, two individuals carried a serogroup W135 strain, sequence type (ST)-11, similar to the clone that was responsible for the epidemic in Burkina Faso in 2002. Our study further demonstrates the geographical spread of serogroup W135 ST-11 strain and thus the potential epidemic risk.

Ashley E, McGready R, Singhasivanon P, Nosten F, Carrara V, Price R. 2006. Untitled TROPICAL MEDICINE & INTERNATIONAL HEALTH, 11 (12), pp. 1898-1899. | Citations: 3 (Web of Science Lite) | Read more

von Seidlein L. 2006. Editorial: A small step for WHO, a big step for cholera control. Trop Med Int Health, 11 (12), pp. 1773-1774. | Citations: 4 (Scopus) | Read more

Han KH, Choi SY, Lee JH, Lee H, Shin EH, Agtini MD, von Seidlein L, Ochiai RL, Clemens JD, Wain J et al. 2006. Isolation of Salmonella enterica subspecies enterica serovar Paratyphi B dT+, or Salmonella Java, from Indonesia and alteration of the d-tartrate fermentation phenotype by disrupting the ORF STM 3356. J Med Microbiol, 55 (Pt 12), pp. 1661-1665. | Citations: 6 (Scopus) | Show Abstract | Read more

Salmonella enterica subspecies enterica serovar Paratyphi B [O1,4,(5),12 : Hb : 1,2] can cause either an enteric fever (paratyphoid fever) or self-limiting gastroenteritis in humans. The d-tartrate non-fermenting variant S. enterica subsp. enterica serovar Paratyphi B dT- (S. Paratyphi B) is the causative agent of paratyphoid fever, and the d-tartrate fermenting variant S. enterica subsp. enterica serovar Paratyphi B dT+ (S. Paratyphi B dT+; formerly called Salmonella Java) causes gastroenteritis. S. Java is currently recognized as an emerging problem worldwide. Twelve dT+ S. Java isolates were collected in Indonesia between 2000 and 2002. One-third of them contained Salmonella genomic island 1 (SGI1), which gives the multidrug-resistant phenotype to the bacteria. In this study, a PCR-based method to detect a single nucleotide difference responsible for the inability to ferment d-tartrate, reported elsewhere, was validated. The d-tartrate fermenting phenotype of S. Java was converted to the non-fermenting phenotype by the disruption of the ORF STM 3356, and the d-tartrate non-fermenting phenotype of the ORF STM 3356-disrupted strain and the dT- reference strain was changed to the dT+ phenotype by complementing ORF STM 3356 in trans. The results show that the dT+ phenotype requires a functional product encoded by STM 3356, and support the use of the PCR-based discrimination method for S. Paratyphi B and S. Java as the standard differentiation method.

Orr HJ, Christensen H, Smyth B, Dance DAB, Carrington D, Paul I, Stuart JM, South West Q Fever Project Group. 2006. Case-control study for risk factors for Q fever in southwest England and Northern Ireland. Euro Surveill, 11 (10), pp. 260-262. | Citations: 14 (Scopus) | Show Abstract

Q fever (Coxiella burnetti) is thought to account for 1% (700 cases) of community acquired pneumonia in the United Kingdom each year, and can result in serious complications such as endocarditis. Although outbreaks have frequently been reported worldwide, the causes are often not clearly identified and there have been few studies of risk factors in sporadic cases. We conducted a matched case-control study. Cases of acute Q fever in people aged over 15 years in southwest England and Northern Ireland were identified from January 2002 to December 2004. Controls were matched for age, sex and the general practice at which they were registered. Questionnaires asking about contact with animals, and leisure and work activities, were posted to cases and controls. Questionnaires were completed by 39/50 (78%) of the cases and 90/180 (50%) of the controls. In the single variable analysis, occupational exposure to animals or animal products was the only risk factor associated with cases at the 5% level (P=0.05, odds ratio (OR) 3.4). Long term illness appeared to be significantly protective (P=0.03, OR 0.3). In multivariable analysis the strength of association between occupational exposure and illness remained high (OR 3.6, 95% confidence interval (CI) 0.9 to 14.8) and smoking emerged as a possible risk factor. This is the first case-control study to identify occupational exposure to animals or animal products as the most likely route of infection in sporadic cases as opposed to outbreaks.

Wertheim HFL, Verbrugh HA. 2006. Global prevalence of meticillin-resistant Staphylococcus aureus. Lancet, 368 (9550), pp. 1866. | Citations: 3 (Scopus) | Read more

Roumagnac P, Weill F-X, Dolecek C, Baker S, Brisse S, Chinh NT, Le TAH, Acosta CJ, Farrar J, Dougan G, Achtman M. 2006. Evolutionary history of Salmonella typhi. Science, 314 (5803), pp. 1301-1304. | Citations: 211 (Scopus) | Show Abstract | Read more

For microbial pathogens, phylogeographic differentiation seems to be relatively common. However, the neutral population structure of Salmonella enterica serovar Typhi reflects the continued existence of ubiquitous haplotypes over millennia. In contrast, clinical use of fluoroquinolones has yielded at least 15 independent gyrA mutations within a decade and stimulated clonal expansion of haplotype H58 in Asia and Africa. Yet, antibiotic-sensitive strains and haplotypes other than H58 still persist despite selection for antibiotic resistance. Neutral evolution in Typhi appears to reflect the asymptomatic carrier state, and adaptive evolution depends on the rapid transmission of phenotypic changes through acute infections.

Ricci KA, Girosi F, Tarr PI, Lim Y-W, Mason C, Miller M, Hughes J, von Seidlein L, Agosti JM, Guerrant RL. 2006. Reducing stunting among children: the potential contribution of diagnostics. Nature, 444 Suppl 1 pp. 29-38. | Citations: 37 (Scopus) | Read more

White NJ. 2006. Malaria--time to act. N Engl J Med, 355 (19), pp. 1956-1957. | Citations: 19 (Scopus) | Read more

Brooker S, Clements ACA, Hotez PJ, Hay SI, Tatem AJ, Bundy DAP, Snow RW. 2006. The co-distribution of Plasmodium falciparum and hookworm among African schoolchildren. Malar J, 5 pp. 99. | Citations: 103 (Scopus) | Show Abstract | Read more

BACKGROUND: Surprisingly little is known about the geographical overlap between malaria and other tropical diseases, including helminth infections. This is despite the potential public health importance of co-infection and synergistic opportunities for control. METHODS: Statistical models are presented that predict the large-scale distribution of hookworm in sub-Saharan Africa (SSA), based on the relationship between prevalence of infection among schoolchildren and remotely sensed environmental variables. Using a climate-based spatial model of the transmission potential for Plasmodium falciparum malaria, adjusted for urbanization, the spatial congruence of populations at coincident risk of infection is determined. RESULTS: The model of hookworm indicates that the infection is widespread throughout Africa and that, of the 179.3 million school-aged children who live on the continent, 50.0 (95% CI: 48.9-51.1) million (27.9% of total population) are infected with hookworm and 45.1 (95% CI: 43.9-46) million are estimated to be at risk of coincident infection. CONCLUSION: Malaria and hookworm infection are widespread throughout SSA and over a quarter of school-aged children in sub-Saharan Africa appear to be at risk of coincident infection and thus at enhanced risk of clinical disease. The results suggest that the control of parasitic helminths and of malaria in school children could be viewed as essential co-contributors to promoting the health of schoolchildren.

Phetsouvanh R, Phongmany S, Soukaloun D, Rasachak B, Soukhaseum V, Soukhaseum S, Frichithavong K, Khounnorath S, Pengdee B, Phiasakha K et al. 2006. Causes of community-acquired bacteremia and patterns of antimicrobial resistance in Vientiane, Laos. Am J Trop Med Hyg, 75 (5), pp. 978-985. | Citations: 59 (Scopus) | Show Abstract

There is no published information on the causes of bacteremia in the Lao PDR (Laos). Between 2000 and 2004, 4512 blood culture pairs were taken from patients admitted to Mahosot Hospital, Vientiane, Laos, with suspected community-acquired bacteremia; 483 (10.7%) cultures grew a clinically significant community-acquired organism, most commonly Salmonella enterica serovar typhi (50.9%), Staphylococcus aureus (19.0%), and Escherichia coli (12.4%). S. aureus bacteremia was common among infants (69.2%), while children 1-5 years had a high frequency of typhoid (44%). Multi-drug-resistant S. Typhi was rare (6%). On multiple logistic regression analysis, typhoid was associated with younger age, longer illness, diarrhea, higher admission temperature, and lower peripheral white blood cell count than non-typhoidal bacteremia. Empirical parenteral ampicillin and gentamicin would have some activity against approximately 88% of clinically significant isolates at a cost of US $1.4/day, an important exception being B. pseudomallei. Bacteremic infants in this setting require an anti-staphylococcal antibiotic.

Nantakomon D, Udomsangpetch R, Pattanapunyasat K, Looareesuwan S, White NJ, Day NP, Chotivanich K. 2006. Circulating cell-derived microparticles in malaria patients AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 45-45.

Ashley EA, Lwin KM, McGready R, Simon WH, Phaiphun L, Proux S, Wangseang N, Taylor W, Stepniewska K, Nawamaneerat W et al. 2006. An open label randomized comparison of mefloquine-artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. Trop Med Int Health, 11 (11), pp. 1653-1660. | Citations: 35 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. METHODS: On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. RESULTS: The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P=0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. CONCLUSION: This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.

Simpson JA, Agbenyega T, Barnes KI, Di Perri G, Folb P, Gomes M, Krishna S, Krudsood S, Looareesuwan S, Mansor S et al. 2006. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Med, 3 (11), pp. e444. | Citations: 34 (Scopus) | Show Abstract | Read more

BACKGROUND: Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. METHODS AND FINDINGS: Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0-6h were observed. CONCLUSIONS: The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations.

Hall KA, Newton PN, Green MD, De Veij M, Vandenabeele P, Pizzanelli D, Mayxay M, Dondorp A, Fernandez FM. 2006. Characterization of counterfeit artesunate antimalarial tablets from southeast Asia. Am J Trop Med Hyg, 75 (5), pp. 804-811. | Citations: 64 (Scopus) | Show Abstract

In southeast Asia, the widespread high prevalence of counterfeits tablets of the vital antimalarial artesunate is of great public health concern. To assess the seriousness of this problem, we quantified the amount of active ingredient present in artesunate tablets by liquid chromatography coupled to mass spectrometry. This method, in conjunction with analysis of the packaging, classified tablets as genuine, substandard, or fake and validated results of the colorimetric Fast Red TR test. Eight (35%) of 23 fake artesunate samples contained the wrong active ingredients, which were identified as different erythromycins and paracetamol. Raman spectroscopy identified calcium carbonate as an excipient in 9 (39%) of 23 fake samples. Multivariate unsupervised pattern recognition results indicated two major clusters of artesunate counterfeits, those with counterfeit foil stickers and containing calcium carbonate, erythromycin, and paracetamol, and those with counterfeit holograms and containing starch but without evidence of erythromycin or paracetamol.

Blacksell SD, Khounsy S, Phetsouvanh R, Newton PN. 2006. A simple and inexpensive container for the transport of biological specimens in limited resource situations. Trans R Soc Trop Med Hyg, 100 (11), pp. 1084-1086. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

We describe a diagnostic specimen transport container that is appropriate for limited resource or emergency settings. The transport container is constructed from polyvinyl chloride (PVC) plumbing pipe, which is readily available and inexpensive (US$1-2, depending on size) and has wide flexibility of size due to the range of PVC pipe dimensions available. The PVC transporters are durable, water-resistant and may be easily decontaminated. They have been adapted for the transport of blood culture bottles from provincial hospitals in Laos, where, during a 2-year period, 380 PVC tubes containing blood culture bottles were transported without any leakage or breakage. We have found the PVC transporter to be a useful and cost-efficient durable alternative that meets IATA Packing Instruction 650 biological transport container requirements.

Wuthiekanun V, Langa S, Swaddiwudhipong W, Jedsadapanpong W, Kaengnet Y, Chierakul W, Day NP, Peacock SJ. 2006. Short report: Melioidosis in Myanmar: forgotten but not gone? Am J Trop Med Hyg, 75 (5), pp. 945-946. | Citations: 11 (Scopus) | Show Abstract

A serologic survey of adults resident in Myanmar was conducted to define the presence of antibodies to Burkholderia pseudomallei, the cause of melioidosis. Antibodies were detectable by indirect hemagglutination assay (IHA) in 757 (78%) of 968 adults, of whom 69 (7%) had an IHA titer > or =1:160.

Caws M, Thwaites G, Stepniewska K, Nguyen TNL, Nguyen THD, Nguyen TP, Mai NTH, Phan MD, Tran HL, Tran THC et al. 2006. Beijing genotype of Mycobacterium tuberculosis is significantly associated with human immunodeficiency virus infection and multidrug resistance in cases of tuberculous meningitis. J Clin Microbiol, 44 (11), pp. 3934-3939. | Citations: 60 (Scopus) | Show Abstract | Read more

Multidrug-resistant tuberculous meningitis is fatal without rapid diagnosis and use of second-line therapy. It is more common in human immunodeficiency virus (HIV)-positive patients. Beijing genotype strains of Mycobacterium tuberculosis are associated with drug resistance, particularly multidrug resistance, and their prevalence is increasing worldwide. The prevalence of Beijing genotype strains among Mycobacterium tuberculosis isolates from the cerebrospinal fluid of HIV-positive (n = 35) and HIV-negative (n = 187) patients in Ho Chi Minh City was determined. The Beijing genotype was significantly associated with HIV status (odds ratio [OR] = 2.95 [95% confidence interval {CI}, 1.38 to 6.44]; P = 0.016), resistance to any drug (OR = 3.34 [95% CI, 1.87 to 5.95]; P < 0.001) and multidrug resistance (Fisher's exact test; P = 0.001). The association of the Beijing genotype with drug resistance was independent of HIV status. This is the first report of Beijing genotype association with HIV status, which may be an association unique to tuberculous meningitis.

Qureshi NR, Hien TT, Farrar J, Gleeson FV. 2006. The radiologic manifestations of H5N1 avian influenza. J Thorac Imaging, 21 (4), pp. 259-264. | Citations: 27 (Scopus) | Show Abstract | Read more

Avian influenza is caused by the H5N1 subtype of the influenza A virus. Human transmission is either directly through close contact with infected birds usually poultry or their secretions. To date 178 people throughout South East Asia have been infected with 85 deaths. Patients usually present with a rapidly progressive pneumonia that can result in respiratory failure and acute respiratory distress syndrome. The chest radiograph therefore remains the most convenient and accessible imaging modality. Studies have shown that most radiographs are abnormal at the time of presentation with multifocal consolidation the commonest radiographic finding. During the course of disease, pleural effusions and cavitation can also develop. Consolidation that involves > or = 4 zones on presentation or at day 7 after the onset of symptoms and subsequent development of acute respiratory distress syndrome are generally associated with an adverse outcome. Chest CT examinations performed during the convalescent period have demonstrated persistent ground glass attenuation and segmental consolidation. Additional features included pseudocavitation, pneumatocoele formation, lymphadenopathy, and centrilobular nodules. Overall the appearances are suggestive of mild fibrosis.

Bejon P, Keating S, Mwacharo J, Kai OK, Dunachie S, Walther M, Berthoud T, Lang T, Epstein J, Carucci D et al. 2006. Early gamma interferon and interleukin-2 responses to vaccination predict the late resting memory in malaria-naïve and malaria-exposed individuals. Infect Immun, 74 (11), pp. 6331-6338. | Citations: 18 (Scopus) | Show Abstract | Read more

Two different cell populations respond to potent T-cell-inducing vaccinations. The induction and loss of effector cells can be seen using an ex vivo enzyme-linked immunospot (ELISPOT) assay, but the more durable resting memory response is demonstrable by a cultured ELISPOT assay. The relationship of the early effector response to durable resting memory is incompletely understood. Effector phenotype is usually identified by gamma interferon (IFN-gamma) production, but interleukin-2 (IL-2) has been specifically linked to the differentiation of memory cells. Here, IFN-gamma- and IL-2-secreting effector cells were identified by an ex vivo ELISPOT assay 1 week after vaccination and compared with the resting memory responses detected by a cultured ELISPOT assay 3 months later. The different kinetics and induction of IL-2 by different vaccines and natural exposure are described. Furthermore, both early IFN-gamma and IL-2 production independently predicted subsequent memory responses at 3 months in malaria-naïve volunteers, but only IFN-gamma predicted memory in malaria-exposed volunteers. However, dual ELISPOT assays were also performed on malaria-exposed volunteers to identify cells producing both cytokines simultaneously. This demonstrated that double-cytokine-producing cells were highly predictive of memory. This assay may be useful in predicting vaccinations most likely to generate stable, long-term memory responses.

Jenkins NE, Chakravorty SJ, Urban BC, Kai OK, Marsh K, Craig AG. 2006. The effect of Plasmodium falciparum infection on expression of monocyte surface molecules. Trans R Soc Trop Med Hyg, 100 (11), pp. 1007-1012. | Citations: 12 (Scopus) | Show Abstract | Read more

Plasmodium falciparum infection may result in severe malaria in susceptible individuals. The pathogenesis of severe disease is probably a combination of the sequestration of infected erythrocytes and overstimulation of the immune response. Monocytes are a key source of many of the pro-inflammatory agents implicated but also are found sequestered in blood vessels. However, little is known about the monocyte phenotype in malaria disease. Flow cytometry was performed on fresh whole blood to determine surface expression of four receptors during acute severe and non-severe malaria and again during convalescence when uninfected. Three hundred and fifty-six children with P. falciparum infection were studied and were found to show increased expression of intercellular adhesion molecule-1 (ICAM-1), urokinase plasminogen activator receptor (uPAR), CD23 and chemokine receptor 5 (CCR5) (P<0.001) during acute disease compared with convalescent levels. Using multivariate analysis, it was found that large increases in expression of ICAM-1 (odds ratio (OR) 2.44, 95% CI 1.80-3.32) and uPAR (OR 3.14, 95% CI 1.93-5.09) but small increases in expression of CD23 (OR 0.82, 95% CI 0.68-0.96) were independently associated with severe malaria. These results give an insight into the cellular processes occurring in severe malaria and suggest that pathology is based on a complex repertoire of pro- and anti-inflammatory processes.

Golding M, Williams T, Marsh K, Hill A. 2006. Single nucleotide polymorphisms in trap associate with severe malarial disease: A novel parasite virulence gene AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 151-151.

Nguyen D, Dong T, Nguyen VVC, Nguyen MD, Wills B, Rowland-Jones S, Farrar J, Simmons C. 2006. Spectrum and kinetic of T cell responses to dengue virus epitopes and the influence of hla polymorphisms in dengue disease pathogenesis AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 289-290.

Hoang LT, Hibberd ML, Farrar J, Simmons CP. 2006. Global gene expression profiles during acute dengue revealed by microarray analysis AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 290-290.

Popper S, Simmons CP, Dolecek C, Chau TNB, Griffiths M, Dung NTP, Long TH, Hoang DM, Van Vinh Chau N, Thao LTT et al. 2006. Gene expression programs in adults with acute dengue infections AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 290-290.

Flohr C, Tuyen LN, Lewis S, Quinnell R, Minh TT, Liem HT, Campbell J, Pritchard D, Hien TT, Farrar J et al. 2006. Poor sanitation and helminth infection protect against skin sensitization in Vietnamese children: A cross-sectional study AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 321-321. | Citations: 1 (Web of Science Lite)

Lampah DA, Yeo TW, Kenangalem E, Gitawati R, Waramori G, Price RN, Lopansri B, Granger D, Sly P, Tjitra E, Anstey NM. 2006. Real-time bedside measurement of nitric oxide demonstrates impaired production in adults with severe malaria in papua, Indonesia AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 47-47.

Yeo TW, Lampah DA, Kenangalem E, Gitawati R, Tjitra E, McNeil Y, Granger D, Lopansri B, Celermajer D, Price RN et al. 2006. L-arginine infusion increases no production and reverses endothelial dysfunction in adults with moderately severe falciparum malaria in Papua, Indonesia AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 98-99.

Armedy R, Hotma L, Kanagalem E, Rumaseuw R, Ebsworth EP, Anstey NM, Tjitra E, Price RN. 2006. Amodiaquine plus artesunate versus dihydroartemisinin-piperaquine for drug resistant P.falciparum and P.vivax in Papua, Indonesia AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 208-208.

Yeo TW, Lampah DA, Kenangalem E, Gitawati R, Waramori G, McNeil Y, Duffull S, Tjitra E, Price RN, Celermajer D, Anstey NM. 2006. Impaired endothelial function in adults with severe falciparum malaria in Papua, Indonesia AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 286-286.

Guerin PJ, Naess LM, Fogg C, Rosenqvist E, Pinoges L, Bajunirwe F, Twesigye R, Borrow R, Froholm O, Batwala V et al. 2006. Use of fractional dose tetravalent A, C, W135 and Y meningococcal polysaccharide vaccine: A non inferiority trial AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 202-202.

Grais RF, Conlan AC, Ferrari MJ, Djibo A, Fermon F, Guerin PJ, Dubray C, Bjornstad ON, Grenfell BT. 2006. Emergency vaccination responses during large measles outbreaks: Early intervention leads to a high proportion of averted cases AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 191-191. | Citations: 2 (Web of Science Lite)

Le MVT, Le MLN, Campbell J, Nguyen TT, Thi DN, Dolecek C, Schultsz C. 2006. High rates of carriage of drug-resistant Enterobacteriaceae in healthy volunteers in Ho Chi Minh City AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 83-83.

Jain S, Lan NTP, Tai DT, Rang NN, La TTP, Bird M, Dolecek C, Van Sach N, Bang BX, Mintz ED et al. 2006. An evaluation of a rapid serodiagnostic test for typhoid fever - An giang, Vietnam 2005-2006 AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 314-314.

Fleming V, Feil E, Sewell AK, Day N, Buckling A, Massey RC. 2006. Agr interference between clinical Staphylococcus aureus strains in an insect model of virulence. J Bacteriol, 188 (21), pp. 7686-7688. | Citations: 30 (Scopus) | Show Abstract | Read more

Repression of virulence by Staphylococcus aureus strains from different Agr groups has been demonstrated in vitro and is proposed as a means of competitive interference. Here, using the insect Manduca sexta, we show for the first time that this interference also occurs in vivo within a mixed population.

Sanjana P, Barcus MJ, Bangs MJ, Ompusunggu S, Elyazar I, Marwoto H, Tuti S, Sururi M, Tjokrosonto S, Baird JK. 2006. Survey of community knowledge, attitudes, and practices during a malaria epidemic in central Java, Indonesia. Am J Trop Med Hyg, 75 (5), pp. 783-789. | Citations: 18 (Web of Science Lite) | Show Abstract

We surveyed adults in a randomly selected sample of 1,000 households in 50 villages in nine malarial sub-districts in Purworejo, central Java, Indonesia from May to July 2001. The survey assessed malaria knowledge, attitudes, and practices in communities experiencing epidemic malaria to begin exploring broad strategies for controlling the disease in the region. A pre-tested survey instrument consisting of 93 questions addressed demographic characteristics, socioeconomic factors, knowledge and perceptions of malaria, burden and severity of disease, treatment-seeking behavior, malaria prevention practices, and perceptions of government malaria control efforts. The survey was taken by in-person interview of all subjects. Most (97%) subjects were aware of malaria and more than two-thirds correctly identified mosquitoes as the vector. Forty-one percent of households in both forest/hilly and agricultural/urban areas reported malaria illness in the past year. Thirty-six percent (357 households) owned at least one bed net, 92% of these had been purchased by the owners. However, only 36% of households with bed nets affirmed their use as a means of preventing malaria. Nearly all respondents reported a willingness to accept spraying of residual insecticides for malaria prevention, yet less than 5% were willing to pay a nominal fee (US $3) for this service. Fifty-two percent of respondents reported self-treatment of malaria illness without visiting a health facility. This assessment of knowledge, attitudes, and practices showed a broad awareness of malaria and its consequences among residents of malarial areas in the Menoreh Hills of Central Java.

Beeson JG, Kelly G, Hallamore S, Persson K, Chesson J, Cortes A, Rogerson S, Reeder J, Brown G, Marsh K. 2006. Limited global diversity of antibody epitopes expressed by placental binding Plasmodium falciparum variants AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 104-104.

Persson KE, McCallum FJ, Reiling L, Stubbs J, Lister N, Williams T, Marsh K, Cowman AF, Beeson JG. 2006. Phenotypic variation in P-falciparum invasion of erythrocytes is a mechanism of immune evasion AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 283-283.

Thwaites G. 2006. Tuberculosis: where are we going? Clin Med (Lond), 6 (6), pp. 523-525. | Read more

Alifrangis C, Thompson P, Thwaites G, Churchill D. 2006. Primary pneumococcal peritonitis as a presenting feature of HIV infection. Int J STD AIDS, 17 (11), pp. 779-780. | Citations: 4 (Scopus) | Show Abstract | Read more

We report a case of primary pneumococcal peritonitis in a 28-year old previously healthy woman. There are no previously reported associations between this rare form of spontaneous peritonitis and HIV infection, and it is usually associated with underlying cirrhosis, ascites or other immune compromise. In this case this was the presenting illness of HIV infection. When atypical infections such as this arise in previously healthy adults the clinician must have a high index of suspicion of HIV or other underlying immunodeficiency.

Chompook P, Todd J, Wheeler JG, von Seidlein L, Clemens J, Chaicumpa W. 2006. Risk factors for shigellosis in Thailand. Int J Infect Dis, 10 (6), pp. 425-433. | Citations: 22 (Scopus) | Show Abstract | Read more

OBJECTIVES: To assess the potential risk factors for shigellosis including housefly density. METHODS: A matched case-control study to investigate potential risk factors for shigellosis was conducted in a semi-urban area, Kaengkhoi District, Saraburi Province, central Thailand. Shigella cases were ascertained from a two-year population-based surveillance study detecting diarrhea and shigellosis in the area. The study evaluated a wide range of exposures, which were assessed by odds ratios (OR) adjusted for proxy markers of socioeconomic status: family income, and type of residence, using conditional logistic regression analysis. RESULTS: Hygiene behaviors such as regular hand washing (p<0.05), a clean environment surrounding the household (p<0.001), and the availability of water to flush the toilet (p=0.08) were associated with a reduced risk for shigellosis in the multivariate model. In contrast factors indicating a lower than average socioeconomic status, such as having to rent instead of owning one's housing (p<0.001) and a low family income (p<0.01) were associated with an increased risk for shigellosis. For children, breastfeeding showed a strong protective effect in reducing the risk of shigellosis (p<0.01). Prior to adjustment for environmental factors, fly density in the kitchen area was associated with an increased risk of shigellosis (p<0.01). CONCLUSIONS: We found a correlation between socioeconomic status and the risk for shigellosis. To reduce shigellosis in this setting, we recommend interventions focused on three aspects: improved water supply and sanitation (especially latrines and garbage disposal) including fly control, health education on hand washing, and the promotion of breastfeeding.

Woods CW, Murdoch DR, Zimmerman MD, Glover WA, Basnyat B, Wolf L, Belbase RH, Reller LB. 2006. Emergence of Salmonella enterica serotype Paratyphi A as a major cause of enteric fever in Kathmandu, Nepal. Trans R Soc Trop Med Hyg, 100 (11), pp. 1063-1067. | Citations: 41 (Scopus) | Show Abstract | Read more

We performed pulsed-field gel electrophoresis (XbaI) on 114 bloodstream isolates of Salmonella enterica serotype Paratyphi A and S. enterica serotype Typhi collected from febrile patients in Kathmandu, Nepal. Of the 56 S. Paratyphi A isolates, 51 (91%) were indistinguishable, which suggests the emergence of a single clone. In contrast, only 21 (36%) of the 58 S. Typhi isolates exhibited a common genotype, which is consistent with endemic disease from multiple sources.

Tjon GMS, Coutinho RA, van den Hoek A, Esman S, Wijkmans CJ, Hoebe CJPA, Wolters B, Swaan C, Geskus RB, Dukers N, Bruisten SM. 2006. High and persistent excretion of hepatitis A virus in immunocompetent patients. J Med Virol, 78 (11), pp. 1398-1405. | Citations: 22 (Scopus) | Show Abstract | Read more

The duration and level of virus excretion in blood and faeces of patients with hepatitis A virus (HAV) infection were studied in relation to levels of alanine aminotransferase (ALT), disease severity and HAV genotype. Clinical data, blood and faeces were collected from 27 patients with acute hepatitis A (median age: 33 years) for a maximum of 26 weeks. Single blood donations from 55 other patients with acute HAV (median age: 32 years) were also used. Virus loads were quantified by competitive nested RT-PCR. HAV was excreted in faeces for a median period of 81 days after disease onset, with 50% of patients still excreting high levels at Day 36 (2 x 10(6) - 2 x 10(8) copies/ml faeces suspension). Viraemia was detected, but not quantifiable, for a median period of 42 days. In the first 10 days of illness, higher ALT levels were correlated with higher viraemia levels. Comparison of patients infected with genotype 1a with those infected with type 1b did not differ significantly in terms of the duration of HAV excretion or jaundice. In conclusion, faecal excretion of HAV is at a high titre in the first month, perhaps making patients infectious for a longer period than assumed currently. Blood banks should be aware that viraemia may be present for more than 1 month, and genotype did not affect the duration of virus excretion or jaundice.

Imoukhuede EB, Berthoud T, Milligan P, Bojang K, Ismaili J, Keating S, Nwakanma D, Keita S, Njie F, Sowe M et al. 2006. Safety and immunogenicity of the malaria candidate vaccines FP9 CS and MVA CS in adult Gambian men. Vaccine, 24 (42-43), pp. 6526-6533. | Citations: 25 (Scopus) | Show Abstract | Read more

We assessed the safety and immunogenicity of prime-boost vectors encoding the Plasmodium falciparum circumsporozoite (CS) protein expressed either in the attenuated fowl-pox virus (FP9) or modified vaccinia virus Ankara (MVA). Thirty-two adult Gambians in groups of four to eight received one, two or three doses of FP9 CS and/or MVA CS. No serious adverse event was observed following vaccination. The most immunogenic regimen was two doses of FP9 followed by a single dose of MVA 4 weeks later (an average of 1000 IFN-gamma spot forming units/million PBMCs). This level of effector T-cell responses appears higher than that seen in previously reported studies of CS-based candidate malaria vaccines.

Thwaites CL, Yen LM, Loan HT, Thuy TTD, Thwaites GE, Stepniewska K, Soni N, White NJ, Farrar JJ. 2006. Magnesium sulphate for treatment of severe tetanus: a randomised controlled trial. Lancet, 368 (9545), pp. 1436-1443. | Citations: 84 (Scopus) | Show Abstract | Read more

BACKGROUND: The most common cause of death in individuals with severe tetanus in the absence of mechanical ventilation is spasm-related respiratory failure, whereas in ventilated patients it is tetanus-associated autonomic dysfunction. Our aim was to determine whether continuous magnesium sulphate infusion reduces the need for mechanical ventilation and improves control of muscle spasms and autonomic instability. METHODS: We did a randomised, double blind, placebo controlled trial in 256 Vietnamese patients over age 15 years with severe tetanus admitted to the Hospital for Tropical Medicine, Ho Chi Minh City, Vietnam. Participants were randomly assigned magnesium sulphate (n=97) or placebo solution (n=98) intravenously for 7 days. The primary outcomes were requirement of assisted ventilation and of drugs to control muscle spasms and cardiovascular instability within the 7-day study period. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN74651862. FINDINGS: No patients were lost to follow-up. There was no difference in requirement for mechanical ventilation between individuals treated with magnesium and those receiving placebo (odds ratio 0.71, 95% CI 0.36-1.40; p=0.324); survival was also much the same in the two groups. However, compared with the placebo group, patients receiving magnesium required significantly less midazolam (7.1 mg/kg per day [0.1-47.9] vs 1.4 mg/kg per day [0.0-17.3]; p=0.026) and pipecuronium (2.3 mg/kg per day [0.0-33.0] vs 0.0 mg/kg per day [0.0-14.8]; p=0.005) to control muscle spasms and associated tachycardia. Individuals receiving magnesium were 4.7 (1.4-15.9) times less likely to require verapamil to treat cardiovascular instability than those in the placebo group. The incidence of adverse events was not different between the groups. INTERPRETATION: Magnesium infusion does not reduce the need for mechanical ventilation in adults with severe tetanus but does reduce the requirement for other drugs to control muscle spasms and cardiovascular instability.

Bejon P, Mwacharo J, Kai O, Mwangi T, Milligan P, Todryk S, Keating S, Lang T, Lowe B, Gikonyo C et al. 2006. A phase 2b randomised trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya. PLoS Clin Trials, 1 (6), pp. e29. | Citations: 103 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: The objective was to measure the efficacy of the vaccination regimen FFM ME-TRAP in preventing episodes of clinical malaria among children in a malaria endemic area. FFM ME-TRAP is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara), which both deliver the pre-erythrocytic malaria antigen construct multiple epitope-thrombospondin-related adhesion protein (ME-TRAP). DESIGN: The trial was randomised and double-blinded. SETTING: The setting was a rural, malaria-endemic area of coastal Kenya. PARTICIPANTS: We vaccinated 405 healthy 1- to 6-year-old children. INTERVENTIONS: Participants were randomised to vaccination with either FFM ME-TRAP or control (rabies vaccine). OUTCOME MEASURES: Following antimalarial drug treatment children were seen weekly and whenever they were unwell during nine months of monitoring. The axillary temperature was measured, and blood films taken when febrile. The primary analysis was time to a parasitaemia of over 2,500 parasites/mul. RESULTS: The regime was moderately immunogenic, but the magnitude of T cell responses was lower than in previous studies. In intention to treat (ITT) analysis, time to first episode was shorter in the FFM ME-TRAP group. The cumulative incidence of febrile malaria was 52/190 (27%) for FFM ME-TRAP and 40/197 (20%) among controls (hazard ratio = 1.52). This was not statistically significant (95% confidence interval [CI] 1.0-2.3; p = 0.14 by log-rank). A group of 346 children were vaccinated according to protocol (ATP). Among these children, the hazard ratio was 1.3 (95% CI 0.8-2.1; p = 0.55 by log-rank). When multiple malaria episodes were included in the analyses, the incidence rate ratios were 1.6 (95% CI 1.1-2.3); p = 0.017 for ITT, and 1.4 (95% CI 0.9-2.1); p = 0.16 for ATP. Haemoglobin and parasitaemia in cross-sectional surveys at 3 and 9 mo did not differ by treatment group. Among children vaccinated with FFM ME-TRAP, there was no correlation between immunogenicity and malaria incidence. CONCLUSIONS: No protection was induced against febrile malaria by this vaccine regimen. Future field studies will require vaccinations with stronger immunogenicity in children living in malarious areas.

