Tropical Medicine publications 2005

de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJD, Nguyen VC, Bach VC, Phan TQ, Do QH, Guan Y et al. 2005. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med, 353 (25), pp. 2667-2672. | Citations: 697 (Scopus) | Show Abstract | Read more

Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents.

Lang T, Hill AVS, McShane H, Shah R, Towse A, Pritchard C, Garau M. 2005. New TB vaccine granted orphan drug status. BMJ, 331 (7530), pp. 1476. | Citations: 8 (Scopus) | Read more

Thwaites GE, Duc Bang N, Huy Dung N, Thi Quy H, Thi Tuong Oanh D, Thi Cam Thoa N, Quang Hien N, Tri Thuc N, Ngoc Hai N, Thi Ngoc Lan N et al. 2005. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with Tuberculous meningitis. J Infect Dis, 192 (12), pp. 2134-2141. | Citations: 114 (Scopus) | Show Abstract | Read more

BACKGROUND: Tuberculous meningitis occurs more commonly in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals, but whether HIV infection alters the presentation and outcome of tuberculous meningitis is unknown. METHODS: We performed a prospective comparison of the presenting clinical features and response to treatment in 528 adults treated consecutively for tuberculous meningitis (96 were infected with HIV and 432 were uninfected with HIV) in 2 tertiary-care referral hospitals in Ho Chi Minh City, Vietnam. Logistic regression was used to model variables associated independently with HIV infection, 9-month survival, and the likelihood of having a relapse or an adverse drug event. Kaplan-Meier estimates were used to compare survival rates and times to fever clearance, coma clearance, relapse, and adverse events. RESULTS: HIV infection did not alter the neurological presentation of tuberculous meningitis, although additional extrapulmonary tuberculosis was more likely to occur in HIV-infected patients. The 9-month survival rate was significantly decreased in HIV-infected patients (relative risk of death from any cause, 2.91 [95% confidence interval, 2.14-3.96]; P < .001), although the times to fever clearance and coma clearance and the number or timing of relapses or adverse drug events were not significantly different between the groups. CONCLUSIONS: HIV infection does not alter the neurological features of tuberculous meningitis but significantly reduces the survival rate.

Jenkins NE, Mwangi TW, Kortok M, Marsh K, Craig AG, Williams TN. 2005. A polymorphism of intercellular adhesion molecule-1 is associated with a reduced incidence of nonmalarial febrile illness in Kenyan children. Clin Infect Dis, 41 (12), pp. 1817-1819. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

An intercellular adhesion molecule-1 polymorphism (ICAM-1(Kilifi)) is present at a high frequency across sub-Saharan Africa, and its presence may increase susceptibility to cerebral malaria. Here, we report that, compared with children in whom wild-type intercellular adhesion molecule-1 is present, the incidence of nonmalarial fever is significantly lower among those homozygous for ICAM-1(Kilifi). We propose that ICAM-1(Kilifi) may be associated with reduced rates of tissue damage and of death due to sepsis.

Wills BA, Dung NM, Farrar JJ. 2005. Fluid solutions in dengue shock syndrome - Reply NEW ENGLAND JOURNAL OF MEDICINE, 353 (23), pp. 2511-2511.

Williams JT, Nair S, Sudimack D, Nosten F, Goring HHH, Anderson TJC. 2005. Genome-wide significance level for linkage analysis in Plasmodium falciparum AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 121-121.

Chierakul W, Wuthiekanun V, Chaowagul W, Amornchai P, Cheng AC, White NJ, Day NPJ, Peacock SJ. 2005. Short report: disease severity and outcome of melioidosis in HIV coinfected individuals. Am J Trop Med Hyg, 73 (6), pp. 1165-1166. | Citations: 32 (Scopus) | Show Abstract

This study examined whether coinfection with HIV and Burkholderia pseudomallei leads to altered disease severity or outcome associated with melioidosis. Coinfection was detected in only 8 of 524 (1.5%) adults with melioidosis in northeast Thailand. Clinical presentation and acute outcome were similar in HIV-positive and HIV-negative patients.

Anderson TJC, Nair S, Sudimack D, Williams JT, Mayxay M, Newton PN, Guthmann J-P, Smithuis FM, Tran TH, van den Broek IVF et al. 2005. Geographical distribution of selected and putatively neutral SNPs in Southeast Asian malaria parasites. Mol Biol Evol, 22 (12), pp. 2362-2374. | Citations: 40 (Scopus) | Show Abstract | Read more

Loci targeted by directional selection are expected to show elevated geographical population structure relative to neutral loci, and a flurry of recent papers have used this rationale to search for genome regions involved in adaptation. Studies of functional mutations that are known to be under selection are particularly useful for assessing the utility of this approach. Antimalarial drug treatment regimes vary considerably between countries in Southeast Asia selecting for local adaptation at parasite loci underlying resistance. We compared the population structure revealed by 10 nonsynonymous mutations (nonsynonymous single-nucleotide polymorphisms [nsSNPs]) in four loci that are known to be involved in antimalarial drug resistance, with patterns revealed by 10 synonymous mutations (synonymous single-nucleotide polymorphisms [sSNPs]) in housekeeping genes or genes of unknown function in 755 Plasmodium falciparum infections collected from 13 populations in six Southeast Asian countries. Allele frequencies at known nsSNPs underlying resistance varied markedly between locations (F(ST) = 0.18-0.66), with the highest frequencies on the Thailand-Burma border and the lowest frequencies in neighboring Lao PDR. In contrast, we found weak but significant geographic structure (F(ST) = 0-0.14) for 8 of 10 sSNPs. Importantly, all 10 nsSNPs showed significantly higher F(ST) (P < 8 x 10(-5)) than simulated neutral expectations based on observed F(ST) values in the putatively neutral sSNPs. This result was unaffected by the methods used to estimate allele frequencies or the number of populations used in the simulations. Given that dense single-nucleotide polymorphism (SNP) maps and rapid SNP assay methods are now available for P. falciparum, comparing genetic differentiation across the genome may provide a valuable aid to identifying parasite loci underlying local adaptation to drug treatment regimes or other selective forces. However, the high proportion of polymorphic sites that appear to be under balancing selection (or linked to selected sites) in the P. falciparum genome violates the central assumption that selected sites are rare, which complicates identification of outlier loci, and suggests that caution is needed when using this approach.

Newton PN, Day NPJ, White NJ. 2005. Misattribution of central nervous system dysfunction to artesunate. Clin Infect Dis, 41 (11), pp. 1687-1688. | Citations: 12 (Web of Science Lite) | Read more

Tarning J, Lindegårdh N, Annerberg A, Singtoroj T, Day NPJ, Ashton M, White NJ. 2005. Pitfalls in estimating piperaquine elimination. Antimicrob Agents Chemother, 49 (12), pp. 5127-5128. | Citations: 50 (Scopus) | Show Abstract | Read more

By using a sensitive new assay, the terminal elimination half-life of the antimalarial piperaquine in a healthy volunteer was estimated to be 33 days, which is longer than estimated previously. This result illustrates the importance of extended sampling duration and sensitive assay methodologies in characterizing the disposition of slowly eliminated antimalarial drugs.

Green MD, Vongsack L, Manolin O, Sengaloundeth S, Khounsaknalath L, Pamanivong C, Rojas OV, Newton PN. 2005. Use of a refractometer to assess the quality of antimalarial drugs collected in the Lao Pdr AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 346-346.

Maharjan B, Chantratita N, Vesaratchavest M, Cheng A, Wuthiekanun V, Chierakul W, Chaowagul W, Day NPJ, Peacock SJ. 2005. Recurrent melioidosis in patients in northeast Thailand is frequently due to reinfection rather than relapse. J Clin Microbiol, 43 (12), pp. 6032-6034. | Citations: 54 (Scopus) | Show Abstract | Read more

Human melioidosis is associated with a high rate of recurrent disease, despite adequate antimicrobial treatment. Here, we define the rate of relapse versus the rate of reinfection in 116 patients with 123 episodes of recurrent melioidosis who were treated at Sappasithiprasong Hospital in Northeast Thailand between 1986 and 2005. Pulsed-field gel electrophoresis was performed on all isolates; isolates from primary and recurrent disease for a given patient different by one or more bands were examined by a sequence-based approach based on multilocus sequence typing. Overall, 92 episodes (75%) of recurrent disease were caused by the same strain (relapse) and 31 episodes (25%) were due to infection with a new strain (reinfection). The interval to recurrence differed between patients with relapse and reinfection; those with relapses had a median time to relapse of 228 days (range, 15 to 3,757 days; interquartile range [IQR], 99.5 to 608 days), while those with reinfection had a median time to reinfection of 823 days (range, 17 to 2,931 days; IQR, 453 to 1,211 days) (P = 0.0001). A total of 64 episodes (52%) occurred within 12 months of the primary infection. Relapse was responsible for 57 of 64 (89%) episodes of recurrent infection within the first year after primary disease, whereas relapse was responsible for 35 of 59 (59%) episodes after 1 year (P < 0.0001). Our data indicate that in this setting of endemicity, reinfection is responsible for one-quarter of recurrent cases. This finding has important implications for the clinical management of melioidosis patients and for antibiotic treatment studies that use recurrent disease as a marker for treatment failure.

Nair S, Nash D, Suclimack D, Nosten F, Anderson T. 2005. Characterization of segmental amplifications on CHR 5 associated with multidrug resistance in Plasmodium falciparum AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 197-197. | Citations: 1 (Web of Science Lite)

Tran CT, Dolecek C, Ochiai RLR, Campbell JI, Yang Y, Nguyen HMV, Bhutta ZA, Bhattacharya SK, Vu TD, Agtini M et al. 2005. Investigating the molecular mechanisms of nalidixic acid resistance and reduced susceptibility to fluoroquinolones in Salmonella typhi AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 191-191.

Wills B, Dung NM, Loan HT, Tam DT, Thu TT, Minh LT, Diet TV, Hao NT, Chau NV, Stepniewska K et al. 2005. Fluid resuscitation for dengue shock syndrome - The evidence from formal randomised and blinded intervention trials in Vietnam AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 361-361.

Ashley EA, White NJ. 2005. Artemisinin-based combinations. Curr Opin Infect Dis, 18 (6), pp. 531-536. | Citations: 116 (Scopus) | Show Abstract | Read more

PURPOSE OF REVIEW: Artemisinin-based combination treatments have been the mainstay of treatment for falciparum malaria in Southeast Asia for more than 10 years and are now increasingly recommended as first-line treatment throughout the rest of the world. RECENT FINDINGS: A large multicentre randomised trial conducted in East Asia has shown a 35% reduction in mortality from severe malaria following treatment with parenteral artesunate compared with quinine. There is increasing evidence that artemisinin-based combination treatments are safe and rapidly effective. Artemether-lumefantrine (six doses) has been shown to be very effective in large trials reported from Uganda and Tanzania. A once daily three-dose treatment of dihydroartemisinin piperaquine, a newer fixed combination, was a highly efficacious and well tolerated treatment for multi-drug resistant falciparum malaria in Southeast Asia. SUMMARY: Early diagnosis and treatment of uncomplicated malaria with effective drugs remains a priority as part of a comprehensive malaria control strategy. Artemisinin-based combination treatments have consistently been shown to be highly effective and safe. The challenge is to make them accessible in tropical countries.

Amin AA, Snow RW, Kokwaro GO. 2005. The quality of sulphadoxine-pyrimethamine and amodiaquine products in the Kenyan retail sector. J Clin Pharm Ther, 30 (6), pp. 559-565. | Citations: 40 (Scopus) | Show Abstract | Read more

BACKGROUND AND OBJECTIVE: Malaria is a disease of major public health importance in Kenya killing 26,000 children under 5 years of age annually. This paper seeks to assess the quality of sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) products available over-the-counter to communities in Kenya as most malaria fevers are self-medicated using drugs from the informal retail sector. METHODS: A retail audit of 880 retail outlets was carried in 2002 in four districts in Kenya, in which antimalarial drug stocks and their primary wholesale sources were noted. In addition, the expiry dates on audited products and the basic storage conditions were recorded on a proforma. The most commonly stocked SP and AQ products were then sampled from the top 10 wholesalers in each district and samples subjected to standard United States Pharmacopoeia (USP) tests of content and dissolution. RESULTS AND DISCUSSION: SP and AQ were the most frequently stocked antimalarial drugs, accounting for approximately 75% of all the antimalarial drugs stocked in the four districts. Of 116 SP and AQ samples analysed, 47 (40.5%) did not meet the USP specifications for content and/or dissolution. Overall, approximately 45.3% of SP and 33.0% of AQ samples were found to be sub-standard. Of the sub-standard SP products, 55.2% were suspensions while 61.1% of the substandard AQ products were tablets. Most SP failures were because of the pyrimethamine component. CONCLUSION: There is a need to strengthen post-marketing surveillance systems to protect patients from being treated with sub-standard and counterfeit antimalarial drugs in Kenya.

Newton PN, Phongmany S, Rolain JM, Phetsouvanh R, Blacksell S, Soukkhaserm V, Rasachack B, Phiasakha K, Soukkhaserm S, Frichithavong K et al. 2005. Rickettsial infections are common causes of fever amongst adults in the Lao PDR AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 223-223.

Olliaro PL, Guerin PJ, Gerstl S, Haaskjold AA, Rottingen J-A, Sundar S. 2005. Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980-2004. Lancet Infect Dis, 5 (12), pp. 763-774. | Citations: 154 (Scopus) | Show Abstract | Read more

The state of Bihar in India carries the largest share of the world's burden of antimony-resistant visceral leishmaniasis. We analysed clinical studies done in Bihar with different treatments between 1980 and 2004. Overall, 53 studies were included (all but one published), of which 15 were comparative (randomised, quasi-randomised, or non-randomised), 23 dose-finding, and 15 non-comparative. Data from comparative studies were pooled when appropriate for meta-analysis. Overall, these studies enrolled 7263 patients in 123 treatment arms. Adequacy of methods used to do the studies and report on them varied. Unresponsiveness to antimony has developed steadily in the past to such an extent that antimony must now be replaced, despite attempts to stop its progression by increasing dose and duration of therapy. The classic second-line treatments are unsuited: pentamidine is toxic and its efficacy has also declined, and amphotericin B deoxycholate is effective but requires hospitalisation for long periods and toxicity is common. Liposomal amphotericin B is very effective and safe but currently unaffordable because of its high price. Miltefosine-the first oral drug for visceral leishmaniasis-is now registered and marketed in India and is effective, but should be used under supervision to prevent misuse. Paromomycin (or aminosidine) is effective and safe, and although not yet available, a regulatory submission is due soon. To preserve the limited armamentarium of drugs to treat visceral leishmaniasis, drugs should not be deployed unprotected; combinations can make drugs last longer, improve treatment, and reduce costs to households and health systems. India, Bangladesh, and Nepal agreed recently to undertake measures towards the elimination of visceral leishmaniasis. The lessons learnt in Bihar could help inform policy decisions both regionally and elsewhere.

Wertheim HFL, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, Nouwen JL. 2005. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis, 5 (12), pp. 751-762. | Citations: 1015 (Scopus) | Show Abstract | Read more

Staphylococcus aureus is a frequent cause of infections in both the community and hospital. Worldwide, the increasing resistance of this pathogen to various antibiotics complicates treatment of S aureus infections. Effective measures to prevent S aureus infections are therefore urgently needed. It has been shown that nasal carriers of S aureus have an increased risk of acquiring an infection with this pathogen. The nose is the main ecological niche where S aureus resides in human beings, but the determinants of the carrier state are incompletely understood. Eradication of S aureus from nasal carriers prevents infection in specific patient categories-eg, haemodialysis and general surgery patients. However, recent randomised clinical trials in orthopaedic and non-surgical patients failed to show the efficacy of eliminating S aureus from the nose to prevent subsequent infection. Thus we must elucidate the mechanisms behind S aureus nasal carriage and infection to be able to develop new preventive strategies. We present an overview of the current knowledge of the determinants (both human and bacterial) and risks of S aureus nasal carriage. Studies on the population dynamics of S aureus are also summarised.

Mekonnen Y, Sanders E, Messele T, Wolday D, Dorigo-Zestma W, Schaap A, Mekonnen W, Meless H, Mihret W, Fontanet A et al. 2005. Prevalence and incidence of, and risk factors for, HIV-1 infection among factory workers in Ethiopia, 1997-2001. J Health Popul Nutr, 23 (4), pp. 358-368. | Citations: 12 (Web of Science Lite) | Show Abstract

The study was conducted to determine the prevalence, incidence, and risk factors for HIV infection among factory workers at two sites in Ethiopia. During February 1997-December 2001, a structured questionnaire was used for obtaining information on sociodemographics, sexual behaviour, and reported sexually transmitted infections (STIs) from a cohort of 1679 individuals. Serum samples were screened for antibodies against HIV, Treponema pallidum haemaglutination (TPHA), and herpes simplex virus type 2 (HSV-2). The overall baseline prevalence of HIV was 9.4%-8.5% among males and 12.4% among females. For both the sexes, the factors independently associated with an increased risk of HIV infection were widowhood and having had antibodies against TPHA and HSV-2. The risk factors specific for males were being orthodox Christian, having had a higher lifetime number of sexual partners, and genital discharge in the past five years. The risk factors for females, included low income, one or more rape(s) over lifetime, and casual sex in the last year. The overall incidence of HIV infection was 0.4 per 100 person-years. The highest rate of incidence was observed among young women aged less than 30 years (1 per 100 person-years). The study confirmed that high-risk sexual behaviour and STIs play major roles in the spread of HIV infection in the Ethiopians of both the sexes, but the factors, such as rape and low economic status, make women more vulnerable than men.

Mackinnon MJ, Mwangi TW, Snow RW, Marsh K, Williams TN. 2005. Heritability of malaria in Africa. PLoS Med, 2 (12), pp. e340. | Citations: 131 (Scopus) | Show Abstract | Read more

BACKGROUND: While many individual genes have been identified that confer protection against malaria, the overall impact of host genetics on malarial risk remains unknown. METHODS AND FINDINGS: We have used pedigree-based genetic variance component analysis to determine the relative contributions of genetic and other factors to the variability in incidence of malaria and other infectious diseases in two cohorts of children living on the coast of Kenya. In the first, we monitored the incidence of mild clinical malaria and other febrile diseases through active surveillance of 640 children 10 y old or younger, living in 77 different households for an average of 2.7 y. In the second, we recorded hospital admissions with malaria and other infectious diseases in a birth cohort of 2,914 children for an average of 4.1 y. Mean annual incidence rates for mild and hospital-admitted malaria were 1.6 and 0.054 episodes per person per year, respectively. Twenty-four percent and 25% of the total variation in these outcomes was explained by additively acting host genes, and household explained a further 29% and 14%, respectively. The haemoglobin S gene explained only 2% of the total variation. For nonmalarial infections, additive genetics explained 39% and 13% of the variability in fevers and hospital-admitted infections, while household explained a further 9% and 30%, respectively. CONCLUSION: Genetic and unidentified household factors each accounted for around one quarter of the total variability in malaria incidence in our study population. The genetic effect was well beyond that explained by the anticipated effects of the haemoglobinopathies alone, suggesting the existence of many protective genes, each individually resulting in small population effects. While studying these genes may well provide insights into pathogenesis and resistance in human malaria, identifying and tackling the household effects must be the more efficient route to reducing the burden of disease in malaria-endemic areas.

Anjum MF, Marooney C, Fookes M, Baker S, Dougan G, Ivens A, Woodward MJ. 2005. Identification of core and variable components of the Salmonella enterica subspecies I genome by microarray. Infect Immun, 73 (12), pp. 7894-7905. | Citations: 40 (Web of Science Lite) | Show Abstract | Read more

We have performed microarray hybridization studies on 40 clinical isolates from 12 common serovars within Salmonella enterica subspecies I to identify the conserved chromosomal gene pool. We were able to separate the core invariant portion of the genome by a novel mathematical approach using a decision tree based on genes ranked by increasing variance. All genes within the core component were confirmed using available sequence and microarray information for S. enterica subspecies I strains. The majority of genes within the core component had conserved homologues in Escherichia coli K-12 strain MG1655. However, many genes present in the conserved set which were absent or highly divergent in K-12 had close homologues in pathogenic bacteria such as Shigella flexneri and Pseudomonas aeruginosa. Genes within previously established virulence determinants such as SPI1 to SPI5 were conserved. In addition several genes within SPI6, all of SPI9, and three fimbrial operons (fim, bcf, and stb) were conserved within all S. enterica strains included in this study. Although many phage and insertion sequence elements were missing from the core component, approximately half the pseudogenes present in S. enterica serovar Typhi were conserved. Furthermore, approximately half the genes conserved in the core set encoded hypothetical proteins. Separation of the core and variant gene sets within S.enterica subspecies I has offered fundamental biological insight into the genetic basis of phenotypic similarity and diversity across S. enterica subspecies I and shown how the core genome of these pathogens differs from the closely related E. coli K-12 laboratory strain.

Blacksell SD, Khounsy S, Boyle DB, Gleeson LJ, Westbury HA, Mackenzie JS. 2005. Genetic typing of classical swine fever viruses from Lao PDR by analysis of the 5' non-coding region. Virus Genes, 31 (3), pp. 349-355. | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

The 5' non-coding region (5'-NCR) of 27 classical swine fever virus (CSFV) isolates from Lao People's Democratic Republic (Lao PDR) during 1997 and 1999 were amplified by RT-PCR. A 150-bp region of the 5'-NCR amplicons was analysed and compared with reference CSFV of European and Asian origin and a phylogenetic dendrogram constructed. Following analysis, all viruses were determined to belong to genogroup 2. Viruses from Lao PDR grouped on a geographical basis with the majority of northern/central isolates falling into subgroup 2.1 and southern/central isolates falling into subgroup 2.2. These results concur with previous studies of CSF viruses from Lao PDR, although this study recognized the first occurrence of subgroup 2.1 in southern Lao PDR.

Heinrichs V, Mundorff E, Lohre JA, West LL, Kuznetsova MA, Howard TA, Kortok MM, Marsh K, Makobongo MO, Liu X et al. 2005. Improvement of Plasmodium Falciparum erythrocyte membrane protein-1 (PfEMP-1) vaccine antigens using directed molecular evolution AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 339-339.

Price RN, Ratcliff A, Siswantoro H, Kanangalem E, Rumaseuw R, Ebsworth EP, Anstey N, Tjitra E. 2005. Alternative treatment options for chloroquine resistant Plasmodium vivax in Papua, Indonesia AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (6), pp. 44-44.

Bhattacharya AK, Basnyat B. 2005. Decentralisation and community forestry programmes in Nepal: issues and challenges International Forestry Review, 7 (2), pp. 147-155. | Citations: 7 (Scopus) | Show Abstract | Read more

This paper critically examines the application of a decentralisation principle in the community forestry (CF) programme of Nepal and discusses the implications of decentralisation efforts. Decentralisation applied in the forestry sector is devolution, which involves the transfer of functions or decision-making authority. The Local Self-Governance Act (LSGA) 1999 provides the framework for decentralised governance in Nepal. While assessing the LSGA 1999 and Forest Act 1993, it emerges that in many instances, forest legislation bypasses the local government. There exist conflicts and contradictions between the FA 1993 and LSGA 1999 which adds further confusion in the community forestry programme. Local government (LG) has always claimed any natural resources lying within its jurisdiction and initiated claiming ownership of the forest situated in their jurisdiction as per LSGA 1999. But local communities or community forestry user groups (CFUGs) reject any move of the government leading towards handing over of the forests to the LGs. Nevertheless they want an active role of the LGs in the community forestry programme, mainly in user group identification. Sustainable management of the forests is unlikely without the constructive support, cooperation and active role of the LGs. Thus, role clarification between different actors and stakeholders of CFs, especially LGs, user groups and District Forest Officers with regard to CF is essential to put decentralisation into practice.

Gonçalves G, Machado E, Gouveia E, Santos MA, Castro L, Aguas R, Gomes G. 2005. Resurgence of pertussis in northern Portugal: two severe cases in very young children. Euro Surveill, 10 (6), pp. E050623.3. | Citations: 2 (Scopus)

Kramer GWPM, Wanders SL, Noordijk EM, Vonk EJA, van Houwelingen HC, van den Hout WB, Geskus RB, Scholten M, Leer J-WH. 2005. Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol, 23 (13), pp. 2962-2970. | Citations: 74 (Scopus) | Show Abstract | Read more

PURPOSE: A national multicenter randomized study compared the efficacy of 2 x 8 Gy versus our standard 10 x 3 Gy in patients with inoperable stage IIIA/B (with an Eastern Cooperative Oncology Group score of 3 to 4 and/or substantial weight loss) and stage IV non-small-cell lung cancer. PATIENTS AND METHODS: Between January 1999 and June 2002, 297 patients were eligible and randomized to receive either 10 x 3 Gy or 2 x 8 Gy by external-beam irradiation. The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist. Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment. The time course of symptom scores were also evaluated, and other secondary end points were toxicity and survival. RESULTS: Both treatment arms were equally effective, as the average total symptom score over the initial 39 weeks did not differ. However, the pattern in time of these scores differed significantly (P < .001). Palliation in the 10 x 3-Gy arm was more prolonged (until week 22) with less worsening symptoms than in 2 x 8-Gy. Survival in the 10 x 3-Gy arm was significantly (P = .03) better than in the 2 x 8-Gy arm with 1-year survival of 19.6% (95%CI, 14.1% to 27.3%) v 10.9% (95%CI, 6.9% to 17.3%). CONCLUSION: The 10 x 3-Gy radiotherapy schedule is preferred over the 2 x 8-Gy schedule for palliative treatment, as it improves survival and results in a longer duration of the palliative response.

Warrell DA. 2005. Treatment of bites by adders and exotic venomous snakes. BMJ, 331 (7527), pp. 1244-1247. | Citations: 88 (Scopus) | Read more

Smith DL, Dushoff J, Snow RW, Hay SI. 2005. The entomological inoculation rate and Plasmodium falciparum infection in African children. Nature, 438 (7067), pp. 492-495. | Citations: 206 (Scopus) | Show Abstract | Read more

Malaria is an important cause of global morbidity and mortality. The fact that some people are bitten more often than others has a large effect on the relationship between risk factors and prevalence of vector-borne diseases. Here we develop a mathematical framework that allows us to estimate the heterogeneity of infection rates from the relationship between rates of infectious bites and community prevalence. We apply this framework to a large, published data set that combines malaria measurements from more than 90 communities. We find strong evidence that heterogeneous biting or heterogeneous susceptibility to infection are important and pervasive factors determining the prevalence of infection: 20% of people receive 80% of all infections. We also find that individual infections last about six months on average, per infectious bite, and children who clear infections are not immune to new infections. The results have important implications for public health interventions: the success of malaria control will depend heavily on whether efforts are targeted at those who are most at risk of infection.

Hogness CG. 2005. Severe malnutrition assessment in children in rural Kenya. JAMA, 294 (20), pp. 2577. | Citations: 5 (Scopus) | Read more

Basnyat B, Maskey AP, Zimmerman MD, Murdoch DR. 2005. Enteric (typhoid) fever in travelers. Clin Infect Dis, 41 (10), pp. 1467-1472. | Citations: 63 (Scopus) | Show Abstract | Read more

The incidence of enteric (typhoid) fever in travelers is estimated to be approximately 3-30 cases per 100,000 travelers to developing countries. Recently, it is become clear that travelers who are visiting friends and relatives, especially travelers to the Indian subcontinent, seem to be the most vulnerable to enteric fever and require special attention for prevention. Recent concerns are the increasing incidence of paratyphoid fever in Asia, which is not covered by available typhoid vaccines, and the emergence of infections caused by antibiotic-resistant strains (including strains resistant to fluoroquinolones). Typhoid vaccination is recommended for most travelers to moderate- to high-risk countries. Because of the nonspecific clinical presentation of enteric fever, a high index of suspicion is important in febrile travelers who have traveled to areas of endemicity.

Basnyat B. 2005. Typhoid and paratyphoid fever. Lancet, 366 (9497), pp. 1603. | Citations: 12 (Scopus) | Read more

Hasan R, Cooke FJ, Nair S, Harish BN, Wain J. 2005. Typhoid and paratyphoid fever. Lancet, 366 (9497), pp. 1603-1604. | Citations: 3 (Scopus) | Read more

Bull PC, Berriman M, Kyes S, Quail MA, Hall N, Kortok MM, Marsh K, Newbold CI. 2005. Plasmodium falciparum variant surface antigen expression patterns during malaria. PLoS Pathog, 1 (3), pp. e26. | Citations: 111 (Web of Science Lite) | Show Abstract | Read more

The variant surface antigens expressed on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria and are encoded, at least in part, by a family of var genes, about 60 of which are present within every parasite genome. Here we use semi-conserved regions within short var gene sequence "tags" to make direct comparisons of var gene expression in 12 clinical parasite isolates from Kenyan children. A total of 1,746 var clones were sequenced from genomic and cDNA and assigned to one of six sequence groups using specific sequence features. The results show the following. (1) The relative numbers of genomic clones falling in each of the sequence groups was similar between parasite isolates and corresponded well with the numbers of genes found in the genome of a single, fully sequenced parasite isolate. In contrast, the relative numbers of cDNA clones falling in each group varied considerably between isolates. (2) Expression of sequences belonging to a relatively conserved group was negatively associated with the repertoire of variant surface antigen antibodies carried by the infected child at the time of disease, whereas expression of sequences belonging to another group was associated with the parasite "rosetting" phenotype, a well established virulence determinant. Our results suggest that information on the state of the host-parasite relationship in vivo can be provided by measurements of the differential expression of different var groups, and need only be defined by short stretches of sequence data.

Keating SM, Bejon P, Berthoud T, Vuola JM, Todryk S, Webster DP, Dunachie SJ, Moorthy VS, McConkey SJ, Gilbert SC, Hill AVS. 2005. Durable human memory T cells quantifiable by cultured enzyme-linked immunospot assays are induced by heterologous prime boost immunization and correlate with protection against malaria. J Immunol, 175 (9), pp. 5675-5680. | Citations: 102 (Web of Science Lite) | Show Abstract | Read more

Immunological memory is a required component of protective antimalarial responses raised by T cell-inducing vaccines. The magnitude of ex vivo IFN-gamma T cell responses is widely used to identify immunogenic vaccines although this response usually wanes and may disappear within weeks. However, protection in the field is likely to depend on durable central memory T cells that are not detected by this assay. To identify longer-lived memory T cells, PBMC from malaria-naive vaccinated volunteers who had received prime boost vaccinations with a combination of DNA and/or viral vectors encoding the multiepitope string-thrombospondin-related adhesion protein Ag were cultured in vitro with Ag for 10 days before the ELISPOT assay. Ex vivo T cell responses peaked at 7 days after the final immunization and declined substantially over 6 mo, but responses identified after T cell culture increased over the 6-mo period after the final immunization. Moreover, individual cultured ELISPOT responses at the day of challenge time point correlated significantly with degree of protection against malaria sporozoite challenge, whereas ex vivo responses did not, despite a correlation between the peak ex vivo response and magnitude of memory responses 6 mo later. This cultured assay identifies long-lasting protective T cell responses and therefore offers an attractive option for assessments of vaccine immunogenicity.

Williams TN, Mwangi TW, Wambua S, Peto TEA, Weatherall DJ, Gupta S, Recker M, Penman BS, Uyoga S, Macharia A et al. 2005. Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait. Nat Genet, 37 (11), pp. 1253-1257. | Citations: 156 (Scopus) | Show Abstract | Read more

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and alpha(+)-thalassemia, a condition characterized by reduced production of the normal alpha-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa.

Barnes KI, Durrheim DN, Little F, Jackson A, Mehta U, Allen E, Dlamini SS, Tsoka J, Bredenkamp B, Mthembu DJ et al. 2005. Effect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa. PLoS Med, 2 (11), pp. e330. | Citations: 191 (Scopus) | Show Abstract | Read more

BACKGROUND: Between 1995 and 2000, KwaZulu-Natal province, South Africa, experienced a marked increase in Plasmodium falciparum malaria, fuelled by pyrethroid and sulfadoxine-pyrimethamine resistance. In response, vector control was strengthened and artemether-lumefantrine (AL) was deployed in the first Ministry of Health artemisinin-based combination treatment policy in Africa. In South Africa, effective vector and parasite control had historically ensured low-intensity malaria transmission. Malaria is diagnosed definitively and treatment is provided free of charge in reasonably accessible public-sector health-care facilities. METHODS AND FINDINGS: We reviewed four years of malaria morbidity and mortality data at four sentinel health-care facilities within KwaZulu-Natal's malaria-endemic area. In the year following improved vector control and implementation of AL treatment, malaria-related admissions and deaths both declined by 89%, and outpatient visits decreased by 85% at the sentinel facilities. By 2003, malaria-related outpatient cases and admissions had fallen by 99%, and malaria-related deaths had decreased by 97%. There was a concomitant marked and sustained decline in notified malaria throughout the province. No serious adverse events were associated causally with AL treatment in an active sentinel pharmacovigilance survey. In a prospective study with 42 d follow up, AL cured 97/98 (99%) and prevented gametocyte developing in all patients. Consistent with the findings of focus group discussions, a household survey found self-reported adherence to the six-dose AL regimen was 96%. CONCLUSION: Together with concurrent strengthening of vector control measures, the antimalarial treatment policy change to AL in KwaZulu-Natal contributed to a marked and sustained decrease in malaria cases, admissions, and deaths, by greatly improving clinical and parasitological cure rates and reducing gametocyte carriage.

Tran HH, Bjune G, Nguyen BM, Rottingen JA, Grais RF, Guerin PJ. 2005. Risk factors associated with typhoid fever in Son La province, northern Vietnam. Trans R Soc Trop Med Hyg, 99 (11), pp. 819-826. | Citations: 23 (Scopus) | Show Abstract | Read more

Between July and December 2002, we undertook a hospital-based case-control study to identify risk factors associated with typhoid fever in Son La province, northern Vietnam. Among 617 suspected cases, 90 cases of typhoid fever were confirmed by blood or stool culture. One hundred and eighty controls (neighbours of typhoid cases matched for gender and age) were chosen. Participants were interviewed at home using a standardized questionnaire. Seventy-five per cent of cases were aged 10-44 years. No cases in patients aged less than 5 years were recorded in this study. In a conditional logistic regression analysis recent contact with a typhoid patient (OR = 3.3, 95% CI 1.7-6.2, P < 0.001), no education (OR = 2.0, 95% CI 1.0-3.7, P = 0.03) and drinking untreated water (OR = 3.9, 95% CI 2.0-7.5, P < 0.001) were independently associated with typhoid fever. Improving quality of drinking water must be a priority and health education strategies targeted at individuals with no schooling, and contacts of patients, would be expected to decrease the burden of typhoid fever.

Prommano O, Chaisri U, Turner GDH, Wilairatana P, Ferguson DJP, Viriyavejakul P, White NJ, Pongponratn E. 2005. A quantitative ultrastructural study of the liver and the spleen in fatal falciparum malaria. Southeast Asian J Trop Med Public Health, 36 (6), pp. 1359-1370. | Citations: 28 (Scopus) | Show Abstract

We performed a retrospective study of 25 patients who died of severe falciparum malaria in Thailand and Vietnam using electron microscopy. The aims of the study were: to determine if there was any significant association between parasitized red blood cells (PRBC) sequestered in liver and spleen and particular pre-mortem clinical complications, and to compare the degree of parasite load between the liver and spleen within the same patients. PRBC sequestrations in each organ were compared with the pre-mortem parasitemia, to calculate the sequestration index (S.I.). The S.I. showed that the degree of PRBC sequestration in the spleen was higher than the liver (S.I. median = 3.13, 0.87, respectively) (p < 0.05). The results of quantitative ultrastructural study showed a significantly high parasite load in the liver of patients with jaundice, hepatomegaly and liver enzyme elevation (p < 0.05). We found a significant correlation between PRBC sequestration in the liver and a high serum bilirubin level, a high aspartate aminotransferase (AST) level and an increase in the size of the liver (Spearman's correlation coefficient = 0.688, 0.572, 0.736, respectively). Furthermore, a higher parasite load was found in the liver of patients with acute renal failure (ARF) compared to patients without ARF (p < 0.05). These findings suggest that PRBC sequestration in the liver is quantitatively associated with pre-mortem hepatic dysfunction and renal impairment. There was no significant difference between splenomegaly and PRBC sequestration. The size of a palpable spleen was not correlated with parasite load in the spleen. When ultrastructural features were compared between the two reticuloendothelial organs, we found that the spleen had more PRBC and phagocytes than the liver. The spleen of non-cerebral malaria (NCM) patients had more phagocytes than cerebral malaria (CM) patients. This observation reveals that the spleen plays a major role in malaria parasite clearance, and is associated with host defence mechanisms against malaria.