Hawn TR, Dunstan SJ, Thwaites GE, Simmons CP, Thuong NT, Lan NTN, Quy HT, Chau TTH, Hieu NT, Rodrigues S et al. 2006. A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. J Infect Dis, 194 (8), pp. 1127-1134. | Citations: 123 (Scopus) | Show Abstract | Read more

BACKGROUND: Although meningitis is the most severe form of infection caused by Mycobacterium tuberculosis, the immunopathogenesis of this disease is poorly understood. We tested the hypothesis that polymorphisms in Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), an adaptor protein that mediates signals from Toll-like receptors activated by mycobacteria, are associated with susceptibility to tuberculosis (TB). METHODS: We used a case-population study design in Vietnam with cord-blood control samples (n = 392) and case patients (n = 358) who had either pulmonary (n = 183) or meningeal (n = 175) TB. RESULTS: The TIRAP single-nucleotide polymorphism (SNP) C558T was associated with increased susceptibility to TB, with a 558T allele frequency of 0.035 in control samples versus 0.074 in case patients (odds ratio [OR], 2.25; P < .001). Subgroup analysis revealed that SNP 558T was more strongly associated with susceptibility to meningeal TB (OR, 3.02; P < .001) than to pulmonary TB (OR, 1.55; P = .22). In comparison to the 558CC genotype, the 558TT genotype was associated with decreased whole-blood interleukin-6 production, which suggests that TIRAP influences disease susceptibility by modulating the inflammatory response. CONCLUSIONS: These results provide the first evidence of an association of a TIRAP SNP with the risk of any disease and also suggest that the Toll-like receptor pathway influences susceptibility to meningeal and pulmonary TB by different immune mechanisms.

Walther M, Woodruff J, Edele F, Jeffries D, Tongren JE, King E, Andrews L, Bejon P, Gilbert SC, De Souza JB et al. 2006. Innate immune responses to human malaria: heterogeneous cytokine responses to blood-stage Plasmodium falciparum correlate with parasitological and clinical outcomes. J Immunol, 177 (8), pp. 5736-5745. | Citations: 87 (Scopus) | Show Abstract | Read more

Taking advantage of a sporozoite challenge model established to evaluate the efficacy of new malaria vaccine candidates, we have explored the kinetics of systemic cytokine responses during the prepatent period of Plasmodium falciparum infection in 18 unvaccinated, previously malaria-naive subjects, using a highly sensitive, bead-based multiplex assay, and relate these data to peripheral parasite densities as measured by quantitative real-time PCR. These data are complemented with the analysis of cytokine production measured in vitro from whole blood or PBMC, stimulated with P. falciparum-infected RBC. We found considerable qualitative and quantitative interindividual variability in the innate responses, with subjects falling into three groups according to the strength of their inflammatory response. One group secreted moderate levels of IFN-gamma and IL-10, but no detectable IL-12p70. A second group produced detectable levels of circulating IL-12p70 and developed very high levels of IFN-gamma and IL-10. The third group failed to up-regulate any significant proinflammatory responses, but showed the highest levels of TGF-beta. Proinflammatory responses were associated with more rapid control of parasite growth but only at the cost of developing clinical symptoms, suggesting that the initial innate response may have far-reaching consequences on disease outcome. Furthermore, the in vitro observations on cytokine kinetics presented here, suggest that intact schizont-stage infected RBC can trigger innate responses before rupture of the infected RBC.

Lindegårdh N, Hien TT, Farrar J, Singhasivanon P, White NJ, Day NPJ. 2006. A simple and rapid liquid chromatographic assay for evaluation of potentially counterfeit Tamiflu. J Pharm Biomed Anal, 42 (4), pp. 430-433. | Citations: 54 (Scopus) | Show Abstract | Read more

A simple and rapid liquid chromatographic assay for the evaluation of potentially counterfeit oseltamivir (Tamiflu has been developed and assessed. The assay uses approximately 1mg Tamiflu powder when used for authentication and content estimate. The procedure was validated using 50 replicates analysed during five independent series with a total R.S.D. of 11.2%. The assay can also be used to monitor the exact content of oseltamivir in Tamiflu capsules. One Tamiflu capsule was transferred to a 250mL volumetric flask and 150mL water was added. The flask was placed in an ultrasonic bath at 40 degrees C for 20min to dissolve the capsule. The solution was allowed to cool to room temperature before the flask was filled up to the mark (250mL). A small aliquot was centrifuged and then directly injected into the LC-system for quantification. Oseltamivir was analysed by liquid chromatography with UV detection on a Hypersil Gold column (150mmx4.6mm) using a mobile phase containing methanol-phosphate buffer (pH 2.5; 0.1M) (50:50, v/v) at a flow rate of 1.0mL/min. The assay was implemented for the analysis of Tamiflu purchased over the Internet and at local pharmacies in Thailand and Vietnam.

Rentenaar RJ, van Doorn HR, Rijneveld AW. 2006. [Acute anaemia in a Vietnamese patient with alpha-thalassaemia and a parvovirus infection]. Ned Tijdschr Geneeskd, 150 (40), pp. 2223.

Siswantoro H, Ratclif A, Kenangalem E, Wuwung M, Maristela R, Rumaseuw R, Laihad F, Ebsworth P, Anstey NM, Price RN, Tjitra E. 2006. Efficacy of existing antimalarial drugs for uncomplicated malaria in Timika, Papua, Indonesia Medical Journal of Indonesia, 15 (4), pp. 251-251. | Citations: 3 (Scopus) | Show Abstract | Read more

© 2006 Faculty of Medicine, Universitas Indonesia. All rights reserved. Chloroquine resistant malaria is a serious problem in Indonesia particularly in Papua. A trial of the existing antimalarial drugs was conducted in Timika, Papua. The objective of the study was to determine the efficacy of cloroquine (CQ) ± sulfadoxine-pyrimethamine (SP). Patients with uncomplicated malaria due to Plasmodium falciparum, P. vivax, P. ovale or P. malariae were enrolled and treated with supervised CQ+SP (P. falciparum) or CQ (non-P. falciparum). Patients were followed for 28-42 days. Patients failing therapy were retreated with unsupervised quinine±doxycycline. 207 patients were enrolled in the study (88 P. falciparum, 40 P. vivax, 15 mixed infections, 50 P. malariae and 14 P. ovale). Early treatment failures occurred in 4 of 86 (5%) patients with falciparum malaria, 6 of 37 (16%) patients with vivax malaria and none of those with P. ovale or P. malariae infections. The failure rate by day 28 for P. vivax was 22 of 30 (73%) patients, with all recurrences occurring in the presence of plasma chloroquine concentration above the minimum effective concentration (MEC > 15ng/ml). After correcting for reinfections the day 42 recrudescence rate for falciparum malaria was 48% [95%CI:31-65] and in 61% of cases this was in the presence of chloroquine levels above 30 ng/ml. Retreatment with unsupervised quinine±doxycycline resulted in further recurrence of malaria in 48% [95%CI:31-65] of P. falciparum infections and 70% [95%CI:37-100] of P. vivax infections. None of the patients with P. ovale or P. malariae had treatment failures within 28 days. There is a high prevalence of antimalarial drug resistance of P. falciparum and P. vivax to the existing antimalarial drugs. However chloroquine retains adequate efficacy against P. ovale and P. malariae in Papua.

Dunachie SJ, Walther M, Epstein JE, Keating S, Berthoud T, Andrews L, Andersen RF, Bejon P, Goonetilleke N, Poulton I et al. 2006. A DNA prime-modified vaccinia virus ankara boost vaccine encoding thrombospondin-related adhesion protein but not circumsporozoite protein partially protects healthy malaria-naive adults against Plasmodium falciparum sporozoite challenge. Infect Immun, 74 (10), pp. 5933-5942. | Citations: 131 (Web of Science Lite) | Show Abstract | Read more

The safety, immunogenicity, and efficacy of DNA and modified vaccinia virus Ankara (MVA) prime-boost regimes were assessed by using either thrombospondin-related adhesion protein (TRAP) with a multiple-epitope string ME (ME-TRAP) or the circumsporozoite protein (CS) of Plasmodium falciparum. Sixteen healthy subjects who never had malaria (malaria-naive subjects) received two priming vaccinations with DNA, followed by one boosting immunization with MVA, with either ME-TRAP or CS as the antigen. Immunogenicity was assessed by ex vivo gamma interferon (IFN-gamma) enzyme-linked immunospot assay (ELISPOT) and antibody assay. Two weeks after the final vaccination, the subjects underwent P. falciparum sporozoite challenge, with six unvaccinated controls. The vaccines were well tolerated and immunogenic, with the DDM-ME TRAP regimen producing stronger ex vivo IFN-gamma ELISPOT responses than DDM-CS. One of eight subjects receiving the DDM-ME TRAP regimen was completely protected against malaria challenge, with this group as a whole showing significant delay to parasitemia compared to controls (P = 0.045). The peak ex vivo IFN-gamma ELISPOT response in this group correlated strongly with the number of days to parasitemia (P = 0.033). No protection was observed in the DDM-CS group. Prime-boost vaccination with DNA and MVA encoding ME-TRAP but not CS resulted in partial protection against P. falciparum sporozoite challenge in the present study.

Aslam A, Kessler B, Batycka M, O'Callaghan CA, Misbah SA, Warrell DA, Ogg G. 2006. Defining the T cell antigen proteome of wasp venom. Clin Exp Allergy, 36 (10), pp. 1274-1280. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: While modulation of T cell function is believed to be important in the successful acquisition of clinical tolerance during venom immunotherapy, little is known of the role of wasp venom specific T cell antigens. OBJECTIVE: We sought comprehensively to characterize the T cell proteome for wasp venom to facilitate the future development of T cell-based immunotherapeutic approaches. METHODS: Using peripheral blood mononuclear cells from wasp venom-allergic individuals and IL-4 ELISPOT analysis, we characterized T cell responses to whole venom and gel filtration/ion exchange-fractionated venom. Reactive fractions were purified and identified using highly sensitive electrospray ion-trap mass spectrometry. RESULTS: Wasp venom-allergic individuals have detectable whole wasp venom-specific T cells directly ex vivo, which show rapid IL-4 effector function. T cell responses to gel filtration/ion exchange fractionated venom were dominated by responses to phospholipase A(1), hyaluronidase and antigen 5. CONCLUSION: Although it is likely that there are many T cell antigens within wasp venom, the main responses are to proteins coincident with the known IgE-binding proteins.

Blacksell SD, Smythe L, Phetsouvanh R, Dohnt M, Hartskeerl R, Symonds M, Slack A, Vongsouvath M, Davong V, Lattana O et al. 2006. Limited diagnostic capacities of two commercial assays for the detection of Leptospira immunoglobulin M antibodies in Laos. Clin Vaccine Immunol, 13 (10), pp. 1166-1169. | Citations: 37 (Web of Science Lite) | Show Abstract | Read more

The diagnostic utility of immunochromatographic (Leptotek) and enzyme-linked immunosorbent assay (ELISA; Panbio) tests for the detection of Leptospira immunoglobulin M antibodies was assessed in febrile adults admitted in Vientiane, Laos. Both tests demonstrated poor diagnostic accuracy using admission serum (Leptotek sensitivity of 47.3% and specificity of 75.5%: ELISA sensitivity of 60.9% and specificity of 65.6%) compared to the Leptospira "gold standard" microscopic agglutination test.

de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJD, Chau TNB, Hoang DM, Chau NVV, Khanh TH, Dong VC et al. 2006. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med, 12 (10), pp. 1203-1207. | Citations: 1048 (Scopus) | Show Abstract | Read more

Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, we performed virological and immunological studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was associated with higher pharyngeal viral loads. We observed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex associated with mammalian adaptation and virulence. Our observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment.

Thuong NTT, Dunstan SJ, Dung NM, Charlieu J-P, Loan HT, Wills B, Solomon T, Farrar JJ. 2006. Polymorphisms of the gene coding for copper/zinc superoxide dismutase (SOD1) in patients with Japanese encephalitis. Ann Trop Med Parasitol, 100 (7), pp. 631-636. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

Japanese encephalitis is the commonest form of encephalitis globally. Most cases develop characteristic encephalitis but some also present with flaccid paralysis. The paralysis is secondary to damage at the alpha motor neurone, the site that is also damaged in amyotrophic lateral sclerosis (ALS). The gene coding for superoxide dismutase 1 (SOD1) is thought to be involved in ALS and may also be linked to susceptibility to Japanese encephalitis. To investigate this possibility, polymorphisms in the SOD1 gene were investigated, in 61 cases of Japanese encephalitis, 61 matched controls and 171 population controls, in Vietnam. Novel polymorphisms, found only in three of the cases and one of the population controls, may be involved with susceptibility to Japanese encephalitis and potentially to other flavivirus infections that lead to damage to the cells of the anterior horn. Further research on this possible association is required.

Borel T, Rose AMC, Guillerm M, Sidikou F, Gerstl S, Djibo A, Nathan N, Chanteau S, Guerin PJ. 2006. High sensitivity and specificity of the Pastorex latex agglutination test for Neisseria meningitidis serogroup A during a clinical trial in Niger. Trans R Soc Trop Med Hyg, 100 (10), pp. 964-969. | Citations: 16 (Scopus) | Show Abstract | Read more

There is a great need for a rapid diagnostic test to guide vaccine choice during outbreaks of meningococcal meningitis in resource-poor countries. During a randomised clinical trial conducted during an epidemic of Neisseria meningitidis serogroup A in Niger in 2003, the sensitivity and specificity of the Pastorex latex agglutination test for this serogroup under optimal field conditions were assessed, using culture and/or PCR as the gold standard. Results from 484 samples showed a sensitivity of 88% (95% CI 85-91%) and a specificity of 93% (95% CI 90-95%). Pastorex could be a good alternative to current methods, as it can be performed in a local laboratory with rapid results and is highly specific. Sensitivity can be improved with prior microscopy where feasible. A study specifically to evaluate the Pastorex test under epidemic conditions, using laboratories with limited resources, is recommended.

Zurovac D, Rowe AK. 2006. Quality of treatment for febrile illness among children at outpatient facilities in sub-Saharan Africa (vol 100, pg 283, 2006) ANNALS OF TROPICAL MEDICINE AND PARASITOLOGY, 100 (7), pp. 642-642.

Checchi F, Cox J, Balkan S, Tamrat A, Priotto G, Alberti KP, Guthmann J-P. 2006. Malaria epidemics and interventions, Kenya, Burundi, southern Sudan, and Ethiopia, 1999-2004. Emerg Infect Dis, 12 (10), pp. 1477-1485. | Citations: 38 (Scopus) | Show Abstract | Read more

Quantitative data on the onset and evolution of malaria epidemics are scarce. We review case studies from recent African Plasmodium falciparum epidemics (Kisii and Gucha Districts, Kenya, 1999; Kayanza Province, Burundi, 2000-2001; Aweil East, southern Sudan, 2003; Gutten and Damot Gale, Ethiopia, 2003-2004). We highlight possible epidemic risk factors and review delays in epidemic detection and response (up to 20 weeks), essentially due to poor case reporting and analysis or low use of public facilities. Epidemics lasted 15-36 weeks, and patients' age profiles suggested departures from classical notions of epidemic malaria everywhere but Burundi. Although emergency interventions were mounted to expand inpatient and outpatient treatment access, we believe their effects were lessened because of delays, insufficient evaluation of disease burden, lack of evidence on how to increase treatment coverage in emergencies, and use of ineffective drugs.

van Doorn HR, Bruijnesteijn van Coppenraet ES, Duim B, Vandenbroucke-Grauls CMJE, Weel JF, Dankert J, Kuijper EJ, de Jong MD. 2006. Silica-guanidinium thiocyanate-based nucleic acid isolation protocol does not improve sensitivity of two commercial tests for detection of Mycobacterium tuberculosis in respiratory samples. Eur J Clin Microbiol Infect Dis, 25 (10), pp. 673-675. | Citations: 2 (Scopus) | Read more

Verra F, Chokejindachai W, Weedall GD, Polley SD, Mwangi TW, Marsh K, Conway DJ. 2006. Contrasting signatures of selection on the Plasmodium falciparum erythrocyte binding antigen gene family. Mol Biochem Parasitol, 149 (2), pp. 182-190. | Citations: 27 (Web of Science Lite) | Show Abstract | Read more

Erythrocyte binding antigens of Plasmodium falciparum are involved in erythrocyte invasion, and may be targets of acquired immunity. Of the five eba genes, protein products have been detected for eba-175, eba-181 and eba-140, but not for psieba-165 or ebl-1, providing opportunity for comparative analysis of genetic variation to identify selection. Region II of each of these genes was sequenced from a cross-sectional sample of parasites in an endemic Kenyan population, and the frequency distributions of polymorphisms analysed. A positive value of Tajima's D was observed for eba-175 (D=1.13) indicating an excess of intermediate frequency polymorphisms, while all other genes had negative values, the most negative being ebl-1 (D=-2.35) followed by psieba-165 (D=-1.79). The eba-175 and ebl-1 genes were then studied in a sample of parasites from Thailand, for which a positive Tajima's D value was again observed for eba-175 (D=1.79), and a negative value for ebl-1 (D=-1.85). This indicates that eba-175 is under balancing selection in each population, in strong contrast to the other members of the gene family, particularly ebl-1 and psieba-165 that may have been under recent directional selection. Population expansion simulations were performed under a neutral model, further supporting the departures from neutrality of these genes.

Nery S, Deans A-M, Mosobo M, Marsh K, Rowe JA, Conway DJ. 2006. Expression of Plasmodium falciparum genes involved in erythrocyte invasion varies among isolates cultured directly from patients. Mol Biochem Parasitol, 149 (2), pp. 208-215. | Citations: 41 (Web of Science Lite) | Show Abstract | Read more

Plasmodium falciparum merozoites invade erythrocytes using a range of alternative ligands that includes erythrocyte binding antigenic proteins (EBAs) and reticulocyte binding protein homologues (Rh). Variation in the expression of some of these genes among culture-adapted parasite lines correlates with the use of different erythrocyte receptors. Here, expression profiles of four Rh genes and eba175 are analysed in a sample of 42 isolates cultured from malaria patients in Kenya. The profiles cluster into distinct groups, largely because of very strong negative correlations between the levels of expression of particular gene pairs (Rh1 versus Rh2b, eba175 versus Rh2b, and eba175 versus Rh4), previously associated with alternative invasion pathways in culture-adapted parasite lines. High levels of eba175 are seen in isolates in expression profile group I, and may be associated with sialic acid-dependent invasion. Groups II and III are, respectively, characterized by high levels of Rh2b and Rh4, and are more likely to be associated with sialic acid-independent invasion.

Ayieko P, English M. 2006. In children aged 2-59 months with pneumonia, which clinical signs best predict hypoxaemia? J Trop Pediatr, 52 (5), pp. 307-310. | Citations: 22 (Scopus) | Read more

Newton O, English M. 2006. Newborn resuscitation: defining best practice for low-income settings. Trans R Soc Trop Med Hyg, 100 (10), pp. 899-908. | Citations: 33 (Scopus) | Show Abstract | Read more

Current resuscitation practices are often poor in low-income settings. The purpose of this review was to summarise recent evidence, relevant to developing countries, on best practice in the provision of newborn resuscitation. Potential studies for inclusion were identified using structured searches of MEDLINE via PubMed. Two reviewers independently evaluated retrieved studies for inclusion. The methodological quality of the selected articles was assessed using the Oxford Centre for Evidence-Based Medicine (CEBM) levels of evidence, whilst the Scottish Intercollegiate Guidelines Network (SIGN) grading system was used for subsequent recommendations. Based on available evidence, where there is meconium-stained liquor, routine perineal suction of all babies and endotracheal suction of active babies do not prevent meconium aspiration syndrome and have potential risks. Adequate ventilation is possible with a bag-valve-mask device and room air is just as efficient as oxygen for initial resuscitation. This review supports the view that effective resuscitation is possible with basic equipment and minimal skills. Thus, where resources are limited, it should be possible to improve neonatal outcomes through promotion of the effective use of a bag-valve-mask alone, without access to more sophisticated and expensive technologies. Basic, effective resuscitation should therefore be available at all health facilities and potentially in the community.

Le Bas C, Tran TH, Nguyen TT, Dang DT, Ngo CT. 2006. Prevalence and epidemiology of Salmonella spp. in small pig abattoirs of Hanoi, Vietnam. Ann N Y Acad Sci, 1081 (1), pp. 269-272. | Show Abstract | Read more

The prevalence of Salmonella spp. in pigs was evaluated in a survey of small abattoirs in Hanoi, Vietnam. Cecal contents, carcass swabs, and tank water samples were collected for bacterial isolation in various media. Prevalence rates exceeded 50% in pig samples and 62% in water samples. This increased prevalence indicates the need for risk assessment evaluations along the entire production chain.

Na-Ubol M, Samosornsuk S, Von Seidlein L, Tapchaisri P, Ali M, Clemens JD, Chaicumpa W. 2006. Molecular characteristics of Shigella spp. isolated from patients with diarrhoea in a new industrialized area of Thailand. Epidemiol Infect, 134 (5), pp. 997-1003. | Citations: 7 (Scopus) | Show Abstract | Read more

In this study, we used plasmid profile analysis, XbaI macrorestriction with pulsed-field gel electrophoresis (PFGE), and PCR of the ipaH gene, to study the molecular characteristics of 183 Shigella spp. isolated during May 2000 to April 2003 from rectal swabs of patients with watery and/or bloody diarrhoea in a new industrialized area of Thailand. Among the 183 isolates, 167 were S. sonnei and 16 were S. flexneri. For plasmid profile analysis, the 183 isolates revealed 16 different plasmid patterns, designated patterns A to P. The sizes of the plasmid bands were: 6, 5.5, 5, 4.5, 4, 3.25, 2.75, 2.5, 2, 1.75, 1.5 and/or 1.25 kb. The frequency of each plasmid band was 4.5 kb (165 isolates), 3.25 kb (161 isolates), 5.5 kb (129 isolates), 1.75 kb (121 isolates), 1.5 kb (35 isolates), 5 kb (21 isolates), 2 kb (16 isolates), 2.75 kb (12 isolates), 1.25 kb (9 isolates), and 6 kb (8 isolates). PFGE analysis revealed 45 different XbaI macrorestricted DNA banding patterns which could be grouped into 11 groups. All the isolates gave PCR amplicons of the ipaH gene. Plasmid profile analysis and PFGE are powerful tools for differentiation of the Shigella spp. This study provides important data on the molecular characteristics of Shigella isolates in Thailand, which could be useful as an epidemiological baseline for identifying relationships with strains that may emerge in the future.

Hamers R, Bontemps S, van den Akker M, Souza R, Penaforte J, Chavannes N. 2006. Chronic obstructive pulmonary disease in Brazilian primary care: Diagnostic competence and case-finding. Prim Care Respir J, 15 (5), pp. 299-306. | Citations: 10 (Scopus) | Show Abstract | Read more

AIMS: The developing world is particularly at risk of an increasing health burden due to an increased prevalence of Chronic Obstructive Pulmonary Disease (COPD) secondary to increasing tobacco consumption. However, research is scarce. The objectives of this study were to assess the current competence for diagnosing COPD in primary care in a resource-limited setting in Brazil, and to develop a local patient profile for case-finding. METHODS: 34 general practitioners (GPs) in five areas of northern Brazil recruited adult patients with principal complaints of cough and/or shortness of breath who then had spirometry (n = 142). RESULTS: For the dichotomous variable 'COPD' the degree of agreement between GP diagnosis (n = 64, 18.3%) and spirometric outcome (n = 36, 25.4%) was poor, with Kappa = 0.055 (SE 0.087) and DOR = 1.35. False-positive and false-negative diagnosis proportions were 19.8% and 75%, respectively. Independent risk factors were 'smoking history of more than five pack years' and 'presence of both dyspnoea and cough'. It requires the testing of 2.2 smokers with more than five pack years to detect one patient at risk. CONCLUSIONS: COPD is a common yet underdiagnosed disease in Brazilian primary care. Spirometry improves diagnostic competence and case-finding substantially. If applied in a pre-selected high-risk population, we believe spirometry can be a cost-effective diagnostic tool for case-finding in the resource-limited setting. This study provides important baseline information for effective guideline implementation.

Day N. 2006. Fluid resuscitation in malaria: the need for new randomised clinical trials. PLoS Clin Trials, 1 (5), pp. e24. | Citations: 4 (Web of Science Lite) | Read more

Newton PN, Green MD, Fernández FM, Day NPJ, White NJ. 2006. Counterfeit anti-infective drugs. Lancet Infect Dis, 6 (9), pp. 602-613. | Citations: 206 (Scopus) | Show Abstract | Read more

The production of counterfeit or substandard anti-infective drugs is a widespread and under-recognised problem that contributes to morbidity, mortality, and drug resistance, and leads to spurious reporting of resistance and toxicity and loss of confidence in health-care systems. Counterfeit drugs particularly affect the most disadvantaged people in poor countries. Although advances in forensic chemical analysis and simple field tests will enhance drug quality monitoring, improved access to inexpensive genuine medicines, support of drug regulatory authorities, more open reporting, vigorous law enforcement, and more international cooperation with determined political leadership will be essential to counter this threat.

Kosaisavee V, Suwanarusk R, Nosten F, Kyle DE, Barrends M, Jones J, Price R, Russell B, Lek-Uthai U. 2006. Plasmodium vivax: isotopic, PicoGreen, and microscopic assays for measuring chloroquine sensitivity in fresh and cryopreserved isolates. Exp Parasitol, 114 (1), pp. 34-39. | Citations: 35 (Scopus) | Show Abstract | Read more

In vitro susceptibility tests provide information on the intrinsic response of Plasmodium vivax to antimalarials, free from confounding factors such as host immunity or relapse. This study examined the utility of radioisotope and PicoGreen assays as alternatives to the traditional microscopic examination for assessing response of P. vivax to antimalarial drugs. There was no significant difference in the mean chloroquine IC(50) of P. vivax (n=40) as determined by the microscopic (33.4 ng/ml), isotopic (33.6 ng/ml), and PicoGreen (39.1 ng/ml) assays, respectively (F=0.239, df=2, 51, and p=0.788). However measurement of IC(50)s by the microscopic method was slightly more successful in producing valid assays (57%), compared to the isotopic (32.5%) and PicoGreen (45.5%) methods. In a paired comparison of 20 fresh and cryopreserved isolates as examined by the microscopic method, there were no significant differences between the mean IC(50) responses (T=1.58, df=15, and p=0.34). Detailed methodologies for the short time culture of field and cryopreserved P. vivax are described. Although the microscopic in vitro assay provides a useful method for characterizing the drug susceptibility phenotype of P. vivax isolates, its utility is limited by a laborious methodology and need for highly skilled microscopists. Future efforts should focus on further development of high throughput assays such as the PicoGreen assay as described in this study.

Lindegardh N, Davies GR, Tran TH, Farrar J, Singhasivanon P, Day NPJ, White NJ. 2006. Rapid degradation of oseltamivir phosphate in clinical samples by plasma esterases. Antimicrob Agents Chemother, 50 (9), pp. 3197-3199. | Citations: 38 (Scopus) | Show Abstract | Read more

The anti-influenza drug oseltamivir is an ester prodrug activated by hepatic carboxylesterases. Plasma esterases also convert up to 31.8% of the parent compound to the active metabolite after 4 h ex vivo, with wide interindividual variation. This source of error is removed by adding the esterase inhibitor dichlorvos to blood collection tubes.

Eddleston M, Dissanayake M, Sheriff MHR, Warrell DA, Gunnell D. 2006. Physical vulnerability and fatal self-harm in the elderly. Br J Psychiatry, 189 (3), pp. 278-279. | Citations: 10 (Scopus) | Show Abstract | Read more

Although the high rate of suicide in elderly people is conventionally explained as being due to greater intent to die, we have noted elderly Sri Lankans dying after relatively mild poisoning. Using data from cases of yellow oleander poisoning, we investigated the effect of age on outcome in 1697 patients, controlling for gender and amount ingested. In fully adjusted models, people over 64 years old were 13.8 (95% CI 3.6-53.0) times more likely to die than those less than 25 years old. The high number of suicides in elderly people globally is likely to be due, in part, to the difficulty they face in surviving the effects of both the poisoning and its treatment.

Kariuki S, Revathi G, Kiiru J, Lowe B, Berkley JA, Hart CA. 2006. Decreasing prevalence of antimicrobial resistance in non-typhoidal Salmonella isolated from children with bacteraemia in a rural district hospital, Kenya. Int J Antimicrob Agents, 28 (3), pp. 166-171. | Citations: 14 (Web of Science Lite) | Show Abstract | Read more

We analysed 336 non-typhoidal Salmonella (NTS) isolated from children <13 years of age with bacteraemia admitted to a rural district hospital in Kenya from 1994 to 2005. Pulsed-field gel electrophoresis was used to determine genetic relatedness of strains, and antimicrobial susceptibility testing was also performed. Most NTS were either Salmonella enterica serovar Typhimurium (n=114; 33.9%) or S. enterica serovar Enteritidis (n=128; 38.1%), with minimal genotypic diversity over the study period. The NTS showed a remarkable decrease in levels of resistance especially to two commonly available antimicrobials (amoxicillin and co-trimoxazole), from high of 69.2% and 68.4% during 1994-1997 to 11% and 13%, respectively, in 2002-2005 (P<0.01). All NTS remained fully susceptible to cefotaxime and ciprofloxacin. Our findings show that commonly available drugs may still be useful for treatment of invasive NTS infections in this rural population.

Grais RF, Ferrari MJ, Dubray C, Bjørnstad ON, Grenfell BT, Djibo A, Fermon F, Guerin PJ. 2006. Estimating transmission intensity for a measles epidemic in Niamey, Niger: lessons for intervention. Trans R Soc Trop Med Hyg, 100 (9), pp. 867-873. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

The objective of this study is to estimate the effective reproductive ratio for the 2003-2004 measles epidemic in Niamey, Niger. Using the results of a retrospective and prospective study of reported cases within Niamey during the 2003-2004 epidemic, we estimate the basic reproductive ratio, effective reproductive ratio (RE) and minimal vaccination coverage necessary to avert future epidemics using a recent method allowing for estimation based on the epidemic case series. We provide these estimates for geographic areas within Niamey, thereby identifying neighbourhoods at high risk. The estimated citywide RE was 2.8, considerably lower than previous estimates, which may help explain the long duration of the epidemic. Transmission intensity varied during the course of the epidemic and within different neighbourhoods (RE range: 1.4-4.7). Our results indicate that vaccination coverage in currently susceptible children should be increased by at least 67% (vaccine efficacy 90%) to produce a citywide vaccine coverage of 90%. This research highlights the importance of local differences in vaccination coverage on the potential impact of epidemic control measures. The spatial-temporal spread of the epidemic from district to district in Niamey over 30 weeks suggests that targeted interventions within the city could have an impact.

Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ. 2006. Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg, 75 (3), pp. 402-415. | Citations: 170 (Web of Science Lite) | Show Abstract

Primaquine phosphate has been used for preventing relapse of Plasmodium vivax and P. ovale malaria since the early 1950s, based on its ability to kill latent (hypnozoite) and developing liver stages of these parasites. There are three uses for primaquine in malaria: radical cure of established infection with P. vivax or P. ovale malaria; presumptive anti-relapse therapy (PART; terminal prophylaxis) in persons with extensive exposure to these parasites; and primary prophylaxis against all malaria species. All persons for whom primaquine is being considered must have a glucose-6-phosphate dehydrogenase (G6PD) enzyme level checked before use, and persons who have a deficiency of G6PD must not take primaquine for prophylaxis or PART. The recommended adult dose for PART based on clinical trials and expert opinion is 30 mg base daily for 14 days, started on return from a malarious region and overlapping with a blood schizonticide. The adult dose for primary prophylaxis is 30 mg daily begun 1 day before travel and continued for 7 days after return. This review will examine the evidence for these recommendations.

Waris M, White LJ. 2006. Seasonality of respiratory syncytial virus infection. Clin Infect Dis, 43 (4), pp. 541. | Citations: 4 (Web of Science Lite) | Read more

Kim J-R, Imwong M, Nandy A, Chotivanich K, Nontprasert A, Tonomsing N, Maji A, Addy M, Day NPJ, White NJ, Pukrittayakamee S. 2006. Genetic diversity of Plasmodium vivax in Kolkata, India. Malar J, 5 pp. 71. | Citations: 60 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium vivax malaria accounts for approximately 60% of malaria cases in Kolkata, India. There has been limited information on the genotypic polymorphism of P. vivax in this malaria endemic area. Three highly polymorphic and single copy genes were selected for a study of genetic diversity in Kolkata strains. METHODS: Blood from 151 patients with P. vivax infection diagnosed in Kolkata between April 2003 and September 2004 was genotyped at three polymorphic loci: the P. vivax circumsporozoite protein (pvcs), the merozoite surface protein 1 (pvmsp1) and the merozoite surface protein 3-alpha (pvmsp3-alpha). RESULTS: Analysis of these three genetic markers revealed that P. vivax populations in Kolkata are highly diverse. A large number of distinguishable alleles were found from three genetic markers: 11 for pvcs, 35 for pvmsp1 and 37 for pvmsp3-alpha. These were, in general, randomly distributed amongst the isolates. Among the 151 isolates, 142 unique genotypes were detected the commonest genotype at a frequency of less than 2% (3/151). The overall rate of mixed genotype infections was 10.6%. CONCLUSION: These results indicate that the P. vivax parasite population is highly diverse in Kolkata, despite the low level of transmission. The genotyping protocols used in this study may be useful for differentiating re-infection from relapse and recrudescence in studies assessing of malarial drug efficacy in vivax malaria.

Cowgill KD, Ndiritu M, Nyiro J, Slack MPE, Chiphatsi S, Ismail A, Kamau T, Mwangi I, English M, Newton CRJC et al. 2006. Effectiveness of Haemophilus influenzae type b Conjugate vaccine introduction into routine childhood immunization in Kenya. JAMA, 296 (6), pp. 671-678. | Citations: 122 (Scopus) | Show Abstract | Read more

CONTEXT: Haemophilus influenzae type b (Hib) conjugate vaccine is not perceived as a public health priority in Africa because data on Hib disease burden and vaccine effectiveness are scarce. Hib immunization was introduced in Kenyan infants in 2001. OBJECTIVE: To define invasive Hib disease incidence and Hib vaccine program effectiveness in Kenya. DESIGN, SETTING, AND PATIENTS: Culture-based surveillance for invasive Hib disease at Kilifi District Hospital from 2000 through 2005 was linked to demographic surveillance of 38,000 children younger than 5 years in Kilifi District, Kenya. Human immunodeficiency virus (HIV) infection and Hib vaccination status were determined for children with Hib disease admitted 2002-2005. INTERVENTIONS: Introduction of conjugate Hib vaccine within the routine childhood immunization program at ages 6, 10, and 14 weeks beginning November 2001. MAIN OUTCOME MEASURES: Incidence of culture-proven Hib invasive disease before and after vaccine introduction and vaccine program effectiveness. RESULTS: Prior to vaccine introduction, the median age of children with Hib was 8 months; case fatality was 23%. Among children younger than 5 years, the annual incidence of invasive Hib disease 1 year before and 1 and 3 years after vaccine introduction was 66, 47, and 7.6 per 100,000, respectively. For children younger than 2 years, incidence was 119, 82, and 16 per 100,000, respectively. In 2004-2005, vaccine effectiveness was 88% (95% confidence interval, 73%-96%) among children younger than 5 years and 87% (95% confidence interval, 66%-96%) among children younger than 2 years. Of 53 children with Hib admitted during 2002-2005, 29 (55%) were age-ineligible to have received vaccine, 12 (23%) had not been vaccinated despite being eligible, and 12 (23%) had received 2 or more doses of vaccine (2 were HIV positive). CONCLUSIONS: In Kenya, introduction of Hib vaccine into the routine childhood immunization program reduced Hib disease incidence among children younger than 5 years to 12% of its baseline level. This impact was not observed until the third year after vaccine introduction.