Gordon AL, English M, Tumaini Dzombo J, Karisa M, Newton CRJC. 2005. Neurological and developmental outcome of neonatal jaundice and sepsis in rural Kenya. Trop Med Int Health, 10 (11), pp. 1114-1120. | Citations: 33 (Scopus) | Show Abstract | Read more

Neonatal jaundice (NJ) and sepsis are common causes of neonatal mortality in sub-Saharan Africa, but little is known about the long-term morbidity in this setting. This study aimed to describe the neurological and developmental sequelae of severe neonatal hyperbilirubinaemia and neonatal sepsis (NS) in a district hospital in rural Kenya. Twenty-three term infants with NJ [total serum bilirubin (TSB) >300 mumol/l] and 24 infants with a history of NS were identified from hospital records. These children were compared to 40 children from the community (CC) without neonatal problems. At ages 18-32 months, the children's neurological, motor and developmental status were assessed, and blood groups of the NJ and NS subjects and their mothers were determined. Ten (43%) of the NJ subjects were unable to sit and/or stand independently. The NJ subjects had significantly more neurological, motor and developmental difficulties and caused greater maternal concern than the CCs. Five (21%) of the NJ subjects had possible blood group incompatibility. The NS subjects had significantly more motor and eye-hand difficulties and maternal concerns expressed than the CCs. Severe NJ in term infants (of mainly non-haemolytic origin) was associated with a high prevalence of neurological and developmental sequelae at ages 18-32 months. The NS is also associated with neuro-developmental sequelae, but the pattern is different to those seen in NJ. Since NS is common in resource poor countries, this may be an important cause of neuro-developmental impairment in children living in this setting.

Pitman RJ, Cooper BS, Trotter CL, Gay NJ, Edmunds WJ. 2005. Entry screening for severe acute respiratory syndrome (SARS) or influenza: policy evaluation. BMJ, 331 (7527), pp. 1242-1243. | Citations: 47 (Scopus) | Read more

Ochiai RL, Wang X, von Seidlein L, Yang J, Bhutta ZA, Bhattacharya SK, Agtini M, Deen JL, Wain J, Kim DR et al. 2005. Salmonella paratyphi A rates, Asia. Emerg Infect Dis, 11 (11), pp. 1764-1766. | Citations: 126 (Scopus) | Show Abstract | Read more

Little is known about the causes of enteric fever in Asia. Most cases are believed to be caused by Salmonella enterica serovar Typhi and the remainder by S. Paratyphi A. We compared their incidences by using standardized methods from population-based studies in China, Indonesia, India, and Pakistan.

Basnyat B. 2005. High altitude cerebral and pulmonary edema. Travel Med Infect Dis, 3 (4), pp. 199-211. | Citations: 15 (Scopus) | Show Abstract | Read more

Altitude illness, which comprises of acute mountain sickness (AMS) and its life threatening complications, high altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE) is now a well recognized disease process. AMS and HACE are generally thought to be a continuum. Some historical facts about the illness, its new intriguing pathophysiological processes, and clinical picture are discussed here. Although the review deals with both HACE and HAPE, HAPE is covered in greater detail due to the recent important findings related to its pathophysiology and prevention mechanisms. Relevant clinical correlation, the differential diagnosis of altitude sickness for a more sophisticated approach to the disease phenomenon, the possibility of dehydration being a risk factor for altitude sickness, the hypothetical role of angiogenesis in cerebral edema, and the emphasis on some vulnerable groups at high altitude are some of the other newer material discussed in this review. A clear-cut treatment and basic prevention guidelines are included in two panels, and finally the limited literature on the role of genetic factors on susceptibility to altitude sickness is briefly discussed.

Basnyat B. 2005. A different kind of medicine. Natl Med J India, 18 (6), pp. 321.

van Doorn HR, van Vugt M, Wetsteyn JCFM, van Gool T. 2005. [Infestation with the tapeworm Diphyllobothrium latum after eating raw fish]. Ned Tijdschr Geneeskd, 149 (44), pp. 2470-2472. | Citations: 4 (Scopus) | Show Abstract

A 31-year-old man with no relevant medical history encountered a white, ribbon-shaped object, 15 cm long and approximately 1 cm wide, in his faeces. It turned out to be Diphyllobothrium latum, a tapeworm that has fish as the intermediate host. The patient had eaten raw fish and shellfish during a holiday in Brazil 5 months before. He recovered after a single dose of praziquantel.

Agtini MD, Soeharno R, Lesmana M, Punjabi NH, Simanjuntak C, Wangsasaputra F, Nurdin D, Pulungsih SP, Rofiq A, Santoso H et al. 2005. The burden of diarrhoea, shigellosis, and cholera in North Jakarta, Indonesia: findings from 24 months surveillance. BMC Infect Dis, 5 (1), pp. 89. | Citations: 66 (Scopus) | Show Abstract | Read more

BACKGROUND: In preparation of vaccines trials to estimate protection against shigellosis and cholera we conducted a two-year community-based surveillance study in an impoverished area of North Jakarta which provided updated information on the disease burden in the area. METHODS: We conducted a two-year community-based surveillance study from August 2001 to July 2003 in an impoverished area of North Jakarta to assess the burden of diarrhoea, shigellosis, and cholera. At participating health care providers, a case report form was completed and stool sample collected from cases presenting with diarrhoea. RESULTS: Infants had the highest incidences of diarrhoea (759/1,000/year) and cholera (4/1,000/year). Diarrhea incidence was significantly higher in boys under 5 years (387/1,000/year) than girls under 5 years (309/1,000/year; p < 0.001). Children aged 1 to 2 years had the highest incidence of shigellosis (32/1,000/year). Shigella flexneri was the most common Shigella species isolated and 73% to 95% of these isolates were resistant to ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol and tetracycline but remain susceptible to nalidixic acid, ciprofloxacin, and ceftriaxone. We found an overall incidence of cholera of 0.5/1,000/year. Cholera was most common in children, with the highest incidence at 4/1,000/year in those less than 1 year of age. Of the 154 V. cholerae O1 isolates, 89 (58%) were of the El Tor Ogawa serotype and 65 (42%) were El Tor Inaba. Thirty-four percent of patients with cholera were intravenously rehydrated and 22% required hospitalization. V. parahaemolyticus infections were detected sporadically but increased from July 2002 onwards. CONCLUSION: Diarrhoea causes a heavy public health burden in Jakarta particularly in young children. The impact of shigellosis is exacerbated by the threat of antimicrobial resistance, whereas that of cholera is aggravated by its severe manifestations.

Chierakul W, Anunnatsiri S, Short JM, Maharjan B, Mootsikapun P, Simpson AJH, Limmathurotsakul D, Cheng AC, Stepniewska K, Newton PN et al. 2005. Two randomized controlled trials of ceftazidime alone versus ceftazidime in combination with trimethoprim-sulfamethoxazole for the treatment of severe melioidosis. Clin Infect Dis, 41 (8), pp. 1105-1113. | Citations: 45 (Scopus) | Show Abstract | Read more

BACKGROUND: Two antibiotic regimens are used commonly in Thailand for the initial treatment of severe melioidosis: ceftazidime in combination with trimethoprim-sulfamethoxazole (TMP-SMX) and ceftazidime monotherapy. It is not known whether TMP-SMX provides an additional benefit. METHODS: Two prospective, randomized trials that compared these regimens for patients presenting with acute severe melioidosis were started independently at tertiary care hospitals in Ubon Ratchathani and Khon Kaen (in northeastern Thailand), and the results were analyzed together as a prospective, individual-patient data meta-analysis. The primary end point was in-hospital mortality rate. RESULTS: The in-hospital mortality rate among all enrolled patients (n=449) was not significantly different between those randomized to ceftazidime alone (25.1%; 56 of 223 subjects) and those randomized to ceftazidime with TMP-SMX (26.6%; 60 of 226 subjects; odds ratio [OR], 1.08; 95% confidence interval [CI], 0.7-1.7; stratified P=.73). Of the 241 patients with culture-confirmed melioidosis, 51 (21.2%) died. Of these 241 patients, 31 (12.9%) died > or =48 h after the time of study entry. Among patients with melioidosis, there was no difference in death rate between the 2 treatment groups for either all deaths (OR, 0.88; 95% CI, 0.48-1.6; stratified P=.70) or for deaths that occurred > or =48 h after hospital admission (OR, 0.88; 95% CI, 0.41-1.9; stratified P=.73). Conditional logistic regression analysis revealed that bacteremia, respiratory failure, and renal failure were independently associated with death and treatment failure. Drug regimens were not associated with death or treatment failure in this model. CONCLUSION: We conclude that the addition of TMP-SMX to ceftazidime therapy during initial treatment of severe melioidosis does not reduce the acute mortality rate.

Chierakul W, Winothai W, Wattanawaitunechai C, Wuthiekanun V, Rugtaengan T, Rattanalertnavee J, Jitpratoom P, Chaowagul W, Singhasivanon P, White NJ et al. 2005. Melioidosis in 6 tsunami survivors in southern Thailand. Clin Infect Dis, 41 (7), pp. 982-990. | Citations: 77 (Scopus) | Show Abstract | Read more

BACKGROUND: Six cases of melioidosis were identified in survivors of the 26 December 2004 tsunami who were admitted to Takuapa General Hospital in Phangnga, a region in southern Thailand where melioidosis is not endemic. All 6 cases were associated with aspiration, and 4 were also associated with laceration. METHODS: We compared the clinical, laboratory, and radiographic findings and the outcomes for these 6 patients with those for 22 patients with aspiration-related melioidosis acquired during 1987-2003 in a melioidosis-endemic region in northeast Thailand. Results of tests for detection of Burkholderia pseudomallei in soil specimens from Phangnga and from northeast Thailand were compared. RESULTS: The 6 patients (age range, 25-65 years) presented with signs and symptoms of pneumonia 3-38 days (median duration, 6.5 days) after the tsunami. Chest radiograph findings at the onset of pneumonia were abnormal in all cases; 1 patient developed a lung abscess. B. pseudomallei was grown in blood cultures in 3 cases and in cultures of respiratory secretions in 4 cases. Two patients required ventilation and inotropes; 1 patient died. Compared with tsunami survivors, patients with aspiration-related melioidosis in northeast Thailand had a shorter interval (median duration, 1 day) between aspiration and onset of pneumonia; were more likely to exhibit shock, respiratory failure, renal failure, and/or altered consciousness (P=.03); and had a higher in-hospital mortality (64% [14 of 22 patients]; P=.07). These differences may be related to the severity of the near-drowning episode, the inhalation of sea water versus fresh water, the size of bacterial inoculum, and the possible acquisition (among tsunami survivors) of B. pseudomallei via laceration. Only 3 (0.8%) of 360 soil samples from Phangnga were positive for B. pseudomallei, compared with 26 (20%) of 133 samples from northeast Thailand (P<.0001). CONCLUSIONS: Tsunami survivors are at increased risk of melioidosis if they are injured in an environment containing B. pseudomallei.

Peacock SJ, Chieng G, Cheng AC, Dance DAB, Amornchai P, Wongsuvan G, Teerawattanasook N, Chierakul W, Day NPJ, Wuthiekanun V. 2005. Comparison of Ashdown's medium, Burkholderia cepacia medium, and Burkholderia pseudomallei selective agar for clinical isolation of Burkholderia pseudomallei. J Clin Microbiol, 43 (10), pp. 5359-5361. | Citations: 37 (Scopus) | Show Abstract | Read more

Ashdown's medium, Burkholderia pseudomallei selective agar (BPSA), and a commercial Burkholderia cepacia medium were compared for their abilities to grow B. pseudomallei from 155 clinical specimens that proved positive for this organism. The sensitivity of each was equivalent; the selectivity of BPSA was lower than that of Ashdown's or B. cepacia medium.

T'Veld DH, Wuthiekanun V, Cheng AC, Chierakul W, Chaowagul W, Brouwer AE, White NJ, Day NPJ, Peacock SJ. 2005. Short report: The role and significance of sputum cultures in the diagnosis of melioidosis AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 73 (4), pp. 657-661. | Citations: 10 (Scopus) | Show Abstract

Pneumonia is a common manifestation of melioidosis, the disease caused by Burkholderia pseudomallei. In this study, we defined the prognostic significance of a positive sputum culture. A total of 712 patients presenting to Sappasithiprasong Hospital, Ubon Ratchathani, Thailand, with melioidosis between January 1992 and December 2002 had a sputum culture performed during admission, which was positive for B. pseudomallei in 444 patients (62%). The median duration of sputum positivity was 9 days (range, 1 to 49 days). Sputum cultures were negative in 32% of patients with radiologic changes suggestive of pulmonary involvement. Overall in-hospital mortality was 48%. A positive sputum culture was associated with mortality (adjusted OR 2.8, 95% CI: 1.9, 4.0; P < 0.001). This was independent of renal disease, a prior history of melioidosis, positive blood cultures, and other potential confounders. The presence of B. pseudomallei in the sputum of patients with melioidosis is associated with a poorer prognosis. Copyright © 2005 by The American Society of Tropical Medicine and Hygiene.

Chaowagul W, Chierakul W, Simpson AJ, Short JM, Stepniewska K, Maharjan B, Rajchanuvong A, Busarawong D, Limmathurotsakul D, Cheng AC et al. 2005. Open-label randomized trial of oral trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol compared with trimethoprim-sulfamethoxazole and doxycycline for maintenance therapy of melioidosis. Antimicrob Agents Chemother, 49 (10), pp. 4020-4025. | Citations: 57 (Scopus) | Show Abstract | Read more

Melioidosis (infection caused by Burkholderia pseudomallei) requires a prolonged course of oral antibiotics following initial intravenous therapy to reduce the risk of relapse after cessation of treatment. The current recommendation is a four-drug regimen (trimethoprim [TMP], sulfamethoxazole [SMX], doxycycline, and chloramphenicol) and a total treatment time of 12 to 20 weeks. Drug side effects are common; the aim of this study was to compare the efficacy and tolerance of the four-drug regimen with a three-drug regimen (TMP-SMX and doxycycline). An open-label, randomized trial was conducted in northeast Thailand. A total of 180 adult Thai patients were enrolled, of which 91 were allocated to the four-drug regimen and 89 to the three-drug regimen. The trial was terminated early due to poor drug tolerance, particularly of the four-drug regimen. The culture-confirmed relapse rates at 1 year were 6.6% and 5.6% for the four- and three-drug regimens, respectively (P = 0.79). The three-drug regimen was better tolerated than the four-drug regimen; 36% of patients receiving four drugs and 19% of patients receiving three drugs required a switch in therapy due to side effects (P = 0.01). The duration of oral therapy was significantly associated with relapse; after adjustment for confounders, patients receiving less than 12 weeks of oral therapy had a 5.7-fold increase of relapse or death. A combination of TMP-SMX and doxycycline is as effective as and better tolerated than the conventional four-drug regimen for the oral treatment phase of melioidosis.

Molyneux CS, Peshu N, Marsh K. 2005. Trust and informed consent: insights from community members on the Kenyan coast. Soc Sci Med, 61 (7), pp. 1463-1473. | Citations: 94 (Scopus) | Show Abstract | Read more

Trust is an important theme running through the literature on the ethics of biomedical research, but it is rarely given centre stage. In this paper, we present data gathered from a study aimed at exploring community views regarding the informed consent processes carried out by a large research centre on the Kenyan Coast. The findings point to the centrality of trust and elements of mistrust in general community views, in parents' (mis)understanding of studies they consent their children to be involved in, in refusals and concerns, and in community members' views about whether informed consent is a relevant and practical model to follow. Tentative ideas on how trust and a healthy mistrust might be balanced highlight the importance of strengthening communication surrounding basic health care as well as research, and of fostering 'an inner generated ethic of service'. The latter is particularly fundamental, but cannot be built and regulated through the laws, policies and guidelines that currently govern biomedical research practice.

Ochola LB, Marsh K, Lowe B, Gal S, Pluschke G, Smith T. 2005. Estimation of the sequestered parasite load in severe malaria patients using both host and parasite markers. Parasitology, 131 (Pt 4), pp. 449-458. | Citations: 21 (Web of Science Lite) | Show Abstract | Read more

The virulence of the malaria parasite Plasmodium falciparum is due, in part, to its ability to cytoadhere in deep vascular beds. Our inability to quantify the load of sequestered parasites hampers our understanding of the pathophysiological mechanisms involved in disease progression and complicates diagnosis. In this study we evaluate potential biochemical markers of sequestered load by comparing them with estimates of the sequestered load from a statistical model fitted to longitudinal patterns of peripheral parasite densities in a series of 22 patients with severe Plasmodium falciparum malaria. The markers comprised the host factors: haematocrit, circulating host DNA, sTNF-R75 and parasite derived products HRP2, pLDH, pigments and circulating parasite DNA. We investigated the suitability of these markers in determining sequestered loads in patients on quinine treatment. Observed peripheral parasitaemia, plasma levels of sTNF-R75 and circulating parasite DNA were most strongly correlated with estimates of sequestered loads on admission. However the dynamics of both sTNF-R75 and circulating parasite DNA during follow-up were very different from those of the estimated sequestered mass. These analyses suggest that none of the markers gave reliable estimates of the current sequestered load, though they may reflect the history of infection. Longitudinal analyses are needed that allow for the clearance rates of the marker molecules and for variations between hosts in the history of parasitaemia.

Imwong M, Pukrittayakamee S, Cheng Q, Moore C, Looareesuwan S, Snounou G, White NJ, Day NPJ. 2005. Limited polymorphism in the dihydropteroate synthetase gene (dhps) of Plasmodium vivax isolates from Thailand. Antimicrob Agents Chemother, 49 (10), pp. 4393-4395. | Citations: 44 (Scopus) | Show Abstract | Read more

The dhps sequences of 55 Plasmodium vivax isolates (39 from Thailand and 16 from elsewhere) revealed mutant Pvdhps at codons 383 and/or 553 (A --> G) in 33 isolates, all from Thailand. Mutations of Pvdhps and Pvdhfr were correlated. Multiple mutations were associated with high-grade sulfadoxine-pyrimethamine resistance.

Ndungu FM, Urban BC, Marsh K, Langhorne J. 2005. Regulation of immune response by Plasmodium-infected red blood cells. Parasite Immunol, 27 (10-11), pp. 373-384. | Citations: 25 (Scopus) | Show Abstract | Read more

During the asexual blood stage infection of the human malaria parasite, Plasmodium falciparum, parasite-derived proteins are inserted onto the surface of the host red blood cell membrane. These proteins are highly variable and were originally thought only to mediate antigenic variation, and sequestration of parasites from peripheral circulation, thus enabling immune evasion. Recent studies have revealed that PfEMP-1 and other molecules on the P. falciparum-infected red blood cell (PfRBC) activate and modulate the immune response. In this review, we discuss how PfRBCs interact with antigen-presenting cells (APCs) and other cells of the immune system, and how such interactions could modulate the host response to Plasmodium infections.

Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K, Chotivanich K, Newton PN, Pitisuttithum P, Smithyman AM, White NJ, Day NPJ. 2005. Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2 (vol 2, art. no. e204, 2005) PLOS MEDICINE, 2 (10), pp. 1047-1047. | Citations: 3 (Web of Science Lite) | Read more

Wertheim HFL, van Leeuwen WB, Snijders S, Vos MC, Voss A, Vandenbroucke-Grauls CMJE, Kluytmans JAJW, Verbrugh HA, van Belkum A. 2005. Associations between Staphylococcus aureus Genotype, Infection, and In-Hospital Mortality: A Nested Case-Control Study. J Infect Dis, 192 (7), pp. 1196-1200. | Citations: 39 (Scopus) | Show Abstract | Read more

We screened 14,008 adult nonsurgical patients for Staphylococcus aureus nasal carriage at hospital admission and assessed them for invasive S. aureus disease and in-hospital mortality. Multilocus sequence typing was performed on endogenous invasive strains and nasal strains of matched asymptomatic carriers to investigate whether virulent clones could be identified in nasal carriers. Clonal complex (CC) 45 was significantly underrepresented (odds ratio [OR], 0.16 [95% confidence interval {CI}, 0.04-0.59]) and CC30 was overrepresented (not statistically significant) among invasive strains (OR, 1.91 [95% CI, 0.91-4.0]). The distribution of CCs of invasive S. aureus strains in noncarriers did not differ from that in carriers. Those infected with S. aureus strains belonging to a CC had higher mortality than those infected with strains not belonging to a CC (P<.05), which indicates the coevolution of S. aureus virulence and spread in humans.

Scott JAG, Mlacha Z, Nyiro J, Njenga S, Lewa P, Obiero J, Otieno H, Sampson JS, Carlone GM. 2005. Diagnosis of invasive pneumococcal disease among children in Kenya with enzyme-linked immunosorbent assay for immunoglobulin G antibodies to pneumococcal surface adhesin A. Clin Diagn Lab Immunol, 12 (10), pp. 1195-1201. | Citations: 18 (Web of Science Lite) | Show Abstract | Read more

Diagnostic techniques for invasive pneumococcal disease (IPD) in children are insensitive and underestimate both the burden of disease and the cost-effectiveness of pneumococcal conjugate vaccination (PCV). Consequently, there is little demand for the highly effective PCV outside the United States and Europe. In Kenya, diagnosis of pneumococcal pneumonia in adults was achieved with a sensitivity of 0.70 and a specificity of 0.98 using enzyme-linked immunosorbent assays (ELISAs) of paired plasma samples for immunoglobulin G (IgG) to pneumococcal surface adhesin A (PsaA). We aimed to validate the same technique in children. We assayed paired blood samples from 98 children with IPD, 95 age-matched children with malaria/anemia, and 97 age-matched healthy controls by using an ELISA for anti-PsaA IgG. Sensitivity and specificity were determined in IPD patients and healthy controls. Specificity (0.97; 95% confidence interval [CI], 0.91 to 0.99) and sensitivity (0.42; 95% CI, 0.32 to 0.52) were optimized at a 2.7-fold rise in anti-PsaA antibody concentration. Sensitivity was improved to a maximum of 0.50 by restricting testing to children of <2 years old, by excluding IPD patients who were not sampled on the first day of presentation, and by incorporating high existing antibody concentrations in the analysis. Assay performance was independent of nasopharyngeal carriage of pneumococci at recruitment. This assay improves on existing diagnostic tools for IPD in children but would still leave over half of all cases undetected in epidemiological studies. Effective diagnosis of pneumococcal disease in children is urgently required but poorly served by existing technology.

Bruce MG, Sanders EJ, Leake JAD, Zaidel O, Bragg SL, Aye T, Shutt KA, Deseda CC, Rigau-Perez JG, Tappero JW et al. 2005. Leptospirosis among patients presenting with dengue-like illness in Puerto Rico. Acta Trop, 96 (1), pp. 36-46. | Citations: 40 (Web of Science Lite) | Show Abstract | Read more

Leptospirosis is difficult to distinguish from dengue fever without laboratory confirmation. Sporadic cases/clusters of leptospirosis occur in Puerto Rico, but surveillance is passive and laboratory confirmation is rare. We tested for leptospirosis using an IgM ELISA on sera testing negative for dengue virus IgM antibody and conducted a case-control study assessing risk factors for leptospirosis, comparing clinical/laboratory findings between leptospirosis (case-patients) and dengue patients (controls). Among 730 dengue-negative sera, 36 (5%) were positive for leptospirosis. We performed post mortem testing for leptospirosis on 12 available specimens from suspected dengue-related fatalities; 10 (83%) tested positive. Among these 10 fatal cases, pulmonary hemorrhage and renal failure were the most common causes of death. We enrolled 42 case-patients and 84 controls. Jaundice, elevated BUN, hyperbilirubinemia, anemia, and leukocytosis were associated with leptospirosis (p < .01 for all). Male sex, walking in puddles, rural habitation, and owning horses were independently associated with leptospirosis. Epidemiological, clinical, and laboratory criteria may help distinguish leptospirosis from dengue and identify patients who would benefit from early antibiotic treatment.

Huis in 't Veld D, Wuthiekanun V, Cheng AC, Chierakul W, Chaowagul W, Brouwer AE, White NJ, Day NPJ, Peacock SJ. 2005. The role and significance of sputum cultures in the diagnosis of melioidosis. Am J Trop Med Hyg, 73 (4), pp. 657-661. | Show Abstract

Pneumonia is a common manifestation of melioidosis, the disease caused by Burkholderia pseudomallei. In this study, we defined the prognostic significance of a positive sputum culture. A total of 712 patients presenting to Sappasithiprasong Hospital, Ubon Ratchathani, Thailand, with melioidosis between January 1992 and December 2002 had a sputum culture performed during admission, which was positive for B. pseudomallei in 444 patients (62%). The median duration of sputum positivity was 9 days (range, 1 to 49 days). Sputum cultures were negative in 32% of patients with radiologic changes suggestive of pulmonary involvement. Overall in-hospital mortality was 48%. A positive sputum culture was associated with mortality (adjusted OR 2.8, 95% CI: 1.9, 4.0; P < 0.001). This was independent of renal disease, a prior history of melioidosis, positive blood cultures, and other potential confounders. The presence of B. pseudomallei in the sputum of patients with melioidosis is associated with a poorer prognosis.

Zurovac D, Ndhlovu M, Rowe AK, Hamer DH, Thea DM, Snow RW. 2005. Treatment of paediatric malaria during a period of drug transition to artemether-lumefantrine in Zambia: cross sectional study. BMJ, 331 (7519), pp. 734. | Citations: 59 (Scopus) | Show Abstract | Read more

OBJECTIVE: To evaluate treatment practices for uncomplicated malaria after the policy change from chloroquine to sulfadoxine-pyrimethamine and to artemether-lumefantrine in Zambia. DESIGN: Cross sectional survey. SETTING: Outpatient departments of all government and mission facilities in four districts in Zambia. PARTICIPANTS: 944 children with uncomplicated malaria seen by 103 health workers at 94 health facilities. MAIN OUTCOME MEASURES: Antimalarial prescriptions in accordance with national guidelines and influence of factors on health workers' decision to prescribe artemether-lumefantrine. RESULTS: Artemether-lumefantrine, sulfadoxine-pyrimethamine, and chloroquine were available, respectively, at 48 (51%), 94 (100%), and 71 (76%) of the 94 facilities. Of 944 children with uncomplicated malaria, only one child (0.1%) received chloroquine. Among children weighing less than 10 kg, sulfadoxine-pyrimethamine was commonly prescribed in accordance with guidelines (439/550, 79.8%). Among the children weighing 10 kg or more, sulfadoxine-pyrimethamine was commonly prescribed (266/394, 68%), whereas recommended artemether-lumefantrine was prescribed for only 42/394 (11%) children. Among children weighing 10 kg or more seen at facilities where artemether-lumefantrine was available, the same pattern was observed: artemether-lumefantrine was prescribed for only 42/192 (22%) children and sulfadoxine-pyrimethamine remained the drug of choice (103/192, 54%). Programmatic activities such as in-service training and provision of job aids did not seem to influence the prescribing of artemether with lumefantrine. CONCLUSION: Although the use of chloroquine for uncomplicated malaria was successfully discontinued in Zambia, the change of drug policy towards artemether-lumefantrine does not necessarily translate into adequate use of this drug at the point of care.

Dance D. 2005. A glanders-like disease in Rangoon: Whitmore A. J Hyg 1913; 13: 1-34. Epidemiol Infect, 133 Suppl 1 (S1), pp. S9-S10. | Read more

Chompook P, Samosornsuk S, von Seidlein L, Jitsanguansuk S, Sirima N, Sudjai S, Mangjit P, Kim DR, Wheeler JG, Todd J et al. 2005. Estimating the burden of shigellosis in Thailand: 36-month population-based surveillance study. Bull World Health Organ, 83 (10), pp. 739-746. | Citations: 44 (Scopus) | Show Abstract

OBJECTIVE: To estimate incidence of shigellosis in the Kaengkhoi district, Saraburi Province, Thailand. METHODS: Population-based surveillance of shigellosis based in treatment centres. The detected rates of treated shigellosis were corrected for the number of cases missed due to the low sensitivity of microbiological culture methods and participants' use of health-care providers not participating in the study. FINDINGS: The overall uncorrected incidence of shigellosis was 0.6/1000 population per year (95% confidence interval (CI) = 0.5-0.8). The unadjusted incidence of treated shigellosis was highest among children less than 5 years old (4/1000 children per year; 95% CI = 3-6) and significantly lower among people aged > 5 years (0.3/1000 population per year; 95% CI = 0.2-0.5; P < 0.001). Adjusting for cases likely to be missed as a result of culture and surveillance methods increased estimates approximately five times. The majority of Shigella isolates (122/146; 84%) were S. sonnei; the rest were S. flexneri. Of the 22 S. flexneri isolates, the three most frequently encountered serotypes were 2a (36%), 1b (23%) and 3b (28%). A total of 90-95% of S. sonnei and S. flexneri isolates were resistant to tetracycline and co-trimoxazole. In contrast to S. sonnei isolates, more than 90% of the S. flexneri isolates were also resistant to ampicillin and chloramphenicol (P < 0.0001). CONCLUSION: Estimates of incidence of Shigella infection in the community are 10-fold to 100-fold greater than those found from routine government surveillance. The high prevalence of Shigella strains resistant to multiple antibiotics adds urgency to the development of a vaccine to protect against shigellosis in this region of Thailand.

Xiridou M, Kretzschmar M, Geskus R. 2005. Competition of pathogen strains leading to infection with variable infectivity and the effect of treatment. Math Biosci, 197 (2), pp. 153-172. | Citations: 3 (Scopus) | Show Abstract | Read more

A model for the spread of two strains of a pathogen leading to an infection with variable infectivity is considered. The course of infection is described by two stages with different infectivity levels. The model is extended to account for treatment by including a third stage with different infectivity and survival for those treated. The contribution of each stage to incidence and prevalence is investigated and the effect of infectivity and survival on the basic reproduction ratio is examined. Standard equilibrium analysis is performed for both models, revealing that the successful strain is the one with highest reproduction ratio. If therapy, however, is more effective against the strain that wins in the absence of treatment and its reproduction ratio is sufficiently reduced, it might be outcompeted by the other strain after treatment becomes widely available. In this case, early introduction of treatment can prevent a major outbreak.

van der Lugt JCT, Geskus RB, Rozing PM. 2005. Limited influence of prosthetic position on aseptic loosening of elbow replacements: 125 elbows followed for an average period of 5.6 years. Acta Orthop, 76 (5), pp. 654-661. | Citations: 10 (Scopus) | Show Abstract | Read more

BACKGROUND: Aseptic loosening of elbow replacements, seen in long-term follow-up, remains a problem. In this study, we attempted to determine the influence of cementing technique, prosthetic position, different component sizes, use of a bone plug, and intraoperative fractures on the development and progression of radiolucent lines and aseptic loosening. METHODS: We studied standard radiographs of 125 primary Souter-Strathclyde total elbow prostheses using the Wrightington method. Additionally, 104 preoperative radiographs were available for analysis. We used a Markow statistical model to detect relationships between all factors described above. RESULTS: After a mean follow-up time of 5.5 (2-19) years, 21 (17%) prostheses had loosened radiographically (10-year survival: 65%). When the humeral component was tilted more medially or more anteriorly, we found development of radiolucent lines at the medial condyle and at the posterior side of the humeral component. However, the progression of these lines was not influenced by these positions. No other prognostic factors for radiolucent lines or aseptic loosening were found. INTERPRETATION: Despite the small number of elbows studied, the weak influence of prosthetic position on aseptic loosening gives more ground for a multifactorial cause for aseptic loosening of the Souter-Strathclyde total elbow prosthesis.

Lindegårdh N, White NJ, Day NPJ. 2005. High throughput assay for the determination of piperaquine in plasma. J Pharm Biomed Anal, 39 (3-4), pp. 601-605. | Citations: 30 (Scopus) | Show Abstract | Read more

A high throughput assay for the determination of the antimalarial piperaquine in plasma has been developed and validated. The assay utilises 96-wellplate formats throughout the whole procedure, and easily enables a throughput of 192 samples a day using a single LC system. Buffer (pH 2.0; 0.05 M) containing internal standard was added to 0.25 mL plasma in a 96-wellplate (2 mL wells). The samples were extracted on a MPC solid phase extraction deep well 96-wellplate (3M Empore). Piperaquine and internal standard were analysed by liquid chromatography with UV detection on a Chromolith Performance (100 mm x 4.6 mm) column with a mobile phase containing acetonitrile-phosphate buffer (pH 2.5; 0.1 M) (8:92, v/v) at a flow rate of 3.0 mL/min. The within-day precisions for piperaquine were 3.3 and 2.3% at 40 and 1250 ng/mL, respectively. The between-day precisions for piperaquine were 5.8 and 1.3% at 40 and 1250 ng/mL, respectively. The total assay precisions using 29 replicates over 5 days were 6.7, 4.5 and 2.7% at 40, 200 and 1250 ng/mL, respectively. The lower limit of quantification (LLOQ) and the limit of detection (LOD) were 10 and 5 ng/mL, respectively using 0.25 mL plasma. Using 1 mL of plasma, it was possible to decrease LLOQ and LOD to 2.5 and 1.25 ng/mL, respectively.

Kumkhaek C, Phra-Ek K, Rénia L, Singhasivanon P, Looareesuwan S, Hirunpetcharat C, White NJ, Brockman A, Grüner AC, Lebrun N et al. 2005. Are extensive T cell epitope polymorphisms in the Plasmodium falciparum circumsporozoite antigen, a leading sporozoite vaccine candidate, selected by immune pressure? J Immunol, 175 (6), pp. 3935-3939. | Citations: 31 (Scopus) | Show Abstract | Read more

Protective cellular immune responses depend on MHC presentation of pathogen-derived Ag fragments. MHC diversity renders this process sensitive to point mutations coding for altered amino acid sequence of the short target Ag-derived peptides epitopes. Thus, in a given host, a pathogen with an altered epitope sequence will be more likely to escape detection and elimination by the immune system. At a population level, selection by immune pressure will increase the likelihood of polymorphism in important pathogen antigenic epitopes. This mechanism of immune evasion is found in viruses and other pathogens. The detection of polymorphic hot spots in an Ag is often taken as a strong indication of its role in protective immunity. We provide evidence that polymorphisms in the T cell epitopes of a malaria vaccine candidate are unlikely to have been selected by immune pressure in the human host.