Blacksell SD, Doust JA, Newton PN, Peacock SJ, Day NPJ, Dondorp AM. 2006. A systematic review and meta-analysis of the diagnostic accuracy of rapid immunochromatographic assays for the detection of dengue virus IgM antibodies during acute infection. Trans R Soc Trop Med Hyg, 100 (8), pp. 775-784. | Citations: 31 (Scopus) | Show Abstract | Read more

A meta-analysis of rapid (</=60 min) dengue diagnostic assays was conducted to determine accuracy and identify causes of between-study heterogeneity. A systematic review identified 302 potentially suitable studies, of which 11 were selected for meta-analysis. All selected studies evaluated the immunochromatographic test (ICT) manufactured by Panbio Pty Ltd. Individual study results for sensitivity ranged from 0.45 to 1.0, specificity 0.57-1.0, diagnostic odds ratio 4.5-1287, and positive:negative likelihood ratios 2.3-59 and 0.01-0.56, respectively. Results indicated that the ICT evaluated in the selected studies can both rule in and rule out disease but is more accurate when samples are collected later in the acute phase of infection. Limitations of this meta-analysis were significant between-study heterogeneity caused by inconsistencies in evaluation methodologies, and the evaluation of only the Panbio ICT. It is recommended that additional, standardized evaluations are required for other dengue ICTs.

Mayxay M, Thongpraseuth V, Khanthavong M, Lindegårdh N, Barends M, Keola S, Pongvongsa T, Phompida S, Phetsouvanh R, Stepniewska K et al. 2006. An open, randomized comparison of artesunate plus mefloquine vs. dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People's Democratic Republic (Laos). Trop Med Int Health, 11 (8), pp. 1157-1165. | Citations: 46 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To determine the efficacy and safety of oral dihydroartemisinin-piperaquine (DP, Artekin) in the treatment of uncomplicated Plasmodium falciparum malaria in southern Laos. METHODS: An open, randomized clinical trial of oral artesunate-mefloquine (AM) vs. DP in 220 patients with acute uncomplicated falciparum malaria in Savannakhet Province, Laos. RESULTS: The 42-day cure rates (95% CI), as determined by survival analysis and adjusted for reinfection, were excellent and similar for the two groups [99 (94-100)% and 100 (100-100)% for AM and DP, respectively]. The median (range) fever and parasite clearance times for the AM and DP groups were also similar [20 (4-63) h and 2 (1-4) days vs. 20 (7-57) and 2 (1-4) days, logrank P = 0.4 and 0.17, respectively]. There were more patients with at least one potential side effect following treatment in the AM group when compared with the DP group [64/110 (58%) vs. 48/110 (44%), respectively, P = 0.031]. CONCLUSION: Dihydroartemisinin-piperaquine did not have superior efficacy to AM for the treatment of uncomplicated falciparum malaria in Laos but was associated with fewer adverse effects.

Guerra CA, Snow RW, Hay SI. 2006. Mapping the global extent of malaria in 2005. Trends Parasitol, 22 (8), pp. 353-358. | Citations: 185 (Scopus) | Show Abstract | Read more

Guidelines for travellers on malaria chemoprophylaxis, the altitude limits of dominant vector species, climate suitability for malaria transmission and human population density thresholds have been used to map the crude spatial limits of Plasmodium falciparum and Plasmodium vivax transmission on a global scale. These maps suggest that 2.510 and 2.596 billion people were at possible risk of transmission of P. falciparum and P. vivax, respectively, in 2005. Globally, 75 per cent of humans who are exposed to P. falciparum risk live in only ten countries.

Tatem AJ, Snow RW, Hay SI. 2006. Mapping the environmental coverage of the INDEPTH demographic surveillance system network in rural Africa. Trop Med Int Health, 11 (8), pp. 1318-1326. | Citations: 14 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: The INDEPTH DSS network was founded in 1998 to provide an international network of field sites for continuous demographic evaluation of populations and their health. Results from the network have been used to derive estimates of mortality, morbidity and health equity. Spatial extrapolation and logical summaries of these findings are dependent on the network covering a representative sample of the environments in a region and their interrelationships being known. Here, we investigate how comprehensive is the coverage of the network of rural DSS sites in Africa in terms of the range of ecological zones found across the continent. METHODS: We used satellite imagery to define an environmental signature for each INDEPTH DSS site, and then calculate Euclidean distances from these signatures to the environmental signatures of every image pixel across Africa. These distances were then mapped and a gridded population surface used to mask uninhabited areas to illustrate the extent of the environmental coverage of the INDEPTH network. Environmental similarities between DSS sites were also calculated, hierarchically clustered and visualized as a dendrogram to examine between site relationships. Finally, an ecozonation of Africa was used to analyse the per-ecozone environmental similarity of the INDEPTH DSS network. RESULTS AND CONCLUSIONS: The current INDEPTH DSS network in Africa spans all the major environmental zones, but within these zones the environmental coverage of the network varies. These variations were mapped by ecozone. These maps provide valuable information in determining the confidence with which relationships derived from rural INDEPTH DSS sites can be extended to other areas. The results also indicate suites of sites that form environmentally cohesive groups and from which data can be logically summarized. Finally, the results highlight areas where the location of new INDEPTH DSS sites would increase significantly the environmental coverage of the network.

Zurovac D, Larson BA, Akhwale W, Snow RW. 2006. The financial and clinical implications of adult malaria diagnosis using microscopy in Kenya. Trop Med Int Health, 11 (8), pp. 1185-1194. | Citations: 34 (Scopus) | Show Abstract | Read more

OBJECTIVE: A recent observational study undertaken at 17 health facilities with microscopy in Kenya revealed that potential benefits of malaria microscopy are not realized because of irrational clinical practices and the low accuracy of routine microscopy. Using these data, we modelled financial and clinical implications of revised clinical practices and improved accuracy of malaria microscopy among adult outpatients under the artemether-lumefantrine (AL) treatment policy for uncomplicated malaria in Kenya. METHODS: The cost of AL, antibiotics and malaria microscopy and the expected number of malaria diagnosis errors were estimated per 1,000 adult outpatients presenting at a facility with microscopy under three scenarios: (1) current clinical practice and accuracy of microscopy (option A), (2) revised clinical practice with current accuracy of microscopy (option B) and (3) revised clinical practice with improved accuracy of microscopy (option C). Revised clinical practice was defined as performing a blood slide for all febrile adults and prescribing antimalarial treatment only for positive results. Improved accuracy of routine microscopy was defined as 90% sensitivity and specificity. In the sensitivity analysis, the implications of changes in the cost of drugs and malaria microscopy and changes in background malaria prevalence were examined for each option. RESULTS: The costs of AL, antibiotics and malaria microscopy decreased from 2,154 dollars under option A to 1,254 dollars under option B and 892 dollars under option C. Of the cost savings from option C, 72% was from changes in clinical practice, while 28% was from improvements in the accuracy of microscopy. Compared with 638 malaria overdiagnosis errors per 1,000 adults under option A, 375 and 548 fewer overdiagnosis errors were estimated, respectively, under options B and C. At the same time, the number of missed malaria diagnoses remained generally low under all options. Sensitivity analysis showed that both options B and C are robust to a wide range of assumptions on the costs of drugs, costs of blood slides and malaria prevalence. CONCLUSIONS: Even with the imperfect microscopy conditions at Kenyan facilities, implementation of revised clinical practice (option B) would substantially reduce the costs and errors from malaria overdiagnosis. Additional interventions to improve the accuracy of microscopy (option C) can achieve further benefits; however, improved microscopy in the absence of revised clinical practice is unlikely to generate significant cost savings. Revision of guidelines to state explicitly age-specific indications for the use and interpretation of malaria microscopy is urgently needed. Further prospective studies are required to evaluate the effectiveness and costs of interventions to improve clinical practice and the accuracy of malaria microscopy.

Bejon P, Kai OK, Mwacharo J, Keating S, Lang T, Gilbert SC, Peshu N, Marsh K, Hill AVS. 2006. Alternating vector immunizations encoding pre-erythrocytic malaria antigens enhance memory responses in a malaria endemic area. Eur J Immunol, 36 (8), pp. 2264-2272. | Citations: 18 (Scopus) | Show Abstract | Read more

A heterologous prime-boost strategy has been developed to potently induce T cell responses to pre-erythrocytic malaria antigens. Efficacy in the field is likely to depend on both peak immunogenicity and the durability of responses. To improve both immunogenicity and durability of responses, 54 adult males from a malaria endemic area were immunized with different vaccination regimens, systematically varying antigenic insert and the number and sequence of component vaccinations. The component vaccinations were recombinant attenuated viruses, either fowlpox (FP) 9 or modified vaccinia virus Ankara (MVA). These were recombinant for either of two pre-erythrocytic malaria antigens (multiple epitope-thrombospondin-related adhesion protein, ME-TRAP, or circumsporozoite antigen (CS). ELISPOT assays were used to measure the effector and resting memory T cell responses. Sequence, antigen insert and number of vaccinations influenced immunogenicity, but the novel alternating vector immunizations generated the largest resting memory T cell populations. Effector responses were maintained at 84% of the peak response after 270 days. This durability of response is unprecedented. Classical prime-boost vaccination responses were at 5% of the peak after 270 days. Vaccines administered by heterologous prime-boost regimes are being developed for diverse pathogens and cancer. These data suggest these vaccines should also be administered by alternating vector regimens in clinical development.

Grais RF, DE Radiguès X, Dubray C, Fermon F, Guerin PJ. 2006. Exploring the time to intervene with a reactive mass vaccination campaign in measles epidemics. Epidemiol Infect, 134 (4), pp. 845-849. | Citations: 21 (Web of Science Lite) | Show Abstract | Read more

The current WHO policy during measles outbreaks focuses on case management rather than reactive vaccination campaigns in urban areas of resource-poor countries having low vaccine coverage. Vaccination campaigns may be costly, or not timely enough to impact significantly on morbidity and mortality. We explored the time available for intervention during two recent epidemics. Our analysis suggests that the spread of measles in African urban settings may not be as fast as expected. Examining measles epidemic spread in Kinshasa (DRC), and Niamey (Niger) reveals a progression of smaller epidemics. Intervening with a mass campaign or in areas where cases have not yet been reported could slow the epidemic spread. The results of this preliminary analysis illustrate the importance of revisiting outbreak response plans.

Wertheim HFL, van Kleef M, Vos MC, Ott A, Verbrugh HA, Fokkens W. 2006. Nose picking and nasal carriage of Staphylococcus aureus. Infect Control Hosp Epidemiol, 27 (8), pp. 863-867. | Citations: 24 (Scopus) | Show Abstract | Read more

OBJECTIVE: Nasal carriage of Staphylococcus aureus is an important risk factor for S. aureus infection and a reservoir for methicillin-resistant S. aureus. We investigated whether nose picking was among the determinants of S. aureus nasal carriage. SETTING AND PARTICIPANTS: The study cohort comprised 238 patients who visited the ear, nose, and throat (ENT) disease outpatient clinic of a tertiary care hospital and did not have a nose-specific complaint (defined as ENT patients) and 86 healthy hospital employees (including medical students and laboratory personnel). MEASUREMENTS: All participants completed a questionnaire on behavior regarding the nose and were screened for S. aureus nasal carriage; only ENT patients underwent nasal examination by an ear, nose, and throat physician for clinical signs of nose picking. RESULTS: Among ENT patients, nose pickers were significantly more likely than non-nose pickers to carry S. aureus (37 [53.6%] of 69 vs 60 [35.5%] of 169 patients; relative risk, 1.51 [95% confidence interval, 1.03-2.19]). Among healthy volunteers, there was a statistically significant positive correlation between the self-perceived frequency of nose picking and both the frequency of positive culture results (R=0.31; P=.004) and the load of S. aureus present in the nose (R=0.32; P=.003). CONCLUSION: Nose picking is associated with S. aureus nasal carriage. The role of nose picking in nasal carriage may well be causal in certain cases. Overcoming the habit of nose picking may aid S. aureus decolonization strategies.

Enouf V, Dos Reis G, Guthmann JP, Guerin PJ, Caron M, Marechal V, Nicand E. 2006. Validation of single real-time TaqMan PCR assay for the detection and quantitation of four major genotypes of hepatitis E virus in clinical specimens. J Med Virol, 78 (8), pp. 1076-1082. | Citations: 43 (Scopus) | Show Abstract | Read more

Since the characterization of the genome of the hepatitis E virus (HEV) in 1990, a large genetic diversity has been described. A single real-time reverse transcription (RT)-PCR assay with TaqMan technology has been validated which uses only one set of primers and probe within the ORF2 HEV region (nt 5207-5292) for the detection and quantification of the four major genotypes of HEV. This assay proved to be as efficient as the conventional RT-PCR methodology for the detection of HEV in clinical samples testing positive previously. The real-time RT-PCR and conventional RT-PCR were performed comparatively on 60 pairs of sera and stools collected during a recent outbreak of hepatitis E in Darfur. The real-time RT-PCR assay was 10- to 100-fold sensitive than for conventional RT-PCR assays used in this study with a range quantitation from 1.8 x 10(1) to 7.2 x 10(3) RNA copies/microl in clinical samples (serum and stools).

van Doorn HR, de Haas PEW, Kremer K, Vandenbroucke-Grauls CMJE, Borgdorff MW, van Soolingen D. 2006. Public health impact of isoniazid-resistant Mycobacterium tuberculosis strains with a mutation at amino-acid position 315 of katG: a decade of experience in The Netherlands. Clin Microbiol Infect, 12 (8), pp. 769-775. | Citations: 49 (Scopus) | Show Abstract | Read more

A previous limited study demonstrated that Mycobacterium tuberculosis isolates with a mutation at amino-acid position 315 of katG (Delta315) exhibited high-level resistance to isoniazid and were more frequently resistant to streptomycin. In the present study, isoniazid-resistant M. tuberculosis isolates from 8,332 patients in The Netherlands (1993-2002) were screened for the Delta315 mutation. Isoniazid resistance was found in 592 (7%) isolates, of which 323 (55%) carried Delta315. IS6110 restriction fragment length polymorphism analysis showed that Delta315 isolates occurred in clusters, suggesting recent transmission, at the same frequency as isoniazid-susceptible isolates. In contrast, other isoniazid-resistant isolates clustered significantly less frequently. Delta315 isolates were high-level isoniazid-resistant, streptomycin-resistant and multidrug-resistant significantly more often, and may have a greater impact on public health, than other isoniazid-resistant isolates.

Cooper B. 2006. Poxy models and rash decisions. Proc Natl Acad Sci U S A, 103 (33), pp. 12221-12222. | Citations: 11 (Scopus) | Read more

Larner MJ, Larner AJ. 2006. Normal pressure hydrocephalus: false positives Practical Neurology, 6 (4), pp. 264-264. | Read more

Roberton SI, Bell DJ, Smith GJD, Nicholls JM, Chan KH, Nguyen DT, Tran PQ, Streicher U, Poon LLM, Chen H et al. 2006. Avian influenza H5N1 in viverrids: implications for wildlife health and conservation. Proc Biol Sci, 273 (1595), pp. 1729-1732. | Citations: 52 (Web of Science Lite) | Show Abstract | Read more

The Asian countries chronically infected with avian influenza A H5N1 are 'global hotspots' for biodiversity conservation in terms of species diversity, endemism and levels of threat. Since 2003, avian influenza A H5N1 viruses have naturally infected and killed a range of wild bird species, four felid species and a mustelid. Here, we report fatal disseminated H5N1 infection in a globally threatened viverrid, the Owston's civet, in Vietnam, highlighting the risk that avian influenza H5N1 poses to mammalian and avian biodiversity across its expanding geographic range.

Deen JL, Harris E, Wills B, Balmaseda A, Hammond SN, Rocha C, Dung NM, Hung NT, Hien TT, Farrar JJ. 2006. The WHO dengue classification and case definitions: time for a reassessment. Lancet, 368 (9530), pp. 170-173. | Citations: 215 (Scopus) | Read more

Smith GJD, Naipospos TSP, Nguyen TD, de Jong MD, Vijaykrishna D, Usman TB, Hassan SS, Nguyen TV, Dao TV, Bui NA et al. 2006. Evolution and adaptation of H5N1 influenza virus in avian and human hosts in Indonesia and Vietnam. Virology, 350 (2), pp. 258-268. | Citations: 180 (Scopus) | Show Abstract | Read more

Highly pathogenic avian influenza virus H5N1 is endemic in poultry in East and Southeast Asia with disease outbreaks recently spreading to parts of central Asia, Europe and Africa. Continued interspecies transmission to humans has been reported in Vietnam, Thailand, Cambodia, Indonesia and China, causing pandemic concern. Here, we genetically characterize 82 H5N1 viruses isolated from poultry throughout Indonesia and Vietnam and 11 human isolates from southern Vietnam together with sequence data available in public databases to address questions relevant to virus introduction, endemicity and evolution. Phylogenetic analysis shows that all viruses from Indonesia form a distinct sublineage of H5N1 genotype Z viruses suggesting this outbreak likely originated from a single introduction that spread throughout the country during the past two years. Continued virus activities in Indonesia were attributed to transmission via poultry movement within the country rather than through repeated introductions by bird migration. Within Indonesia and Vietnam, H5N1 viruses have evolved over time into geographically distinct groups within each country. Molecular analysis of the H5N1 genotype Z genome shows that only the M2 and PB1-F2 genes were under positive selection, suggesting that these genes might be involved in adaptation of this virus to new hosts following interspecies transmission. At the amino acid level 12 residues were under positive selection in those genotype Z viruses, in the HA and PB1-F2 proteins. Some of these residues were more frequently observed in human isolates than in avian isolates and are related to viral antigenicity and receptor binding. Our study provides insight into the ongoing evolution of H5N1 influenza viruses that are transmitting in diverse avian species and at the interface between avian and human hosts.

Vesaratchavest M, Tumapa S, Day NPJ, Wuthiekanun V, Chierakul W, Holden MTG, White NJ, Currie BJ, Spratt BG, Feil EJ, Peacock SJ. 2006. Nonrandom distribution of Burkholderia pseudomallei clones in relation to geographical location and virulence. J Clin Microbiol, 44 (7), pp. 2553-2557. | Citations: 59 (Scopus) | Show Abstract | Read more

Burkholderia pseudomallei is a soil-dwelling saprophyte and the causative agent of melioidosis, a life-threatening human infection. Most cases are reported from northeast Thailand and northern Australia. Using multilocus sequence typing (MLST), we have compared (i) soil and invasive isolates from northeast Thailand and (ii) invasive isolates from Thailand and Australia. A total of 266 Thai B. pseudomallei isolates were characterized (83 soil and 183 invasive). These corresponded to 123 sequence types (STs), the most abundant being ST70 (n=21), ST167 (n=15), ST54 (n=12), and ST58 (n=11). Two clusters of related STs (clonal complexes) were identified; the larger clonal complex (CC48) did not conform to a simple pattern of radial expansion from an assumed ancestor, while a second (CC70) corresponded to a simple radial expansion from ST70. Despite the large number of STs, overall nucleotide diversity was low. Of the Thai isolates, those isolated from patients with melioidosis were overrepresented in the 10 largest clones (P<0.0001). There was a significant difference in the classification index between environmental and disease isolates (P<0.001), confirming that genotypes were not distributed randomly between the two samples. MLST profiles for 158 isolates from Australia (mainly disease associated) contained a number of STs (96) similar to that seen with the Thai invasive isolates, but no ST was found in both populations. There were also differences in diversity and allele frequency distribution between the two populations. This analysis reveals strong genetic differentiation on the basis of geographical isolation and a significant differentiation on the basis of virulence potential.

Nosten F, Ashley E, McGready R, Price R. 2006. We still need artesunate monotherapy. BMJ, 333 (7557), pp. 45. | Citations: 8 (Scopus) | Read more

Ashley EA, Stepniewska K, Lindegårdh N, McGready R, Hutagalung R, Hae R, Singhasivanon P, White NJ, Nosten F. 2006. Population pharmacokinetic assessment of a new regimen of mefloquine used in combination treatment of uncomplicated falciparum malaria. Antimicrob Agents Chemother, 50 (7), pp. 2281-2285. | Citations: 34 (Scopus) | Show Abstract | Read more

A fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood sampling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modeling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life (t1/2) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t1/2 estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.

Osier FHA, Berkley JA, Newton CRJC. 2006. Life-threatening hyponatraemia and neurotoxicity during chemotherapy for Burkitt's lymphoma. Trop Doct, 36 (3), pp. 177-178. | Citations: 3 (Web of Science Lite) | Read more

Sebaihia M, Wren BW, Mullany P, Fairweather NF, Minton N, Stabler R, Thomson NR, Roberts AP, Cerdeño-Tárraga AM, Wang H et al. 2006. The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat Genet, 38 (7), pp. 779-786. | Citations: 457 (Web of Science Lite) | Show Abstract | Read more

We determined the complete genome sequence of Clostridium difficile strain 630, a virulent and multidrug-resistant strain. Our analysis indicates that a large proportion (11%) of the genome consists of mobile genetic elements, mainly in the form of conjugative transposons. These mobile elements are putatively responsible for the acquisition by C. difficile of an extensive array of genes involved in antimicrobial resistance, virulence, host interaction and the production of surface structures. The metabolic capabilities encoded in the genome show multiple adaptations for survival and growth within the gut environment. The extreme genome variability was confirmed by whole-genome microarray analysis; it may reflect the organism's niche in the gut and should provide information on the evolution of virulence in this organism.

van Doorn HR, Lo-A-Njoe SM, Ottenkamp J, Pajkrt D. 2006. Widened coronary arteries in a feverish child. Pediatr Cardiol, 27 (4), pp. 515-518. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

A 3-year-old girl with fever of unknown origin after a visit to Surinam was seen at our hospital. Signs and symptoms were indicative of either Kawasaki syndrome or an acute viral or (atypical) bacterial illness. No cardiac abnormalities were noted at echocardiography. She was treated with intravenous immunoglobulin and clarithromycin and made a quick recovery. Serologically, the diagnosis of murine typhus was made; a flea-borne rickettsiosis caused by Rickettsia typhi. A follow-up echocardiography 1 week later showed a dilated left coronary artery, which was normal again 4 weeks later. We suggest that this phenomenon was a manifestation of rickettsial vasculitis.

Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, Lindegardh N, Singtoroj T, Ashley E, Lwin S et al. 2006. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison. Lancet, 367 (9528), pp. 2075-2085. | Citations: 105 (Scopus) | Show Abstract | Read more

BACKGROUND: Artemisinin-based combinations are judged the best treatments for multidrug-resistant Plasmodium falciparum malaria. Artesunate-mefloquine is widely recommended in southeast Asia, but its high cost and tolerability profile remain obstacles to widespread deployment. To assess whether dihydroartemisinin-piperaquine is a suitable alternative to artesunate-mefloquine, we compared the safety, tolerability, efficacy, and effectiveness of the two regimens for the treatment of uncomplicated falciparum in western Myanmar (Burma). METHODS: We did an open randomised comparison of 3-day regimens of artesunate-mefloquine (12/25 mg/kg) versus dihydroartemisinin-piperaquine (6.3/50 mg/kg) for the treatment of children aged 1 year or older and in adults with uncomplicated falciparum malaria in Rakhine State, western Myanmar. Within each group, patients were randomly assigned supervised or non-supervised treatment. The primary endpoint was the PCR-confirmed parasitological failure rate by day 42. Failure rates at day 42 were estimated by Kaplan-Meier survival analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN27914471. FINDINGS: Of 652 patients enrolled, 327 were assigned dihydroartemisinin-piperaquine (156 supervised and 171 not supervised), and 325 artesunate-mefloquine (162 and 163, respectively). 16 patients were lost to follow-up, and one patient died 22 days after receiving dihydroartemisinin-piperaquine. Recrudescent parasitaemias were confirmed in only two patients; the day 42 failure rate was 0.6% (95% CI 0.2-2.5) for dihydroartemisinin-piperaquine and 0 (0-1.2) for artesunate-mefloquine. Whole-blood piperaquine concentrations at day 7 were similar for patients with observed and non-observed dihydroartemisinin-piperaquine treatment. Gametocytaemia developed more frequently in patients who had received dihydroartemisinin-piperaquine than in those on artesunate-mefloquine: day 7, 18 (10%) of 188 versus five (2%) of 218; relative risk 4.2 (1.6-11.0) p=0.011. INTERPRETATION: Dihydroartemisinin-piperaquine is a highly efficacious and inexpensive treatment of multidrug-resistant falciparum malaria and is well tolerated by all age groups. The effectiveness of the unsupervised treatment, as in the usual context of use, equalled its supervised efficacy, indicating good adherence without supervision. Dihydroartemisinin-piperaquine is a good alternative to artesunate-mefloquine.

Stuetz W, McGready R, Cho T, Prapamontol T, Biesalski HK, Stepniewska K, Nosten F. 2006. Relation of DDT residues to plasma retinol, alpha-tocopherol, and beta-carotene during pregnancy and malaria infection: a case-control study in Karen women in northern Thailand. Sci Total Environ, 363 (1-3), pp. 78-86. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

Populations living in endemic malaria areas maybe exposed simultaneously to DDT and malaria infection. DDT may impair status of vitamins, which are implicated in the immunity and pathophysiology of malaria. To explore possible interactions, DDT residues, retinol, alpha-tocopherol, beta-carotene and cholesterol were measured in plasma samples of malaria-infected pregnant women (cases, n=50) and age matched malaria-free controls (n=58). DDT residues were found in all samples: mean (sd) total DDT levels of 29.7 and 32.7 ng/ml in cases and controls, respectively. Mean (sd) p,p'-DDT was higher in the controls than the cases (13.5 vs. 9.5 ng/ml, p=0.006). Malaria infection was associated with lower mean (sd) plasma retinol (0.69 vs. 1.23 micromol/L) and cholesterol (2.62 vs. 3.48 mmol/L) compared to controls (p<0.001). Mean (sd) plasma alpha-tocopherol (7.65 vs. 15.58 micromol/L) and alpha-tocopherol/cholesterol ratio (2.3 vs. 6.7 micromol/L/mmol/L) were significantly lower among the controls (p<0.001). Mean (sd) plasma beta-carotene was low (<0.3 micromol/L) in both groups, but higher among malaria cases (0.19 vs. 0.15 micromol/L). Plasma retinol among the controls showed highly significant positive correlations with individual DDT compounds, particularly with p,p'-DDT (r=0.51, p<0.001). Plasma alpha-tocopherol and beta-carotene seemed not to be affected by DDT residues.

Guthmann J-P, Klovstad H, Boccia D, Hamid N, Pinoges L, Nizou J-Y, Tatay M, Diaz F, Moren A, Grais RF et al. 2006. A large outbreak of hepatitis E among a displaced population in Darfur, Sudan, 2004: the role of water treatment methods. Clin Infect Dis, 42 (12), pp. 1685-1691. | Citations: 109 (Scopus) | Show Abstract | Read more

BACKGROUND: The conflict in Darfur, Sudan, was responsible for the displacement of 1.8 million civilians. We investigated a large outbreak of hepatitis E virus (HEV) infection in Mornay camp (78,800 inhabitants) in western Darfur. METHODS: To describe the outbreak, we used clinical and demographic information from cases recorded at the camp between 26 July and 31 December 2004. We conducted a case-cohort study and a retrospective cohort study to identify risk factors for clinical and asymptomatic hepatitis E, respectively. We collected stool and serum samples from animals and performed a bacteriological analysis of water samples. Human samples were tested for immunoglobulin G and immunoglobulin M antibody to HEV (for serum samples) and for amplification of the HEV genome (for serum and stool samples). RESULTS: In 6 months, 2621 hepatitis E cases were recorded (attack rate, 3.3%), with a case-fatality rate of 1.7% (45 deaths, 19 of which involved were pregnant women). Risk factors for clinical HEV infection included age of 15-45 years (odds ratio, 2.13; 95% confidence interval, 1.02-4.46) and drinking chlorinated surface water (odds ratio, 2.49; 95% confidence interval, 1.22-5.08). Both factors were also suggestive of increased risk for asymptomatic HEV infection, although this was not found to be statistically significant. HEV RNA was positively identified in serum samples obtained from 2 donkeys. No bacteria were identified from any sample of chlorinated water tested. CONCLUSIONS: Current recommendations to ensure a safe water supply may have been insufficient to inactivate HEV and control this epidemic. This research highlights the need to evaluate current water treatment methods and to identify alternative solutions adapted to complex emergencies.

Boccia D, Guthmann J-P, Klovstad H, Hamid N, Tatay M, Ciglenecki I, Nizou J-Y, Nicand E, Guerin PJ. 2006. High mortality associated with an outbreak of hepatitis E among displaced persons in Darfur, Sudan. Clin Infect Dis, 42 (12), pp. 1679-1684. | Citations: 105 (Scopus) | Show Abstract | Read more

BACKGROUND: Hepatitis E virus (HEV) causes acute onset of jaundice and a high case-fatality ratio in pregnant women. We provide a clinical description of hospitalized case patients and assess the specific impact on pregnant women during a large epidemic of HEV infection in a displaced population in Mornay camp (78,800 inhabitants), western Darfur, Sudan. METHODS: We reviewed hospital records. A sample of 20 clinical cases underwent laboratory confirmation. These patients were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody to HEV (serum) and for amplification of the HEV genome (serum and stool). We performed a cross-sectional survey in the community to determine the attack rate and case-fatality ratio in pregnant women. RESULTS: Over 6 months, 253 HEV cases were recorded at the hospital, of which 61 (24.1%) were in pregnant women. A total of 72 cases (39.1% of those for whom clinical records were available) had a diagnosis of hepatic encephalopathy. Of the 45 who died (case-fatality ratio, 17.8%), 19 were pregnant women (specific case-fatality ratio, 31.1%). Acute hepatitis E was confirmed in 95% (19/20) of cases sampled; 18 case-patients were positive for IgG (optical density ratio > or =3), for IgM (optical density ratio >2 ), or for both, whereas 1 was negative for IgG and IgM but positive for HEV RNA in serum. The survey identified 220 jaundiced women among the 1133 pregnant women recorded over 3 months (attack rate, 19.4%). A total of 18 deaths were recorded among these jaundiced pregnant women (specific case-fatality ratio, 8.2%). CONCLUSIONS: This large epidemic of HEV infection illustrates the dramatic impact of this disease on pregnant women. Timely interventions and a vaccine are urgently needed to prevent mortality in this special group.

Levine OS, O'Brien KL, Knoll M, Adegbola RA, Black S, Cherian T, Dagan R, Goldblatt D, Grange A, Greenwood B et al. 2006. Pneumococcal vaccination in developing countries. Lancet, 367 (9526), pp. 1880-1882. | Citations: 121 (Scopus) | Read more

Wuthiekanun V, Chierakul W, Langa S, Chaowagul W, Panpitpat C, Saipan P, Thoujaikong T, Day NP, Peacock SJ. 2006. Development of antibodies to Burkholderia pseudomallei during childhood in melioidosis-endemic northeast Thailand. Am J Trop Med Hyg, 74 (6), pp. 1074-1075. | Citations: 57 (Scopus) | Show Abstract

A cross-sectional serological survey of 2,214 children living in northeast Thailand was conducted to define the antibody response to Burkholderia pseudomallei from birth to 14 years. There was a sharp rise in detectable antibodies from birth to 4 years followed by reactivity in approximately 60-70% of children thereafter.

Nosten F, Hutagalung R, Carrara VI, Ashley E, White N. 2006. Untitled AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 74 (6), pp. 940-940. | Citations: 1 (Web of Science Lite)

Price RN, Uhlemann A-C, van Vugt M, Brockman A, Hutagalung R, Nair S, Nash D, Singhasivanon P, Anderson TJC, Krishna S et al. 2006. Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis, 42 (11), pp. 1570-1577. | Citations: 182 (Scopus) | Show Abstract | Read more

BACKGROUND: Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). METHODS: On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. RESULTS: All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration(50) (P=.001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P=.008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. CONCLUSIONS: The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic.

Chotivanich K, Sattabongkot J, Udomsangpetch R, Looareesuwan S, Day NPJ, Coleman RE, White NJ. 2006. Transmission-blocking activities of quinine, primaquine, and artesunate. Antimicrob Agents Chemother, 50 (6), pp. 1927-1930. | Citations: 53 (Web of Science Lite) | Show Abstract | Read more

The infectivity of Plasmodium falciparum gametocytes after exposure in vitro to quinine, artesunate, and primaquine was assessed in Anopheles dirus, a major vector of malaria in Southeast Asia. Mature gametocytes (stage 5) of a Thai isolate of P. falciparum were exposed to the drugs for 24 h in vitro before membrane feeding to A. dirus. After 10 days, the mosquito midguts were dissected and the oocysts were counted. In this system, artesunate showed the most potent transmission-blocking activity; the mean (standard deviation [SD]) 50% and 90% effective concentrations (EC(50), and EC(90), respectively, in nanograms per milliliter) were 0.1 (0.02) and 0.4 (0.15), respectively. Transmission-blocking activity of quinine and primaquine was observed at relatively high concentrations (SDs): EC(50) of quinine, 642 (111) ng/ml; EC(50) of primaquine, 181 (23) ng/ml; EC(90) of quinine, 816 (96) ng/ml; EC(90) of primaquine, 543 (43) ng/ml. Artesunate both prevents the maturation of immature P. falciparum gametocytes and reduces the transmission potential of mature gametocytes. Both of these effects may contribute to reducing malaria transmission.

Gething PW, Noor AM, Gikandi PW, Ogara EAA, Hay SI, Nixon MS, Snow RW, Atkinson PM. 2006. Improving imperfect data from health management information systems in Africa using space-time geostatistics. PLoS Med, 3 (6), pp. e271. | Citations: 64 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Reliable and timely information on disease-specific treatment burdens within a health system is critical for the planning and monitoring of service provision. Health management information systems (HMIS) exist to address this need at national scales across Africa but are failing to deliver adequate data because of widespread underreporting by health facilities. Faced with this inadequacy, vital public health decisions often rely on crudely adjusted regional and national estimates of treatment burdens. METHODS AND FINDINGS: This study has taken the example of presumed malaria in outpatients within the largely incomplete Kenyan HMIS database and has defined a geostatistical modelling framework that can predict values for all data that are missing through space and time. The resulting complete set can then be used to define treatment burdens for presumed malaria at any level of spatial and temporal aggregation. Validation of the model has shown that these burdens are quantified to an acceptable level of accuracy at the district, provincial, and national scale. CONCLUSIONS: The modelling framework presented here provides, to our knowledge for the first time, reliable information from imperfect HMIS data to support evidence-based decision-making at national and sub-national levels.