Bull PC, Pain A, Ndungu FM, Kinyanjui SM, Roberts DJ, Newbold CI, Marsh K. 2005. Plasmodium falciparum antigenic variation: relationships between in vivo selection, acquired antibody response, and disease severity. J Infect Dis, 192 (6), pp. 1119-1126. | Citations: 30 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Variant surface antigens (VSA) on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria. We previously identified a VSA phenotype--VSA with a high frequency of antibody recognition (VSA(FoRH))--that is associated with young host age and severe malaria. We hypothesized that VSA(FoRH) are positively selected by host molecules such as intercellular adhesion molecule 1 (ICAM1) and CD36 and dominate in the absence of an effective immune response. Here, we assessed, in 115 Kenyan children, the potential role played by in vivo selection pressures in either favoring or selecting against VSA(FoRH) among parasites that cause malaria. METHODS: We tested for associations between VSA(FoRH) and (1) the repertoire of VSA antibodies carried by children at the time of acute malaria and (2) polymorphisms in ICAM1 (K29M) and CD36 (T188G) that could potentially reduce the positive selection of VSA(FoRH). RESULTS: An expected negative association between VSA antibody repertoire and VSA(FoRH) was observed in children with nonsevere malaria. However, this association did not extend to children with severe malaria, many of whom apparently had well-developed VSA antibody responses despite being infected by parasites expressing VSA(FoRH). There was no evidence for involvement of CD36 or ICAM1 in positive selection of VSA(FoRH). On the contrary, a weak positive association between carriage of the CD36 (T188G) allele and VSA(FoRH) was observed in children with severe malaria. CONCLUSION: The association between the VSA(FoRH) parasite phenotype and severe malaria cannot be explained simply in terms of the total repertoire of VSA antibodies carried at the time of acute disease.

Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. 2005. Malaria risk - Reply NATURE, 437 (7056), pp. E4-E5. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

We have provided an evidence-based framework for estimating the public-health burden of P. falciparum malaria by using a uniform series of structured, transparent and reproducible data and methods to define the cartography of this parasite's clinical impact at a global scale. This contribution to global disease modelling is questioned by Nahlen et al. for United Nations agencies responsible for measuring development targets (see also ref. 3), and our estimation of the malaria burden outside Africa is challenged by Bell et al. © Nature Publishing Group.

Gomes MGM, White LJ, Medley GF. 2005. The reinfection threshold. J Theor Biol, 236 (1), pp. 111-113. | Citations: 40 (Scopus) | Show Abstract | Read more

Thresholds in transmission are responsible for critical changes in infectious disease epidemiology. The epidemic threshold indicates whether infection invades a totally susceptible population. The reinfection threshold indicates whether self-sustained transmission occurs in a population that has developed a degree of partial immunity to the pathogen (by previous infection or vaccination). In models that combine susceptible and partially immune individuals, the reinfection threshold is technically not a bifurcation of equilibria as correctly pointed out by Breban and Blower. However, we show that a branch of equilibria to a reinfection submodel bifurcates from the disease-free equilibrium as transmission crosses this threshold. Consequently, the full model indicates that levels of infection increase by two orders of magnitude and the effect of mass vaccination becomes negligible as transmission increases across the reinfection threshold.

Tiyawisutsri R, Peacock SJ, Langa S, Limmathurotsakul D, Cheng AC, Chierakul W, Chaowagul W, Day NPJ, Wuthiekanun V. 2005. Antibodies from patients with melioidosis recognize Burkholderia mallei but not Burkholderia thailandensis antigens in the indirect hemagglutination assay. J Clin Microbiol, 43 (9), pp. 4872-4874. | Citations: 18 (Scopus) | Show Abstract | Read more

The indirect hemagglutination assay routinely used to detect antibodies to Burkholderia pseudomallei was modified to detect cross-reactivity of antibodies to B. pseudomallei, B. mallei, and B. thailandensis antigens. We demonstrate a lack of cross-reactivity between B. pseudomallei and B. thailandensis but marked cross-reactivity between B. pseudomallei and B. mallei.

Newton PN, Chung W-H, Phetsouvanh R, White NJ. 2005. Sporotrichosis, Plain of Jars, Lao People's Democratic Republic. Emerg Infect Dis, 11 (9), pp. 1496-1497. | Citations: 3 (Scopus) | Read more

McGready R, Ashley EA, Moo E, Cho T, Barends M, Hutagalung R, Looareesuwan S, White NJ, Nosten F. 2005. A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. J Infect Dis, 192 (5), pp. 846-853. | Citations: 76 (Scopus) | Show Abstract | Read more

BACKGROUND: There is no safe, practical, and effective treatment for pregnant women infected with multidrug-resistant Plasmodium falciparum. METHODS: We recruited pregnant Karen women in the second or third trimesters of pregnancy who had uncomplicated falciparum malaria for a randomized, open-label trial with a restricted sequential trial design of 7 days of supervised quinine (SQ7) versus 3 days of artesunate-atovaquone-proguanil (AAP). RESULTS: Eight-one pregnant women entered the study between December 2001 and July 2003; 42 were treated with SQ7 and 39 were treated with AAP. Fever, parasite clearance, and duration of anemia were significantly better with AAP; the treatment failure rate was 7 times lower (5% [2/39] vs. 37% [15/41]; relative risk, 7.1 [95% confidence interval, 1.7-29.2]; P = .001). There were no significant differences in birth weight, duration of gestation, or congenital abnormality rates in newborns or in growth and developmental parameters of infants monitored for 1 year. CONCLUSION: AAP is a well-tolerated, effective, practical, but expensive treatment for multidrug-resistant falciparum malaria during the second or third trimesters of pregnancy. Despite the small number of subjects, our results add to the growing body of evidence that AAP is safe for the mother and the fetus.

Wills BA, Nguyen MD, Ha TL, Dong THT, Tran TNT, Le TTM, Tran VD, Nguyen TH, Nguyen VC, Stepniewska K et al. 2005. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med, 353 (9), pp. 877-889. | Citations: 267 (Scopus) | Show Abstract | Read more

BACKGROUND: Dengue shock syndrome is characterized by severe vascular leakage and disordered hemostasis and progresses to death in 1 to 5 percent of cases. Although volume replacement is recognized as the critical therapeutic intervention, World Health Organization management guidelines remain empirical rather than evidence-based. METHODS: We performed a double-blind, randomized comparison of three fluids for initial resuscitation of Vietnamese children with dengue shock syndrome. We randomly assigned 383 children with moderately severe shock to receive Ringer's lactate, 6 percent dextran 70 (a colloid), or 6 percent hydroxyethyl starch (a colloid) and 129 children with severe shock to receive one of the colloids. The primary outcome measure was requirement for rescue colloid at any time after administration of the study fluid. RESULTS: Only one patient died (<0.2 percent mortality). The primary outcome measure--requirement for rescue colloid--was similar for the different fluids in the two severity groups. The relative risk of requirement for rescue colloid was 1.08 (95 percent confidence interval, 0.78 to 1.47; P=0.65) among children with moderate shock who received Ringer's lactate as compared with either of the colloid solutions, 1.13 (95 percent confidence interval, 0.74 to 1.74; P=0.59) among children who received dextran as compared with starch in the group with severe shock, and 0.88 (95 percent confidence interval, 0.66 to 1.17; P=0.38) among children who received dextran as compared with starch in the combined analysis. Although treatment with Ringer's lactate resulted in less rapid improvement in the hematocrit and a marginally longer time to initial recovery than did treatment with either of the colloid solutions, there were no differences in all other measures of treatment response. Only minor differences in efficacy were detected between the two colloids, but significantly more recipients of dextran than of starch had adverse reactions. Bleeding manifestations, coagulation derangements, and severity of fluid overload were similar for all fluid-treatment groups. CONCLUSIONS: Initial resuscitation with Ringer's lactate is indicated for children with moderately severe dengue shock syndrome. Dextran 70 and 6 percent hydroxyethyl starch perform similarly in children with severe shock, but given the adverse reactions associated with the use of dextran, starch may be preferable for this group.

Walther M, Tongren JE, Andrews L, Korbel D, King E, Fletcher H, Andersen RF, Bejon P, Thompson F, Dunachie SJ et al. 2005. Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity, 23 (3), pp. 287-296. | Citations: 250 (Scopus) | Show Abstract | Read more

Understanding the regulation of immune responses is central for control of autoimmune and infectious disease. In murine models of autoimmunity and chronic inflammatory disease, potent regulatory T lymphocytes have recently been characterized. Despite an explosion of interest in these cells, their relevance to human disease has been uncertain. In a longitudinal study of malaria sporozoite infection via the natural route, we provide evidence that regulatory T cells have modifying effects on blood-stage infection in vivo in humans. Cells with the characteristics of regulatory T cells are rapidly induced following blood-stage infection and are associated with a burst of TGF-beta production, decreased proinflammatory cytokine production, and decreased antigen-specific immune responses. Both the production of TGF-beta and the presence of CD4+CD25+FOXP3+ regulatory T cells are associated with higher rates of parasite growth in vivo. P. falciparum-mediated induction of regulatory T cells may represent a parasite-specific virulence factor.

House D, Chinh NT, Diep TS, Parry CM, Wain J, Dougan G, White NJ, Hien TT, Farrar JJ. 2005. Use of paired serum samples for serodiagnosis of typhoid fever. J Clin Microbiol, 43 (9), pp. 4889-4890. | Citations: 28 (Web of Science Lite) | Show Abstract | Read more

Using an enzyme-linked immunosorbent assay we demonstrate that, in adult patients with typhoid fever, the sensitivity of a serological test based on the detection of anti-lipopolysaccharide immunoglobulin G is increased when used with paired serum samples taken 1 week apart.

Shanks GD, Hay SI, Omumbo JA, Snow RW. 2005. Malaria in Kenya's western highlands. Emerg Infect Dis, 11 (9), pp. 1425-1432. | Citations: 50 (Scopus) | Show Abstract | Read more

Records from tea estates in the Kericho district in Kenya show that malaria reemerged in the 1980s. Renewed epidemic activity coincided with the emergence of chloroquine-resistant Plasmodium falciparum malaria and may have been triggered by the failure of antimalarial drugs. Meteorologic changes, population movements, degradation of health services, and changes in Anopheles vector populations are possible contributing factors. The highland malaria epidemics of the 1940s were stopped largely by sporontocidal drugs, and combination chemotherapy has recently limited transmission. Antimalarial drugs can limit the pool of gametocytes available to infect mosquitoes during the brief transmission season.

Baker S, Sarwar Y, Aziz H, Haque A, Ali A, Dougan G, Wain J, Haque A. 2005. Detection of Vi-negative Salmonella enterica serovar typhi in the peripheral blood of patients with typhoid fever in the Faisalabad region of Pakistan. J Clin Microbiol, 43 (9), pp. 4418-4425. | Show Abstract | Read more

The synthesis and transportation proteins of the Vi capsular polysaccharide of Salmonella enterica serovar Typhi (serovar Typhi) are encoded by the viaB operon, which resides on a 134-kb pathogenicity island known as SPI-7. In recent years, Vi-negative strains of serovar Typhi have been reported in regions where typhoid fever is endemic. However, because Vi negativity can arise during in vitro passage, the clinical significance of Vi-negative serovar Typhi is not clear. To investigate the loss of Vi expression at the genetic level, 60 stored strains of serovar Typhi from the Faisalabad region of Pakistan were analyzed by PCR for the presence of SPI-7 and two genes essential for Vi production: tviA and tviB. Nine of the sixty strains analyzed (15%) tested negative for both tviA and tviB; only two of these strains lacked SPI-7. In order to investigate whether this phenomenon occurred in vivo, blood samples from patients with the clinical symptoms of typhoid fever were also investigated. Of 48 blood samples tested, 42 tested positive by fliC PCR for serovar Typhi; 4 of these were negative for tviA and tviB. Three of these samples tested positive for SPI-7. These results demonstrate that viaB-negative, SPI-7-positive serovar Typhi is naturally occurring and can be detected by PCR in the peripheral blood of typhoid patients in this region. The method described here can be used to monitor the incidence of Vi-negative serovar Typhi in regions where the Vi vaccine is used.

van Doorn HR, Hofwegen H, Koelewijn R, Gilis H, Peek R, Wetsteyn JCFM, van Genderen PJJ, Vervoort T, van Gool T. 2005. Use of rapid dipstick and latex agglutination tests and enzyme-linked immunosorbent assay for serodiagnosis of amebic liver abscess, amebic Colitis, and Entamoeba histolytica Cyst Passage. J Clin Microbiol, 43 (9), pp. 4801-4806. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

A homemade enzyme-linked immunosorbent assay (ELISA) and a dipstick assay (Dipstick) for the detection of anti-Entamoeba histolytica antibodies in serum were developed and evaluated together with a commercially available latex agglutination test (LAT; Laboratoires Fumouze) for their use in serodiagnosis of amebiasis. The sensitivity of these assays was evaluated with sera from 27 patients with radiologically proven, cellulose acetate precipitation (CAP) test-positive amebic liver abscess, 7 patients with parasitologically and PCR-proven amebic colitis, and 11 patients with parasitologically and PCR-proven E. histolytica cyst passage. The sensitivities of the ELISA, Dipstick, and LAT were all 93.3% (42/45). With a combination of Dipstick and LAT, all abscess and colitis patients had at least one positive result. The specificity was assessed with 238 sera from patients with various parasitic, bacterial, viral, and fungal infectious diseases, sera containing autoimmune antibodies, and sera from healthy blood donors. The specificities of the ELISA, Dipstick, and LAT were 97.1%, 98.1%, and 99.5%, respectively. Of 61 sera from patients with PCR-proven E. dispar infection, 60 (98.4%) were negative in both Dipstick and LAT and 59 (96.7%) were negative in ELISA. Our data suggest that all three assays are sensitive serological tests. The rapid LAT and Dipstick provide fast results and can easily be applied in routine laboratories in order to facilitate the diagnosis of amebiasis.

Baker S, Sarwar Y, Aziz H, Haque A, Ali A, Dougan G, Wain J, Haque A. 2005. Detection of Vi-negative Salmonella enterica serovar Typhi in the peripheral blood of patients with typhoid fever in the Faisalabad region of Pakistan JOURNAL OF CLINICAL MICROBIOLOGY, 43 (9), pp. 4418-4425. | Citations: 43 (Web of Science Lite) | Read more

English M. 2005. Child survival: district hospitals and paediatricians. Arch Dis Child, 90 (9), pp. 974-978. | Show Abstract | Read more

In a previous article in this series, Zulfiquar Bhutta outlined many of the key sociopolitical issues, both national and international, that currently affect the delivery of health care to children in developing countries. The clear summary of our situation is that we are failing to provide even basic health care (both preventive and curative) that could reduce child mortality globally by more than half. Paediatricians, who have perhaps in the past felt they were at the forefront of articulating and promoting a global health agenda, should be challenged by these conclusions. The successful ratification of the United Nations Convention on the Rights of the Child that unequivocally target health was not a finishing line, a goal achieved, but rather a foundation for action. Therefore while researchers might have felt some satisfaction at successes in defining optimum treatment approaches, the pathways to delivering services were, and remain, far from clear. Progress is further complicated by the diverse conditions and obstacles that may be encountered worldwide.

Mekonnen Y, Geskus RB, Hendriks JCM, Messele T, Borghans J, Miedema F, Wolday D, Coutinho RA, Dukers NHTM. 2005. Low CD4 T cell counts before HIV-1 seroconversion do not affect disease progression in Ethiopian factory workers. J Infect Dis, 192 (5), pp. 739-748. | Citations: 20 (Scopus) | Show Abstract | Read more

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1)-uninfected Ethiopians have lower CD4 T cell counts than do other populations in Africa and industrialized countries. We studied whether this unique immunological profile results in shorter survival times in HIV-1-infected Ethiopians. METHODS: Data from an open cohort study of 149 HIV-1-infected factory workers in Ethiopia for 1997-2002 were used. To estimate survival times, a continuous-time Markov model was designed on the basis of CD4 T cell counts and World Health Organization clinical staging. By use of a random-effects model, decline in CD4 T cell counts was compared between HIV-1-infected Ethiopian and Dutch individuals. RESULTS: Median survival times were in the range of 9.1-13.7 years, depending on the approach used. This range is similar to that for populations in industrialized countries before the advent of antiretroviral therapy. Ethiopians had a lower annual decline in CD4 T cell counts than did Dutch individuals, which remained when groups with similar CD4 T cell count categories were compared. Moreover, the slower decline in CD4 T cell counts was not due merely to lower HIV-1 RNA loads or an absence of syncytium-inducing/X4 HIV-1 subtype C strains in Ethiopians. CONCLUSIONS: Low baseline CD4 T cell counts do not imply shorter survival times in Ethiopians than in other populations, presumably because of a slower decline in CD4 T cell counts.

Faiz MA, Bin Yunus E, Rahman MR, Islam F, Hoque MG, Hasan MU, Samad R, Aung S, Thein S, Than M et al. 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial LANCET, 366 (9487), pp. 717-725. | Citations: 501 (Web of Science Lite) | Read more

Dondorp A, Nosten F, Stepniewska K, Day N, White N, South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet, 366 (9487), pp. 717-725. | Citations: 557 (Scopus) | Show Abstract | Read more

BACKGROUND: In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. METHODS: We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731). Oral medication was substituted when possible to complete treatment. Our primary endpoint was death from severe malaria, and analysis was by intention to treat. FINDINGS: We assessed all patients randomised for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; p=0.009). INTERPRETATION: Artesunate should become the treatment of choice for severe falciparum malaria in adults.

Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K, Chotivanich K, Newton PN, Pitisuttithum P, Smithyman AM, White NJ, Day NPJ. 2005. Estimation of the Total Parasite Biomass in Acute Falciparum Malaria from Plasma PfHRP2 PLoS Medicine, 2 (8), pp. e204-e204. | Read more

Ashley EA, McGready R, Hutagalung R, Phaiphun L, Slight T, Proux S, Thwai KL, Barends M, Looareesuwan S, White NJ, Nosten F. 2005. A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. Clin Infect Dis, 41 (4), pp. 425-432. | Citations: 93 (Scopus) | Show Abstract | Read more

BACKGROUND: Dihydroartemisinin-piperaquine (DP) is a fixed-combination antimalarial drug increasingly deployed in Southeast Asia. The current regimen involves 4 doses given over 3 days. Simplification of the dose regimen should facilitate treatment adherence and thereby increase effectiveness. METHODS: In a randomized, controlled, 3-arm trial conducted along the northwestern border of Thailand, the standard 4-dose course of DP (DP4) was compared to an equivalent dose given as a once-daily regimen (DP3) and to the standard treatment of mefloquine-artesunate (MAS3). RESULTS: A total of 499 patients were included in the study. Times to fever and parasite clearance were similar in all groups. The PCR genotyping-adjusted cure rates at day 63 after treatment initiation were 95.7% (95% confidence interval [95% CI], 92.2%-98.9%) for MAS3, 100% for DP4, and 99.4% (95% CI, 98.1%-100%) for DP3. The DP4 and DP3 cure rates were significantly higher than that for MAS3 (P=.008 and P=.03, respectively). All regimens were well tolerated. There were 3 deaths (1 in the MAS3 group and 2 in the DP3 group), all of which were considered to be unrelated to treatment. Rates of other adverse events were comparable between the groups, except for diarrhea, which was more common in the DP4 group (P=.05 vs. the MAS3 group). CONCLUSIONS: A once-daily, 3-dose regimen of DP is a highly efficacious treatment for multidrug-resistant falciparum malaria. This simple, safe, and relatively inexpensive fixed combination could become the treatment of choice for falciparum malaria.

Brouwer AE, Teparrukkul P, Pinpraphaporn S, Larsen RA, Chierakul W, Peacock S, Day N, White NJ, Harrison TS. 2005. Baseline correlation and comparative kinetics of cerebrospinal fluid colony-forming unit counts and antigen titers in cryptococcal meningitis. J Infect Dis, 192 (4), pp. 681-684. | Citations: 33 (Web of Science Lite) | Show Abstract | Read more

Cerebrospinal fluid (CSF) cryptococcal colony-forming unit counts and CSF cryptococcal antigen titers serve as alternative measures of organism load in cryptococcal meningitis. For these measures, we correlated baseline values and rates of decline during the first 2 weeks of therapy in 68 human immunodeficiency virus--seropositive patients with cryptococcal meningitis. At baseline, there was a strong correlation between CSF cryptococcal colony-forming unit counts and CSF cryptococcal antigen titers. During the first 2 weeks of therapy, CSF cryptococcal colony-forming unit counts decreased by >5 logs, and CSF cryptococcal antigen titers decreased by 1.5 dilutions. In individual patients, there was no correlation between the rate of decline in CSF cryptococcal colony-forming unit counts and that in CSF cryptococcal antigen titers.

Annerberg A, Singtoroj T, Tipmanee P, White NJ, Day NPJ, Lindegårdh N. 2005. High throughput assay for the determination of lumefantrine in plasma. J Chromatogr B Analyt Technol Biomed Life Sci, 822 (1-2), pp. 330-333. | Citations: 38 (Scopus) | Show Abstract | Read more

A high throughput bioanalytical assay for the determination of lumefantrine in plasma has been developed and validated extensively. The within-day precisions for lumefantrine were 5.2, 3.5 and 2.5% at 200, 2000 and 15000 ng/mL, respectively. The between-day precisions were 4.0, 2.8 and 3.1% at 200, 2000 and 15000 ng/mL, respectively. The lower limits of quantification (LLOQ) and the limits of detection (LOD) were 25 and 10 ng/mL, respectively using 0.250 mL plasma. The average recovery of lumefantrine was 85% and independent upon concentration. The use of 96-well plate format and short chromatographic run has increased the daily sample throughput four times. The assay is particularly suitable for large therapeutic drug monitoring studies using day 7 sampling.

Berkley J, Mwangi I, Griffiths K, Ahmed I, Mithwani S, English M, Newton C, Maitland K. 2005. Assessment of severe malnutrition among hospitalized children in rural Kenya: comparison of weight for height and mid upper arm circumference. JAMA, 294 (5), pp. 591-597. | Citations: 82 (Scopus) | Show Abstract | Read more

CONTEXT: Severe malnutrition has a high mortality rate among hospitalized children in sub-Saharan Africa. However, reports suggest that malnutrition is often poorly assessed. The World Health Organization recommends using weight for height, but this method is problematic and often not undertaken in practice. Mid upper arm circumference (MUAC) and the clinical sign "visible severe wasting" are simple and inexpensive methods but have not been evaluated in this setting. OBJECTIVES: To evaluate MUAC and visible severe wasting as predictors of inpatient mortality at a district hospital in sub-Saharan Africa and to compare these with weight-for-height z score (WHZ). DESIGN, SETTING, AND PARTICIPANTS: Cohort study with data collected at admission and at discharge or death. Predictive values for inpatient death were determined using the area under receiver operating characteristic curves. Participants were children aged 12 to 59 months admitted to a district hospital in rural Kenya between April 1, 1999, and July 31, 2002. MAIN OUTCOME MEASURE: MUAC, WHZ, and visible severe wasting as predictors of inpatient death. RESULTS: Overall, 4.4% (359) of children included in the study died while in the hospital. Sixteen percent (1282/8190) of admitted children had severe wasting (WHZ < or =-3) (n = 756), kwashiorkor (n = 778), or both. The areas under the receiver operating characteristic curves for predicting inpatient death did not significantly differ (MUAC: 0.75 [95% confidence interval, 0.72-0.78]; WHZ: 0.74 [95% confidence interval, 0.71-0.77]) (P = .39). Although sensitivity and specificity for subsequent inpatient death were 46% and 91%, respectively, for MUAC less than or equal to 11.5 cm, 42% and 92% for WHZ less than or equal to -3, and 47% and 93% for visible severe wasting, the 3 indices identified different sets of children and were independently associated with mortality. Clinical features of malnutrition were significantly more common among children with MUAC less than or equal to 11.5 cm than among those with WHZ less than or equal to -3. CONCLUSIONS: MUAC is a practical screening tool that performs at least as well as WHZ in predicting subsequent inpatient mortality among severely malnourished children hospitalized in rural Kenya. Visible severe wasting is also a potentially useful sign at this level, providing appropriate training has been given.

Gupta RK, Van Vugt M, Paiphun L, Slight T, Looareesuwan S, White NJ, Nosten F. 2005. Short report: no evidence of cardiotoxicity of atovaquone-proguanil alone or in combination with artesunate. Am J Trop Med Hyg, 73 (2), pp. 267-268. | Citations: 10 (Scopus) | Show Abstract

Combinations are set to become the mainstay in treatment and prophylaxis of malaria due to Plasmodium falciparum. Various antimalarials have been implicated in cardiotoxicity via prolongation of the QTc interval. Atovaquone-proguanil is an effective and increasingly popular antimalarial choice when used alone or with artesunate in areas of drug resistance. We report the results of an investigation carried out on the Thai-Burmese border in 42 patients randomized to receive either atovaquone-proguanil or atovaquone-proguanil-artesunate for three days. Electrocardiographic recordings were made at baseline and one hour after each dose. There was no statistically significant change in QTc interval between baseline and any subsequent readings in either treatment group or the cohort as a whole. We conclude that atovaquone-proguanil shows no evidence of cardiotoxicity either alone or when combined with artesunate.

Medana IM, Lindert R-B, Wurster U, Hien TT, Day NPJ, Phu NH, Mai NTH, Chuong LV, Chau TTH, Turner GDH et al. 2005. Cerebrospinal fluid levels of markers of brain parenchymal damage in Vietnamese adults with severe malaria. Trans R Soc Trop Med Hyg, 99 (8), pp. 610-617. | Citations: 17 (Scopus) | Show Abstract | Read more

A retrospective study of cerebrospinal fluid (CSF) markers of brain parenchymal damage was conducted in Vietnamese adults with severe malaria. Three markers were analysed by immunoassays: the microtubule-associated protein tau, for degenerated axons; neuron-specific enolase (NSE), for neurons; and S100B for astrocytes. The mean concentration of tau proteins in the CSF was significantly raised in patients with severe malaria compared with controls (P=0.0003) as reported for other central nervous system diseases. By contrast, the mean concentration of NSE and S100B remained within the normal range. Tau levels were associated with duration of coma (P=0.004) and S100B was associated with convulsions (P=0.006). Concentrations of axonal and astrocyte degeneration markers also were associated with vital organ dysfunction. No association was found between the level of markers of brain parenchymal damage on admission and a fatal outcome. On admission to hospital, patients with severe malaria had biochemical evidence of brain parenchymal damage predominantly affecting axons.

Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K, Chotivanich K, Newton PN, Pitisuttithum P, Smithyman AM, White NJ, Day NPJ. 2005. Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2. PLoS Med, 2 (8), pp. e204. | Citations: 225 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: In falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden sequestered parasite load in vivo has not previously been possible. The peripheral blood parasite count measures only the circulating, relatively non-pathogenic parasite numbers. P. falciparum releases a specific histidine-rich protein (PfHRP2) into plasma. Quantitative measurement of plasma PfHRP2 concentrations may reflect the total parasite biomass in falciparum malaria. METHODS AND FINDINGS: We measured plasma concentrations of PfHRP2, using a quantitative antigen-capture enzyme-linked immunosorbent assay, in 337 adult patients with falciparum malaria of varying severity hospitalised on the Thai-Burmese border. Based on in vitro production rates, we constructed a model to link this measure to the total parasite burden in the patient. The estimated geometric mean parasite burden was 7 x 10(11) (95% confidence interval [CI] 5.8 x 10(11) to 8.5 x 10(11)) parasites per body, and was over six times higher in severe malaria (geometric mean 1.7 x 10(12), 95% CI 1.3 x 10(12) to 2.3 x 10(12)) than in patients hospitalised without signs of severity (geometric mean 2.8 x 10(11), 95% CI 2.3 x 10(11) to 3.5 x 10(11); p < 0.001). Parasite burden was highest in patients who died (geometric mean 3.4 x 10(12), 95% CI 1.9 x 10(12) to 6.3 x 10(12); p = 0.03). The calculated number of sequestered parasites increased with disease severity and was higher in patients with late developmental stages of P. falciparum present on peripheral blood smears. Comparing model and laboratory estimates of the time of sequestration suggested that admission to hospital with uncomplicated malaria often follows schizogony-but in severe malaria is unrelated to stage of parasite development. CONCLUSION: Plasma PfHRP2 concentrations may be used to estimate the total body parasite biomass in acute falciparum malaria. Severe malaria results from extensive sequestration of parasitised erythrocytes.

Lindegårdh N, Singtoroj T, Annerberg A, White NJ, Day NPJ. 2005. Development and validation of a solid-phase extraction-liquid chromatographic method for determination of amoxicillin in plasma. Ther Drug Monit, 27 (4), pp. 503-508. | Citations: 14 (Web of Science Lite) | Show Abstract | Read more

A bioanalytic method for the determination of amoxicillin in plasma by hydrophilic interaction solid-phase extraction and liquid chromatography has been developed and validated. Plasma was precipitated with acetonitrile before samples were loaded onto a zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) solid-phase extraction column. Amoxicillin was analyzed by liquid chromatography on an Aquasil (150 x 4.6 mm) LC column with mobile-phase acetonitrile: phosphate buffer (pH 2.5; 0.1 mol/L) (7:93, v/v) and UV detection at 230 nm. A regression model using 1/concentration weighting was found the most appropriate for quantification. The intraassay precision for plasma was 3.3% at 15.0 microg/mL and 10.9% at 0.200 microg/mL. The interassay precision for plasma was 1.8% at 15.0 microg/mL and 7.5% at 0.200 microg/mL. The total-assay precision for plasma over 4 days using a total of 20 replicates was 13.2%, 5.5%, and 3.8% at 0.200 microg/mL, 3.00 microg/mL, and 15.0 microg/mL, respectively. The lower limit of quantification and the limit of detection were 0.050 microg/mL and 0.025 microg/mL, respectively, for 100 microL plasma. Long-term storage stability studies of amoxicillin in plasma indicate that a temperature of -80 degrees C is necessary to prevent degradation of amoxicillin.

White NJ, Silamut K. 2005. Postmortem brain smear assessment of fatal malaria. J Infect Dis, 192 (3), pp. 547. | Citations: 3 (Web of Science Lite) | Read more

Bryant JE, Crabtree MB, Nam VS, Yen NT, Duc HM, Miller BR. 2005. Isolation of arboviruses from mosquitoes collected in northern Vietnam. Am J Trop Med Hyg, 73 (2), pp. 470-473. | Citations: 37 (Scopus) | Show Abstract

In response to recent increases in cases of pediatric encephalitis with unknown etiology in northern Vietnam, surveillance for arbovirus activity was conducted in four provinces surrounding the city of Hanoi during June 2002 and July-August 2004. A total of 20,615 mosquitoes consisting of 19 species in 1,122 pools were processed for virus isolation; virus isolates were obtained from 44 pools. Sagiyama virus (11 isolates), Getah virus (15 isolates), Oya virus (13 isolates), and Akabane virus (4 isolates) were identified by immunofluorescence assay and sequence analysis of reverse transcription-polymerase chain reaction fragments. Surprisingly, no isolates of Japanese encephalitis (JE) virus were obtained. Isolation of Akabane virus, Oya virus, Getah virus, and Sagiyama virus is reported for the first time from Vietnam.

Salje J, Ludwig B, Richter O-MH. 2005. Is a third proton-conducting pathway operative in bacterial cytochrome c oxidase? Biochem Soc Trans, 33 (Pt 4), pp. 829-831. | Citations: 18 (Scopus) | Show Abstract | Read more

Despite the existence of several three-dimensional structures of cytochrome c oxidases, a detailed understanding of pathways involved in proton movements through the complex remains largely elusive. Next to the two well-established pathways (termed D and K), an additional proton-conducting network ('H-channel') has been proposed for the beef heart enzyme. Yet, our recent mutational studies on corresponding residues of the Paracoccus denitrificans cytochrome c oxidase provide no clues that such a pathway operates in the prokaryotic enzyme.

Ali M, Canh GD, Clemens JD, Park J-K, von Seidlein L, Minh TT, Thiem DV, Tho HL, Trach DD, Vaccine Safety Datalink Group. 2005. The use of a computerized database to monitor vaccine safety in Viet Nam. Bull World Health Organ, 83 (8), pp. 604-610. | Citations: 21 (Scopus) | Show Abstract

Health information systems to monitor vaccine safety are used in industrialized countries to detect adverse medical events related to vaccinations or to prove the safety of vaccines. There are no such information systems in the developing world, but they are urgently needed. A large linked database for the monitoring of vaccine-related adverse events has been established in Khanh Hoa province, Viet Nam. Data collected during the first 2 years of surveillance, a period which included a mass measles vaccination campaign, were used to evaluate the system. For this purpose the discharge diagnoses of individuals admitted to polyclinics and hospitals were coded according to the International Classification of Diseases (ICD)-10 guidelines and linked in a dynamic population database with vaccination histories. A case-series analysis was applied to the cohort of children vaccinated during the mass measles vaccination campaign. The study recorded 107,022 immunizations in a catchment area with a population of 357,458 and confirmed vaccine coverage of 87% or higher for completed routine childhood vaccinations. The measles vaccination campaign immunized at least 86% of the targeted children aged 9 months to 10 years. No medical event was detected significantly more frequently during the 14 days after measles vaccination than before it. The experience in Viet Nam confirmed the safety of a measles vaccination campaign and shows that it is feasible to establish health information systems such as a large linked database which can provide reliable data in a developing country for a modest increase in use of resources.

Wang X-Y, Du L, Von Seidlein L, Xu Z-Y, Zhang Y-L, Hao Z-Y, Han O-P, Ma J-C, Lee H-J, Ali M et al. 2005. Occurrence of shigellosis in the young and elderly in rural China: results of a 12-month population-based surveillance study. Am J Trop Med Hyg, 73 (2), pp. 416-422. | Citations: 36 (Scopus) | Show Abstract

In 2002, population- and treatment center-based surveillance was used to study the disease burden of shigellosis in rural Hebei Province in the People's Republic of China. A total of 10,105 children with diarrhea or dysentery were enrolled. Infants were treated most frequently for diarrhea (1,388/1,000/year) followed by children < or = 5 years old (618/1,000/year). Shigellosis was treated most often in children 3-4 years old (32/1,000/year) and people > 60 years of age (7/1,000/year). Fifty-six percent (184 of 331) Shigella isolates were detected in patients who had non-bloody diarrhea. Shigella flexneri was identified in 93% of 306 isolates. The most common S. flexneri serotypes were 1a (34%), X (33%), and 2a (28%). More than 90% of the Shigella isolates were resistant to cotrimoxazole and nalidixic acid, but remained susceptible to ciprofloxacin, norfloxacin, and gentamicin. Widespread resistance to antibiotics adds urgency to the development and use of vaccines to control shigellosis.

von Seidlein L. 2005. The need for another typhoid fever vaccine. J Infect Dis, 192 (3), pp. 357-359. | Citations: 6 (Scopus) | Read more

Termorshuizen F, Krol A, Prins M, Geskus R, van den Brink W, van Ameijden EJC. 2005. Prediction of relapse to frequent heroin use and the role of methadone prescription: an analysis of the Amsterdam Cohort Study among drug users. Drug Alcohol Depend, 79 (2), pp. 231-240. | Citations: 52 (Scopus) | Show Abstract | Read more

The risk of relapse into frequent heroin use was studied among 732 participants of the Amsterdam Cohort Study (ACS) on HIV/AIDS among drug users, who experienced an episode of abstinence from or occasional use of heroin. Participants of the ACS were recruited primarily from easy access ("low-threshold") methadone programs. The duration of abstinence/occasional use and relative risks (RR) of relapse were estimated by analyzing 1577 episodes by means of survival analysis using characteristics of patients and methadone treatment as covariates. The majority of episodes (85.8%) were followed by relapse within 5 years. Less education, intense use of heroin prior to the episode of abstinence or well-controlled use, occasional use of heroin and intense use of cocaine during the episode, and having a drug-using partner or having no partner were significantly associated with a higher risk of relapse. Among frequent attendees of a "low-threshold" methadone program, relapse was associated with the daily dose of methadone: RR for dosages <40 and 40-60 mg, compared with doses of >100mg, were 1.45 (P<0.01) and 1.59 (P<0.01), respectively. No beneficial influence was revealed of methadone dosage or program attendance in itself on the risk of relapse into cocaine. High doses of methadone in a harm-reduction setting extend the duration of an episode of no or occasional use of heroin. Other factors, such as no occasional use of heroin during the episode, no use of cocaine, and having a non-using partner, seem to be equally important.