Rowe AK, Rowe SY, Snow RW, Korenromp EL, Schellenberg JRA, Stein C, Nahlen BL, Bryce J, Black RE, Steketee RW. 2006. The burden of malaria mortality among African children in the year 2000. Int J Epidemiol, 35 (3), pp. 691-704. | Citations: 177 (Scopus) | Show Abstract | Read more

BACKGROUND: Although malaria is a leading cause of child deaths, few well-documented estimates of its direct and indirect burden exist. Our objective was to estimate the number of deaths directly attributable to malaria among children <5 years old in sub-Saharan Africa for the year 2000. METHODS: We divided the population into six sub-populations and, using results of studies identified in a literature review, estimated a malaria mortality rate for each sub-population. Malaria deaths were estimated by multiplying each sub-population by its corresponding rate. Sensitivity analyses were performed to assess the impact of varying key assumptions. RESULTS: The literature review identified 31 studies from 14 countries in middle Africa and 17 studies and reports from four countries in southern Africa. In 2000, we estimated that approximately 100 million children lived in areas where malaria transmission occurs and that 803 620 (precision estimate: 705 821-901 418) children died from the direct effects of malaria. For all of sub-Saharan Africa, including populations not exposed to malaria, malaria accounted for 18.0% (precision estimate: 15.8-20.2%) of child deaths. These estimates were sensitive to extreme assumptions about the causes of deaths with no known cause. CONCLUSIONS: These estimates, based on the best available data and methods, clearly demonstrate malaria's enormous mortality burden. We emphasize that these estimates are an approximation with many limitations and that the estimates do not account for malaria's large indirect burden. We describe information needs that, if filled, might improve the validity of future estimates.

Gutiérrez JM, Theakston RDG, Warrell DA. 2006. Confronting the neglected problem of snake bite envenoming: the need for a global partnership. PLoS Med, 3 (6), pp. e150. | Citations: 213 (Web of Science Lite) | Read more

Antarasena C, Sirimujalin R, Prommuang P, Blacksell SD, Promkuntod N, Prommuang P. 2006. Tissue tropism of a Thailand strain of high-pathogenicity avian influenza virus (H5N1) in tissues of naturally infected native chickens (Gallus gallus), Japanese quail (Coturnix coturnix japonica) and ducks (Anas spp.). Avian Pathol, 35 (3), pp. 250-253. | Citations: 31 (Scopus) | Show Abstract | Read more

The tropism of a Thailand strain of highly pathogenic avian influenza H5N1 virus was demonstrated on tissues (lung, trachea, heart, liver, spleen, pancreas, rectum, kidney, brain, skeletal muscle, duodenum, and oviduct) from naturally infected native chickens (Gallus gallus), Japanese quail (Coturnix coturnix japonica) and ducks (Anas spp.) by indirect immunofluorescence assay. In chickens and quail, the distribution and localization of nucleoprotein viral antigen was similar and detected at the highest level in cardiac myocytes, at 88% (chickens) and 89% (quail), and respiratory, digestive and urinary systems all showed high levels of antigen. Antigen in duck tissues were detected at significantly lower levels (P < 0.05) with the exception of brain and skeletal muscle samples. In most cases, antigen in duck tissue was absent in the digestive organs but present in respiratory organs, which supports the hypothesis that aerosol and oral-oral transmission are the main method of highly pathogenic avian influenza virus transmission from this species.

Cheng AC, Wuthiekanun V, Limmathurosakul D, Wongsuvan G, Day NPJ, Peacock SJ. 2006. Role of selective and nonselective media for isolation of Burkholderia pseudomallei from throat swabs of patients with melioidosis. J Clin Microbiol, 44 (6), pp. 2316. | Citations: 7 (Scopus) | Read more

Zurovac D, Rowe AK. 2006. Quality of treatment for febrile illness among children at outpatient facilities in sub-Saharan Africa. Ann Trop Med Parasitol, 100 (4), pp. 283-296. | Citations: 46 (Web of Science Lite) | Show Abstract | Read more

For the prompt and effective management of malaria cases (a key strategy for reducing the enormous burden of the disease), healthworkers must prescribe antimalarial drugs according to evidence-based guidelines. In sub-Saharan Africa, the guidelines for use in outpatient settings generally recommend that febrile illness in children should be suspected to be malaria and be treated with an antimalarial drug. The quality of treatment offered to febrile children at outpatient facilities in this region has now been investigated in a literature review. The results of five methodologically comparable studies were also used to explore the determinants of malaria-treatment practices. The quality of treatment prescribed to febrile children was found to have been generally sub-optimal, with low levels of adherence to national guidelines, the frequent selection of non-recommended antimalarials, and the use of incorrect dosages. Several factors might be to responsible for these shortcomings. Although interventions such as the Integrated Management of Childhood Illness (IMCI) strategy can lead to improvements, a better understanding of the practices of the healthworkers responsible for treating febrile children will be needed before treatment is made much better. The failure to provide treatment of good quality will become an increasingly important problem as antimalarial policies involving drugs with more complex dosing regimens, such as artemisinin-based combination therapies (ACT), are implemented. If the malaria burden in Africa is to be greatly reduced, the deployment of ACT must be accompanied by interventions to ensure the correct treatment of children at the point of care. Some interventions, such as IMCI, can improve the treatment of not only malaria but also other potentially life-threatening illnesses.

Cooper BS, Pitman RJ, Edmunds WJ, Gay NJ. 2006. Delaying the international spread of pandemic influenza. PLoS Med, 3 (6), pp. e212. | Citations: 158 (Scopus) | Show Abstract | Read more

BACKGROUND: The recent emergence of hypervirulent subtypes of avian influenza has underlined the potentially devastating effects of pandemic influenza. Were such a virus to acquire the ability to spread efficiently between humans, control would almost certainly be hampered by limited vaccine supplies unless global spread could be substantially delayed. Moreover, the large increases that have occurred in international air travel might be expected to lead to more rapid global dissemination than in previous pandemics. METHODS AND FINDINGS: To evaluate the potential of local control measures and travel restrictions to impede global dissemination, we developed stochastic models of the international spread of influenza based on extensions of coupled epidemic transmission models. These models have been shown to be capable of accurately forecasting local and global spread of epidemic and pandemic influenza. We show that under most scenarios restrictions on air travel are likely to be of surprisingly little value in delaying epidemics, unless almost all travel ceases very soon after epidemics are detected. CONCLUSIONS: Interventions to reduce local transmission of influenza are likely to be more effective at reducing the rate of global spread and less vulnerable to implementation delays than air travel restrictions. Nevertheless, under the most plausible scenarios, achievable delays are small compared with the time needed to accumulate substantial vaccine stocks.

Bejon P, Mwacharo J, Kai OK, Todryk S, Keating S, Lang T, Gilbert SC, Peshu N, Marsh K, Hill AVS. 2006. Immunogenicity of the candidate malaria vaccines FP9 and modified vaccinia virus Ankara encoding the pre-erythrocytic antigen ME-TRAP in 1-6 year old children in a malaria endemic area. Vaccine, 24 (22), pp. 4709-4715. | Citations: 39 (Web of Science Lite) | Show Abstract | Read more

In a phase 1 trial, 22 children in a malaria endemic area were immunised with candidate malaria vaccination regimes. The regimes used two recombinant viral vectors, attenuated fowlpox strain FP9 and modified vaccinia virus Ankara (MVA). Both encoded the pre-erythrocytic malaria antigen construct ME-TRAP. Strong T cell responses were detected by both ex vivo and cultured ELISpot assays. Data from phase 1 trials in adults on anti-vector responses raised by FP9 is presented. These responses partially cross-reacted with MVA, and detectably reduced the immunogenicity of vaccination with MVA. This prompted the comparison of half dose and full dose FP9 priming vaccinations in children. Regimes using half dose FP9 priming tended to be more immunogenic than full dose. The potential for enhanced immunogenicity with half doses of priming vectors warrants further investigation, and larger studies to determine protection against malaria in children are required.

Cavailler P, Lucas M, Perroud V, McChesney M, Ampuero S, Guérin PJ, Legros D, Nierle T, Mahoudeau C, Lab B et al. 2006. Feasibility of a mass vaccination campaign using a two-dose oral cholera vaccine in an urban cholera-endemic setting in Mozambique. Vaccine, 24 (22), pp. 4890-4895. | Citations: 35 (Scopus) | Show Abstract | Read more

We conducted a study to assess the feasibility and the potential vaccine coverage of a mass vaccination campaign using a two-dose oral cholera vaccine in an urban endemic neighbourhood of Beira, Mozambique. The campaign was conducted from December 2003 to January 2004. Overall 98,152 doses were administered, and vaccine coverage of the target population was 58.6% and 53.6% for the first and second rounds, respectively. The direct cost of the campaign, which excludes the price of the vaccine, amounted to slightly over 90,000 dollars, resulting in the cost per fully vaccinated person of 2.09 dollars, which is relatively high. However, in endemic settings where outbreaks are likely to occur, integrating cholera vaccination into the routine activities of the public health system could reduce such costs.

Khan MI, Ochiai RL, Hamza HB, Sahito SM, Habib MA, Soofi SB, Bhutto NS, Rasool S, Puri MK, Ali M et al. 2006. Lessons and implications from a mass immunization campaign in squatter settlements of Karachi, Pakistan: an experience from a cluster-randomized double-blinded vaccine trial [NCT00125047]. Trials, 7 (1), pp. 17. | Citations: 20 (Scopus) | Show Abstract | Read more

OBJECTIVE: To determine the safety and logistic feasibility of a mass immunization strategy outside the local immunization program in the pediatric population of urban squatter settlements in Karachi, Pakistan. METHODS: A cluster-randomized double blind preventive trial was launched in August 2003 in 60 geographic clusters covering 21,059 children ages 2 to 16 years. After consent was obtained from parents or guardians, eligible children were immunized parenterally at vaccination posts in each cluster with Vi polysaccharide or hepatitis A vaccine. Safety, logistics, and standards were monitored and documented. RESULTS: The vaccine coverage of the population was 74% and was higher in those under age 10 years. No life-threatening serious adverse events were reported. Adverse events occurred in less than 1% of all vaccine recipients and the main reactions reported were fever and local pain. The proportion of adverse events in Vi polysaccharide and hepatitis A recipients will not be known until the end of the trial when the code is broken. Throughout the vaccination campaign safe injection practices were maintained and the cold chain was not interrupted. Mass vaccination in slums had good acceptance. Because populations in such areas are highly mobile, settlement conditions could affect coverage. Systemic reactions were uncommon and local reactions were mild and transient. Close community involvement was pivotal for information dissemination and immunization coverage. CONCLUSION: This vaccine strategy described together with other information that will soon be available in the area (cost/effectiveness, vaccine delivery costs, etc) will make typhoid fever control become a reality in the near future.

Ndiritu M, Cowgill KD, Ismail A, Chiphatsi S, Kamau T, Fegan G, Feikin DR, Newton CRJC, Scott JAG. 2006. Immunization coverage and risk factors for failure to immunize within the Expanded Programme on Immunization in Kenya after introduction of new Haemophilus influenzae type b and hepatitis b virus antigens. BMC Public Health, 6 (1), pp. 132. | Citations: 62 (Scopus) | Show Abstract | Read more

BACKGROUND: Kenya introduced a pentavalent vaccine including the DTP, Haemophilus influenzae type b and hepatitis b virus antigens in Nov 2001 and strengthened immunization services. We estimated immunization coverage before and after introduction, timeliness of vaccination and risk factors for failure to immunize in Kilifi district, Kenya. METHODS: In Nov 2002 we performed WHO cluster-sample surveys of >200 children scheduled for vaccination before or after introduction of pentavalent vaccine. In Mar 2004 we conducted a simple random sample (SRS) survey of 204 children aged 9-23 months. Coverage was estimated by inverse Kaplan-Meier survival analysis of vaccine-card and mothers' recall data and corroborated by reviewing administrative records from national and provincial vaccine stores. The contribution to timely immunization of distance from clinic, seasonal rainfall, mother's age, and family size was estimated by a proportional hazards model. RESULTS: Immunization coverage for three DTP and pentavalent doses was 100% before and 91% after pentavalent vaccine introduction, respectively. By SRS survey, coverage was 88% for three pentavalent doses. The median age at first, second and third vaccine dose was 8, 13 and 18 weeks. Vials dispatched to Kilifi District during 2001-2003 would provide three immunizations for 92% of the birth cohort. Immunization rate ratios were reduced with every kilometre of distance from home to vaccine clinic (HR 0.95, CI 0.91-1.00), rainy seasons (HR 0.73, 95% CI 0.61-0.89) and family size, increasing progressively up to 4 children (HR 0.55, 95% CI 0.41-0.73). CONCLUSION: Vaccine coverage was high before and after introduction of pentavalent vaccine, but most doses were given late. Coverage is limited by seasonal factors and family size.

Thiem VD, Deen JL, von Seidlein L, Canh DG, Anh DD, Park J-K, Ali M, Danovaro-Holliday MC, Son ND, Hoa NT et al. 2006. Long-term effectiveness against cholera of oral killed whole-cell vaccine produced in Vietnam. Vaccine, 24 (20), pp. 4297-4303. | Citations: 57 (Scopus) | Show Abstract | Read more

We assessed the long-term protection afforded by a killed whole-cell oral cholera vaccine produced in Vietnam. A mass immunization of children and adults with the killed whole-cell oral cholera vaccine was undertaken in half of the communes of Hue, Vietnam, in 1998; the remaining communes were immunized in 2000. No cholera was observed in Hue until 2003, when an outbreak of El Tor cholera made it possible to conduct a case-control study. The overall vaccine effectiveness 3-5 years after vaccination was 50% (9-63%). This low-cost, easily administered vaccine should be considered as a tool for the control of cholera.

Basnyat B, Belbase RH, Zimmerman MD, Woods CW, Reller LB, Murdoch DR. 2006. Clinical features of scrub typhus. Clin Infect Dis, 42 (10), pp. 1505-1506. | Citations: 18 (Scopus) | Read more

Polley SD, Conway DJ, Cavanagh DR, McBride JS, Lowe BS, Williams TN, Mwangi TW, Marsh K. 2006. High levels of serum antibodies to merozoite surface protein 2 of Plasmodium falciparum are associated with reduced risk of clinical malaria in coastal Kenya. Vaccine, 24 (19), pp. 4233-4246. | Citations: 88 (Scopus) | Show Abstract | Read more

The merozoite surface protein (MSP) 2 is a vaccine candidate antigen of Plasmodium falciparum that is polymorphic in natural populations. In a prospective cohort study in two coastal populations of Kenya using recombinant proteins derived from the two major allelic types of MSP2, high serum levels of IgG to MSP2 were associated with protection from clinical malaria. This protection was independent of that associated with antibodies to another vaccine candidate antigen (AMA1) in these populations. However, low antibody levels to MSP2 appeared to be associated with increased susceptibility to malaria within people who were parasite negative at the time of serum collection. These data suggest that an MSP2 based vaccine should be designed to induce high level antibody responses against the different MSP2 types present globally in P. falciparum populations and that MSP2 could be combined with other P. falciparum antigens to form a multi-component malaria vaccine.

Chapman SJ, Khor CC, Vannberg FO, Maskell NA, Davies CWH, Hedley EL, Segal S, Moore CE, Knox K, Day NP et al. 2006. PTPN22 and invasive bacterial disease. Nat Genet, 38 (5), pp. 499-500. | Citations: 44 (Web of Science Lite) | Read more

Ashley E, McGready R, Proux S, Nosten F. 2006. Malaria. Travel Med Infect Dis, 4 (3-4), pp. 159-173. | Citations: 41 (Scopus) | Show Abstract | Read more

Malaria is increasing worldwide due to the emergence and spread of drug resistant strains. This poses major health and economic problems for the population living in endemic areas and increases the risk of infections in travelers. The diagnosis of malaria relies on a biological proof of infection by microscopy or with a rapid test. The treatment must be initiated without delay preferably with an artemisinin containing regimen. Uncomplicated malaria can be treated with oral drugs while severe infections will be hospitalized and treated with injectables. Special attention will be given to the most susceptible groups: children and pregnant women.

McGready R, Stepniewska K, Ward SA, Cho T, Gilveray G, Looareesuwan S, White NJ, Nosten F. 2006. Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria. Eur J Clin Pharmacol, 62 (5), pp. 367-371. | Citations: 71 (Scopus) | Show Abstract | Read more

OBJECTIVE: To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug resistant falciparum malaria, in the second and third trimesters of pregnancy. METHODS: Serial plasma concentrations of artesunate and DHA were measured in 24 women after the final dose of a 3 day treatment with artesunate (4 mg kg(-1) day(-1)) and atovaquone (20 mg kg(-1) day(-1)) plus proguanil (8 mg kg(-1) day(-1)), daily. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data. RESULTS: Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8-20.7] l hour(-1) kg(-1), total apparent volume of distribution (Vd/f) was 3.4 [0.9-60.7] l/kg, and terminal elimination half-life was 1.0 [0.6-2.4] h. CONCLUSION: The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower than reported previously in non-pregnant adults. Dose-optimisation studies in pregnant women are needed.

Ndungu FM, Sanni L, Urban B, Stephens R, Newbold CI, Marsh K, Langhorne J. 2006. CD4 T cells from malaria-nonexposed individuals respond to the CD36-Binding Domain of Plasmodium falciparum erythrocyte membrane protein-1 via an MHC class II-TCR-independent pathway. J Immunol, 176 (9), pp. 5504-5512. | Citations: 16 (Web of Science Lite) | Show Abstract | Read more

We have studied the human CD4 T cell response to a functionally conserved domain of Plasmodium falciparum erythrocyte membrane protein-1, cysteine interdomain region-1alpha (CIDR-1alpha). Responses to CIDR-1alpha were striking in that both exposed and nonexposed donors responded. The IFN-gamma response to CIDR-1alpha in the nonexposed donors was partially independent of TCR engagement of MHC class II and peptide. Contrastingly, CD4 T cell and IFN-gamma responses in malaria-exposed donors were MHC class II restricted, suggesting that the CD4 T cell response to CIDR-1alpha in malaria semi-immune adults also has a TCR-mediated component, which may represent a memory response. Dendritic cells isolated from human peripheral blood were activated by CIDR-1alpha to produce IL-12, IL-10, and IL-18. IL-12 was detectable only between 6 and 12 h of culture, whereas the IL-10 continued to increase throughout the 24-h time course. These data strengthen previous observations that P. falciparum interacts directly with human dendritic cells, and suggests that the interaction between CIDR-1alpha and the host cell may be responsible for regulation of the CD4 T cell and cytokine responses to P. falciparum-infected erythrocytes reported previously.

Turner MR, Madkhana A, Ebers GC, Clover L, Vincent A, McGavin G, Sarrigiannis P, Kennett R, Warrell DA. 2006. Wasp sting induced autoimmune neuromyotonia. J Neurol Neurosurg Psychiatry, 77 (5), pp. 704-705. | Citations: 9 (Web of Science Lite) | Read more

Walther M, Thompson FM, Dunachie S, Keating S, Todryk S, Berthoud T, Andrews L, Andersen RF, Moore A, Gilbert SC et al. 2006. Safety, immunogenicity, and efficacy of prime-boost immunization with recombinant poxvirus FP9 and modified vaccinia virus Ankara encoding the full-length Plasmodium falciparum circumsporozoite protein. Infect Immun, 74 (5), pp. 2706-2716. | Citations: 53 (Scopus) | Show Abstract | Read more

Heterologous prime-boost immunization with DNA and various recombinant poxviruses encoding malaria antigens is capable of inducing strong cell-mediated immune responses and partial protection in human sporozoite challenges. Here we report a series of trials assessing recombinant fowlpox virus and modified vaccinia virus Ankara encoding the Plasmodium falciparum circumsporozoite protein in various prime-boost combinations, doses, and application routes. For the first time, these vaccines were administered intramuscularly and at doses of up to 5 x 10(8) PFU. Vaccines containing this antigen proved safe and induced modest immune responses but showed no evidence of efficacy in a sporozoite challenge.

Imwong M, Sudimack D, Pukrittayakamee S, Osorio L, Carlton JM, Day NPJ, White NJ, Anderson TJC. 2006. Microsatellite variation, repeat array length, and population history of Plasmodium vivax. Mol Biol Evol, 23 (5), pp. 1016-1018. | Citations: 78 (Scopus) | Read more

White NJ. 2006. Modelling malaria control. PLoS Med, 3 (5), pp. e111. | Citations: 3 (Web of Science Lite) | Read more

Wambua S, Mwangi TW, Kortok M, Uyoga SM, Macharia AW, Mwacharo JK, Weatherall DJ, Snow RW, Marsh K, Williams TN. 2006. The effect of alpha+-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya. PLoS Med, 3 (5), pp. e158. | Citations: 80 (Scopus) | Show Abstract | Read more

BACKGROUND: The alpha-thalassaemias are the commonest genetic disorders of humans. It is generally believed that this high frequency reflects selection through a survival advantage against death from malaria; nevertheless, the epidemiological description of the relationships between alpha-thalassaemia, malaria, and other common causes of child mortality remains incomplete. METHODS AND FINDINGS: We studied the alpha+-thalassaemia-specific incidence of malaria and other common childhood diseases in two cohorts of children living on the coast of Kenya. We found no associations between alpha+-thalassaemia and the prevalence of symptomless Plasmodium falciparum parasitaemia, the incidence of uncomplicated P. falciparum disease, or parasite densities during mild or severe malaria episodes. However, we found significant negative associations between alpha+-thalassaemia and the incidence rates of severe malaria and severe anaemia (haemoglobin concentration < 50 g/l). The strongest associations were for severe malaria anaemia (> 10,000 P. falciparum parasites/mul) and severe nonmalaria anaemia; the incidence rate ratios and 95% confidence intervals (CIs) for alpha+-thalassaemia heterozygotes and homozygotes combined compared to normal children were, for severe malaria anaemia, 0.33 (95% CI, 0.15,0.73; p = 0.006), and for severe nonmalaria anaemia, 0.26 (95% CI, 0.09,0.77; p = 0.015). CONCLUSIONS: Our observations suggest, first that selection for alpha+-thalassaemia might be mediated by a specific effect against severe anaemia, an observation that may lead to fresh insights into the aetiology of this important condition. Second, although alpha+-thalassaemia is strongly protective against severe and fatal malaria, its effects are not detectable at the level of any other malaria outcome; this result provides a cautionary example for studies aimed at testing malaria interventions or identifying new malaria-protective genes.

Senis YA, Kim PY, Fuller GLJ, García A, Prabhakar S, Wilkinson MC, Brittan H, Zitzmann N, Wait R, Warrell DA et al. 2006. Isolation and characterization of cotiaractivase, a novel low molecular weight prothrombin activator from the venom of Bothrops cotiara. Biochim Biophys Acta, 1764 (5), pp. 863-871. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

In this study, we isolated a novel prothrombin activator from the venom of Bothrops cotiara, a Brazilian lance-headed pit viper (Cotiara, Jararaca preta, Biocotiara), which we have designated "cotiaractivase" (prefix: cotiar- from B. cotiara; suffix: -activase, from prothrombin activating activity). Cotiaractivase was purified using a phenyl-Superose hydrophobic interaction column followed by a Mono-Q anion exchange column. It is a single-chain polypeptide with a molecular weight of 22,931 Da as measured by mass spectroscopy. Cotiaractivase generated active alpha-thrombin from purified human prothrombin in a Ca2+-dependent manner as assessed by S2238 chromogenic substrate assay and SDS-PAGE. Cotiaractivase cleaved prothrombin at positions Arg271-Thr272 and Arg320-Ile321, which are also cleaved by factor Xa. However, the rate of thrombin generation by cotiaractivase was approximately 60-fold less than factor Xa alone and 17 x 10(6)-fold less than the prothrombinase complex. The enzymatic activity of cotiaractivase was inhibited by the chelating agent EDTA, whereas the serine protease inhibitor PMSF had no effect on its activity, suggesting that it is a metalloproteinase. Interestingly, S2238 inhibited cotiaractivase activity non-competitively, suggesting that this toxin contains an exosite that allows it to bind prothrombin independently of its active site. Tandem mass spectrometry and N-terminal sequencing of purified cotiaractivase identified peptides that were identical to regions of the cysteine-rich and disintegrin-like domains of known snake venom metalloproteinases. Cotiaractivase is a unique low molecular weight snake venom prothrombin activator that likely belongs to the metalloproteinase family of proteins.

Dubray C, Gervelmeyer A, Djibo A, Jeanne I, Fermon F, Soulier M-H, Grais RF, Guerin PJ. 2006. Late vaccination reinforcement during a measles epidemic in Niamey, Niger (2003-2004). Vaccine, 24 (18), pp. 3984-3989. | Citations: 16 (Scopus) | Show Abstract | Read more

Low measles vaccination coverage (VC) leads to recurrent epidemics in many African countries. We describe VC before and after late reinforcement of vaccination activities during a measles epidemic in Niamey, Niger (2003-2004) assessed by Lot Quality Assurance Sampling (LQAS). Neighborhoods of Niamey were grouped into 46 lots based on geographic proximity and population homogeneity. Before reinforcement activities, 96% of lots had a VC below 70%. After reinforcement, this proportion fell to 78%. During the intervention 50% of children who had no previous record of measles vaccination received their first dose (vaccination card or parental recall). Our results highlight the benefits and limitations of vaccine reinforcement activities performed late in the epidemic.

Choudhurry RSR, Melles DC, Eadie K, Vos M, Wertheim HFL, Verbrugh HA, van Belkum A, van Leeuwen WB. 2006. Direct detection of human Staphylococcus aureus carriage in the nose using the Lightcycler Staphylococcus kit. J Microbiol Methods, 65 (2), pp. 354-356. | Citations: 7 (Scopus) | Show Abstract | Read more

The Lightcycler Staphylococcus kit is a diagnostic tool for direct real-time detection of Staphylococcus aureus in clinical materials. We show here that detection of S. aureus nasal carriage using this test is hampered by competition of DNA from coagulase-negative staphylococci. However the test is well suited for species identification after culture and the identification of high-load S. aureus carriers.

Sirigul C, Wongwit W, Phanprasit W, Paveenkittiporn W, Blacksell SD, Ramasoota P. 2006. Development of a combined air sampling and quantitative real-time PCR method for detection of Legionella spp. Southeast Asian J Trop Med Public Health, 37 (3), pp. 503-507. | Citations: 4 (Scopus) | Show Abstract

The objective of this study was to develop and optimize the combined methods of air sampling and real time polymerase chain reaction (real-time PCR) for quantifying aerosol Legionella spp. Primers and TaqMan hydrolysis probe based on 5S rRNA gene specific for Legionella spp were used to amplify a specific DNA product of 84 bp. The impinger air sampler plus T-100 sampling pump was used to collect aerosol Legionella and as low as 10 fg of Legionella DNA per reaction could detected. Preliminary studies demonstrated that the developed method could detect aerosol Legionella spp 1.5-185 organisms /500 l of air within 5 hours, in contrast to culture method, that required a minimum of 7-10 days.

Sasi P, English M, Berkley J, Lowe B, Shebe M, Mwakesi R, Kokwaro G. 2006. Characterisation of metabolic acidosis in Kenyan children admitted to hospital for acute non-surgical conditions. Trans R Soc Trop Med Hyg, 100 (5), pp. 401-409. | Citations: 15 (Scopus) | Show Abstract | Read more

Metabolic acidosis is associated with most severe malaria deaths in African children, and most deaths occur before maximum antimalarial action is achieved. Thus, specific acidosis treatment may reduce mortality. However, the underlying mechanisms remain poorly understood and no specific interventions have been developed. A detailed characterisation of this acidosis is critical in treatment development. We used the traditional and Stewart's approach to characterise acidosis in consecutive paediatric admissions for malaria and other acute non-surgical conditions to Kilifi District Hospital in Kenya. The overall acidosis prevalence was 21%. Gastroenteritis had the highest prevalence (61%). Both the mean albumin-corrected anion gap and the strong ion gap were high (>13 mmol/l and >0 mmol/l, respectively) in malaria, gastroenteritis, lower respiratory tract infection and malnutrition. Presence of salicylate in plasma was not associated with acidosis but was associated with signs of severe illness (odds ratio 2.11, 95% CI 1.1-4.2). In malaria, mean (95% CI) strong ion gap was 15 (14-7) mmol/l, and lactate, creatinine and inorganic phosphorous explained only approximately 40% of the variability in base excess (adjusted R2 = 0.397). Acidosis may be more common than previously recognised amongst paediatric admissions in Africa and is characterised by the presence of currently unidentified strong anions. In malaria, lactate and ketones, but not salicylate, are associated with acidosis. However, unidentified anions may be more important.

Persson KEM, Lee CT, Marsh K, Beeson JG. 2006. Development and optimization of high-throughput methods to measure Plasmodium falciparum-specific growth inhibitory antibodies. J Clin Microbiol, 44 (5), pp. 1665-1673. | Citations: 83 (Web of Science Lite) | Show Abstract | Read more

Antibodies that inhibit replication of Plasmodium falciparum in erythrocytes are thought to be important both in acquired immunity to malaria and as mediators of immunity generated by candidate blood-stage vaccines. However, several constraints have limited the study of these functional antibodies in population studies and vaccine trials. We report the development and optimization of high-throughput growth inhibition assays with improved sensitivity that use minimal volumes of test serum. The major inhibitory activity of serum from exposed donors was antibody mediated, but nonspecific inhibitory factors were found in untreated serum. Culture volumes could be effectively reduced to 25 microl to limit amounts of test serum or inhibitors used in assays. Performing inhibition assays over two cycles of parasite replication gave greater sensitivity than single-cycle assays, and a simple two-cycle inhibition assay was developed that yielded highly reproducible results. Determination of parasite growth by flow cytometry was most suitable for high-throughput assays using small culture volumes and was more sensitive than parasite lactate dehydrogenase assays and less prone to error and variation than microscopy. We evaluated and optimized methods to remove antimalarials and nonspecific inhibitory factors from serum that are suitable for use with small volumes of samples that are typically obtained from clinical studies. Both microdialysis and immunoglobulin purification by ammonium sulfate precipitation were effective and practical. These methods should facilitate evaluation of vaccine trials and clinical studies of immunity and are also suitable for testing drugs and other compounds for antimalarial activity.

Siddiqui FJ, Bhutto NS, von Seidlein L, Khurram I, Rasool S, Ali M, Zafar A, Deen JL, Clemens JD, Nizami Q, Bhutta ZA. 2006. Consecutive outbreaks of Vibrio cholerae O139 and V. cholerae O1 cholera in a fishing village near Karachi, Pakistan. Trans R Soc Trop Med Hyg, 100 (5), pp. 476-482. | Citations: 21 (Scopus) | Show Abstract | Read more

In July 2002 and June 2003, cholera outbreaks were detected by a diarrhoea surveillance system in a village outside Karachi, Pakistan. Specimens were culture confirmed. The first outbreak was caused by Vibrio cholerae O139 (n = 30) and the second outbreak by V. cholerae O1 (n = 39). Demographic and clinical features of patients were recorded and case-control studies were conducted following each outbreak. Clinical information was obtained for 29 of the 30 patients in the first outbreak, and 2 of the patients in the second outbreak were either out of the area or lost to follow-up, leaving 29 and 37 cases in the analysis for the first and second outbreak, respectively. Eighteen (49%) of the 37 V. cholerae O1 patients were under 2 years of age compared with 6 (21%) of the 29 V. cholerae O139 patients (P = 0.02). Vibrio cholerae O139-infected patients were more likely to be febrile (16/29) than those infected with V. cholerae O1 (2/37; P<0.001). A household contact with cholera was a risk factor in both outbreaks; water source was a risk factor in the first outbreak only. Geographically, cases were clustered during the first outbreak but not during the second. Person-to-person contact and water reservoirs appear to be the main transmission routes for cholera in this setting.

Guerra CA, Snow RW, Hay SI. 2006. Defining the global spatial limits of malaria transmission in 2005. Adv Parasitol, 62 pp. 157-179. | Citations: 46 (Scopus) | Show Abstract | Read more

There is no accurate contemporary global map of the distribution of malaria. We show how guidelines formulated to advise travellers on appropriate chemoprophylaxis for areas of reported Plasmodium falciparum and Plasmodium vivax malaria risk can be used to generate crude spatial limits. We first review and amalgamate information on these guidelines to define malaria risk at national and sub-national administrative boundary levels globally. We then adopt an iterative approach to reduce these extents by applying a series of biological limits imposed by altitude, climate and population density to malaria transmission, specific to the local dominant vector species. Global areas of, and population at risk from, P. falciparum and often-neglected P. vivax malaria are presented for 2005 for all malaria endemic countries. These results reveal that more than 3 billion people were at risk of malaria in 2005.

Ferradini L, Jeannin A, Pinoges L, Izopet J, Odhiambo D, Mankhambo L, Karungi G, Szumilin E, Balandine S, Fedida G et al. 2006. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Lancet, 367 (9519), pp. 1335-1342. | Citations: 364 (Scopus) | Show Abstract | Read more

BACKGROUND: The recording of outcomes from large-scale, simplified HAART (highly active antiretroviral therapy) programmes in sub-Saharan Africa is critical. We aimed to assess the effectiveness of such a programme held by Médecins Sans Frontières (MSF) in the Chiradzulu district, Malawi. METHODS: We scaled up and simplified HAART in this programme since August, 2002. We analysed survival indicators, CD4 count evolution, virological response, and adherence to treatment. We included adults who all started HAART 6 months or more before the analysis. HIV-1 RNA plasma viral load and self-reported adherence were assessed on a subsample of patients, and antiretroviral resistance mutations were analysed in plasma with viral loads greater than 1000 copies per mL. Analysis was by intention to treat. FINDINGS: Of the 1308 patients who were eligible, 827 (64%) were female, the median age was 34.9 years (IQR 29.9-41.0), and 1023 (78%) received d4T/3TC/NVP (stavudine, lamivudine, and nevirapine) as a fixed-dose combination. At baseline, 1266 individuals (97%) were HAART-naive, 357 (27%) were at WHO stage IV, 311 (33%) had a body-mass index of less than 18.5 kg/m2, and 208 (21%) had a CD4 count lower than 50 cells per muL. At follow-up (median 8.3 months, IQR 5.5-13.1), 967 (74%) were still on HAART, 243 (19%) had died, 91 (7%) were lost to follow-up, and seven (0.5%) discontinued treatment. Low body-mass index, WHO stage IV, male sex, and baseline CD4 count lower than 50 cells per muL were independent determinants of death in the first 6 months. At 12 months, the probability of individuals still in care was 0.76 (95% CI 0.73-0.78) and the median CD4 gain was 165 (IQR 67-259) cells per muL. In the cross-sectional survey (n=398), 334 (84%) had a viral load of less than 400 copies per mL. Of several indicators measuring adherence, self-reported poor adherence (<80%) in the past 4 days was the best predictor of detectable viral load (odds ratio 5.4, 95% CI 1.9-15.6). INTERPRETATION: These data show that large numbers of people can rapidly benefit from antiretroviral therapy in rural resource-poor settings and strongly supports the implementation of such large-scale simplified programmes in Africa.