Ziglam HM, Elliott I, Wilson V, Hill K, Nathwani D. 2005. Clinical audit of linezolid use in a large teaching hospital Journal of Antimicrobial Chemotherapy, 56 (2), pp. 423-426. | Read more

Amin AA, Snow RW. 2005. Brands, costs and registration status of antimalarial drugs in the Kenyan retail sector. Malar J, 4 pp. 36. | Citations: 26 (Scopus) | Show Abstract | Read more

BACKGROUND: Although an important source of treatment for fevers, little is known about the structure of the retail sector in Africa with regard to antimalarial drugs. This study aimed to assess the range, costs, sources and registration of antimalarial drugs in the Kenyan retail sector. METHODS: In 2002, antimalarial drug registration and trade prices were established by triangulating national registration lists, government gazettes and trade price indices. Data on registration status and trade prices were compared with similar data generated through a retail audit undertaken among 880 randomly sampled retailers in four districts of Kenya. RESULTS: Two hundred and eighteen antimalarial drugs were in circulation in Kenya in 2002. These included 65 "sulfur"-pyrimethamine (sulfadoxine-pyrimethamine and sulfalene-pyrimethamine (SP), the first-line recommended drug in 2002) and 33 amodiaquine (AQ, the second-line recommended drug) preparations. Only half of SP and AQ products were registered with the Pharmacy and Poisons Board. Of SP and AQ brands at district level, 40% and 44% were officially within legal registration requirements. 29% of retailers at district level stocked SP and 95% stocked AQ. The retail price of adult doses of SP and AQ were on average 0.38 and 0.76 US dollars, 100% and 347% higher than trade prices from manufacturers and importers. Artemether-lumefantrine, the newly announced first-line recommended antimalarial drug in 2004, was found in less than 1% of all retail outlets at a median cost of 7.6 US dollars. CONCLUSION: There is a need to ensure that all antimalarial drugs are registered with the Pharmacy and Poisons Board to facilitate a more stringent post-marketing surveillance system to ensure drugs are safe and of good quality post-registration.

Nathan N, Borel T, Djibo A, Evans D, Djibo S, Corty JF, Guillerm M, Alberti KP, Pinoges L, Guerin PJ, Legros D. 2005. Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study. Lancet, 366 (9482), pp. 308-313. | Citations: 70 (Scopus) | Show Abstract | Read more

BACKGROUND: In sub-Saharan Africa in the 1990s, more than 600,000 people had epidemic meningococcal meningitis, of whom 10% died. The current recommended treatment by WHO is short-course long-acting oily chloramphenicol. Continuation of the production of this drug is uncertain, so simple alternatives need to be found. We assessed whether the efficacy of single-dose treatment of ceftriaxone was non-inferior to that of oily chloramphenicol for epidemic meningococcal meningitis. METHODS: In 2003, we undertook a randomised, open-label, non-inferiority trial in nine health-care facilities in Niger. Participants with suspected disease who were older than 2 months were randomly assigned to receive either chloramphenicol or ceftriaxone. Primary outcome was treatment failure (defined as death or clinical failure) at 72 h, measured with intention-to-treat and per-protocol analyses. FINDINGS: Of 510 individuals with suspected disease, 247 received ceftriaxone, 256 received chloramphenicol, and seven were lost to follow-up. The treatment failure rate at 72 h for the intention-to-treat analysis was 9% (22 patients) for both drug groups (risk difference 0.3%, 90% CI -3.8 to 4.5). Case fatality rates and clinical failure rates were equivalent in both treatment groups (14 [6%] ceftriaxone vs 12 [5%] chloramphenicol). Results were also similar for both treatment groups in individuals with confirmed meningitis caused by Neisseria meningitidis. No adverse side-effects were reported. INTERPRETATION: Single-dose ceftriaxone provides an alternative treatment for epidemic meningococcal meningitis--its efficacy, ease of use, and low cost favour its use. National and international health partners should consider ceftriaxone as an alternative first-line treatment to chloramphenicol for epidemic meningococcal meningitis.

Ali M, Emch M, von Seidlein L, Yunus M, Sack DA, Rao M, Holmgren J, Clemens JD. 2005. Herd immunity conferred by killed oral cholera vaccines in Bangladesh: a reanalysis. Lancet, 366 (9479), pp. 44-49. | Citations: 191 (Scopus) | Show Abstract | Read more

BACKGROUND: Decisions about the use of killed oral cholera vaccines, which confer moderate levels of direct protection to vaccinees, can depend on whether the vaccines also provide indirect (herd) protection when high levels of vaccine coverage are attained. We reanalysed data from a field trial in Bangladesh to ascertain whether there is evidence of indirect protection from killed oral cholera vaccines. METHODS: We analysed the first year of surveillance data from a placebo-controlled trial of B subunit-killed whole-cell and killed whole-cell-only oral cholera vaccines in children and adult women in Bangladesh. We calculated whether there was an inverse, monotonic trend for the relation between the level of vaccine coverage in a residential cluster and the incidence of cholera in individual vaccine recipients or placebo recipients residing in the cluster after controlling for potential confounding variables. FINDINGS: Vaccine coverage of the targeted population ranged from 4% to 65%. Incidence rates of cholera among placebo recipients were inversely related to levels of vaccine coverage (7.01 cases per 1000 in the lowest quintile of coverage vs 1.47 cases per 1000 in the highest quintile; p<0.0001 for trend). Receipt of vaccine by an individual and the level of vaccine coverage of the individual's cluster were independently related to a reduced risk of cholera. Moreover, after adjustment for the level of vaccine coverage of the cluster, vaccine protective efficacy remained significant (55% [95% CI 41-66], p<0.0001). INTERPRETATION: In addition to providing direct protection to vaccine recipients, killed oral cholera vaccines confer significant herd protection to neighbouring non-vaccinated individuals. Use of these vaccines could have a major effect on the burden of cholera in endemic settings.

Desakorn V, Dondorp AM, Silamut K, Pongtavornpinyo W, Sahassananda D, Chotivanich K, Pitisuttithum P, Smithyman AM, Day NPJ, White NJ. 2005. Stage-dependent production and release of histidine-rich protein 2 by Plasmodium falciparum. Trans R Soc Trop Med Hyg, 99 (7), pp. 517-524. | Citations: 59 (Web of Science Lite) | Show Abstract | Read more

Because of their sequestration in the microcirculation, the pathogenic late stages of Plasmodium falciparum are under-represented in peripheral blood samples from patients with falciparum malaria. Excreted products of the parasite might help to estimate this sequestered biomass. We quantified the stage-dependent production and release per parasite of P. falciparum histidine-rich protein 2 (PfHRP2) with the objective of measuring the sequestered biomass. A simple method to relate parasite stage to parasite age was developed to facilitate this. In four isolates of P. falciparum, the median (range) PfHRP2 content was 2.0fg (0.5-4.3fg) for a young ring stage infected erythrocyte, and 5.4fg (2.1-10.2fg) for the schizont stage. The amount of PfHRP2 in the parasitized erythrocyte increased most during development to the mature trophozoite stage. The median (range) amount of PfHRP2 secreted per parasite per entire erythrocytic cycle was 5.2fg (1.1-13.0fg). A median of 89% of the total PfHRP2 was excreted at the moment of schizont rupture. This assessment of the stage-dependent release of PfHRP2 is an essential prerequisite for future studies aimed at estimating the total patient parasite mass from the peripheral blood PfHRP2 concentration.

Molyneux CS, Wassenaar DR, Peshu N, Marsh K. 2005. 'Even if they ask you to stand by a tree all day, you will have to do it (laughter)...!': community voices on the notion and practice of informed consent for biomedical research in developing countries. Soc Sci Med, 61 (2), pp. 443-454. | Citations: 106 (Scopus) | Show Abstract | Read more

Ethical dilemmas in biomedical research, especially in vulnerable populations, often spark heated debate. Despite recommendations and guidelines, many issues remain controversial, including the relevance, prioritisation and application of individual voluntary informed consent in non-Western settings. The voices of the people likely to be the subjects of research have been notably absent from the debate. We held discussions with groups of community members living in the rural study area of a large research unit in Kenya. Discussions were facilitated by three research study vignettes outlining one field-based and two hospital-based studies being planned or taking place at the time. In addition to gathering general views about the aims and activities of the research unit, questions focused on whether consent should be sought for studies, and if so from whom (chiefs, elders, men/women, children), and on ascertaining whether there are any special concerns about the physical act of signing consent forms. The findings revealed the community's difficulty in distinguishing research from clinical investigations conducted in clinical settings. There was a spectrum of views regarding perceived appropriateness of consent procedures, in part because of difficulty in disentangling clinical from research aims, and because of other challenges to applying consent in practice. Debates between community members highlight the inadequacy of simplistic assumptions about community members' views on informed consent, and the complexity of incorporating lay opinions into biomedical research. Failure to appreciate these issues risks exaggerating differences between settings, and underestimating the time and resources required to ensure meaningful community involvement in research processes. Ultimately, it risks inadequately responding to the needs and values of those on whom the success of most biomedical research depends. Although compliance with community views does not necessarily make the research more ethical, it is argued that community opinions on local issues and practices should inform ethical decision-making in health research.

Thwaites GE, Lan NTN, Dung NH, Quy HT, Oanh DTT, Thoa NTC, Hien NQ, Thuc NT, Hai NN, Bang ND et al. 2005. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. J Infect Dis, 192 (1), pp. 79-88. | Citations: 95 (Scopus) | Show Abstract | Read more

BACKGROUND: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to 1 or more antituberculosis drugs is an increasingly common clinical problem, although the impact on outcome is uncertain. METHODS: We performed a prospective study of 180 Vietnamese adults admitted consecutively for TBM. M. tuberculosis was cultured from the cerebrospinal fluid (CSF) of all patients and was tested for susceptibility to first-line antituberculosis drugs. Presenting clinical features, time to CSF bacterial clearance, clinical response to treatment, and 9-month morbidity and mortality were compared between adults infected with susceptible and those infected with drug-resistant organisms. RESULTS: Of 180 isolates, 72 (40.0%) were resistant to at least 1 antituberculosis drug, and 10 (5.6%) were resistant to at least isoniazid and rifampicin. Isoniazid and/or streptomycin resistance was associated with slower CSF bacterial clearance but not with any differences in clinical response or outcome. Combined isoniazid and rifampicin resistance was strongly predictive of death (relative risk of death, 11.63 [95% confidence interval, 5.21-26.32]) and was independently associated with human immunodeficiency virus infection. CONCLUSIONS: Isoniazid and/or streptomycin resistance probably has no detrimental effect on the outcome of TBM when patients are treated with first-line antituberculosis drugs, but combined isoniazid and rifampicin resistance is strongly predictive of death.

Simmons CP, Thwaites GE, Quyen NTH, Chau TTH, Mai PP, Dung NT, Stepniewska K, White NJ, Hien TT, Farrar J. 2005. The clinical benefit of adjunctive dexamethasone in tuberculous meningitis is not associated with measurable attenuation of peripheral or local immune responses. J Immunol, 175 (1), pp. 579-590. | Citations: 63 (Scopus) | Show Abstract | Read more

Outcome from tuberculous meningitis (TBM) is believed to be dependent on the severity of the intracerebral inflammatory response. We have recently shown that dexamethasone improved survival in adults with TBM and postulated that the clinical effect would be associated with a measurable systemic and intracerebral impact on immunological markers of inflammation. Prolonged inflammatory responses were detected in all TBM patients irrespective of treatment assignment (placebo or dexamethasone). The inflammatory response in the cerebrospinal fluid was characterized by a leukocytosis (predominantly CD3(+)CD4(+) T lymphocytes, phenotypically distinct from those in the peripheral blood), elevated concentrations of inflammatory and anti-inflammatory cytokines, chemokines, and evidence of prolonged blood-brain barrier dysfunction. Dexamethasone significantly modulated acute cerebrospinal fluid protein concentrations and marginally reduced IFN-gamma concentrations; other immunological and routine biochemical indices of inflammation were unaffected. Peripheral blood monocyte and T cell responses to Mycobacterium tuberculosis Ags were also unaffected. Dexamethasone does not appear to improve survival from TBM by attenuating immunological mediators of inflammation in the subarachnoid space or by suppressing peripheral T cell responses to mycobacterial Ags. These findings challenge previously held theories of corticosteroid action in this disease. An understanding of how dexamethasone acts in TBM may suggest novel and more effective treatment strategies.

Andrews L, Andersen RF, Webster D, Dunachie S, Walther RM, Bejon P, Hunt-Cooke A, Bergson G, Sanderson F, Hill AVS, Gilbert SC. 2005. Quantitative real-time polymerase chain reaction for malaria diagnosis and its use in malaria vaccine clinical trials. Am J Trop Med Hyg, 73 (1), pp. 191-198. | Citations: 81 (Scopus) | Show Abstract

The demand for an effective malaria vaccine is high, with millions of people being affected by the disease every year. A large variety of potential vaccines are under investigation worldwide, and when tested in clinical trials, researchers need to extract as much data as possible from every vaccinated and control volunteer. The use of quantitative real-time polymerase chain reaction (PCR), carried out in real-time during the clinical trials of vaccines designed to act against the liver stage of the parasite's life cycle, provides more information than the gold standard method of microscopy alone and increases both safety and accuracy. PCR can detect malaria parasites in the blood up to 5 days before experienced microscopists see parasites on blood films, with a sensitivity of 20 parasites/mL blood. This PCR method has so far been used to follow 137 vaccinee and control volunteers in Phase IIa trials in Oxford and on 220 volunteer samples during a Phase IIb field trial in The Gambia.

Schultsz C, Dong VC, Chau NVV, Le NTH, Lim W, Thanh TT, Dolecek C, de Jong MD, Hien TT, Farrar J. 2005. Avian influenza H5N1 and healthcare workers. Emerg Infect Dis, 11 (7), pp. 1158-1159. | Citations: 63 (Scopus) | Read more

Scott JAG, Mwarumba S, Ngetsa C, Njenga S, Lowe BS, Slack MPE, Berkley JA, Mwangi I, Maitland K, English M, Marsh K. 2005. Progressive increase in antimicrobial resistance among invasive isolates of Haemophilus influenzae obtained from children admitted to a hospital in Kilifi, Kenya, from 1994 to 2002. Antimicrob Agents Chemother, 49 (7), pp. 3021-3024. | Citations: 21 (Scopus) | Show Abstract | Read more

Etest susceptibilities to amoxicillin, chloramphenicol, and trimethoprim-sulfamethoxazole of 240 invasive isolates of Haemophilus influenzae cultured from children in rural Kenya were 66%, 66%, and 38%, respectively. Resistance increased markedly over 9 years and was concentrated among serotype b isolates. In Africa, the increasing cost of treating resistant infections supports economic arguments for prevention through conjugate H. influenzae type b immunization.

Williams TN, Mwangi TW, Wambua S, Alexander ND, Kortok M, Snow RW, Marsh K. 2005. Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. J Infect Dis, 192 (1), pp. 178-186. | Citations: 163 (Scopus) | Show Abstract | Read more

BACKGROUND: The gene for sickle hemoglobin (HbS) is a prime example of natural selection. It is generally believed that its current prevalence in many tropical populations reflects selection for the carrier form (sickle cell trait [HbAS]) through a survival advantage against death from malaria. Nevertheless, >50 years after this hypothesis was first proposed, the epidemiological description of the relationships between HbAS, malaria, and other common causes of child mortality remains incomplete. METHODS: We studied the incidence of falciparum malaria and other childhood diseases in 2 cohorts of children living on the coast of Kenya. RESULTS: The protective effect of HbAS was remarkably specific for falciparum malaria, having no significant impact on any other disease. HbAS had no effect on the prevalence of symptomless parasitemia but was 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria. The effect of HbAS on episodes of clinical malaria was mirrored in its effect on parasite densities during such episodes. CONCLUSIONS: The present data are useful in that they confirm the mechanisms by which HbAS confers protection against malaria and shed light on the relationships between HbAS, malaria, and other childhood diseases.

Bejon P, Mwangi I, Ngetsa C, Mwarumba S, Berkley JA, Lowe BS, Maitland K, Marsh K, English M, Scott JAG. 2005. Invasive Gram-negative bacilli are frequently resistant to standard antibiotics for children admitted to hospital in Kilifi, Kenya. J Antimicrob Chemother, 56 (1), pp. 232-235. | Citations: 29 (Scopus) | Show Abstract | Read more

OBJECTIVES: To determine the pattern of resistance among Gram-negative bacilli causing invasive bacterial disease for the antibiotics that are already in common use in Kilifi, Kenya and for two potential alternatives, ciprofloxacin and cefotaxime. Also, to determine whether prevalence and severity of resistance was increasing over time, to identify patients who are particularly at risk of resistant infections, and to explore which factors are associated with the development of resistance in our setting. METHODS: We used Etest to study antibiotic susceptibility patterns of 90 Gram-negative bacilli cultured in blood or CSF from paediatric inpatients over 8 years. RESULTS: Susceptibility to amoxicillin 28%, cefotaxime 95% and ciprofloxacin 99% did not vary significantly with age. Susceptibilities for isolates from children aged less than 14 days were: chloramphenicol, 81%; trimethoprim/sulfamethoxazole, 71%; and gentamicin, 91%. From older children, susceptibilities were: chloramphenicol, 62%; trimethoprim/sulfamethoxazole, 39%; and gentamicin, 73%. Chloramphenicol susceptibility was significantly more common among non-typhi salmonellae than other species (79% versus 53%, P < 0.0005). The combination of gentamicin and chloramphenicol covered 91% of all isolates. The prevalence of resistance did not increase over time and was not more common in patients with HIV or malnutrition. Age was the only clinical feature that predicted resistance. CONCLUSIONS: Gentamicin or chloramphenicol alone was suboptimal therapy for Gram-negative sepsis, although in this retrospective study, there was no association between resistance and mortality.