Gomes MGM, White LJ, Medley GF. 2006. The reinfection threshold (vol 236, pg 111, 2005) JOURNAL OF THEORETICAL BIOLOGY, 239 (4), pp. 518-518. | Read more

Clarke SR, Brummell KJ, Horsburgh MJ, McDowell PW, Mohamad SAS, Stapleton MR, Acevedo J, Read RC, Day NPJ, Peacock SJ et al. 2006. Identification of in vivo-expressed antigens of Staphylococcus aureus and their use in vaccinations for protection against nasal carriage. J Infect Dis, 193 (8), pp. 1098-1108. | Citations: 135 (Web of Science Lite) | Show Abstract | Read more

A spectrum of in vivo-expressed Staphylococcus aureus antigens was identified by probing bacteriophage expression libraries of S. aureus with serum samples from infected and uninfected individuals. Eleven recombinant antigenic proteins were produced, and specific antibody titers in a large collection of human serum samples were determined. Significantly increased concentrations of reactive immunoglobulin G (IgG) to 7 antigens were found in serum samples from ill individuals, compared with those in healthy individuals. Significantly higher concentrations of reactive IgG to 4 antigens, including iron-responsive surface determinant (Isd) A and IsdH, were found in serum samples from healthy individuals who were not nasal carriers of S. aureus, compared with those in healthy carriers. Vaccination of cotton rats with IsdA or IsdH protected against nasal carriage. Also, IsdA is involved in adherence of S. aureus to human desquamated nasal epithelial cells and is required for nasal colonization in the cotton rat model. Thus, vaccination with these antigens may prevent S. aureus carriage and reduce the prevalence of human disease.

Blacksell SD, Newton PN, Bell D, Kelley J, Mammen MP, Vaughn DW, Wuthiekanun V, Sungkakum A, Nisalak A, Day NPJ. 2006. The comparative accuracy of 8 commercial rapid immunochromatographic assays for the diagnosis of acute dengue virus infection. Clin Infect Dis, 42 (8), pp. 1127-1134. | Citations: 79 (Scopus) | Show Abstract | Read more

BACKGROUND: The serological diagnosis of acute dengue virus infection relies on the detection of dengue-specific immunoglobulin M (IgM) antibodies. Immunochromatographic tests are rapid diagnostic tests (RDTs) that can be performed at the bedside, but they have not been fully validated for diagnosis of dengue infection. METHODS: More than 20 RDTs for diagnosis of acute dengue infection are commercially available. Of these, 8 were selected for evaluation of performance by use of characterized dengue and nondengue serum specimens, and results were compared with those of a previously published dengue IgM/IgG enzyme-linked immunosorbent assay in conjunction with dengue virus serotyping by reverse-transcriptase polymerase chain reaction. RESULTS: Assay sensitivities were low, ranging from 6.4% (95% confidence interval [CI], 4.0%-9.7%) to 65.3% (95% CI, 59.9%-70.5%), and specificities ranged from 69.1% (95% CI, 61.4%-76.0%) to 100% (95% CI, 97.8%-100%). Of the 8 tests, only 2 had sensitivities of >50%, the level considered to be clinically useful, and, of these, 1 had relatively low specificity (69.1%). Samples collected early in the infection were less likely to test positive than those collected later. A thermal stability study demonstrated a loss in performance of some RDTs when they were stored at a high ambient temperature for 3 months. CONCLUSIONS: Users of RDTs for dengue should be aware that many of these tests have a diagnostic accuracy that falls well below the manufacturers' claims. If an acute specimen yields a negative result, a convalescent serum sample should be tested to confirm the result. No RDT adequately differentiated primary and secondary dengue infections, and the tests should not be used for this purpose.

Bejon P, Peshu N, Gilbert SC, Lowe BS, Molyneux CS, Forsdyke J, Lang T, Hill AVS, Marsh K. 2006. Safety profile of the viral vectors of attenuated fowlpox strain FP9 and modified vaccinia virus Ankara recombinant for either of 2 preerythrocytic malaria antigens, ME-TRAP or the circumsporozoite protein, in children and adults in Kenya. Clin Infect Dis, 42 (8), pp. 1102-1110. | Citations: 34 (Scopus) | Show Abstract | Read more

BACKGROUND: We are developing a heterologous prime-boost vaccine strategy against malaria. This approach uses sequential immunization with different vectors to deliver a common preerythrocytic malaria antigen. Preliminary evidence of efficacy and safety has been previously documented in studies from an area where malaria is nonendemic. Additional safety data from an area where malaria is endemic are now required before larger-scale studies are undertaken to determine the efficacy of this vaccine strategy in the field. Other modified vaccinia virus Ankara (MVA) recombinants and prime-boost immunizations are being developed as vaccines against human immunodeficiency virus (HIV) infection, tuberculosis, and cancer, and MVA is a candidate attenuated smallpox vaccine. METHODS: Candidate vaccines against malaria were intradermally administered to 73 adults (7 of whom were HIV positive) and 22 children in Kenya. These vaccines used the attenuated fowlpox strain FP9 and the MVA recombinant for either of 2 preerythrocytic malaria antigens, multiple preerythrocytic-stage epitopes joined with the preerythrocytic-stage antigen TRAP (ME-TRAP) and the circumsporozoite protein (CS). Adverse events were recorded. RESULTS: Reactogenicity was mild. MVA caused less frequent and less severe cutaneous reaction if given after FP9 priming. Half doses reduced the frequency and the severity of systemic reactogenicity, and particular vaccine lots were associated with different reactogenicities. Unexpectedly, prior immunity to the ME-TRAP antigen appeared to be protective against local reactions after immunization. CONCLUSIONS: Where the final intention is to use MVA after FP9 priming, previous testing of MVA alone overestimates reactogenicity. These recombinant vectors appear to be safe and suitable for use in larger-scale studies of children in Africa and of HIV-positive individuals.

Maguire JD, Krisin, Marwoto H, Richie TL, Fryauff DJ, Baird JK. 2006. Mefloquine is highly efficacious against chloroquine-resistant Plasmodium vivax malaria and Plasmodium falciparum malaria in Papua, Indonesia. Clin Infect Dis, 42 (8), pp. 1067-1072. | Citations: 54 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: During the period of 1996-1999, we prospectively monitored 243 Javanese adults and children after arriving in Papua, Indonesia, and microscopically documented each new case of malaria by active surveillance. METHODS: In a randomized, open-label, comparative malaria treatment trial, 72 adults and 50 children received chloroquine for each incident case of malaria, and 74 adults and 47 children received mefloquine. RESULTS: Among 975 primary treatment courses, the cumulative 28-day curative efficacies were 26% and 82% for chloroquine against Plasmodium falciparum malaria and Plasmodium vivax malaria, respectively. Mefloquine cure rates were far superior (96% against P. falciparum malaria and 99.6% against P. vivax malaria). CONCLUSIONS: Mefloquine is a useful alternative treatment for P. vivax malaria and P. falciparum malaria in areas such as Papua, where chloroquine is still recommended as the first-line therapeutic agent.

Singtoroj T, Tarning J, Annerberg A, Ashton M, Bergqvist Y, White NJ, Lindegardh N, Day NPJ. 2006. A new approach to evaluate regression models during validation of bioanalytical assays. J Pharm Biomed Anal, 41 (1), pp. 219-227. | Citations: 35 (Scopus) | Show Abstract | Read more

The quality of bioanalytical data is highly dependent on using an appropriate regression model for calibration curves. Non-weighted linear regression has traditionally been used but is not necessarily the optimal model. Bioanalytical assays generally benefit from using either data transformation and/or weighting since variance normally increases with concentration. A data set with calibrators ranging from 9 to 10000 ng/mL was used to compare a new approach with the traditional approach for selecting an optimal regression model. The new approach used a combination of relative residuals at each calibration level together with precision and accuracy of independent quality control samples over 4 days to select and justify the best regression model. The results showed that log-log transformation without weighting was the simplest model to fit the calibration data and ensure good predictability for this data set.

Tarning J, Singtoroj T, Annerberg A, Ashton M, Bergqvist Y, White NJ, Day NPJ, Lindegardh N. 2006. Development and validation of an automated solid phase extraction and liquid chromatographic method for the determination of piperaquine in urine. J Pharm Biomed Anal, 41 (1), pp. 213-218. | Citations: 21 (Scopus) | Show Abstract | Read more

A sensitive and specific bioanalytical method for determination of piperaquine in urine by automated solid-phase extraction (SPE) and liquid chromatography (LC) has been developed and validated. Buffered urine samples (containing internal standard) were loaded onto mixed phase (cation-exchange and octylsilica) SPE columns using an ASPEC XL SPE robot. Chromatographic separation was achieved on a Chromolith Performance RP-18e (100 mm x 4.6 mm I.D.) LC column with phosphate buffer (pH 2.5; 0.1 mol/L)-acetonitrile (92:8, v/v). Piperaquine was analysed at a flow rate of 3 mL/min with UV detection at 347 nm. A linear regression model on log-log transformed data was used for quantification. Within-day precision for piperaquine was 1.3% at 5000 ng/mL and 6.6% at 50 ng/mL. Between-day precision for piperaquine was 3.7% at 5000 ng/mL and 7.2% at 50 ng/mL. Total-assay precision for piperaquine over 4 days using five replicates each day (n = 20) was 4.0%, 5.2% and 9.8% at 5000, 500 and 50 ng/mL, respectively. The lower limit of quantification (LLOQ) was set to 3 ng/mL using 1 mL of urine, which could be lowered to 0.33 ng/mL when using 9 mL of urine and an increased injection volume.

Dunachie SJ, Walther M, Vuola JM, Webster DP, Keating SM, Berthoud T, Andrews L, Bejon P, Poulton I, Butcher G et al. 2006. A clinical trial of prime-boost immunisation with the candidate malaria vaccines RTS,S/AS02A and MVA-CS. Vaccine, 24 (15), pp. 2850-2859. | Citations: 68 (Web of Science Lite) | Show Abstract | Read more

Heterologous prime-boost immunisation with RTS,S/AS02A and the poxvirus MVA-CS was evaluated in 18 healthy malaria-naïve subjects in Oxford. Both priming with RTS,S and boosting MVA-CS, and the reverse, were found to be safe and well tolerated. T cell responses as measured by IFN-gamma ex vivo ELISPOT were induced, but the responses were low to moderate in both groups, with heterologous boosting yielding only small increments in T cell immunogenicity and no increased antibody response. Protection against 3D7 Plasmodium falciparum sporozoite challenge 4 weeks after the final vaccination was equal for both regimens at 33% (95% C.I. 4.3-77.7%), with one subject remaining fully protected on rechallenge at 5 months.

Webster DP, Dunachie S, McConkey S, Poulton I, Moore AC, Walther M, Laidlaw SM, Peto T, Skinner MA, Gilbert SC, Hill AVS. 2006. Safety of recombinant fowlpox strain FP9 and modified vaccinia virus Ankara vaccines against liver-stage P. falciparum malaria in non-immune volunteers. Vaccine, 24 (15), pp. 3026-3034. | Citations: 54 (Scopus) | Show Abstract | Read more

The ability to generate potent antigen-specific T cell responses by vaccination has been a major hurdle in vaccinology. Vaccinia virus and avipox viruses have been shown to be capable of expressing antigens in mammalian cells and can induce a protective immune response against several mammalian pathogens. We report on two such vaccine constructs, modified vaccinia virus Ankara and FP9 (an attenuated fowlpox virus) both expressing the pre-erythrocytic malaria antigen thrombospondin-related adhesion protein and a string of CD8+ epitopes (ME-TRAP). In prime-boost combinations in a mouse model MVA and FP9 are highly immunogenic and induce substantial protective efficacy. A series of human clinical trials using the recombinant MVA and FP9 malaria vaccines encoding ME-TRAP, both independently and in prime-boost combinations with or without the DNA vaccine DNA ME-TRAP, has shown them to be both immunogenic for CD8+ T cells and capable of inducing protective efficacy. We report here a detailed analysis of the safety profiles of these viral vectors and show that anti-vector antibody responses induced by the vectors are generally low to moderate. We conclude that these vectors are safe and show acceptable side effect profiles for prophylactic vaccination.

Ali M, Park J-K, von Seidlein L, Acosta CJ, Deen JL, Clemens JD. 2006. Organizational aspects and implementation of data systems in large-scale epidemiological studies in less developed countries. BMC Public Health, 6 (1), pp. 86. | Citations: 7 (Scopus) | Show Abstract | Read more

BACKGROUND: In the conduct of epidemiological studies in less developed countries, while great emphasis is placed on study design, data collection, and analysis, often little attention is paid to data management. As a consequence, investigators working in these countries frequently face challenges in cleaning, analyzing and interpreting data. In most research settings, the data management team is formed with temporary and unskilled persons. A proper working environment and training or guidance in constructing a reliable database is rarely available. There is little information available that describes data management problems and solutions to those problems. Usually a line or two can be obtained in the methods section of research papers stating that the data are doubly-entered and that outliers and inconsistencies were removed from the data. Such information provides little assurance that the data are reliable. There are several issues in data management that if not properly practiced may create an unreliable database, and outcomes of this database will be spurious. RESULTS: We have outlined the data management practices for epidemiological studies that we have modeled for our research sites in seven Asian countries and one African country. CONCLUSION: Information from this model data management structure may help others construct reliable databases for large-scale epidemiological studies in less developed countries.

Wiersinga WJ, van der Poll T, White NJ, Day NP, Peacock SJ. 2006. Melioidosis: insights into the pathogenicity of Burkholderia pseudomallei. Nat Rev Microbiol, 4 (4), pp. 272-282. | Citations: 356 (Scopus) | Show Abstract | Read more

Burkholderia pseudomallei is a potential bioterror agent and the causative agent of melioidosis, a severe disease that is endemic in areas of Southeast Asia and Northern Australia. Infection is often associated with bacterial dissemination to distant sites, and there are many possible disease manifestations, with melioidosis septic shock being the most severe. Eradication of the organism following infection is difficult, with a slow fever-clearance time, the need for prolonged antibiotic therapy and a high rate of relapse if therapy is not completed. Mortality from melioidosis septic shock remains high despite appropriate antimicrobial therapy. Prevention of disease and a reduction in mortality and the rate of relapse are priority areas for future research efforts. Studying how the disease is acquired and the host-pathogen interactions involved will underpin these efforts; this review presents an overview of current knowledge in these areas, highlighting key topics for evaluation.

White NJ, Ashley EA, Nosten F. 2006. Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol, 59 (4), pp. 725-726. | Citations: 9 (Web of Science Lite) | Read more

Thwaites CL, Yen LM, Cordon SM, Binh NT, T N, Nga N, White NJ, Soni N, MacDonald IA, Farrar JJ. 2006. Urinary catecholamine excretion in tetanus. Anaesthesia, 61 (4), pp. 355-359. | Citations: 9 (Scopus) | Show Abstract | Read more

Imperfect understanding of the pathophysiology of tetanus has limited therapeutic advances. Autonomic disturbance is a major cause of mortality and is believed to be associated with catecholamine release, predominantly norepinephrine. We measured epinephrine and norepinephrine concentrations in 24-h urine collections from tetanus and critically ill patients suffering from other severe diseases. In patients with severe tetanus, mean (SD) epinephrine was 164.18 (129.37) nmol x day(-1) compared with 45.18 (37.74) nmol x day(-1) in mild-moderate disease (p = 0.008). In the severe group, mean (SD) norepinephrine was 411.64 (208.5), and 121.00 (81.81) nmol x day(-1) in moderately ill patients (p < 0.001). Compared with critically ill control patients, median epinephrine was 331.77 in tetanus patients and 89.70 nmol x day(-1) in controls (p < 0.001). Median norepinephrine concentration was 788.02 nmol x day(-1) in tetanus and 300.05 nmol x day(-1) in control patients, p = 0.006. The study finds a novel result of increased epinephrine excretion in tetanus and confirms that catecholamine excretion in tetanus exceeds that in other critically ill patients. These results should be considered in designing more effective therapeutic strategies.

Urban BC, Shafi MJ, Cordery DV, Macharia A, Lowe B, Marsh K, Williams TN. 2006. Frequencies of peripheral blood myeloid cells in healthy Kenyan children with alpha+ thalassemia and the sickle cell trait. Am J Trop Med Hyg, 74 (4), pp. 578-584. | Citations: 8 (Web of Science Lite) | Show Abstract

The high frequencies of both alpha+ thalassemia and the sickle cell trait (hemoglobin AS [HbAS]) found in many tropical populations are thought to reflect selection pressure from Plasmodium falciparum malaria. For HbAS, but not for alpha+ thalassemia, protection appears to be mediated by the enhanced phagocytic clearance of ring-infected erythrocytes. We have investigated the genotype-specific distributions of peripheral blood leukocyte populations in two groups of children living on the coast of Kenya: a group of healthy P. falciparum parasite-negative children sampled at cross-sectional survey during a period of low malaria transmission, and a group of children attending the hospital with acute malaria. We report distinctive distributions of peripheral blood myeloid dendritic cells and monocytes in children with alpha+ thalassemia and HbAS during healthy periods and disease, and suggest ways in which these might relate to the mechanisms of protection afforded by these conditions.

Guerra CA, Snow RW, Hay SI. 2006. A global assessment of closed forests, deforestation and malaria risk. Ann Trop Med Parasitol, 100 (3), pp. 189-204. | Citations: 61 (Scopus) | Show Abstract | Read more

Global environmental change is expected to affect profoundly the transmission of the parasites that cause human malaria. Amongst the anthropogenic drivers of change, deforestation is arguably the most conspicuous, and its rate is projected to increase in the coming decades. The canonical epidemiological understanding is that deforestation increases malaria risk in Africa and the Americas and diminishes it in South-east Asia. Partial support for this position is provided here, through a systematic review of the published literature on deforestation, malaria and the relevant vector bionomics. By using recently updated boundaries for the spatial limits of malaria and remotely-sensed estimates of tree cover, it has been possible to determine the population at risk of malaria in closed forest, at least for those malaria-endemic countries that lie within the main blocks of tropical forest. Closed forests within areas of malaria risk cover approximately 1.5 million km2 in the Amazon region, 1.4 million km2 in Central Africa, 1.2 million km2 in the Western Pacific, and 0.7 million km2 in South-east Asia. The corresponding human populations at risk of malaria within these forests total 11.7 million, 18.7 million, 35.1 million and 70.1 million, respectively. By coupling these numbers with the country-specific rates of deforestation, it has been possible to rank malaria-endemic countries according to their potential for change in the population at risk of malaria, as the result of deforestation. The on-going research aimed at evaluating these relationships more quantitatively, through the Malaria Atlas Project (MAP), is highlighted.

Zurovac D, Midia B, Ochola SA, English M, Snow RW. 2006. Microscopy and outpatient malaria case management among older children and adults in Kenya. Trop Med Int Health, 11 (4), pp. 432-440. | Citations: 122 (Scopus) | Show Abstract | Read more

OBJECTIVE: To evaluate the accuracy of routine malaria microscopy, and appropriate use and interpretation of malaria slides under operational conditions in Kenya. METHODS: Cross-sectional survey, using a range of quality of care assessment tools, at government facilities with malaria microscopy in two Kenyan districts of different intensity of malaria transmission. All patients older than 5 years presenting to outpatient departments were enrolled. Two expert microscopists assessed the accuracy of the routine malaria slide results. RESULTS: We analysed 359 consultations performed by 31 clinicians at 17 facilities. Clinical assessment was suboptimal. Blood slide microscopy was performed for 72.7% of patients, who represented 78.5% of febrile patients and 51.3% of afebrile patients. About 95.5% of patients with a positive malaria microscopy result and 79.3% of patients with a negative result received antimalarial treatment. Sulphadoxine-pyremethamine monotherapy was more commonly prescribed for patients with a negative test result (60.7%) than for patients with a positive result (32.4%). Conversely, amodiaquine or quinine were prescribed for only 14.7% of patients with a negative malaria microscopy result compared to 57.7% of patients with a positive result. The prevalence of confirmed malaria was low in both high (10.0%) and low-(16.3%) transmission settings. Combining data from both settings, the sensitivity of routine microscopy was 68.6%; its specificity, 61.5%; its positive predictive value, 21.6% and its negative predictive value, 92.7%. CONCLUSIONS: The potential benefits of microscopy are currently not realised because of the poor quality of routine testing and irrational clinical practices. Ambiguous clinical guidelines permitting treatment of older children and adults with a negative blood slide also undermine rational use of antimalarial drugs.

Angus B, ESPRIT, STALWART, SILCAAT trial steering committees. 2006. Interleukin 2 treatment in HIV-1 infection. Lancet, 367 (9516), pp. 1054-1055. | Citations: 2 (Web of Science Lite) | Read more

van Belkum A, Melles DC, Snijders SV, van Leeuwen WB, Wertheim HFL, Nouwen JL, Verbrugh HA, Etienne J. 2006. Clonal distribution and differential occurrence of the enterotoxin gene cluster, egc, in carriage- versus bacteremia-associated isolates of Staphylococcus aureus. J Clin Microbiol, 44 (4), pp. 1555-1557. | Citations: 50 (Scopus) | Show Abstract | Read more

The Staphylococcus aureus enterotoxin gene cluster, egc, was detected in isolates from healthy individuals and in those from patients with bacteremia. The egc genes cooccur and are slightly enriched in strains from healthy carriers (present in 63.7% of carriage-associated isolates versus 52.9% of invasive isolates; P = 0.03). Multilocus sequence typing revealed that successful staphylococcal clones usually harbor the egc locus.

Rolland E, Checchi F, Pinoges L, Balkan S, Guthmann J-P, Guerin PJ. 2006. Operational response to malaria epidemics: are rapid diagnostic tests cost-effective? Trop Med Int Health, 11 (4), pp. 398-408. | Citations: 46 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To compare the cost-effectiveness of malaria treatment based on presumptive diagnosis with that of malaria treatment based on rapid diagnostic tests (RDTs). METHODS: We calculated direct costs (based on experience from Ethiopia and southern Sudan) and effectiveness (in terms of reduced over-treatment) of a free, decentralised treatment programme using artesunate plus amodiaquine (AS + AQ) or artemether-lumefantrine (ART-LUM) in a Plasmodium falciparum epidemic. Our main cost-effectiveness measure was the incremental cost per false positive treatment averted by RDTs. RESULTS: As malaria prevalence increases, the difference in cost between presumptive and RDT-based treatment rises. The threshold prevalence above which the RDT-based strategy becomes more expensive is 21% in the AS + AQ scenario and 55% in the ART-LUM scenario, but these thresholds increase to 58 and 70%, respectively, if the financing body tolerates an incremental cost of 1 euro per false positive averted. However, even at a high (90%) prevalence of malaria consistent with an epidemic peak, an RDT-based strategy would only cost moderately more than the presumptive strategy: +29.9% in the AS + AQ scenario and +19.4% in the ART-LUM scenario. The treatment comparison is insensitive to the age and pregnancy distribution of febrile cases, but is strongly affected by variation in non-biomedical costs. If their unit price were halved, RDTs would be more cost-effective at a malaria prevalence up to 45% in case of AS + AQ treatment and at a prevalence up to 68% in case of ART-LUM treatment. CONCLUSION: In most epidemic prevalence scenarios, RDTs would considerably reduce over-treatment for only a moderate increase in costs over presumptive diagnosis. A substantial decrease in RDT unit price would greatly increase their cost-effectiveness, and should thus be advocated. A tolerated incremental cost of 1 euro is probably justified given overall public health and financial benefits. The RDTs should be considered for malaria epidemics if logistics and human resources allow.

Deans A-M, Lyke KE, Thera MA, Plowe CV, Koné A, Doumbo OK, Kai O, Marsh K, Mackinnon MJ, Raza A, Rowe JA. 2006. Low multiplication rates of African Plasmodium falciparum isolates and lack of association of multiplication rate and red blood cell selectivity with malaria virulence. Am J Trop Med Hyg, 74 (4), pp. 554-563. | Citations: 35 (Web of Science Lite) | Show Abstract

Two potential malaria virulence factors, parasite multiplication rate (PMR) and red blood cell selectivity (measured as selectivity index [SI]), were assessed in Plasmodium falciparum clinical isolates from Mali and Kenya. At both sites, PMRs were low (Kenya median = 2.2, n = 33; Mali median = 2.6, n = 61) and did not differ significantly between uncomplicated and severe malaria cases. Malian isolates from hyperparasitemic patients had significantly lower PMRs (median = 1.8, n = 19) than other Malian isolates (uncomplicated malaria median = 3.1, n = 23; severe malaria median = 2.8, n = 19; P = 0.03, by Kruskal-Wallis test). Selective invasion occurred at both sites (Kenya geometric mean SI = 1.9, n = 98; Mali geometric mean SI = 1.6, n = 104), and there was no significant association between the SI and malaria severity. Therefore, in contrast to previous results from Thailand, we found no association of PMR and SI with malaria severity in African children. This raises the possibility of differences in the mechanisms of malaria virulence between sub-Saharan Africa and Asia.

Zaidi SSH, Seidlein LV, Nizami SQ, Acosta C, Bhutta ZA. 2006. Health care utilization for diarrhea and fever in 4 urban slums in Karachi. J Coll Physicians Surg Pak, 16 (4), pp. 245-248. | Citations: 6 (Scopus) | Show Abstract

OBJECTIVE: To estimate the fraction of fever and diarrhea patients making use of private practitioners, self-treatment, hospital care, drug vendors, community health centers and traditional healers. DESIGN: A cross-sectional survey. PLACE AND DURATION OF STUDY: Four slums in and around Karachi during October and November, 2001. PATIENTS AND METHODS: A sample of 1842 households was selected with probability proportional to size of the slum. The household head or a representative was asked regarding the treatment providers for diarrhea and cases of fever persistent for 3 days or more. Only households with an actual case of fever and/or diarrhea were included in the analysis. RESULTS: The study found that more than half of diarrhea and fever cases are seen by private practitioners. Self medication with medicines available in the home or specifically purchased for the disease episode from a drug vendor combined provides 13% to 18% of health care. Only between 11% and 13% of patients are seen by the public sector, hospitals and community health centers. There was no significant difference between the choice of health care provider for diarrhea and fever cases. CONCLUSION: In this survey, the majority of fever and diarrhea patients presented first to private practitioners and not to drug vendors or the public sector. Successful passive surveillance of febrile or diarrheal illness in these communities has to integrate private practitioners.

Baumeister S, Winterberg M, Duranton C, Huber SM, Lang F, Kirk K, Lingelbach K. 2006. Evidence for the involvement of Plasmodium falciparum proteins in the formation of new permeability pathways in the erythrocyte membrane. Mol Microbiol, 60 (2), pp. 493-504. | Citations: 31 (Scopus) | Show Abstract | Read more

The intraerythrocytic developmental stages of the malaria parasite Plasmodium falciparum are responsible for the clinical symptoms associated with malaria tropica. The non-infected human erythrocyte is a terminally differentiated cell that is unable to synthesize proteins and lipids de novo, and it is incapable of importing a number of solutes that are essential for parasite proliferation. Approximately 12-15 h after invasion the parasitized cell undergoes a marked increase in its permeability to a variety of different solutes present in the extracellular milieu. The increase is due to the induction in the erythrocyte membrane of 'new permeability pathways' which have been characterized in some detail in terms of their transport and electrophysiological properties, but which are yet to be defined at a molecular level. Here we show that these pathways are resistant to trypsin but are abolished by treatment of intact infected erythrocytes with chymotrypsin. On resuspension of chymotrypsinized cells in chymotrypsin-free medium the pathways progressively reappear, a process that can be inhibited by cytotoxic agents, and by brefeldin A which inhibits protein secretion. Our results provide evidence for the involvement of parasite encoded proteins in the generation of the pathways, either as components of the pathways themselves or as auxiliary factors.

Ziem JB, Olsen A, Magnussen P, Horton J, Agongo E, Geskus RB, Polderman AM. 2006. Distribution and clustering of Oesophagostomum bifurcum and hookworm infections in northern Ghana. Parasitology, 132 (Pt 4), pp. 525-534. | Citations: 11 (Scopus) | Show Abstract | Read more

Human Oesophagostomum infections are locally common in northern Ghana. The present study describes the results of a cross-sectional survey involving 1011 subjects, selected by a compound-based random sampling method from 1227 compounds in 24 villages. Selected persons were examined by both Kato and coproculture methods. Hookworm-like eggs, representing ova of Oesophagostomum bifurcum and hookworm were detected in 87.5% of the Kato smears. The geometric mean egg count of the infected subjects was 1018. Upon coproculture, third-stage larvae of O. bifurcum and hookworm were detected in 53.0% and 86.9% of subjects respectively. Oesophagostomum infections were clustered but no clear explanation for aggregation of infections could be found as yet. Subjects infected with hookworm had a 5-fold higher risk of being infected with O. bifurcum. Infection rates in adult women were higher than in adult men. No association was found with family size, level of hygiene or with the presence of animals in the compounds. Representatives of the Bimoba-tribe were significantly more infected than those of the other tribes. It appears, however, that this tribal association is a geographical phenomenon: Bimoba are mostly living in villages with the highest infection rates.

de Jong MD, Hien TT, Farrar J. 2006. Oseltamivir resistance in influenza A (H5N1) infection - Reply NEW ENGLAND JOURNAL OF MEDICINE, 354 (13), pp. 1424-1424.

Smit C, Geskus R, Walker S, Sabin C, Coutinho R, Porter K, Prins M, CASCADE Collaboration. 2006. Effective therapy has altered the spectrum of cause-specific mortality following HIV seroconversion. AIDS, 20 (5), pp. 741-749. | Citations: 162 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: Although HAART has led to a reduction in overall mortality among HIV-infected individuals, its impact on death from specific causes is unknown. METHODS: Twenty-two cohorts of HIV-infected individuals with known dates of seroconversion are pooled in the CASCADE collaboration. Causes of death (COD) were categorized into three AIDS-related and seven non-AIDS-related causes. The unknown causes were assigned a separate category. The cumulative incidence for each COD was calculated in the presence of the other competing COD, for the pre-HAART and HAART eras. A multivariate regression analyses for the cumulative rate of progression to the different COD was performed. RESULTS: A total of 1938 of 7680 HIV-seroconverters died. Pre-HAART, AIDS opportunistic infections (OI) was the most common COD, followed by unknown and HIV/AIDS-unspecified. In the HAART era, the cumulative incidence for all AIDS-related COD decreased, OI remaining the most important. Large reductions in death due to other infections and organ failure were seen. Cumulative death risk decreased in the HAART era for most causes. The effect of HAART was not the same for all risk groups. The cumulative risk of death from AIDS-related malignancies, OI and non-AIDS-related malignancies decreased significantly among homosexual men (MSM), whereas the risk of dying from (un)-intentional death increased significantly among injecting drug users (IDU). A non-significant increase in hepatitis/liver-related death was seen in MSM, IDU and haemophiliacs. CONCLUSION: Overall and cause specific mortality decreased following the introduction of HAART. OI remain the most common COD in the HAART era, suggesting that AIDS-related events will continue to be important in the future. Future trends in COD should be monitored using standardized guidelines.

Chantratita N, Vesaratchavest M, Wuthiekanun V, Tiyawisutsri R, Ulziitogtokh T, Akcay E, Day NPJ, Peacock SJ. 2006. Pulsed-field gel electrophoresis as a discriminatory typing technique for the biothreat agent burkholderia mallei. Am J Trop Med Hyg, 74 (3), pp. 345-347. | Citations: 9 (Scopus) | Show Abstract

Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) was used to type 21 laboratory strains of Burkholderia mallei. We demonstrated good resolution by PFGE together with clustering of some geographically related isolates, and confirmed previous observations that B. mallei is clonal as defined by MLST.

Thwaites CL, Yen LM, Glover C, Tuan PQ, Nga NTN, Parry J, Loan HT, Bethell D, Day NPJ, White NJ et al. 2006. Predicting the clinical outcome of tetanus: the tetanus severity score. Trop Med Int Health, 11 (3), pp. 279-287. | Citations: 18 (Scopus) | Show Abstract | Read more

OBJECTIVES: To create a new tetanus score and compare it with the Phillips and Dakar scores. METHODS: We used prospectively acquired data from consecutive patients admitted to the Hospital for Tropical Diseases, Ho Chi Minh City, to create the Tetanus Severity Score (TSS) with multivariate logistic regression. We compared the new score with Phillips and Dakar scores by means of resubstituted and prospective data, assessing performance in terms of sensitivity, specificity and area under receiver operator characteristic curves. RESULTS: Resubstitution testing yielded a sensitivity of 77% (298/385) and a specificity of 82% (1,183/1,437) for the TSS; 89% (342/385) and 20% (281/1,437) for the Phillips score; and 13% (49/385) and 98% (1,415/1,437) for the Dakar score. The TSS showed greatest discrimination with 0.89 area under the receiver operator characteristic curve (95% CI 0.88-0.90); this was 0.74 for the Dakar score and (95% CI 0.71-0.77) and 0.66 for the Phillips score (95% CI 0.63-0.70; P values <0.001). Prospective testing showed 65% (13/20) sensitivity and 91% (210/230) specificity for the TSS; 80% (16/20) and 51% (118/230) for the Phillips score; and 25% (5/20) and 96% (221/230) for the Dakar score. The TSS achieved the greatest area under TSS of 0.89 (95% CI 0.82-0.96), significantly greater than the Phillips score [0.74 (0.6-0.88), P = 0.049] but not the Dakar score [0.80, (0.71-0.90), P = 0.090]. CONCLUSIONS: The TSS is the first prospectively developed classification scheme for tetanus and should be adopted to aid clinical triage and management and as a basis for clinical research.

Flanagan KL, Plebanski M, Odhiambo K, Sheu E, Mwangi T, Gelder C, Hart K, Kortok M, Lowe B, Robson KJ et al. 2006. Cellular reactivity to the p. Falciparum protein trap in adult kenyans: novel epitopes, complex cytokine patterns, and the impact of natural antigenic variation. Am J Trop Med Hyg, 74 (3), pp. 367-375. | Citations: 18 (Web of Science Lite) | Show Abstract

Malaria vaccines based on thrombospondin-related adhesive protein of Plasmodium falciparum (Pf TRAP) are currently undergoing clinical trials in humans. This study was designed to investigate naturally acquired cellular immunity to Pf TRAP in adults from a target population for future trials of TRAP-based vaccines in Kilifi, Kenya. We first tested reactivity to a panel of 53 peptides spanning Pf TRAP and identified 26 novel T-cell epitopes. A panel of naturally occurring polymorphic variant epitope peptides were made to the most commonly recognized epitope regions and tested for ability to elicit IFN-gamma, IL-4, and IL-10 production. These data provide for the first time a complex cytokine matrix mapping naturally induced T-cell responses to TRAP and suggest that T-cell responses boosted by vaccination with Pf TRAP could stimulate the release of competing pro- and anti-inflammatory cytokines. They further define polymorphic variants able to boost specific Th1, Th2, and possibly Tr1 reactivity.

Anuntagool N, Wuthiekanun V, White NJ, Currie BJ, Sermswan RW, Wongratanacheewin S, Taweechaisupapong S, Chaiyaroj SC, Sirisinha S. 2006. Lipopolysaccharide heterogeneity among Burkholderia pseudomallei from different geographic and clinical origins. Am J Trop Med Hyg, 74 (3), pp. 348-352. | Citations: 38 (Scopus) | Show Abstract

Heterogeneous patterns were obtained for lipopolysaccharide (LPS) from 1,327 Burkholderia pseudomallei isolates by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, silver staining, and immunoblot analysis. Two LPS serotypes (A and B) possessing different ladder profiles and a rough LPS without ladder appearances were identified. All three LPS types were antigenically distinct by immunoblotting. The predominant type A (97%) produced the lowest amount of biofilm. The two less common types (smooth type B and rough type) were found more in clinical than environmental isolates and more in Australian isolates than Thai isolates. These isolates were more often associated with relapse than with primary infection.

Brent AJ, Oundo JO, Mwangi I, Ochola L, Lowe B, Berkley JA. 2006. Salmonella bacteremia in Kenyan children. Pediatr Infect Dis J, 25 (3), pp. 230-236. | Citations: 121 (Scopus) | Show Abstract | Read more

BACKGROUND: Nontyphoidal Salmonella spp. are among the leading causes of childhood bacteremia in sub-Saharan Africa, yet there are few published clinical series, and the risk factors for acquiring infection are not fully understood. METHODS: We examined data from 166 cases of nontyphoidal Salmonella bacteremia identified during a large prospective study of bacteremia among all children admitted to a district hospital in Kenya. We also investigated the importance of comorbidities, including current malaria parasitemia, recent malaria (detectable Plasmodium falciparum histidine rich protein 2 in the absence of parasitemia), sickle cell disease, malnutrition and human immunodeficiency virus (HIV) infection. RESULTS: Nontyphoidal Salmonella bacteremia was associated with severe malnutrition (33% cases), HIV infection (18% cases), a history of illness >7 days, recent hospital admission, splenomegaly, anemia and recent (but not current) malaria but was not associated with diarrhea. Seventy-seven (46%) children with nontyphoidal Salmonella bacteremia fulfilled World Health Organization clinical criteria for a diagnosis of pneumonia. Independent risk factors for death were diarrhea, tachypnea, HIV infection, severe malnutrition, meningitis and young age. CONCLUSIONS: Clinical diagnosis of invasive nontyphoidal Salmonella infection in African children is difficult without microbiology facilities because clinical features overlap with other conditions. The common risk factors for nontyphoidal Salmonella infection differ from developed countries, with high a prevalence of malnutrition, HIV, malaria and anemia. Children with nontyphoidal Salmonella infection who fulfill World Health Organization clinical criteria for severe pneumonia may receive ineffective therapy in the form of penicillin.

Bousema JT, Roeffen W, van der Kolk M, de Vlas SJ, van de Vegte-Bolmer M, Bangs MJ, Teelen K, Kurniawan L, Maguire JD, Baird JK, Sauerwein RW. 2006. Rapid onset of transmission-reducing antibodies in javanese migrants exposed to malaria in papua, indonesia. Am J Trop Med Hyg, 74 (3), pp. 425-431. | Citations: 27 (Web of Science Lite) | Show Abstract

Transmission of Plasmodium falciparum malaria is initiated by sexual stages in the mosquito. Anti-Pfs48/45 and anti-Pfs230 sexual stage antibodies that are ingested together with parasites can reduce parasite development and subsequently malaria transmission. Acquisition of sexual stage immunity was studied in a cohort of 102 non-immune Javanese individuals migrating to hyperendemic Papua Indonesia. Seroprevalence of antibodies against Pfs48/45 and Pfs230 and functional transmission-reducing activity (TRA) were measured upon arrival and at 6, 12, and 24 months. Asexual parasitemia and gametocytemia were assessed every two weeks. The TRA and seroreactivity increased with the number of P. falciparum infections. The longitudinally sustained association between TRA and antibodies against Pfs48/45 (odds ratio [OR] = 3.74, 95% confidence interval [CI] = 1.51-9.29) and Pfs230 (OR = 3.72, 95% CI = 1.36-10.17) suggests that functional transmission reducing immunity is acquired after limited exposure to infection.

Sharma NP, Peacock SJ, Phumratanaprapin W, Day N, White N, Pukrittayakamee S. 2006. A hospital-based study of bloodstream infections in febrile patients in Dhulikhel Hospital Kathmandu University Teaching Hospital, Nepal. Southeast Asian J Trop Med Public Health, 37 (2), pp. 351-356. | Citations: 14 (Scopus) | Show Abstract

The etiology of bloodstream infections in febrile patients remain poorly characterized in Nepal. A retrospective study of febrile patients presenting to Dhulikhel Hospital Kathmandu University Teaching Hospital from July 2002 to June 2004 was performed to evaluate the etiology of bloodstream infections and the drug sensitivity patterns of cultured organisms. The medical and laboratory records of all febrile patients with an axillary temperature > or = 38 degrees C who had a blood culture taken (n = 1,774) were retrieved and analyzed. Of these, 122 (6.9%) patients had positive blood cultures, of which 40.1% were age 11 to 20 years. The male to female ratio was 1.7:1. Antibiotics had been taken prior to hospital presentation by 39 (32%) patients. Salmonella enterica serovar Typhi and serovar Paratyphi A were isolated in 50 (41.0%) and 13 (10.7%) cases, respectively. All S. Typhi and S. Paratyphi isolates were susceptible to ceftriaxone, while susceptibility to ciprofloxacin and chloramphenicol was recorded in 94.8% and 94.5% of cases, respectively. Cephalexin and amoxicillin had the lowest rates of susceptibility (64.2% and 54.1%, respectively). Salmonella spp were usually sensitive to chloramphenicol. These findings provide clinicians in this region of Nepal with a better understanding of the spectrum of pathogens causing bloodstream infections and will help guide empiric antibiotic choice.

Smit C, Lindenburg K, Geskus RB, Brinkman K, Coutinho RA, Prins M. 2006. Highly active antiretroviral therapy (HAART) among HIV-infected drug users: a prospective cohort study of sexual risk and injecting behaviour. Addiction, 101 (3), pp. 433-440. | Citations: 21 (Scopus) | Show Abstract | Read more

AIMS: To study sexual risk and injecting behaviour among HIV-infected drug users (DU) receiving highly active antiretroviral therapy (HAART). DESIGN AND SETTING: As part of an ongoing prospective cohort study, HIV-infected DU who commenced HAART (n=67) were matched with those not starting HAART (n=130) on CD4 cell counts, duration of cohort participation, age and calendar year of visit. Immunological and virological responses of the HAART-treated DU were compared with the HAART-treated homosexual men from the same cohort (n=212). MEASUREMENTS: Trends in behaviour and therapeutic response were tested with a logistic regression model adjusted for repeated measurements and a piecewise random effects model, respectively. FINDINGS: Non-HAART users reported more episodes of injecting than HAART users. In both groups injecting declined over time with no effect of HAART initiation. Before HAART initiation an increase in sexual risk behaviour was observed among those who had been assigned to receive HAART; their sexual risk behaviour declined thereafter. No change in sexual risk behaviour was found among non-HAART users. Relative to homosexual men, DU had a similar initial therapeutic response, but DU started HAART at lower CD4 cell counts and higher viral load levels. Conclusion DU who are treated with HAART are not increasing their risk behaviour, and their early response to HAART is similar to homosexual men. However, before the treated DU received HAART they were seen to inject less often than those not treated with HAART. This suggests that selection of potential HAART starters is based on limited drug use. Although the DU who commence HAART are a selected group, our results show that HIV-infected DU can be treated effectively.

Graham SP, Pellé R, Honda Y, Mwangi DM, Tonukari NJ, Yamage M, Glew EJ, de Villiers EP, Shah T, Bishop R et al. 2006. Theileria parva candidate vaccine antigens recognized by immune bovine cytotoxic T lymphocytes. Proc Natl Acad Sci U S A, 103 (9), pp. 3286-3291. | Citations: 65 (Scopus) | Show Abstract | Read more

East Coast fever, caused by the tick-borne intracellular apicomplexan parasite Theileria parva, is a highly fatal lymphoproliferative disease of cattle. The pathogenic schizont-induced lymphocyte transformation is a unique cancer-like condition that is reversible with parasite removal. Schizont-infected cell-directed CD8(+) cytotoxic T lymphocytes (CTL) constitute the dominant protective bovine immune response after a single exposure to infection. However, the schizont antigens targeted by T. parva-specific CTL are undefined. Here we show the identification of five candidate vaccine antigens that are the targets of MHC class I-restricted CD8(+) CTL from immune cattle. CD8(+) T cell responses to these antigens were boosted in T. parva-immune cattle resolving a challenge infection and, when used to immunize naïve cattle, induced CTL responses that significantly correlated with survival from a lethal parasite challenge. These data provide a basis for developing a CTL-targeted anti-East Coast fever subunit vaccine. In addition, orthologs of these antigens may be vaccine targets for other apicomplexan parasites.

Brent AJ, Ahmed I, Ndiritu M, Lewa P, Ngetsa C, Lowe B, Bauni E, English M, Berkley JA, Scott JAG. 2006. Incidence of clinically significant bacteraemia in children who present to hospital in Kenya: community-based observational study. Lancet, 367 (9509), pp. 482-488. | Citations: 104 (Scopus) | Show Abstract | Read more

BACKGROUND: Estimates of the burden of invasive bacterial disease in sub-Saharan Africa have previously relied on selected groups of patients, such as inpatients; they are, therefore, probably underestimated, potentially hampering vaccine implementation. Our aim was to assess the incidence of bacteraemia in all children presenting to a hospital in Kenya, irrespective of clinical presentation or decision to admit. METHODS: We did a community-based observational study for which we cultured blood from 1093 children who visited a Kenyan hospital outpatient department. We estimated bacteraemia incidence with a Demographic Surveillance System, and investigated the clinical significance of bacteraemia and the capacity of clinical signs to identify cases. RESULTS: The yearly incidence of bacteraemia per 100,000 children aged younger than 2 years and younger than 5 years was 2440 (95% CI 1307-3573) and 1192 (692-1693), respectively. Incidence of pneumococcal bacteraemia was 597 (416-778) per 100,000 person-years of observation in children younger than age 5 years. Three-quarters of episodes had a clinical focus or required admission, or both; one in six was fatal. After exclusion of children with occult bacteraemia, the incidence of clinically significant bacteraemia per 100,000 children younger than age 2 years or 5 years fell to 1741 (790-2692) and 909 (475-1343), respectively, and the yearly incidence of clinically significant pneumococcal bacteraemia was 436 (132-739) per 100,000 children younger than 5 years old. Clinical signs identified bacteraemia poorly. INTERPRETATION: Clinically significant bacteraemia in children in Kilifi is twice as common, and pneumococcal bacteraemia four times as common, as previously estimated. Our data support the introduction of pneumococcal vaccine in sub-Saharan Africa.

Hutagalung R, Htoo H, Nwee P, Arunkamomkiri J, Zwang J, Carrara VI, Ashley E, Singhasivanon P, White NJ, Nosten F. 2006. A case-control auditory evaluation of patients treated with artemether-lumefantrine. Am J Trop Med Hyg, 74 (2), pp. 211-214. | Citations: 39 (Scopus) | Show Abstract

Artemether-lumefantrine is the first registered, fixed, artemisinin-based combination treatment. Artemisinin derivatives are highly effective antimalarials with a favorable safety profile. Concerns remain over their potential neurotoxicity, although there has been no clinical evidence of this in humans. In animals (rats, dogs, and monkeys) artemether, a derivative of artemisinin is associated with an unusual toxicity pattern in specific brain nuclei involving the auditory and vestibular pathways. A recent report from Mozambique described a small but significant and irreversible hearing loss in patients exposed to artemether-lumefantrine. To explore this issue, we conducted a case-control study using tympanometry, audiometry and auditory brain-stem responses. We assessed 68 subjects who had been treated with artemether-lumefantrine within the previous five years and 68 age- and sex-matched controls living in the malarious region along the Thailand-Myanmar border. There were no differences in the test results between cases and controls. There was no neurophysiologic evidence of auditory brainstem toxicity that could be attributed to artemether-lumefantrine in this study population.

Phongmany S, Rolain J-M, Phetsouvanh R, Blacksell SD, Soukkhaseum V, Rasachack B, Phiasakha K, Soukkhaseum S, Frichithavong K, Chu V et al. 2006. Rickettsial infections and fever, Vientiane, Laos. Emerg Infect Dis, 12 (2), pp. 256-262. | Citations: 126 (Scopus) | Show Abstract | Read more

Rickettsial diseases have not been described previously from Laos, but in a prospective study, acute rickettsial infection was identified as the cause of fever in 115 (27%) of 427 adults with negative blood cultures admitted to Mahosot Hospital in Vientiane, Laos. The organisms identified by serologic analysis were Orientia tsutsugamushi (14.8%), Rickettsia typhi (9.6%), and spotted fever group rickettsia (2.6% [8 R. helvetica, 1 R. felis, 1 R. conorii subsp. indica, and 1 Rickettsia "AT1"]). Patients with murine typhus had a lower frequency of peripheral lymphadenopathy than those with scrub typhus (3% vs. 46%, p<0.001). Rickettsioses are an underrecognized cause of undifferentiated febrile illnesses among adults in Laos. This finding has implications for the local empiric treatment of fever.

McGready R, Ashley EA, Tan SO, Brabin B, Nosten F. 2006. Re: Malaria in pregnancy. BJOG, 113 (2), pp. 246. | Citations: 1 (Web of Science Lite) | Read more

Newton PN, Ward S, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. 2006. Early treatment failure in severe malaria resulting from abnormally low plasma quinine concentrations. Trans R Soc Trop Med Hyg, 100 (2), pp. 184-186. | Citations: 14 (Scopus) | Show Abstract | Read more

A patient admitted with severe Plasmodium falciparum malaria in western Thailand had an early treatment failure with quinine, despite full dosing. Plasma quinine concentrations were subtherapeutic. Abnormal quinine pharmacokinetics may explain sporadic reports of quinine treatment failures in severe malaria.

Simmons CP, Thwaites GE, Quyen NTH, Torok E, Hoang DM, Chau TTH, Mai PP, Lan NTN, Dung NH, Quy HT et al. 2006. Pretreatment intracerebral and peripheral blood immune responses in Vietnamese adults with tuberculous meningitis: diagnostic value and relationship to disease severity and outcome. J Immunol, 176 (3), pp. 2007-2014. | Citations: 61 (Scopus) | Show Abstract | Read more

Tuberculous meningitis (TBM) is the most devastating form of tuberculosis. Both intracerebral and peripheral blood immune responses may be relevant to pathogenesis, diagnosis, and outcome. In this study, the relationship between pretreatment host response, disease phenotype, and outcome in Vietnamese adults with TBM was examined. Before treatment, peripheral blood IFN-gamma ELISPOT responses to the Mycobacterium tuberculosis Ags ESAT-6, CFP-10, and purified protein derivative (PPD) were a poor diagnostic predictor of TBM. Cerebrospinal fluid IL-6 concentrations at presentation were independently associated with severe disease presentation, suggesting an immunological correlate of neurological damage before treatment. Surprisingly however, elevated cerebrospinal fluid inflammatory cytokines were not associated with death or disability in HIV-negative TBM patients at presentation. HIV coinfection attenuated multiple cerebrospinal fluid inflammatory indices. Low cerebrospinal fluid IFN-gamma concentrations were independently associated with death in HIV-positive TBM patients, implying that IFN-gamma contributes to immunity and survival. Collectively, these results reveal the effect of HIV coinfection on the pathogenesis of TBM and suggest that intracerebral immune responses, at least in HIV-negative cases, may not be as intimately associated with disease outcome as previously thought.

Noor AM, Amin AA, Gething PW, Atkinson PM, Hay SI, Snow RW. 2006. Modelling distances travelled to government health services in Kenya. Trop Med Int Health, 11 (2), pp. 188-196. | Citations: 72 (Scopus) | Show Abstract | Read more

OBJECTIVE: To systematically evaluate descriptive measures of spatial access to medical treatment, as part of the millennium development goals to reduce the burden of HIV/AIDS, tuberculosis and malaria. METHODS: We obtained high-resolution spatial and epidemiological data on health services, population, transport network, topography, land cover and paediatric fever treatment in four Kenyan districts to develop access and use models for government health services in Kenya. Community survey data were used to model use of government health services by febrile children. A model based on the transport network was then implemented and adjusted for actual use patterns. We compared the predictive accuracy of this refined model to that of Euclidean distance metrics. RESULTS Higher-order facilities were more attractive to patients (54%, 58% and 60% in three scenarios) than lower-order ones. The transport network model, adjusted for competition between facilities, was most accurate and selected as the best-fit model. It estimated that 63% of the population of the study districts were within the 1 h national access benchmark, against 82% estimated by the Euclidean model. CONCLUSIONS: Extrapolating the results from the best-fit model in study districts to the national level shows that approximately six million people are currently incorrectly estimated to have access to government health services within 1 h. Simple Euclidean distance assumptions, which underpin needs assessments and against which millennium development goals are evaluated, thus require reconsideration.

Snow RW, Hay SI. 2006. Comparing methods of estimating the global morbidity burden from Plasmodium falciparum malaria. Am J Trop Med Hyg, 74 (2), pp. 189-190. | Citations: 7 (Scopus)

Nickerson EK, Wuthiekanun V, Day NP, Chaowagul W, Peacock SJ. 2006. Meticillin-resistant Staphylococcus aureus in rural Asia. Lancet Infect Dis, 6 (2), pp. 70-71. | Citations: 22 (Scopus) | Read more

Wang X-Y, Ansaruzzaman M, Vaz R, Mondlane C, Lucas MES, von Seidlein L, Deen JL, Ampuero S, Puri M, Park T et al. 2006. Field evaluation of a rapid immunochromatographic dipstick test for the diagnosis of cholera in a high-risk population. BMC Infect Dis, 6 (1), pp. 17. | Citations: 29 (Scopus) | Show Abstract | Read more

BACKGROUND: Early detection of cholera outbreaks is crucial for the implementation of the most appropriate control strategies. METHODS: The performance of an immunochromatographic dipstick test (Institute Pasteur, Paris, France) specific for Vibrio cholerae O1 was evaluated in a prospective study in Beira, Mozambique, during the 2004 cholera season (January-May). Fecal specimens were collected from 391 patients with acute watery nonbloody diarrhea and tested by dipstick and conventional culture. RESULTS: The overall sensitivity and specificity of the rapid test compared to culture were 95% (95% confidence interval [CI]: 91%-99%) and 89% (95% CI: 86%-93%), respectively. After stratification by type of sample (rectal swab/bulk stool) and severity of diarrhea, the sensitivity ranged between 85% and 98% and specificity between 77% and 97%. CONCLUSION: This one-step dipstick test performed well in the diagnosis of V. cholerae O1 in a setting with seasonal outbreaks where rapid tests are most urgently needed.

Lee JH, Han KH, Choi SY, Lucas MES, Mondlane C, Ansaruzzaman M, Nair GB, Sack DA, von Seidlein L, Clemens JD et al. 2006. Multilocus sequence typing (MLST) analysis of Vibrio cholerae O1 El Tor isolates from Mozambique that harbour the classical CTX prophage. J Med Microbiol, 55 (Pt 2), pp. 165-170. | Citations: 50 (Scopus) | Show Abstract | Read more

Vibrio cholerae O1 isolates belonging to the Ogawa serotype, El Tor biotype, harbouring the classical CTX prophage were first isolated in Mozambique in 2004. Multilocus sequence typing (MLST) analysis using nine genetic loci showed that the Mozambique isolates have the same sequence type (ST) as O1 El Tor N16961, a representative of the current seventh cholera pandemic. Analysis of the CTX prophage in the Mozambique isolates indicated that there is one type of rstR in these isolates: the classical CTX prophage. It was also found that the ctxB-rstR-rstA-rstB-phs-cep fragment was PCR-amplified from these isolates, which indicates the presence of a tandem repeat of the classical CTX prophage in the genome of the Mozambique isolates. The possible origin of these isolates and the presence of the tandem repeat of the classical prophage in them implicate the presence of the classical CTX phage.

Paton C, Al-Ubaydli M. 2006. The doctor's PDA and Smartphone Handbook: the task list. J R Soc Med, 99 (2), pp. 73-76. | Citations: 1 (Scopus) | Read more

Aguas R, Gonçalves G, Gomes MGM. 2006. Pertussis: increasing disease as a consequence of reducing transmission. Lancet Infect Dis, 6 (2), pp. 112-117. | Citations: 69 (Scopus) | Show Abstract | Read more

Since the 1980s, the occurrence of pertussis cases in developed countries has increased and shifted towards older age groups. This resurgence follows 30 years of intense mass vaccination, and has been attributed primarily to three factors: (1) more effective diagnosis of the disease, (2) waning of vaccine-induced immunity, and (3) loss of vaccine efficacy due to the emergence of new Bordetella pertussis strains. Here we develop and analyse a mathematical model to assess the plausibility of these hypotheses. We consider that exposure to B pertussis through natural infection or vaccination induces an immune response that prevents severe disease but does not fully prevent mild infections. We also assume that these protective effects are temporary due to waning of immunity. These assumptions, describing the mode of action of adaptive immunity, are combined with a standard transmission model. Two distinct epidemiological scenarios are detected: under low transmission, most infections lead to severe disease; under high transmission, mild infections are frequent, boosting clinical immunity and maintaining low levels of severe disease. The two behaviours are separated by a reinfection threshold in transmission. As a result, the highest incidence of severe disease is expected to occur at intermediate transmission intensities--near the reinfection threshold--suggesting that pertussis resurgence may be induced by a reduction in transmission, independently of vaccination. The model is extended to interpret the outcomes of current control measures and explore scenarios for future interventions.

Bakker B, Oostdijk W, Geskus RB, Stokvis-Brantsma WH, Vossen JM, Wit JM. 2006. Patterns of growth and body proportions after total-body irradiation and hematopoietic stem cell transplantation during childhood. Pediatr Res, 59 (2), pp. 259-264. | Citations: 17 (Scopus) | Show Abstract | Read more

Patterns of growth and body proportions were studied in 75 children receiving total-body irradiation (TBI) and hematopoietic stem cell transplantation (SCT) before onset of puberty. Of the 19 patients receiving GH, only data obtained before onset of GH were included. Thirty-two patients reached final height (FH). Median change in height SD score (SDS) between SCT and FH was -1.7 in boys and -1.1 in girls. Peak height velocity (PHV) was decreased in the majority of the patients (median PHV 5.7 cm/y in boys and 5.3 cm/y in girls), even though it occurred at appropriate ages. Changes in body proportions were analyzed by linear mixed-effects models. Decrease in sitting height SDS did not differ between boys and girls. In boys, decrease in leg length SDS was of comparable magnitude, whereas, in girls, decrease in leg length was less pronounced, leading to a significant decrease in SDS for sitting height/height ratio in girls only. The sex-specific effects of several variables on height SDS were analyzed by linear mixed-effects modeling, showing a slightly faster decrease in younger children and a more pronounced decrease during puberty in boys compared with girls. We conclude that 1) younger children are more susceptible to growth retardation after TBI and SCT, 2) pubertal growth is more compromised in boys, and 3) leg growth is relatively less affected in girls, possibly due to a high incidence of gonadal failure in girls.

Chen X, Stanton B, Wang X, Nyamette A, Pach A, Kaljee L, Pack R, von Seidlein L, Clemens J, Gong Y, Mao R. 2006. Differences in perception of dysentery and enteric fever and willingness to receive vaccines among rural residents in China. Vaccine, 24 (5), pp. 561-571. | Show Abstract | Read more

BACKGROUND: Enteric diseases including dysentery and enteric fever remain significant public health problems in China. While vaccines offer great potential in controlling these diseases, greater understanding of factors influencing acceptance of vaccines is needed to create effective enteric disease control programs in rural China. DESIGN: Cross-sectional quantitative study with randomly sampled households from two sites in China, one experiencing high rates of shigellosis (Zengding) and the other of typhoid/paratyphoid (Lingchuan). METHODS: Sociobehavioral survey data were collected through face-to-face interviews from 501 respondents (56% female) in Zhengding regarding dysentery and 624 in Lingchuan (51% female) regarding enteric fever. Vaccine acceptability was measured by expressed need for vaccination and willingness to pay. Comparative and associative analyses were conducted to assess disease perception, vaccination service satisfaction, likelihood of improvements in water and sanitation, and vaccine acceptability. RESULTS: Nearly all respondents in Lingchuan considered enteric fever to be prevalent in the community, while only one half of the respondents in Zhengding considered dysentery to be problematic (p < 0.01). Nevertheless, more respondents in Zhengding were fearful that a household member would acquire dysentery than were Lingchuan respondents worried that a household member would acquire enteric fever (p < 0.01). Perceived vulnerability of specific subgroups (odds ratios ranging from 1.6 to 8.1), knowing someone who died of the disease (odds ratio reached infinity) and satisfaction with past vaccination services (odds ratios reached infinity) were consistently associated with perceived need for vaccines of target populations of all age groups while the association between perception of sanitary improvement and vaccine need was limited. Perceived need for a vaccine was associated with willingness to pay for the vaccine. CONCLUSIONS: Perceptions of enhanced vulnerability of specific subgroups to a disease and satisfactory experiences with vaccination services may increase the perceived need for a vaccine, leading to increased willingness to pay for vaccine. Vaccines are not perceived as important for the elderly.

Noor AM, Omumbo JA, Amin AA, Zurovac D, Snow RW. 2006. Wealth, mother's education and physical access as determinants of retail sector net use in rural Kenya. Malar J, 5 pp. 5. | Citations: 46 (Scopus) | Show Abstract | Read more

BACKGROUND: Insecticide-treated bed nets (ITN) provide real hope for the reduction of the malaria burden across Africa. Understanding factors that determine access to ITN is crucial to debates surrounding the optimal delivery systems. The influence of homestead wealth on use of nets purchased from the retail sector is well documented, however, the competing influence of mother's education and physical access to net providers is less well understood. METHODS: Between December 2004 and January 2005, a random sample of 72 rural communities was selected across four Kenyan districts. Demographic, assets, education and net use data were collected at homestead, mother and child (aged < 5 years) levels. An assets-based wealth index was developed using principal components analysis, travel time to net sources was modelled using geographic information systems, and factors influencing the use of retail sector nets explored using a multivariable logistic regression model. RESULTS: Homestead heads and guardians of 3,755 children < 5 years of age were interviewed. Approximately 15% (562) of children slept under a net the night before the interview; 58% (327) of the nets used were purchased from the retail sector. Homestead wealth (adjusted OR = 10.17, 95% CI = 5.45-18.98), travel time to nearest market centres (adjusted OR = 0.51, 95% CI = 0.37-0.72) and mother's education (adjusted OR = 2.92, 95% CI = 1.93-4.41) were significantly associated with use of retail sector nets by children aged less than 5 years. CONCLUSION: Approaches to promoting access to nets through the retail sector disadvantage poor and remote communities where mothers are less well educated.

Pack R, Wang Y, Singh A, von Seidlein L, Pach A, Kaljee L, Butraporn P, Youlong G, Blum L, Bhutta Z et al. 2006. Willingness to be vaccinated against shigella and other forms of dysentery: a comparison of three regions in Asia. Vaccine, 24 (4), pp. 485-494. | Show Abstract | Read more

We conducted a cross sectional survey of 3163 women and men in six Asian countries to examine willingness for children and adults to be vaccinated against shigellosis and other forms of dysentery. The six sites were clustered into three regions for ease of comparison. The regions are: Northeast Asia (China), Southeast Asia (Thailand, Vietnam, and Indonesia) and South Asia (Bangladesh and Pakistan). We used multiple logistic regression to identify region-specific models for vaccination willingness for both adults and children. A vaccine to protect against dysentery, if available would be very much in demand throughout the three Asian regions for children. For adults, the responses indicate that vaccine uptake by adults will vary. A large proportion of respondents in all regions, specifically in China, do not perceive themselves at risk yet still consider a shigellosis vaccine desirable.

Warrell DA. 2006. Treatment of bites by adders and exotic venomous snakes (vol 331, pg 1244, 2005) BRITISH MEDICAL JOURNAL, 332 (7534), pp. 151-151.

White NJ, Dondorp AM, Nosten F, Day NPJ, Grp SEAQUAMATS. 2006. Artesunate versus quinine for severe falciparum malaria - Reply LANCET, 367 (9505), pp. 111-112. | Citations: 2 (Web of Science Lite) | Read more

English M, Snow RW. 2006. Iron and folic acid supplementation and malaria risk. Lancet, 367 (9505), pp. 90-91. | Citations: 25 (Web of Science Lite) | Read more

Lindsay JA, Moore CE, Day NP, Peacock SJ, Witney AA, Stabler RA, Husain SE, Butcher PD, Hinds J. 2006. Microarrays reveal that each of the ten dominant lineages of Staphylococcus aureus has a unique combination of surface-associated and regulatory genes. J Bacteriol, 188 (2), pp. 669-676. | Citations: 214 (Scopus) | Show Abstract | Read more

Staphylococcus aureus is the most common cause of hospital-acquired infection. In healthy hosts outside of the health care setting, S. aureus is a frequent colonizer of the human nose but rarely causes severe invasive infection such as bacteremia, endocarditis, or osteomyelitis. To identify genes associated with community-acquired invasive isolates, regions of genomic variability, and the S. aureus population structure, we compared 61 community-acquired invasive isolates of S. aureus and 100 nasal carriage isolates from healthy donors using a microarray spotted with PCR products representing every gene from the seven S. aureus sequencing projects. The core genes common to all strains were identified, and 10 dominant lineages of S. aureus were clearly discriminated. Each lineage carried a unique combination of hundreds of "core variable" (CV) genes scattered throughout the chromosome, suggesting a common ancestor but early evolutionary divergence. Many CV genes are regulators of virulence genes or known or predicted to be expressed on the bacterial surface and to interact with the host during nasal colonization and infection. Within each lineage, isolates showed substantial variation in the carriage of mobile genetic elements and their associated virulence and resistance genes, indicating frequent horizontal transfer. However, we were unable to identify any association between lineage or gene and invasive isolates. We suggest that the S. aureus gene combinations necessary for invasive disease may also be necessary for nasal colonization and that community-acquired invasive disease is strongly dependent on host factors.

Nosten F, McGready R, d'Alessandro U, Bonell A, Verhoeff F, Menendez C, Mutabingwa T, Brabin B. 2006. Antimalarial drugs in pregnancy: a review. Curr Drug Saf, 1 (1), pp. 1-15. | Citations: 92 (Scopus) | Show Abstract | Read more

In this review we examine the available information on the safety of antimalarials in pregnancy, from both animal and human studies. The antimalarials that can be used in pregnancy include (1) chloroquine, (2) amodiaquine, (3) quinine, (4) azithromycin, (5) sulfadoxine-pyrimethamine, (6) mefloquine, (7) dapsone-chlorproguanil, (8) artemisinin derivatives, (9) atovaquone-proguanil and (10) lumefantrine. Antimalarial drugs that should not be used in pregnancy including (1) halofantrine, (2) tetracycline/doxycycline, and (3) primaquine. There are few studies in humans on the pharmacokinetics, safety and efficacy of antimalarials in pregnancy. This is because pregnant women are systematically excluded from clinical trials. The absence of adequate safety data, especially in the first trimester, is an important obstacle to developing treatment strategies. The pharmacokinetics of most antimalarial drugs are also modified in pregnancy and dosages will need to be adapted. Other factors, including HIV status, drug interactions with antiretrovirals, the influence of haematinics and host genetic polymorphisms may influence safety and efficacy. For these reasons there is an urgent need to assess the safety and efficacy of antimalarial treatments in pregnancy, including artemisinin based combination therapies.

Wuthiekanun V, Chierakul W, Rattanalertnavee J, Langa S, Sirodom D, Wattanawaitunechai C, Winothai W, White NJ, Day N, Peacock SJ. 2006. Serological evidence for increased human exposure to Burkholderia pseudomallei following the tsunami in southern Thailand. J Clin Microbiol, 44 (1), pp. 239-240. | Citations: 21 (Scopus) | Show Abstract | Read more

A serological study was performed to determine recent human exposure to Burkholderia pseudomallei (the cause of melioidosis) in residents of southern Thailand affected by the tsunami of 26 December 2004. The findings were suggestive of increased recent exposure in both tsunami survivors and uninjured bystanders. Survivors of the Thailand tsunami may be at increased risk of melioidosis.

Cheng AC, Peacock SJ, Limmathurotsakul D, Wongsuvan G, Chierakul W, Amornchai P, Getchalarat N, Chaowagul W, White NJ, Day NPJ, Wuthiekanun V. 2006. Prospective evaluation of a rapid immunochromogenic cassette test for the diagnosis of melioidosis in northeast Thailand. Trans R Soc Trop Med Hyg, 100 (1), pp. 64-67. | Citations: 24 (Scopus) | Show Abstract | Read more

A prospective study was performed to compare a rapid immunochromogenic cassette test (ICT) with the indirect haemagglutination assay (IHA) and clinical rules for the diagnosis of melioidosis in an endemic area. The sensitivity and specificity of the IgG ICT was 86% and 47%, and the IgM ICT was 82% and 47%, respectively. These were similar to the results for IHA (sensitivity 73%, specificity 64%) and clinical rules (73% and 37%). ICT lacks clinical utility as a result of high background rates of positive Burkholderia pseudomallei serology in this population. Low sensitivity and specificity of clinical rules is consistent with the protean manifestations of melioidosis and clinical difficulty in identifying patients with melioidosis.

Chuma JM, Thiede M, Molyneux CS. 2006. Rethinking the economic costs of malaria at the household level: evidence from applying a new analytical framework in rural Kenya. Malar J, 5 pp. 76. | Citations: 57 (Scopus) | Show Abstract | Read more

BACKGROUND: Malaria imposes significant costs on households and the poor are disproportionately affected. However, cost data are often from quantitative surveys with a fixed recall period. They do not capture costs that unfold slowly over time, or seasonal variations. Few studies investigate the different pathways through which malaria contributes towards poverty. In this paper, a framework indicating the complex links between malaria, poverty and vulnerability at the household level is developed and applied using data from rural Kenya. METHODS: Cross-sectional surveys in a wet and dry season provide data on treatment-seeking, cost-burdens and coping strategies (n = 294 and n = 285 households respectively). 15 case study households purposively selected from the survey and followed for one year provide in-depth qualitative information on the links between malaria, vulnerability and poverty. RESULTS: Mean direct cost burdens were 7.1% and 5.9% of total household expenditure in the wet and dry seasons respectively. Case study data revealed no clear relationship between cost burdens and vulnerability status at the end of the year. Most important was household vulnerability status at the outset. Households reporting major malaria episodes and other shocks prior to the study descended further into poverty over the year. Wealthier households were better able to cope. CONCLUSION: The impacts of malaria on household economic status unfold slowly over time. Coping strategies adopted can have negative implications, influencing household ability to withstand malaria and other contingencies in future. To protect the poor and vulnerable, malaria control policies need to be integrated into development and poverty reduction programmes.

Casals-Pascual C, Kai O, Lowe B, English M, Williams TN, Maitland K, Newton CRCJ, Peshu N, Roberts DJ. 2006. Lactate levels in severe malarial anaemia are associated with haemozoin-containing neutrophils and low levels of IL-12. Malar J, 5 pp. 101. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Hyperlactataemia is often associated with a poor outcome in severe malaria in African children. To unravel the complex pathophysiology of this condition the relationship between plasma lactate levels, parasite density, pro- and anti-inflammatory cytokines, and haemozoin-containing leucocytes was studied in children with severe falciparum malarial anaemia. METHODS: Twenty-six children with a primary diagnosis of severe malarial anaemia with any asexual Plasmodium falciparum parasite density and Hb < 5 g/dL were studied and the association of plasma lactate levels and haemozoin-containing leucocytes, parasite density, pro- and anti-inflammatory cytokines was measured. The same associations were measured in non-severe malaria controls (N = 60). RESULTS: Parasite density was associated with lactate levels on admission (r = 0.56, P < 0.005). Moreover, haemozoin-containing neutrophils and IL-12 were strongly associated with plasma lactate levels, independently of parasite density (r = 0.60, P = 0.003 and r = -0.46, P = 0.02, respectively). These associations were not found in controls with uncomplicated malarial anaemia. CONCLUSION: These data suggest that blood stage parasites, haemozoin and low levels of IL-12 may be associated with the development of hyperlactataemia in severe malarial anaemia.

Bejon P, Andrews L, Hunt-Cooke A, Sanderson F, Gilbert SC, Hill AVS. 2006. Thick blood film examination for Plasmodium falciparum malaria has reduced sensitivity and underestimates parasite density. Malar J, 5 pp. 104. | Citations: 56 (Scopus) | Show Abstract | Read more

BACKGROUND: Thick blood films are routinely used to diagnose Plasmodium falciparum malaria. Here, they were used to diagnose volunteers exposed to experimental malaria challenge. METHODS: The frequency with which blood films were positive at given parasite densities measured by PCR were analysed. The poisson distribution was used to calculate the theoretical likelihood of diagnosis. Further in vitro studies used serial dilutions to prepare thick films from malaria cultures at known parasitaemia. RESULTS: Even in expert hands, thick blood films were considerably less sensitive than might have been expected from the parasite numbers measured by quantitative PCR. In vitro work showed that thick films prepared from malaria cultures at known parasitaemia consistently underestimated parasite densities. CONCLUSION: It appears large numbers of parasites are lost during staining. This limits their sensitivity, and leads to erroneous estimates of parasite density.

Ajala-Agbo T, Komba A, Makani J, Williams T, Marsh K, Newton C, Kirkham F. 2006. Spectrum of cerebral blood flow velocities measured by transcranial Doppler ultrasonography in children with sickle cell disease in Africa DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY, 48 pp. 13-14.

LaRosa SP, Opal SM, Utterback B, Yan SCB, Helterbrand J, Simpson AJH, Chaowagul W, White NJ, Fisher CJ. 2006. Decreased protein C, protein S, and antithrombin levels are predictive of poor outcome in Gram-negative sepsis caused by Burkholderia pseudomallei. Int J Infect Dis, 10 (1), pp. 25-31. | Citations: 21 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Acute septicemic melioidosis is associated with systemic release of endotoxin and the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin-1, and interleukin-6. Excessive release of these cytokines may lead to endothelial injury, depletion of naturally occurring endothelial modulators, microvascular thrombosis, organ failure, and death. METHOD: Plasma samples drawn at baseline and after initial antimicrobial therapy in 30 patients with suspected acute severe melioidosis were assayed for D-dimer levels, protein C and protein S antigen levels, and antithrombin functional activities. RESULTS: Both baseline and continued deficiencies of protein C, protein S, and antithrombin were statistically associated with a poor outcome by logistic regression. Baseline D-dimer levels were significantly higher in fatal cases than survivors and correlated inversely with protein C and antithrombin, suggesting both increased fibrin deposition and fibrinolysis. CONCLUSION: The inflammatory response to systemic Burkholderia pseudomallei infection leads to depletion of the natural endothelial modulators protein C, protein S, and antithrombin. Both baseline and continued deficiency of these endothelial modulators is predictive of poor outcome in melioidosis.

Lang T, Hughes D, Kanyok T, Kengeya-Kayondo J, Marsh V, Haaland A, Pirmohamed M, Winstanley P. 2006. Beyond registration--measuring the public-health potential of new treatments for malaria in Africa. Lancet Infect Dis, 6 (1), pp. 46-52. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

Malaria claims over one million lives a year in some of the poorest countries of the world. Affected populations and governments cannot afford to pay for expensive new therapies. Most antimalarial treatments are purchased from local shops and administered in the home. These factors make for a complex set of requirements for any new treatment for malaria if a substantial reduction in mortality is ever to be achieved. Thankfully there are several treatments being developed, mostly within public-private partnerships. Typically, the goal of public-private partnerships is the granting of a product license, so work plans end after phase III trials. As these drugs will ultimately be used unsupervised, malaria control programme managers will require further data on safety and whether the drug is as efficacious when used outside of controlled clinical trials before allowing widespread use of these new products. These data need to be collected in highly specific phase IV programmes. We explain why public-private partnerships should extend their development plans well beyond drug registration, and set out the requirements of such a programme. We aim to generate debate and discussion so that guidelines that are internationally accepted and adhered to can be developed not only for antimalarials but for all drugs that are being developed specifically for use in resource-poor settings.

Reynolds MG, Anh BH, Thu VH, Montgomery JM, Bausch DG, Shah JJ, Maloney S, Leitmeyer KC, Huy VQ, Horby P et al. 2006. Factors associated with nosocomial SARS-CoV transmission among healthcare workers in Hanoi, Vietnam, 2003. BMC Public Health, 6 (1), pp. 207. | Citations: 14 (Scopus) | Show Abstract | Read more

BACKGROUND: In March of 2003, an outbreak of Severe Acute Respiratory Syndrome (SARS) occurred in Northern Vietnam. This outbreak began when a traveler arriving from Hong Kong sought medical care at a small hospital (Hospital A) in Hanoi, initiating a serious and substantial transmission event within the hospital, and subsequent limited spread within the community. METHODS: We surveyed Hospital A personnel for exposure to the index patient and for symptoms of disease during the outbreak. Additionally, serum specimens were collected and assayed for antibody to SARS-associated coronavirus (SARS-CoV) antibody and job-specific attack rates were calculated. A nested case-control analysis was performed to assess risk factors for acquiring SARS-CoV infection. RESULTS: One hundred and fifty-three of 193 (79.3%) clinical and non-clinical staff consented to participate. Excluding job categories with < 3 workers, the highest SARS attack rates occurred among nurses who worked in the outpatient and inpatient general wards (57.1, 47.4%, respectively). Nurses assigned to the operating room/intensive care unit, experienced the lowest attack rates (7.1%) among all clinical staff. Serologic evidence of SARS-CoV infection was detected in 4 individuals, including 2 non-clinical workers, who had not previously been identified as SARS cases; none reported having had fever or cough. Entering the index patient's room and having seen (viewed) the patient were the behaviors associated with highest risk for infection by univariate analysis (odds ratios 20.0, 14.0; 95% confidence intervals 4.1-97.1, 3.6-55.3, respectively). CONCLUSION: This study highlights job categories and activities associated with increased risk for SARS-CoV infection and demonstrates that a broad diversity of hospital workers may be vulnerable during an outbreak. These findings may help guide recommendations for the protection of vulnerable occupational groups and may have implications for other respiratory infections such as influenza.

Guerin PJ, Nygard K, Siitonen A, Vold L, Kuusi M, de Jong B, Rottingen JA, Alvseike O, Olsson A, Lassen J et al. 2006. Emerging Salmonella Enteritidis anaerogenic phage type 14b: outbreak in Norwegian, Swedish and Finnish travellers returning from Greece. Euro Surveill, 11 (2), pp. 61-66. | Citations: 11 (Scopus) | Show Abstract

In July 2001, the Norwegian Institute of Public Health (Folkehelseinstituttet, FHI) reported a cluster of Salmonella Enteritidis of phage type 14b infections in Norwegian travellers returning from Greece. An increase in the same uncommon phage type was also registered in Sweden and Finland at the same time. Cases of S. Enteritidis PT 14b in patients returning from Greece were reported in these three Nordic countries in 2001 (303 cases), 2002 (164 cases) and 2003 (199 cases). Case-control studies performed in 2001 in Norway and Sweden indicated that consumption of chicken was associated with illness. In 2002 and 2003, continuing case reports indicated that this uncommon phage type had probably become established in the Greek food chain. Tour operators were informed and contacts were made with Greek public health authorities. Because place of infection is not systematically included in most Salmonella notification systems, the S. Enteritidis phage type 14b outbreak reported here may represent only part of a larger outbreak among travellers visiting Greece. Infections are often reported only in the tourists' home countries and public health authorities in the tourist destinations may not be aware of the problem. Further collaboration between national institutes of public health in Europe is needed to detect outbreaks occurring among tourists.

World Health Organization Writing Group, Bell D, Nicoll A, Fukuda K, Horby P, Monto A, Hayden F, Wylks C, Sanders L, Van Tam J. 2006. Non-pharmaceutical interventions for pandemic influenza, international measures. Emerg Infect Dis, 12 (1), pp. 81-87. | Citations: 176 (Scopus) | Show Abstract | Read more

Since global availability of vaccine and antiviral agents against influenza caused by novel human subtypes is insufficient, the World Health Organization (WHO) recommends non-pharmaceutical public health interventions to contain infection, delay spread, and reduce the impact of pandemic disease. Virus transmission characteristics will not be completely known in advance, but difficulties in influenza control typically include peak infectivity early in illness, a short interval between cases, and to a lesser extent, transmission from persons with incubating or asymptomatic infection. Screening and quarantining entering travelers at international borders did not substantially delay virus introduction in past pandemics, except in some island countries, and will likely be even less effective in the modern era. Instead, WHO recommends providing information to international travelers and possibly screening travelers departing countries with transmissible human infection. The principal focus of interventions against pandemic influenza spread should be at national and community levels rather than international borders.

World Health Organization Writing Group, Bell D, Nicoll A, Fukuda K, Horby P, Monto A, Hayden F, Wylks C, Sanders L, van Tam J. 2006. Non-pharmaceutical interventions for pandemic influenza, national and community measures. Emerg Infect Dis, 12 (1), pp. 88-94. | Citations: 223 (Scopus) | Show Abstract | Read more

The World Health Organization's recommended pandemic influenza interventions, based on limited data, vary by transmission pattern, pandemic phase, and illness severity and extent. In the pandemic alert period, recommendations include isolation of patients and quarantine of contacts, accompanied by antiviral therapy. During the pandemic period, the focus shifts to delaying spread and reducing effects through population-based measures. Ill persons should remain home when they first become symptomatic, but forced isolation and quarantine are ineffective and impractical. If the pandemic is severe, social distancing measures such as school closures should be considered. Nonessential domestic travel to affected areas should be deferred. Hand and respiratory hygiene should be routine; mask use should be based on setting and risk, and contaminated household surfaces should be disinfected. Additional research and field assessments during pandemics are essential to update recommendations. Legal authority and procedures for implementing interventions should be understood in advance and should respect cultural differences and human rights.

Chotivanich K, Silamut K, Day NPJ. 2006. Laboratory diagnosis of malaria infection - A short review of methods Australian Journal of Medical Science, 27 (1), pp. 11-15. | Citations: 4 (Scopus) | Show Abstract

Malaria is one of the most important tropical infectious diseases. The incidence of malaria worldwide is estimated to be 300-500 million clinical cases each year with a mortality of between one and three million people worldwide annually. The accurate and timely diagnosis of malaria infection is essential if severe complications and mortality are to be reduced by early specific antimalarial treatment. This review details the methods for the laboratory diagnosis of malaria infection.

Boonbumrung K, Wuthiekanun V, Rengpipat S, Day NPJ, Peacock SJ. 2006. In vitro motility of a population of clinical Burkholderia pseudomallei isolates. J Med Assoc Thai, 89 (9), pp. 1506-1510. | Citations: 3 (Scopus) | Show Abstract

Melioidosis, a serious infection caused by Burkholderia pseudomallei, is a leading cause of community-acquired sepsis in Northeast Thailand, and the commonest cause of death from community-acquired pneumonia in the Top End of Northern Australia. The causative organism is a Gram-negative, motile bacillus that is a facultative intracellular pathogen. B. pseudomallei flagella have been proposed as a possible vaccine candidate and putative virulence determinant. Flagella expression was highly conserved for 205 clinical B. pseudomallei isolates, as defined by in vitro swim and swarm motility assays. No association was found between motility and clinical factors including bacteremia and death.

Newton PN, McGready R, Fernandez F, Green MD, Sunjio M, Bruneton C, Phanouvong S, Millet P, Whitty CJM, Talisuna AO et al. 2006. Manslaughter by fake artesunate in Asia--will Africa be next? PLoS Med, 3 (6), pp. e197. | Citations: 127 (Scopus) | Read more

Fernández FM, Cody RB, Green MD, Hampton CY, McGready R, Sengaloundeth S, White NJ, Newton PN. 2006. Characterization of solid counterfeit drug samples by desorption electrospray ionization and direct-analysis-in-real-time coupled to time-of-flight mass spectrometry. ChemMedChem, 1 (7), pp. 702-705. | Citations: 156 (Scopus) | Show Abstract | Read more

Vacuum is not the limit: direct analysis in real time (DART), a new MS ionization method, allows probing of pharmaceuticals under atmospheric pressure, thus bypassing lengthy sample preparation steps and enhancing throughput. DART allows rapid screening of solid drugs at almost constant temperature which decreases errors in mass measurement and improves the identification of potentially harmful unknowns. This is important for identifying counterfeit drugs (fake hologram shown). © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

Taylor WRJ, Cañon V, White NJ. 2006. Pulmonary manifestations of malaria : recognition and management. Treat Respir Med, 5 (6), pp. 419-428. | Citations: 56 (Scopus) | Show Abstract | Read more

Lung involvement in malaria has been recognized for more than 200 hundred years, yet our knowledge of its pathogenesis and management is limited. Pulmonary edema is the most severe form of lung involvement. Increased alveolar capillary permeability leading to intravascular fluid loss into the lungs is the main pathophysiologic mechanism. This defines malaria as another cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).Pulmonary edema has been described most often in non-immune individuals with Plasmodium falciparum infections as part of a severe systemic illness or as the main feature of acute malaria. P.vivax and P.ovale have also rarely caused pulmonary edema.Clinically, patients usually present with acute breathlessness that can rapidly progress to respiratory failure either at disease presentation or, interestingly, after treatment when clinical improvement is taking place and the parasitemia is falling. Pregnant women are particularly prone to developing pulmonary edema. Optimal management of malaria-induced ALI/ARDS includes early recognition and diagnosis. Malaria must always be suspected in a returning traveler or a visitor from a malaria-endemic country with an acute febrile illness. Slide microscopy and/or the use of rapid antigen tests are standard diagnostic tools. Malaria must be treated with effective drugs, but current choices are few: e.g. parenteral artemisinins, intravenous quinine or quinidine (in the US only). A recent trial in adults has shown that intravenous artesunate reduces severe malaria mortality by a third compared with adults treated with intravenous quinine. Respiratory compromise should be managed on its merits and may require mechanical ventilation.Patients should be managed in an intensive care unit and particular attention should be paid to the energetic management of other severe malaria complications, notably coma and acute renal failure. ALI/ARDS may also be related to a coincidental bacterial sepsis that may not be clinically obvious. Clinicians should employ a low threshold for starting broad spectrum antibacterials in such patients, after taking pertinent microbiologic specimens. Despite optimal management, the prognosis of severe malaria with ARDS is poor.ALI/ARDS in pediatric malaria appears to be rare. However, falciparum malaria with severe metabolic acidosis or acute pulmonary edema may present with a clinical picture of pneumonia, i.e. with tachypnea, intercostal recession, wheeze or inspiratory crepitations. This results in diagnostic confusion and suboptimal treatment. Whilst this is increasingly being recognized in malaria-endemic countries, clinicians in temperate zones should be aware that malaria may be a possible cause of 'pneumonia' in a visiting or returning child.

Maguire JD, Lederman ER, Barcus MJ, O'Meara WAP, Jordon RG, Duong S, Muth S, Sismadi P, Bangs MJ, Prescott WR et al. 2006. Production and validation of durable, high quality standardized malaria microscopy slides for teaching, testing and quality assurance during an era of declining diagnostic proficiency. Malar J, 5 pp. 92. | Show Abstract | Read more

BACKGROUND: Sets of Giemsa-stained, blood smear slides with systematically verified composite diagnoses would contribute substantially to development of externally validated quality assurance systems for the microscopic diagnosis of malaria. METHODS: whole blood from Plasmodium-positive donors in Cambodia and Indonesia and individuals with no history of risk for malaria was collected. Using standard operating procedures, technicians prepared Giemsa-stained thick and thin smears from each donor. One slide from each of the first 35 donations was distributed to each of 28 individuals acknowledged by reputation as having expertise in the microscopic diagnosis of malaria. These reference readers recorded presence or absence of Plasmodium species and parasite density. A composite diagnosis for each donation was determined based on microscopic findings and species-specific small subunit ribosomal RNA (ssrRNA) DNA polymerase chain reaction (PCR) amplification. RESULTS: More than 12,000 slides were generated from 124 donations. Reference readers correctly identified presence of parasites on 85% of slides with densities <100 parasites/microl, which improved to 100% for densities >350 parasites/microl. Percentages of agreement with composite diagnoses were highest for Plasmodium falciparum (99%), followed by Plasmodium vivax (86%). CONCLUSION: Herein, a standardized method for producing large numbers of consistently high quality, durable Giemsa-stained blood smears and validating composite diagnoses for the purpose of creating a malaria slide repository in support of initiatives to improve training and competency assessment amidst a background of variability in diagnosis is described.

Lederman ER, Maguire JD, Sumawinata IW, Chand K, Elyazar I, Estiana L, Sismadi P, Bangs MJ, Baird JK. 2006. Combined chloroquine, sulfadoxine/pyrimethamine and primaquine against Plasmodium falciparum in Central Java, Indonesia. Malar J, 5 pp. 108. | Citations: 28 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Chloroquine (CQ) or sulfadoxine-pyrimethamine (SP) monotherapy for Plasmodium falciparum often leads to therapeutic failure in Indonesia. Combining CQ with other drugs, like SP, may provide an affordable, available and effective option where artemisinin-combined therapies (ACT) are not licensed or are unavailable. METHODS: This study compared CQ (n = 29 subjects) versus CQ + SP (with or without primaquine; n = 88) for clinical and parasitological cure of uncomplicated falciparum malaria in the Menoreh Hills region of southern Central Java, Indonesia. Gametocyte clearance rates were measured with (n = 56 subjects) and without (n = 61) a single 45 mg dose of primaquine (PQ). RESULTS: After 28 days, 58% of subjects receiving CQ had cleared parasitaemia and remained aparasitaemic, compared to 94% receiving CQ combined with SP (p < 0.001). Msp-2 genotyping permitted reinfection-adjusted cure rates for CQ and CQ combined with SP, 70% and 99%, respectively (p = 0.0006). CONCLUSION: Primaquine exerted no apparent affect on cure of asexual stage parasitaemia, but clearly accelerated clearance of gametocytes. CQ combined with SP was safe and well-tolerated with superior efficacy over CQ for P. falciparum parasitaemia in this study.

Thuong NTT, Dunstan SJ, Dung NM, Charlieu JP, Loan HT, Wills B, Solomon T, Farrar JJ. 2006. Polymorphisms of the gene coding for copper/zinc superoxide dismutase (SOD1) in patients with Japanese encephalitis 100 (7), pp. 631-636. | Citations: 1 (Scopus) | Show Abstract | Read more

Japanese encephalitis is the commonest form of encephalitis globally. Most cases develop characteristic encephalitis but some also present with flaccid paralysis. The paralysis is secondary to damage at the alpha motor neurone, the site that is also damaged in amyotrophic lateral sclerosis (ALS). The gene coding for superoxide dismutase 1 (SOD1) is thought to be involved in ALS and may also be linked to susceptibility to Japanese encephalitis. To investigate this possibility, polymorphisms in the SOD1 gene were investigated, in 61 cases of Japanese encephalitis, 61 matched controls and 171 population controls, in Vietnam. Novel polymorphisms, found only in three of the cases and one of the population controls, may be involved with susceptibility to Japanese encephalitis and potentially to other flavivirus infections that lead to damage to the cells of the anterior horn. Further research on this possible association is required. © 2006 The Liverpool School of Tropical Medicine.

Maskey AP, Day JN, Phung QT, Thwaites GE, Campbell JI, Zimmerman M, Farrar JJ, Basnyat B. 2006. Salmonella enterica serovar Paratyphi A and S. enterica serovar Typhi cause indistinguishable clinical syndromes in Kathmandu, Nepal. Clin Infect Dis, 42 (9), pp. 1247-1253. | Citations: 99 (Scopus) | Show Abstract | Read more

BACKGROUND: Enteric fever is a major global problem. Emergence of antibacterial resistance threatens to render current treatments ineffective. There is little research or public health effort directed toward Salmonella enterica serovar Paratyphi A, because it is assumed to cause less severe enteric fever than does S. enterica serovar Typhi. There are few data on which to base this assumption, little is known of the serovar's antibacterial susceptibilities, and there is no readily available tolerable vaccination. METHODS: A prospective study was conducted of 609 consecutive cases of enteric fever (confirmed by blood culture) to compare the clinical phenotypes and antibacterial susceptibilities in S. Typhi and S. Paratyphi A infections. Variables independently associated with either infection were identified to develop a diagnostic rule to distinguish the infections. All isolates were tested for susceptibility to antibacterials. RESULTS: Six hundred nine patients (409 with S. Typhi infection and 200 with S. Paratyphi A infection) presented during the study period. The infections were clinically indistinguishable and had equal severity. Nalidixic acid resistance, which predicts a poor response to fluoroquinolone treatment, was extremely common (75.25% of S. Paratyphi A isolates and 50.5% of S. Typhi isolates; P < .001). S. Paratyphi A was more likely to be resistant to ofloxacin (3.6% vs. 0.5%; P = .007) or to have intermediate susceptibility to ofloxacin (28.7% vs. 1.8%; P < .001) or ciprofloxacin (39.4% vs. 8.2%; P < .001). MICs for S. Paratyphi A were higher than for S. Typhi (MIC of ciprofloxacin, 0.75 vs. 0.38 microg/mL [P < .001]; MIC of ofloxacin, 2.0 vs. 0.75 microg/mL [P < .001]). CONCLUSIONS: The importance of S. Paratyphi A has been underestimated. Infection is common, the agent causes disease as severe as that caused by S. Typhi and is highly likely to be drug resistant. Drug resistance and lack of effective vaccination suggest that S. Paratyphi A infection may become a major world health problem.

Pandit A, Arjyal A, Farrar J, Basnyat B. 2006. Nepal Practical Neurology, 6 (2), pp. 129-133. | Citations: 4 (Scopus) | Read more

De Jong MD, Tran TH, Farrar J. 2006. Infliximab for Ulcerative Colitis New England Journal of Medicine, 354 (13), pp. 1424-1426. | Read more

Carrara VI, Sirilak S, Thonglairuam J, Rojanawatsirivet C, Proux S, Gilbos V, Brockman A, Ashley EA, McGready R, Krudsood S et al. 2006. Deployment of early diagnosis and mefloquine-artesunate treatment of falciparum malaria in Thailand: the Tak Malaria Initiative. PLoS Med, 3 (6), pp. e183. | Citations: 83 (Scopus) | Show Abstract | Read more

BACKGROUND: Early diagnosis and treatment with artesunate-mefloquine combination therapy (MAS) have reduced the transmission of falciparum malaria dramatically and halted the progression of mefloquine resistance in camps for displaced persons along the Thai-Burmese border, an area of low and seasonal transmission of multidrug-resistant Plasmodium falciparum. We extended the same combination drug strategy to all other communities (estimated population 450,000) living in five border districts of Tak province in northwestern Thailand. METHODS AND FINDINGS: Existing health structures were reinforced. Village volunteers were trained to use rapid diagnostic tests and to treat positive cases with MAS. Cases of malaria, hospitalizations, and malaria-related deaths were recorded in the 6 y before, during, and after the Tak Malaria Initiative (TMI) intervention. Cross-sectional surveys were conducted before and during the TMI period. P. falciparum malaria cases fell by 34% (95% confidence interval [CI], 33.5-34.4) and hospitalisations for falciparum malaria fell by 39% (95% CI, 37.0-39.9) during the TMI period, while hospitalisations for P. vivax malaria remained constant. There were 32 deaths attributed to malaria during, and 22 after the TMI, a 51.5% (95% CI, 39.0-63.9) reduction compared to the average of the previous 3 y. Cross-sectional surveys indicated that P. vivax had become the predominant species in Thai villages, but not in populations living on the Myanmar side of the border. In the displaced persons population, where the original deployment took place 7 y before the TMI, the transmission of P. falciparum continued to be suppressed, the incidence of falciparum malaria remained low, and the in vivo efficacy of the 3-d MAS remained high. CONCLUSIONS: In the remote malarious north western border area of Thailand, the early detection of malaria by trained village volunteers, using rapid diagnostic tests and treatment with mefloquine-artesunate was feasible and reduced the morbidity and mortality of multidrug-resistant P. falciparum.

White NJ, Dondorp AM, Nosten F, Day NPJ. 2006. Authors' reply [9] Lancet, 367 (9505), pp. 111-112. | Read more

Newton PN, McGready R, Fernandez F, Green MD, Sunjio M, Bruneton C, Phanouvong S, Millet P, Whitty CJM, Talisuna AO et al. 2006. Correction: Manslaughter by Fake Artesunate in Asia—Will Africa Be Next? PLoS Medicine, 3 (8), pp. e324-e324. | Citations: 1 (Scopus) | Read more

Nosten F, Hutagalung R, Carrara VI, Ashley E, White N. 2006. Letters to the editor American Journal of Tropical Medicine and Hygiene, 74 (6), pp. 940. | Citations: 1 (Scopus)

Gutiérrez JM, Theakston RDG, Warrell DA. 2006. Confronting the neglected problem of snake bite envenoming: The need for a global partnership PLoS Medicine, 3 (6), pp. 0727-0731. | Citations: 234 (Scopus) | Read more

Dinh PN, Long HT, Tien NTK, Hien NT, Mai LTQ, Phong LH, Tuan LV, Van Tan H, Nguyen NB, Van Tu P et al. 2006. Risk factors for human infection with avian influenza A H5N1, Vietnam, 2004. Emerg Infect Dis, 12 (12), pp. 1841-1847. | Citations: 151 (Scopus) | Show Abstract | Read more

To evaluate risk factors for human infection with influenza A subtype H5N1, we performed a matched case-control study in Vietnam. We enrolled 28 case-patients who had laboratory-confirmed H5N1 infection during 2004 and 106 age-, sex-, and location-matched control-respondents. Data were analyzed by matched-pair analysis and multivariate conditional logistic regression. Factors that were independently associated with H5N1 infection were preparing sick or dead poultry for consumption < or =7 days before illness onset (matched odds ratio [OR] 8.99, 95% confidence interval [CI] 0.98-81.99, p = 0.05), having sick or dead poultry in the household < or =7 days before illness onset (matched OR 4.94, 95% CI 1.21-20.20, p = 0.03), and lack of an indoor water source (matched OR 6.46, 95% CI 1.20-34.81, p = 0.03). Factors not significantly associated with infection were raising healthy poultry, preparing healthy poultry for consumption, and exposure to persons with an acute respiratory illness.

Roberton SI, Bell DJ, Smith GJD, Nicholls JM, Chan KH, Nguyen DT, Tran PQ, Streicher U, Poon LLM, Chen H et al. 2006. Avian influenza H5N1 in viverrids: Implications for wildlife health and conservation Proceedings of the Royal Society B: Biological Sciences, 273 (1595), pp. 1729-1732. | Citations: 42 (Scopus) | Show Abstract | Read more

The Asian countries chronically infected with avian influenza A H5N1 are 'global hotspots' for biodiversity conservation in terms of species diversity, endemism and levels of threat. Since 2003, avian influenza A H5N1 viruses have naturally infected and killed a range of wild bird species, four felid species and a mustelid. Here, we report fatal disseminated H5N1 infection in a globally threatened viverrid, the Owston's civet, in Vietnam, highlighting the risk that avian influenza H5N1 poses to mammalian and avian biodiversity across its expanding geographic range. © 2006 The Royal Society.

Blacksell SD, Khounsy S, Van Aken D, Gleeson LJ, Westbury HA. 2006. Comparative susceptibility of indigenous and improved pig breeds to Classical swine fever virus infection: practical and epidemiological implications in a subsistence-based, developing country setting. Trop Anim Health Prod, 38 (6), pp. 467-474. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

This study investigated the comparative susceptibility of indigenous Moo Laat and improved Large White/Landrace pig breeds to infection with classical swine fever virus (CSFV) under controlled conditions in the Lao People's Democratic Republic (Lao PDR). The Moo Laat (ML) and Large White/Landrace cross-breed (LWC) pigs were inoculated with a standard challenge strain designated Lao/Kham225 (infectivity titre of 10(2.75) TCID50/ml). The results demonstrated that both the native breed and an improved pig breed are fully susceptible to CSFV infection and the mortality rate is high. LWC pigs demonstrated lower (or shorter) survival times (50% survival time: 11 days), earlier and higher pyrexia and earlier onset of viraemia compared to ML pigs (50% survival time: 18 days). In the context of village-based pig production, the longer time from infection to death in native ML pigs means that incubating or early sick pigs are likely to be sold once an outbreak of CSF is recognized in a village. This increased longevity probably contributes to the maintenance and spread of disease in a population where generally the contact rate is low.

Blacksell SD. 2006. Laboratory diagnosis of tropical infections Australian Journal of Medical Science, 27 (1), pp. 3.

Burford B, Blacksell SD. 2006. Diagnosis and management of tropical infections in travellers and expatriates at the Australian Embassy Clinic, Laos: Experience in a limited-resource environment Australian Journal of Medical Science, 27 (1), pp. 34-38. | Show Abstract

The Lao People's Democratic Republic (Lao PDR) is located in South East Asia bordered by Thailand, Vietnam, Cambodia, Myanmar and China. There is a large resident expatriate community as well as many foreign travellers. Health care resources available to this population are limited to a few embassy-based clinics. This review presents a perspective on managing tropical infections in the context of an expatriate clinic in the Lao PDR. Patients present with a variety of tropical infections and are often treated presumptively with minimal local laboratory support. Other laboratory tests that may be helpful to make an accurate diagnosis are detailed and discussed.

Blacksell SD. 2006. Serological and clinical diagnosis of dengue virus infection - A review of current knowledge Australian Journal of Medical Science, 27 (1), pp. 26-33. | Citations: 1 (Scopus) | Show Abstract

Dengue fever, dengue haemorrhagic fever and dengue shock syndrome are tropical diseases that cause significant disease burden. It is estimated that more than 2.5 billion people are at risk of infection and more than 100 countries have endemic dengue virus transmission. This paper reviews the available serological assays for the diagnosis of acute dengue virus infection, differentiation of primary and later infections, and their appropriate application depending on the setting. Dengue clinical syndromes and diagnostic criteria are also described.

White NJ. 2006. Editorial: clinical trials in tropical diseases: a politically incorrect view. Trop Med Int Health, 11 (10), pp. 1483-1484. | Citations: 19 (Scopus) | Read more

White NJ. 2006. Developing drugs for neglected diseases. Trop Med Int Health, 11 (4), pp. 383-384. | Citations: 3 (Scopus) | Read more

Anstey NM, Price RN, White NJ. 2006. Improving the availability of artesunate for treatment of severe malaria. Med J Aust, 184 (1), pp. 3-4. | Citations: 8 (Scopus)

Gething PW, Noor AM, Gikandi PW, Ogara EAA, Hay SI, Nixon MS, Snow RW, Atkinson PM. 2006. Improving imperfect data from health management information systems in Africa using space-time geostatistics PLoS Medicine, 3 (6), pp. 0825-0831. | Citations: 70 (Scopus) | Show Abstract | Read more

Background: Reliable and timely information on disease-specific treatment burdens within a health system is critical for the planning and monitoring of service provision. Health management information systems (HMIS) exist to address this need at national scales across Africa but are failing to deliver adequate data because of widespread underreporting by health facilities. Faced with this inadequacy, vital public health decisions often rely on crudely adjusted regional and national estimates of treatment burdens. Methods and Findings: This study has taken the example of presumed malaria in outpatients within the largely incomplete Kenyan HMIS database and has defined a geos tatistical modelling framework that can predict values for all data that are missing through space and time. The resulting complete set can then be used to define treatment burdens for presumed malaria at any level of spatial and temporal aggregation. Validation of the model has shown that these burdens are quantified to an acceptable level of accuracy at the district, provincial, and national scale. Conclusions: The modelling framework presented here provides, to our knowledge for the first time, reliable information from imperfect HMIS data to support evidence-based decision-making at national and sub-national levels. © 2006 Gething et al.

Dondorp A, White N, Day N. 2006. PfHRP2 measures schizogony, not mechanical blockage - Authors' reply: Response to Ian Clark PLOS MEDICINE, 3 (1), pp. 145-145. | Read more

Grard G, Lemasson J-J, Sylla M, Dubot A, Cook S, Molez J-F, Pourrut X, Charrel R, Gonzalez J-P, Munderloh U et al. 2006. Ngoye virus: a novel evolutionary lineage within the genus Flavivirus. J Gen Virol, 87 (Pt 11), pp. 3273-3277. | Citations: 23 (Scopus) | Show Abstract | Read more

By using degenerate primers deduced from conserved patterns in the flavivirus polymerase gene, a novel RNA virus was discovered in Rhipicephalus ticks sampled from members of the family Bovidae in Senegal. It was named Ngoye virus (NGOV) after the location from which it was isolated. Viral particles could be observed by electron microscopy, but isolation in vertebrate or invertebrate cell lines or by intracerebral infection of newborn mice remained unsuccessful. This is atypical of recognized arboviruses. The characterization of 4176 nt of the non-structural genes revealed that NGOV is a novel flavivirus species. It forms a distinct phylogenetic lineage related distantly to previously identified members of the genus Flavivirus. Analysis of genetic data suggested that the processing of the NGOV polyprotein and the organization of its replication complex are similar to those of flaviviruses. Together with other recent data, these findings suggest that a large number of viruses related distantly to 'classical' arthropod-borne flaviviruses remain to be discovered.

Low BY, Liong ML, Yuen KH, Chong WL, Chee C, Leong WS, Teh CL, Karim N, Yap HW, Cheah PY. 2006. Study of prevalence, treatment-seeking behavior, and risk factors of women with lower urinary tract symptoms in Northern Malaysia. Urology, 68 (4), pp. 751-758. | Citations: 9 (Scopus) | Show Abstract | Read more

OBJECTIVES: To determine the prevalence, severity, and quality-of-life (QOL) impact of female lower urinary tract symptoms (FLUTS); to determine the patterns, reasons, and factors contributing to the women's treatment-seeking behavior; and to describe the relationship between the social demographic characteristics and FLUTS. METHODS: A total of 2732 women older than 19 years of age were recruited by a series of FLUTS Awareness Campaigns held within Northern Malaysia from January to August 2004. Trained interviewers used surveys to collect information on social demographic characteristics, International Prostate Symptom Score, and King's Health Questionnaire to determine the prevalence, severity, QOL impact, treatment-seeking behavior, and risk factors of FLUTS. RESULTS: The prevalence of FLUTS was 19.0% (n = 519), with 88.6% having moderate and 11.4% severe FLUTS. Using the International Prostate Symptom Score QOL assessment index, 55.3% (n = 287) scored 4 or greater. Using the King's Health Questionnaire, the most affected QOL domain was sleep/energy. The patterns of treatment-seeking behavior revealed that only 23.1% (n = 120) of patients with FLUTS actively sought treatment. The major reason for those (76.9%) who failed to seek treatment was that they did not perceive FLUTS as a major health problem (29.1%). Factors that warranted treatment were the severity, bother, and QOL impact of FLUTS (all P <0.001), hematuria (P <0.001), age (P <0.005), parity, body mass index, and suprapubic pain (all P <0.05). The risk factors for FLUTS (defined as an odds ratio of 2 or more) included age 50 years or older, parity of 4 or more, illiteracy, postmenopausal status, and the presence of one or more concomitant chronic medical illness. CONCLUSIONS: Despite the high prevalence of FLUTS in Northern Malaysia (19.0%), many patients do not seek treatment, with ignorance being the major reason.

Cheah PY, Liong ML, Yuen KH, Lee S, Yang JR, Teh CL, Khor T, Yap HW, Krieger JN. 2006. Reliability and validity of the National Institutes of Health: Chronic Prostatitis Symptom Index in a Malaysian population. World J Urol, 24 (1), pp. 79-87. | Citations: 10 (Scopus) | Show Abstract | Read more

The objective of the study is to determine the short- and long-term utility of the Chinese, Malay and English versions of the National Institutes of Health--Chronic Prostatitis Symptom Index (NIH-CPSI) in our ethnically diverse population. The NIH-CPSI was translated into Chinese and Malay, and then verified by back translation into English. Subjects included 100 new chronic prostatitis/chronic pelvic pain (CP/CPPS) patients, 71 new benign prostatic hyperplasia patients and 97 healthy individuals. Reliability was evaluated with test-retest reproducibility (TR) by calculating intraclass correlation coefficients (ICC). Internal consistency was evaluated by calculating Cronbach's alpha (alpha). Validity assessments included discriminant and construct validity. (Presented in the order of Chinese, Malay then English). ICC values for short-term (1 week) TR were 0.90, 0.80 and 0.89, while ICC values for long-term (14 weeks) TR were 0.54, 0.61 and 0.61. Cronbach's alpha values were 0.63, 0.62 and 0.57. The NIH-CPSI total score discriminated CP/CPPS patients (P<0.001) from the control groups with receiver operating curve values of 0.95, 0.98 and 0.94, respectively. Construct validity, reflected by the correlation coefficient values between the International Prostate Symptom Score and the NIH-CPSI of CP/CPPS patients were 0.72, 0.49 and 0.63 (all P<0.05). The Chinese, Malay and English versions of the NIH-CPSI each proved effective in our population. Short-term TR and discriminant validity were excellent for all three versions. However, long-term TR was only moderate, which might reflect variation in patients' perceptions of symptoms over time.

Sur D, von Seidlein L, Manna B, Dutta S, Deb AK, Sarkar BL, Kanungo S, Deen JL, Ali M, Kim DR et al. 2006. The malaria and typhoid fever burden in the slums of Kolkata, India: data from a prospective community-based study. Trans R Soc Trop Med Hyg, 100 (8), pp. 725-733. | Citations: 36 (Scopus) | Show Abstract | Read more

Recent research has indicated that the malaria burden in Asia may have been vastly underestimated. We conducted a prospective community-based study in an impoverished urban site in Kolkata, India, to estimate the burden of malaria and typhoid fever and to identify risk factors for these diseases. In a population of 60452 people, 3605 fever episodes were detected over a 12-month period. The blood films of 93 febrile patients contained Plasmodium (90 P. vivax, 2 P. falciparum and 1 P. malariae). Blood cultures from 95 patients grew Salmonella enterica serotype Typhi. Malaria patients were found to be significantly older (mean age 29 years) compared with patients with typhoid fever (15 years; P<0.001) but had similar clinical features on presentation. Having a household member with malaria, illiteracy, low household income and living in a structure not built of bricks were associated with an increased risk for malaria. Having a household member with typhoid fever and poor hygiene were associated with typhoid fever. A geographic analysis of the spatial distribution of malaria and typhoid fever cases detected high-risk neighbourhoods for each disease. Focal interventions to minimise human-vector contact and improved personal hygiene and targeted vaccination campaigns could help to prevent malaria and typhoid fever in this site.

Dutta S, Sur D, Manna B, Sen B, Deb AK, Deen JL, Wain J, Von Seidlein L, Ochiai L, Clemens JD, Kumar Bhattacharya S. 2006. Evaluation of new-generation serologic tests for the diagnosis of typhoid fever: data from a community-based surveillance in Calcutta, India. Diagn Microbiol Infect Dis, 56 (4), pp. 359-365. | Citations: 47 (Scopus) | Show Abstract | Read more

Although typhoid fever is confirmed by culture of Salmonella enterica serotype Typhi, rapid and simple diagnostic serologic tests would be useful in developing countries. We examined the performance of Widal test in a community field site and compared it with Typhidot and Tubex tests for diagnosis of typhoid fever. Blood samples were collected from 6697 patients with fever for > or =3 days for microscopy, culture, and serologic testing and from randomly selected 172 consenting healthy individuals to assess the baseline Widal anti-Typhi O lipopolysaccharide antibody (anti-TO) and anti-Typhi H flagellar antibody (anti-TH) titers. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the 3 serologic tests were calculated using culture-confirmed typhoid fever cases as "true positives" and paratyphoid fever and malaria cases as "true negatives". Comparing cutoff values for the Widal test, an anti-TO titer of 1/80 was optimal with 58% sensitivity, 85% specificity, 69% PPV, and 77% NPV. Sensitivity was increased to 67% when the Widal test was done on the 5th day of illness and thereafter. The sensitivity, specificity, PPV, and NPV of Typhidot and Tubex were not better than Widal test. There is a need for more efficient rapid diagnostic test for typhoid fever especially during the acute stage of the disease. Until then, culture remains the method of choice.

Mwakyusa S, Wamae A, Wasunna A, Were F, Esamai F, Ogutu B, Muriithi A, Peshu N, English M. 2006. Implementation of a structured paediatric admission record for district hospitals in Kenya – results of a pilot study BMC International Health and Human Rights, 6 (1), | Citations: 16 (Scopus) | Show Abstract | Read more

Background: The structured admission form is an apparently simple measure to improve data quality. Poor motivation, lack of supervision, lack of resources and other factors are conceivably major barriers to their successful use in a Kenyan public hospital setting. Here we have examined the feasibility and acceptability of a structured paediatric admission record (PAR) for district hospitals as a means of improving documentation of illness. Methods: The PAR was primarily based on symptoms and signs included in the Integrated Management of Childhood Illness (IMCI) diagnostic algorithms. It was introduced with a three-hour training session, repeated subsequently for those absent, aiming for complete coverage of admitting clinical staff. Data from consecutive records before (n = 163) and from a 60% random sample of dates after intervention (n = 705) were then collected to evaluate record quality. The post-intervention period was further divided into four 2-month blocks by open, feedback meetings for hospital staff on the uptake and completeness of the PAR. Results: The frequency of use of the PAR increased from 50% in the first 2 months to 84% in the final 2 months, although there was significant variation in use among clinicians. The quality of documentation also improved considerably over t ime. For example documentation of skin turgor in cases of diarrhoea improved from 2% pre-intervention to 83% in the final 2 months of observation. Even in the area of preventive care documentation of immunization status improved from 1% of children before intervention to 21% in the final 2 months. Conclusion: The PAR was well accepted by most clinicians and greatly improved documentation of features recommended by IMCI for identifying and classifying severity of common diseases. The PAR could provide a useful platform for implementing standard referral care treatment guidelines. © 2006 Mwakyusa et al; licensee BioMed Central Ltd.

de Jong MD, Hien TT. 2006. Avian influenza A (H5N1). J Clin Virol, 35 (1), pp. 2-13. | Citations: 148 (Scopus) | Show Abstract | Read more

Since their reemergence in 2003, highly pathogenic avian influenza A (H5N1) viruses have reached endemic levels among poultry in several southeast Asian countries and have caused a still increasing number of more than 100 reported human infections with high mortality. These developments have ignited global fears of an imminent influenza pandemic. The current knowledge of the virology, clinical spectrum, diagnosis and treatment of human influenza H5N1 virus infections is reviewed herein.

PHUONG NT, HAI TN, HIEN TTT, BUI TV, HUONG DTT, SON VN, MOROOKA Y, FUKUDA Y, WILDER MN. 2006. Current status of freshwater prawn culture in Vietnam and the development and transfer of seed production technology Fisheries Science, 72 (1), pp. 1-12. | Citations: 29 (Scopus) | Show Abstract | Read more

In Vietnam, the giant freshwater prawn Macrobrachium rosenbergii is becoming an increasingly important targeted species, as its culture, especially in rice fields, is considered to have the potential to raise income among impoverished farmers. The production of M. rosenbergii based on aquaculture reached over 10 000 tons per year in 2002, having increased from about 2500 tons since the 1990s. Until recently, lack of a stable supply of seed had been an important obstacle to the further expansion and development of M. rosenbergii culture, but cumulative research on larval rearing, especially in the 1990s, has led to the development of new seed production technology based on the 'modified stagnant green water system'. Following its dissemination by the efforts of provincial authorities, hatchery operators, and farmers, the freshwater prawn seed production industry developed rapidly in the Mekong Delta with over 90 hatcheries producing 76.5 million postlarvae in 2003. This is considered to have affected the expansion of rice-prawn farming in the Mekong Delta, leading to increased aquacultural production in the region. This paper reviews the current status of freshwater prawn culture in Vietnam and background history, and presents a socioeconomic evaluation of seed production technology implementation.

Mahfouz ME, Grayson TH, Dance DAB, Gilpin ML. 2006. Characterization of the mrgRS locus of the opportunistic pathogen Burkholderia pseudomallei: temperature regulates the expression of a two-component signal transduction system. BMC Microbiol, 6 pp. 70. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Burkholderia pseudomallei is a saprophyte in tropical environments and an opportunistic human pathogen. This versatility requires a sensing mechanism that allows the bacterium to respond rapidly to altered environmental conditions. We characterized a two-component signal transduction locus from B. pseudomallei 204, mrgR and mrgS, encoding products with extensive homology with response regulators and histidine protein kinases of Escherichia coli, Bordetella pertussis, and Vibrio cholerae. RESULTS: The locus was present and expressed in a variety of B. pseudomallei human and environmental isolates but was absent from other Burkholderia species, B. cepacia, B. cocovenenans, B. plantarii, B. thailandensis, B. vandii, and B. vietnamiensis. A 2128 bp sequence, including the full response regulator mrgR, but not the sensor kinase mrgS, was present in the B. mallei genome. Restriction fragment length polymorphism downstream from mrgRS showed two distinct groups were present among B. pseudomallei isolates. Our analysis of the open reading frames in this region of the genome revealed that transposase and bacteriophage activity may help explain this variation. MrgR and MrgS proteins were expressed in B. pseudomallei 204 cultured at different pH, salinity and temperatures and the expression was substantially reduced at 25 degrees C compared with 37 degrees C or 42 degrees C but was mostly unaffected by pH or salinity, although at 25 degrees C and 0.15% NaCl a small increase in MrgR expression was observed at pH 5. MrgR was recognized by antibodies in convalescent sera pooled from melioidosis patients. CONCLUSION: The results suggest that mrgRS regulates an adaptive response to temperature that may be essential for pathogenesis, particularly during the initial phases of infection. B. pseudomallei and B. mallei are very closely related species that differ in their capacity to adapt to changing environmental conditions. Modifications in this region of the genome may assist our understanding of the reasons for this difference.

Goodman CA, Mutemi WM, Baya EK, Willetts A, Marsh V. 2006. The cost-effectiveness of improving malaria home management: shopkeeper training in rural Kenya. Health Policy Plan, 21 (4), pp. 275-288. | Citations: 41 (Scopus) | Show Abstract | Read more

Home management is a very common approach to the treatment of illnesses such as malaria, acute respiratory infections, tuberculosis, diarrhoea and sexually transmitted infections, frequently through over-the-counter purchase of drugs from shops. Inappropriate drugs and doses are often obtained, but interventions to improve treatment quality are rare. An educational programme for general shopkeepers and communities in Kilifi District, rural Kenya was associated with major improvements in the use of over-the-counter anti-malarial drugs for childhood fevers. The two main components were workshop training for drug retailers and community information activities, with impact maintained through on-going refresher training, monitoring and community mobilization. This paper presents the cost and cost-effectiveness of the programme in terms of additional appropriately treated cases, evaluating both its measured cost-effectiveness in the first area of implementation (early implementation phase) and the estimated cost-effectiveness of the programme recommended for district-level implementation (recommended district programme). The proportion of shop-treated childhood fevers receiving an adequate amount of a recommended antimalarial rose from 2% to 15% in the early implementation phase, at an economic cost of 4.00 US dollars per additional appropriately treated case (2000 US dollars). If the same impact were achieved through the recommended district programme, the economic cost per additional appropriately treated case would be 0.84 US dollars, varying between 0.37 US dollars and 1.36 US dollars in the sensitivity analysis. As with most educational approaches, the programme carries a relatively high initial financial cost, of 11,477 US dollars (0.02 per capita US dollars) for the development phase and 81,450 US dollars (0.17 per capita US dollars) for the set up year, which would be particularly suitable for donor funding, while the annual costs of 18,129 US dollars (0.04 per capita US dollars) thereafter could be contained within the budget of a typical District. To reach the Abuja target of 60% of those suffering from malaria in sub-Saharan Africa having access to affordable and appropriate treatment within 24 hours, improvements in community-based malaria treatment are urgently required. From these results, policymakers can estimate costs for district-scale shopkeeper training programmes, and will be able to assess their relative cost-effectiveness as comparable evaluations become available from home management interventions in the future. Extrapolation of the results using a simple decision tree model to estimate the cost per DALY averted indicates that the intervention is likely to be considered highly cost-effective in comparison with standard benchmarks for interventions in low-income countries.

Dondorp A, White N, Day N. 2006. Authors' Reply: Response to Ian Clark PLoS Medicine, 3 (1), pp. e69-e69. | Read more

Atkinson SH, Rockett K, Sirugo G, Bejon PA, Fulford A, O'Connell MA, Bailey R, Kwiatkowski DP, Prentice AM. 2006. Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype. PLoS Med, 3 (5), pp. e172. | Citations: 34 (Scopus) | Show Abstract | Read more

BACKGROUND: Anaemia is a major cause of morbidity and mortality for children in Africa. The plasma protein haptoglobin (Hp) binds avidly to free haemoglobin released following malaria-induced haemolysis. Haptoglobin polymorphisms result in proteins with altered haemoglobin-binding capacity and different antioxidant, iron-recycling, and immune functions. Previous studies examined the importance of haptoglobin polymorphism in malaria and iron homeostasis, but it is unknown whether haptoglobin genotype might be a risk factor for anaemia in children in a malaria-endemic area. METHODS AND FINDINGS: A cohort of 780 rural Gambian children aged 2-6 y was surveyed at the start and end of the malaria season. Samples were taken to assess haemoglobin (Hb) concentration, iron status (ferritin, zinc protoporphyrin, transferrin saturation, and soluble transferrin receptor concentration), haptoglobin concentration, alpha-1-antichymotrypsin (a measure of inflammation), and malaria parasites on blood film. We extracted DNA and genotyped for haptoglobin, sickle cell, and glucose-6-phosphate (G6PD) deficiency. Mean Hb levels fell over the malaria season. Children with the haptoglobin 2-2 genotype (17%) had a greater mean drop in Hb level over the malaria season (an 8.9 g/l drop; confidence interval [CI] 5.7, 12.1) compared to other children (a 5.1 g/l drop; CI 3.8, 6.4). In multivariate regression analysis, controlling for baseline Hb level, age group, village, malaria parasites on blood film, iron status, haptoglobin concentration, and G6PD deficiency, haptoglobin genotype predicted Hb level at the end of the malaria season (p = 0.0009, coefficient = -4.2). Iron status was not influenced by haptoglobin genotype. CONCLUSIONS: The finding that haptoglobin 2-2 genotype is a risk factor for anaemia in children in a malaria-endemic area may reflect the reduced ability of the Hp2-2 polymer to scavenge free haemoglobin-iron following malaria-induced haemolysis. The magnitude of the effect of haptoglobin genotype (4 g/l Hb difference, p = 0.0009) was comparable to that of G6PD deficiency or HbAS (3 g/l difference, p = 0.03; and 2 g/l difference, p = 0.68, respectively).

Luna C, Hoa NT, Lin H, Zhang L, Nguyen HLA, Kanzok SM, Zheng L. 2006. Expression of immune responsive genes in cell lines from two different Anopheline species. Insect Mol Biol, 15 (6), pp. 721-729. | Citations: 26 (Scopus) | Show Abstract | Read more

Malaria infection results in increased expression of immune responsive genes, including those encoding antimicrobial peptides such as Gambicin (Gam1) and Cecropin A (Cec1). Understanding how these genes are regulated will provide insights how the mosquito immune system is activated by Plasmodium. We previously have shown that Cec1 was primarily regulated by the Imd-Relish (REL2) pathway in the Anopheles gambiae Sua1B cell line. We show here that expression of Defensin A (Def1) and Gam1 was reduced after RNA interference against components of the Imd-REL2 pathway in An. gambiae cell lines. Interestingly, promoter reporters of these antimicrobial peptides were expressed at very low level in the cell line MSQ43 from Anopheles stephensi. Surprisingly, over-expression of either NF-kappaB transcription factor REL1 or REL2 alone is sufficient to induce the expression of Cec1, Gam1 and Def1. These results suggest that expression of these antimicrobial peptides (AMP) in vivo may be regulated by both the Toll and Imd pathways. We also show here for the first time that Tep4, a gene encoding a thioester containing protein, is regulated by REL2. Taken together, these results suggest that there are significant overlaps of genes regulated by the Toll-Rel1 and Imd-Rel2 pathways. Further, the different expression patterns in two different Anopheline cell lines provide a platform to identify other key positive and negative regulators of the antimicrobial peptide genes.

Warrell DA. 2006. Foreword Tropical Infectious Diseases, | Read more

Khan MI, Sahito SM, Khan MJ, Wassan SM, Shaikh AW, Maheshwari AK, Acosta CJ, Galindo CM, Ochiai RL, Rasool S et al. 2006. Enhanced disease surveillance through private health care sector cooperation in Karachi, Pakistan: experience from a vaccine trial. Bull World Health Organ, 84 (1), pp. 72-77. | Citations: 21 (Scopus) | Show Abstract | Read more

INTRODUCTION: In research projects such as vaccine trials, accurate and complete surveillance of all outcomes of interest is critical. In less developed countries where the private sector is the major health-care provider, the private sector must be included in surveillance systems in order to capture all disease of interest. This, however, poses enormous challenges in practice. The process and outcome of recruiting private practice clinics for surveillance in a vaccine trial are described. METHODS: The project started in January 2002 in two urban squatter settlements of Karachi, Pakistan. At the suggestion of private practitioners, a phlebotomy team was formed to provide support for disease surveillance. Children who had a reported history of fever for more than three days were enrolled for a diagnosis. RESULTS: Between May 2003 and April 2004, 5540 children younger than 16 years with fever for three days or more were enrolled in the study. Of the children, 1312 (24%) were seen first by private practitioners; the remainder presented directly to study centres. In total, 5329 blood samples were obtained for microbiology. The annual incidence of Salmonella typhi diagnosed by blood culture was 407 (95% confidence interval (95% CI), 368-448) per 100 000/year and for Salmonella paratyphi A was 198 (95% CI, 171-227) per 100 000/year. Without the contribution of private practitioners, the rates would have been 240 per 100 000/year (95% CI, 211-271) for S. typhi and 114 (95% CI, 94-136) per 100 000/year for S. paratyphi A. CONCLUSION: The private sector plays a major health-care role in Pakistan. Our experience from a surveillance and burden estimation study in Pakistan indicates that this objective is possible to achieve but requires considerable effort and confidence building. Nonetheless, it is essential to include private health care providers when attempting to accurately estimate the burden of disease in such settings.

Wang X-Y, Tao F, Xiao D, Lee H, Deen J, Gong J, Zhao Y, Zhou W, Li W, Shen B et al. 2006. Trend and disease burden of bacillary dysentery in China (1991-2000). Bull World Health Organ, 84 (7), pp. 561-568. | Citations: 77 (Scopus) | Show Abstract | Read more

OBJECTIVE: We aimed to determine the burden of bacillary dysentery in China, its cross-regional variations, trends in morbidity and mortality, the causative bacterial species and antimicrobial resistance patterns. METHODS: We extracted and integrated governmental statistics and relevant medical literature published from 1991 to 2000. Data were also collected from one general hospital each for the six provinces and Jin-an district, Shanghai, representative of six geographical regions and a modern city. FINDINGS: In 2000, 0.8-1.7 million episodes of bacillary dysentery occurred of which 0.5 to 0.7 million were treated at health-care facilities and 0.15-0.20 million patients were hospitalized. The highest morbidity and mortality rates were among the youngest and oldest age groups. Bacillary dysentery peaked during the summer months. The major causative species was Shigella flexneri (86%) and the predominant S. flexneri serotype was 2a (80%). About 74-80% of Shigella isolates remained susceptible to fluorinated quinolones. CONCLUSION: We conclude that while morbidity and mortality due to bacillary dysentery has decreased considerably in China in the past decade due to increasing access to affordable health care and antibiotics, a considerable burden exists among the youngest and oldest age groups and in regions with low economic development. We suggest that while a vaccine would be effective for short- and medium-term control of bacillary dysentery, improved water supply, sanitation, and hygiene are likely to be required for long-term control.

Anh DD, Thiem VD, Fischer TK, Canh DG, Minh TT, Tho LH, Van Man N, Luan LT, Kilgore P, von Seidlein L, Glass RI. 2006. The burden of rotavirus diarrhea in Khanh Hoa Province, Vietnam: baseline assessment for a rotavirus vaccine trial. Pediatr Infect Dis J, 25 (1), pp. 37-40. | Citations: 16 (Scopus) | Show Abstract | Read more

BACKGROUND: In Vietnam, rotavirus is seen as a priority disease because studies have demonstrated that >50% of children hospitalized for treatment of diarrhea have rotavirus as the pathogen. To anticipate the availability of new vaccines, we have examined our field area in Nha Trang, Khanh Hoa Province, Vietnam, as a potential site to conduct a field trial of a future rotavirus vaccine. METHODS: Data from a population census, incidence rates of diarrhea from a previous cholera vaccine trial and hospitalization rates from computerized records collected from the 2 main hospitals in the province were reviewed to estimate the burden of rotavirus-related diarrhea that might be expected during a field trial of a rotavirus vaccine. RESULTS: For a birth cohort of approximately 5000 children, we would expect approximately 2500 clinic visits and 650-850 hospitalizations for treatment of diarrhea, of which approximately 375-425 would be attributable to rotavirus. For the Vietnamese birth cohort of 1,639,000 children, these numbers translate into approximately 820,000 clinic visits, 122,000-140,000 hospitalizations and 2900-5400 deaths annually attributable to rotavirus-related diarrhea. CONCLUSIONS: Vietnam is an early adaptor of new vaccines, has high national coverage rates (>85%) for childhood immunization and receives international donor support for the introduction of new vaccines. We found the epidemiologic features of rotavirus in rural Vietnam to be more similar to those of rotavirus in a developed country than to those of rotavirus in India or Bangladesh.

von Seidlein L, Kim DR, Ali M, Lee H, Wang X, Thiem VD, Canh DG, Chaicumpa W, Agtini MD, Hossain A et al. 2006. A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology. PLoS Med, 3 (9), pp. e353. | Citations: 255 (Scopus) | Show Abstract | Read more

BACKGROUND: The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia. METHODS AND FINDINGS: Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]). CONCLUSIONS: Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.

Droma Y, Hanaoka M, Basnyat B, Arjyal A, Neupane P, Pandit A, Sharma D, Kubo K. 2006. Symptoms of acute mountain sickness in Sherpas exposed to extremely high altitude. High Alt Med Biol, 7 (4), pp. 312-314. | Citations: 9 (Scopus) | Show Abstract | Read more

Droma, Yunden, Masayuki Hanaoka, Buddha Basnyat, Amit Arjyal, Pritam Neupane, Anil Pandit, Dependra Sharma, and Keishi Kubo. Symptoms of acute mountain sickness in Sherpas exposed to extremely high altitude. High Alt. Med. Biol. 7:312-314, 2006.--The aim of this field interview was to investigate the current state of affairs concerning acute mountain sickness (AMS) in high-altitude residents, specifically the Sherpas at 3440 m above sea level, when they are exposed rapidly to altitudes significantly higher than their residing altitudes. Out of 105 Sherpas (44 men and 61 women, 31.2 +/- 0.8 yr), 104 had mountain-climbing experiences to 5701.4 +/- 119.1-m altitude in average 3.5 times each year. On the other hand, only 68 out of 111 non-Sherpas (29.9 +/- 0.8 yr) had experience of 1.4 +/- 1.5 climbs to an average 2688.6 +/- 150.4-m altitude in their mountaineering histories (p < 0.0001). Among the 104 Sherpas, 45 (43.3%) complained of at least one AMS symptom (headache, gastrointestinal symptoms, weakness, dizziness, and difficulty sleeping) in their experiences of mountaineering at an average 5518.9 +/- 195.9-m altitude. And 16 out of the 68 non-Sherpas (23.5%) reported the AMS symptoms at a mean altitude of 2750.0 +/- 288.8 m. Moreover, we also noticed that the Sherpa women showed a significantly higher Sa(O(2) ) (93.9 +/- 0.2%) than did Sherpa men (92.4 +/- 0.3%, p = 0.0001) at an altitude of 3440 m. The brief field interview evidenced that Sherpas might suffer from AMS when exposed to altitudes significantly higher than their residing altitude.

Shah MB, Braude D, Crandall CS, Kwack H, Rabinowitz L, Cumbo TA, Basnyat B, Bhasyal G. 2006. Changes in metabolic and hematologic laboratory values with ascent to altitude and the development of acute mountain sickness in Nepalese pilgrims. Wilderness Environ Med, 17 (3), pp. 171-177. | Citations: 11 (Scopus) | Show Abstract | Read more

OBJECTIVE: During August of each year, thousands of Nepalese religious pilgrims ascend from 2050 m to 4500 m in 1 to 3 days. Our objectives were to evaluate the incidence of acute mountain sickness (AMS) among this large group of native people, to explore changes in serum electrolytes as subjects ascend to high altitude, and to attempt to determine whether decreased effective circulating volume is associated with the development of AMS. METHODS: This was a prospective study with 2 parts. In the first part, demographic, physiologic, and laboratory data were collected from a cohort of 34 pilgrims at both moderate (2050 m) and high altitude (4500 m). Changes that occurred with ascent were compared in subjects who did and did not develop AMS. The second part was a cross sectional study of a different group of 57 pilgrims at the high-altitude site to further determine variables associated with AMS. RESULTS: In the cohort of 34 subjects, Lake Louise score, heart rate, respiratory rate, blood urea nitrogen (BUN), BUN:creatinine ratio, and pH increased at high altitude, whereas oxygen saturation, bicarbonate, creatinine, and PCO2 decreased. Sixteen of these 34 subjects (42%) were diagnosed with AMS; these patients had a statistically significantly lower hematocrit, oxygen saturation, and self-reported water consumption than those without AMS. Of the 57 subjects enrolled in the cross sectional study, 31 (54%) were diagnosed with AMS. These pilgrims had higher heart rates and BUNs than did their non-AMS counterparts. CONCLUSIONS: Fifty-two percent of the subjects developed AMS. With ascent to altitude, subjects showed some evidence of decreased effective circulating volume, though there were no clinically significant changes. The data did not show whether decreased circulating volume is a significant risk factor in the development of AMS at high altitude.

Droma Y, Hanaoka M, Basnyat B, Arjyal A, Neupane P, Pandit A, Sharma D, Miwa N, Ito M, Katsuyama Y et al. 2006. Genetic contribution of the endothelial nitric oxide synthase gene to high altitude adaptation in sherpas. High Alt Med Biol, 7 (3), pp. 209-220. | Citations: 33 (Scopus) | Show Abstract | Read more

The Sherpas' adaptation to high altitude has been hypothesized as being due to a genetic basis since the beginning of the last century, but this has yet to be demonstrated. We randomly enrolled 105 Sherpas in Namche Bazaar (3440 m) and 111 non-Sherpa Nepalis in Kathmandu (1330 m) in Nepal. The genotypes of Glu298Asp and eNOS4b/a polymorphisms of the endothelial nitric oxide synthase (eNOS) gene were identified. The metabolites of nitric oxide (NO( x ): nitrite and nitrate) in serum were measured. The frequencies of the Glu and eNOS4b alleles were significantly higher in Sherpas (Glu: 87.5%; eNOS4b: 96.7%) than in non-Sherpas (Glu: 77.9%, p = 0.036; eNOS4b: 90.5%, p = 0.009). In addition, the combination of the wild types of Glu298Glu and eNOS4b/b was significantly greater in Sherpas (66.7%) than non-Sherpas (47.7%, p = 0.008). However, the serum NO( x ) was significantly lower in Sherpas (53.2 +/- 4.6 micromol/L) than in non-Sherpas (107.3 +/- 9.0 micromol/L, p < 0.0001). The wild alleles of the Glu298Asp and eNOS4b/a polymorphisms of the eNOS gene may be a benefit for the Sherpas' adaptation to high altitude. The nitric oxide metabolites (NO( x )) in serum vary individually, thus it is not a reliable indicator for endogenous nitric oxide production.

Basnyat B. 2006. The pilgrim at high altitude. High Alt Med Biol, 7 (3), pp. 183-184. | Citations: 3 (Scopus) | Read more

Basnyat B, Gertsch JH, Holck PS, Johnson EW, Luks AM, Donham BP, Fleischman RJ, Gowder DW, Hawksworth JS, Jensen BT et al. 2006. Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol, 7 (1), pp. 17-27. | Citations: 63 (Scopus) | Show Abstract | Read more

750 mg per day of acetazolamide in the prevention of acute mountain sickness (AMS), as recommended in the meta-analysis published in 2000 in the British Medical Journal, may be excessive and is controversial. To determine if the efficacy of low-dose acetazolamide 125 mg bd (250 mg), as currently used in the Himalayas, is significantly different from 375 mg bd (750 mg) of acetazolamide in the prevention of AMS, we designed a prospective, double-blind, randomized, placebo-controlled trial. The participants were sampled from a diverse population of (non-Nepali) trekkers at Namche Bazaar (3440 m) in Nepal on the Everest trekking route as they ascended to study midpoints (4280 m/4358 m) and the endpoint, Lobuje (4928 m), where data were collected. Participants were randomly assigned to receive 375 mg bd of acetazolamide (82 participants), 125 mg bd of acetazolamide (74 participants), or a placebo (66 participants), beginning at 3440 m for up to 6 days as they ascended to 4928 m. The results revealed that composite AMS incidence for 125 mg bd was similar to the incidence for 375 mg bd (24% vs. 21%, 95% confidence interval, -12.6%, 19.8%), in contrast to significantly greater AMS (51%) observed in the placebo group (95% confidence interval for differences: 8%, 46%; 12%, 49% for low and high comparisons, respectively). Both doses of acetazolamide improved oxygenation equally (82.9% for 250 mg daily and 82.8% for 750 mg daily), while placebo endpoint oxygen saturation was significantly less at 80.7% (95% confidence interval for differences: 0.5%, 3.9% and 0.4%, 3.7% for low and high comparisons, respectively). There was also more paresthesia in the 375-mg bd group (p < 0.02). We conclude that 125 mg bd of acetazolamide is not significantly different from 375 mg bd in the prevention of AMS; 125 mg bd should be considered the preferred dosage when indicated for persons ascending to altitudes above 2500 m.

Schade RP, Schinkel J, Roelandse FWC, Geskus RB, Visser LG, van Dijk JMC, Voormolen JHC, Van Pelt H, Kuijper EJ. 2006. Lack of value of routine analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis. J Neurosurg, 104 (1), pp. 101-108. | Citations: 74 (Scopus) | Show Abstract | Read more

OBJECT: Routine microbiological and chemical analysis of cerebrospinal fluid (CSF) is often performed to diagnose external drainage-related bacterial meningitis (ED-BM) at an early stage. A cohort study was performed to investigate the value of several commonly used CSF parameters for the prediction and diagnosis of ED-BM. METHODS: In a cohort of 230 consecutive patients in whom external drains had been placed, CSF samples were collected daily, prospectively evaluated for the presence of bacteria using Gram stain and microbiological culture, and analyzed for leukocyte count, protein concentration, glucose concentration, and ratio of CSF glucose to blood glucose. In addition, the CSF concentration of interleukin-6 (IL-6) was determined. The definition of ED-BM was based on positive culture results in combination with clinical symptoms. A matched case-control study was performed to evaluate the cohort longitudinally and to control for biasing factors such as duration of external drainage. External drainage-related bacterial meningitis developed in 22 patients (9.6%). Results from analyses of 1516 CSF samples showed no significant differences between the patients in whom ED-BM developed and a control group without ED-BM during the first 3 days of infection or during the 3 days preceding the infection with regard to leukocyte count, protein concentration, glucose concentration, and CSF/blood glucose ratio. No significant difference between groups was found for the CSF IL-6 concentration during the 3 days preceding the infection. In the matched case-control study, none of the parameters had significant predictive or diagnostic value for ED-BM in analyses using absolute values, ratios, and differences between the current and previous day's values. A comparison of the results from Gram stains and CSF cultures showed that the Gram staining had a very high specificity (99.9%) but a low sensitivity (18% [four of 22 patients] on the 1st day of infection and 60% [nine of 15 patients] on the 2nd day). CONCLUSIONS: Severe disturbances in the CSF of patients with external drains limit the value of routine CSF analysis for prediction or diagnosis of ED-BM. Routine Gram stain of CSF has also limited predictive or diagnostic value due to its low sensitivity in screening for ED-BM.

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