Nzila A, Ward SA, Marsh K, Sims PFG, Hyde JE. 2005. Comparative folate metabolism in humans and malaria parasites (part II): activities as yet untargeted or specific to Plasmodium. Trends Parasitol, 21 (7), pp. 334-339. | Citations: 35 (Scopus) | Show Abstract | Read more

The folate pathway represents a powerful target for combating rapidly dividing systems such as cancer cells, bacteria and malaria parasites. Whereas folate metabolism in mammalian cells and bacteria has been studied extensively, it is understood less well in malaria parasites. In two articles, we attempt to reconstitute the malaria folate pathway based on available information from mammalian and microbial systems, in addition to Plasmodium-genome-sequencing projects. In part I, we focused on folate enzymes that are already used clinically as anticancer drug targets or that are under development in drug-discovery programs. In this article, we discuss mammalian folate enzymes that have not yet been exploited as potential drug targets, and enzymes that function in the de novo folate-synthesis pathway of the parasite--a particularly attractive area of attack because of its absence from the mammalian host.

van Leeuwen WB, Melles DC, Alaidan A, Al-Ahdal M, Boelens HAM, Snijders SV, Wertheim H, van Duijkeren E, Peeters JK, van der Spek PJ et al. 2005. Host- and tissue-specific pathogenic traits of Staphylococcus aureus. J Bacteriol, 187 (13), pp. 4584-4591. | Citations: 73 (Scopus) | Show Abstract | Read more

Comparative genomics were used to assess genetic differences between Staphylococcus aureus strains derived from infected animals versus colonized or infected humans. A total of 77 veterinary isolates were genetically characterized by high-throughput amplified fragment length polymorphism (AFLP). Bacterial genotypes were introduced in a large AFLP database containing similar information for 1,056 human S. aureus strains. All S. aureus strains isolated from animals in close contact with humans (e.g., pet animals) were predominantly classified in one of the five main clusters of the AFLP database (cluster I). In essence, mastitis-associated strains from animals were categorized separately (cluster IVa) and cosegregated with bacteremia-associated strains from humans. Distribution of only 2 out of 10 different virulence genes differed across the clusters. The gene encoding the toxic shock syndrome protein (tst) was more often encountered among veterinary strains (P < 0.0001) and even more in the mastitis-related strains (P<0.0001) compared to human isolate results. The gene encoding the collagen binding protein (cna) was rarely detected among invasive human strains. The virulence potential, as indicated by the number of virulence genes per strain, did not differ significantly between the human- and animal-related strains. Our data show that invasive infections in pets and humans are usually due to S. aureus strains with the same genetic background. Mastitis-associated S. aureus isolated in diverse farm animal species form a distinct genetic cluster, characterized by an overrepresentation of the toxic shock syndrome toxin superantigen-encoding gene.

Pain A, Renauld H, Berriman M, Murphy L, Yeats CA, Weir W, Kerhornou A, Aslett M, Bishop R, Bouchier C et al. 2005. Genome of the host-cell transforming parasite Theileria annulata compared with T. parva. Science, 309 (5731), pp. 131-133. | Citations: 196 (Scopus) | Show Abstract | Read more

Theileria annulata and T. parva are closely related protozoan parasites that cause lymphoproliferative diseases of cattle. We sequenced the genome of T. annulata and compared it with that of T. parva to understand the mechanisms underlying transformation and tropism. Despite high conservation of gene sequences and synteny, the analysis reveals unequally expanded gene families and species-specific genes. We also identify divergent families of putative secreted polypeptides that may reduce immune recognition, candidate regulators of host-cell transformation, and a Theileria-specific protein domain [frequently associated in Theileria (FAINT)] present in a large number of secreted proteins.

Cumbo TA, Braude D, Basnyat B, Rabinowitz L, Lescano AG, Shah MB, Radder DJ, Bashyal G, Gambert SR. 2005. Higher venous bicarbonate concentration associated with hypoxemia, not acute mountain sickness, after ascent to moderate altitude. J Travel Med, 12 (4), pp. 184-189. | Citations: 3 (Scopus) | Show Abstract | Read more

BACKGROUND: The pathophysiology underlying acute mountain sickness (AMS) and excessive hypoxemia at high altitudes is not fully understood. Previous work by our group has demonstrated a significant association between urinary measures of dehydration and bicarbonate retention in subjects developing excessive hypoxemia and AMS at high altitudes. To further characterize these findings, we returned to our original testing site to examine the hypothesis that subjects with lower levels of oxygen saturation and/or AMS would possess higher levels of venous bicarbonate. METHODS: Medical history inquiry, clinical examination, Lake Louise scoring, and the collection of venous levels of bicarbonate concentration and base excess were performed on 52 lowland-dwelling persons after they completed a religious pilgrimage in the Nepal Himalayas to approximately 4,250 m. RESULTS: Oxygen saturation levels were strongly and inversely correlated with serum levels of venous bicarbonate and base excess, whereas AMS and Lake Louise scores were not associated with these measures of alkalosis. CONCLUSIONS: Our data suggest an association between measures of serum bicarbonate anion retention and decreasing oxygen saturation. Our data do not demonstrate an association between AMS or Lake Louise scores and measures of serum bicarbonate level. We propose that excessive hypoxemia at high altitudes may be associated with a compromised ability of the kidney to metabolically compensate for an altitude-induced hypocapnic alkalosis.

Gardner MJ, Bishop R, Shah T, de Villiers EP, Carlton JM, Hall N, Ren Q, Paulsen IT, Pain A, Berriman M et al. 2005. Genome sequence of Theileria parva, a bovine pathogen that transforms lymphocytes. Science, 309 (5731), pp. 134-137. | Show Abstract | Read more

We report the genome sequence of Theileria parva, an apicomplexan pathogen causing economic losses to smallholder farmers in Africa. The parasite chromosomes exhibit limited conservation of gene synteny with Plasmodium falciparum, and its plastid-like genome represents the first example where all apicoplast genes are encoded on one DNA strand. We tentatively identify proteins that facilitate parasite segregation during host cell cytokinesis and contribute to persistent infection of transformed host cells. Several biosynthetic pathways are incomplete or absent, suggesting substantial metabolic dependence on the host cell. One protein family that may generate parasite antigenic diversity is not telomere-associated.

Geskus RB, Meyer L, Hubert J-B, Schuitemaker H, Berkhout B, Rouzioux C, Theodorou ID, Delfraissy J-F, Prins M, Coutinho RA. 2005. Causal pathways of the effects of age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on AIDS development. J Acquir Immune Defic Syndr, 39 (3), pp. 321-326. | Citations: 13 (Scopus) | Show Abstract | Read more

OBJECTIVE: To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS. DESIGN: Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up. METHODS: The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways. RESULTS: Persons of younger age or having the CCR2-64I or SDF-1 3'A mutation have significantly higher CD4 levels. Persons with the CCR5-Delta32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3'A mutation significantly increases the AIDS risk. CONCLUSIONS: Age and the CCR5-Delta32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3'A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.

Aldhous P, Butler D, Giles J, Hopkin M, Peplow M, Schiermeier Q, Mugabe J, Marsh K, Binka F, Murenzi R et al. 2005. A message to the G8 summit NATURE, 435 (7046), pp. 1146-1149. | Citations: 1 (Web of Science Lite) | Read more

Nash D, Nair S, Mayxay M, Newton PN, Guthmann J-P, Nosten F, Anderson TJC. 2005. Selection strength and hitchhiking around two anti-malarial resistance genes. Proc Biol Sci, 272 (1568), pp. 1153-1161. | Citations: 79 (Web of Science Lite) | Show Abstract | Read more

Neutral mutations may hitchhike to high frequency when they are situated close to sites under positive selection, generating local reductions in genetic diversity. This process is thought to be an important determinant of levels of genomic variation in natural populations. The size of genome regions affected by genetic hitchhiking is expected to be dependent on the strength of selection, but there is little empirical data supporting this prediction. Here, we compare microsatellite variation around two drug resistance genes (chloroquine resistance transporter (pfcrt), chromosome 7, and dihydrofolate reductase (dhfr), chromosome 4) in malaria parasite populations exposed to strong (Thailand) or weak selection (Laos) by anti-malarial drugs. In each population, we examined the point mutations underlying resistance and length variation at 22 (chromosome 4) or 25 (chromosome 7) microsatellite markers across these chromosomes. All parasites from Thailand carried the K76T mutation in pfcrt conferring resistance to chloroquine (CQ) and 2-4 mutations in dhfr conferring resistance to pyrimethamine. By contrast, we found both wild-type and resistant alleles at both genes in Laos. There were dramatic differences in the extent of hitchhiking in the two countries. The size of genome regions affected was smaller in Laos than in Thailand. We observed significant reduction in variation relative to sensitive parasites for 34-64 kb (2-4 cM) in Laos on chromosome 4, compared with 98-137 kb (6-8 cM) in Thailand. Similarly, on chromosome 7, we observed reduced variation for 34-69 kb (2-4 cM) around pfcrt in Laos, but for 195-268 kb (11-16 cM) in Thailand. Reduction in genetic variation was also less extreme in Laos than in Thailand. Most loci were monomorphic in a 12 kb region surrounding both genes on resistant chromosomes from Thailand, whereas in Laos, even loci immediately proximal to selective sites showed some variation on resistant chromosomes. Finally, linkage disequilibrium (LD) decayed more rapidly around resistant pfcrt and dhfr alleles from Laos than from Thailand. These results demonstrate that different realizations of the same selective sweeps may vary considerably in size and shape, in a manner broadly consistent with selection history. From a practical perspective, genomic regions containing resistance genes may be most effectively located by genome-wide association in populations exposed to strong drug selection. However, the lower levels of LD surrounding resistance alleles in populations under weak selection may simplify identification of functional mutations.

Phongmany S, Phetsouvanh R, Sisouphone S, Darasavath C, Vongphachane P, Rattanavong O, Mayxay M, Ramsay AC, Blacksell SD, Thammavong C et al. 2005. A randomized comparison of oral chloramphenicol versus ofloxacin in the treatment of uncomplicated typhoid fever in Laos. Trans R Soc Trop Med Hyg, 99 (6), pp. 451-458. | Citations: 13 (Web of Science Lite) | Show Abstract | Read more

We conducted a randomized open trial of oral chloramphenicol (50mg/kg/day in four divided doses for 14 days) versus ofloxacin (15 mg/kg/day in two divided doses for 3 days) in 50 adults with culture-confirmed uncomplicated typhoid fever in Vientiane, Laos. Patients had been ill for a median (range) of 8 (2-30) days. All Salmonella enterica serotype typhi isolates were nalidixic acid-sensitive, four (8%) were chloramphenicol-resistant and three (6%) were multidrug-resistant. Median (range) fever clearance times were 90 (24-224) hours in the chloramphenicol group and 54 (6-93) hours in the ofloxacin group (P<0.001). One patient in the chloramphenicol group developed an ileal perforation. Three days ofloxacin was more effective than 14 days chloramphenicol for the in-patient treatment of typhoid fever, irrespective of antibiotic susceptibility, and was of similar cost.

Wuthiekanun V, Cheng AC, Chierakul W, Amornchai P, Limmathurotsakul D, Chaowagul W, Simpson AJH, Short JM, Wongsuvan G, Maharjan B et al. 2005. Trimethoprim/sulfamethoxazole resistance in clinical isolates of Burkholderia pseudomallei. J Antimicrob Chemother, 55 (6), pp. 1029-1031. | Citations: 57 (Scopus) | Show Abstract | Read more

OBJECTIVES: Trimethoprim/sulfamethoxazole is commonly used to treat melioidosis. Antimicrobial susceptibility testing using the disc diffusion method is commonly used in melioidosis-endemic areas, but may overestimate resistance to trimethoprim/sulfamethoxazole. PATIENTS AND METHODS: We performed disc diffusion and Etest on isolates from the first positive culture for all patients presenting to Sappasithiprasong Hospital, Ubon Ratchathani, Thailand, with culture-confirmed melioidosis between 1992 and 2003. RESULTS: The estimated resistance rate for 1976 clinical Burkholderia pseudomallei isolates was 13% by Etest and 71% by disc diffusion. All isolates classed as either susceptible (n=358) or as having intermediate resistance (n=218) on disc diffusion were susceptible by Etest. Only 258 of the 1400 (18%) isolates classed as resistant on disc diffusion were resistant by Etest. CONCLUSIONS: Disc diffusion testing of B. pseudomallei may be useful as a limited screening tool in resource poor settings. Isolates assigned as 'susceptible' or 'intermediate' by disc diffusion may be viewed as 'susceptible'; those assigned as 'resistant' require further evaluation by MIC methodology.

Anderson TJC, Nair S, Qin H, Singlam S, Brockman A, Paiphun L, Nosten F. 2005. Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance? Antimicrob Agents Chemother, 49 (6), pp. 2180-2188. | Citations: 89 (Scopus) | Show Abstract | Read more

Mu et al. (Mu, J., M. T. Ferdig, X. Feng, D. A. Joy, J. Duan, T. Furuya, G. Subramanian, L. Aravind, R. A. Cooper, J. C. Wootton, M. Xiong, and X. Z. Su, Mol. Microbiol. 49:977-989, 2003) recently reported exciting associations between nine new candidate transporter genes and in vitro resistance to chloroquine (CQ) and quinine (QN), with six of these loci showing association with CQ or QN in a southeast Asian population sample. We replicated and extended this work by examining polymorphisms in these genes and in vitro resistance to eight drugs in parasites collected from the Thailand-Burma border. To minimize problems of multiple testing, we used a two-phase study design, while to minimize problems caused by population structure, we analyzed parasite isolates collected from a single clinic. We first examined associations between genotype and drug response in 108 unique single-clone parasite isolates. We found strong associations between single nucleotide polymorphisms in pfmdr and mefloquine (MFQ), artesunate (AS), and lumefantrine (LUM) response. We also observed associations between an ABC transporter (G7) and response to QN and AS and between another ABC transporter (G49) and response to dihydro-artemisinin (DHA). We reexamined significant associations in an independent sample of 199 unique single-clone infections from the same location. The significant associations with pfmdr-1042 detected in the first survey remained. However, with the exception of the G7-artesunate association, all other associations observed with the nine new candidate transporters disappeared. We also examined linkage disequilibrium (LD) between markers and phenotypic correlations between drug responses. We found minimal LD between genes. Furthermore, we found no correlation between chloroquine and quinine responses, although we did find expected strong correlations between MFQ, QN, AS, DHA, and LUM. To conclude, we found no evidence for an association between 8/9 candidate genes and response to eight different antimalarial drugs. However, the consistent association observed between a 3-bp indel in G7 and AS response merits further investigation.

Omumbo JA, Hay SI, Snow RW, Tatem AJ, Rogers DJ. 2005. Modelling malaria risk in East Africa at high-spatial resolution. Trop Med Int Health, 10 (6), pp. 557-566. | Citations: 65 (Scopus) | Show Abstract | Read more

OBJECTIVES: Malaria risk maps have re-emerged as an important tool for appropriately targeting the limited resources available for malaria control. In Sub-Saharan Africa empirically derived maps using standardized criteria are few and this paper considers the development of a model of malaria risk for East Africa. METHODS: Statistical techniques were applied to high spatial resolution remotely sensed, human settlement and land-use data to predict the intensity of malaria transmission as defined according to the childhood parasite ratio (PR) in East Africa. Discriminant analysis was used to train environmental and human settlement predictor variables to distinguish between four classes of PR risk shown to relate to disease outcomes in the region. RESULTS: Independent empirical estimates of the PR were identified from Kenya, Tanzania and Uganda (n = 330). Surrogate markers of climate recorded on-board earth orbiting satellites, population settlement, elevation and water bodies all contributed significantly to the predictive models of malaria transmission intensity in the sub-region. The accuracy of the model was increased by stratifying East Africa into two ecological zones. In addition, the inclusion of urbanization as a predictor of malaria prevalence, whilst reducing formal accuracy statistics, nevertheless improved the consistency of the predictive map with expert opinion malaria maps. The overall accuracy achieved with ecological zone and urban stratification was 62% with surrogates of precipitation and temperature being among the most discriminating predictors of the PR. CONCLUSIONS: It is possible to achieve a high degree of predictive accuracy for Plasmodium falciparum parasite prevalence in East Africa using high-spatial resolution environmental data. However, discrepancies were evident from mapped outputs from the models which were largely due to poor coverage of malaria training data and the comparable spatial resolution of predictor data. These deficiencies will only be addressed by more random, intensive small areas studies of empirical estimates of PR.

Mwangi TW, Ross A, Snow RW, Marsh K. 2005. Case definitions of clinical malaria under different transmission conditions in Kilifi District, Kenya. J Infect Dis, 191 (11), pp. 1932-1939. | Citations: 129 (Scopus) | Show Abstract | Read more

BACKGROUND: Clear case definitions of malaria are an essential means of evaluating the effectiveness of present and proposed interventions in malaria. The clinical signs of malaria are nonspecific, and parasitemia accompanied by a fever may not be sufficient to define an episode of clinical malaria in endemic areas. We defined and quantified cases of malaria in people of different age groups from 2 areas with different rates of transmission of malaria. METHODS: A total of 1602 people were followed up weekly for 2 years, and all the cases of fever accompanied by parasitemia were identified. Logistic regression methods were used to derive case definitions of malaria. RESULTS: Two case definitions of malaria were derived: 1 for children 1-14 years old and 1 for infants (<1 year old) and older children and adults (> or =15 years old). We also found a higher number of episodes of clinical malaria per person per year in people from an area of low transmission of malaria, compared with the number of episodes in those from an area of higher transmission (0.84 vs. 0.55 episodes/person/year; incidence rate ratio, 0.66 [95% confidence interval, 0.61-0.72]; P<.001). CONCLUSIONS: Case definitions of malaria are bound to be altered by factors that affect immunity, such as age and transmission. Case definitions may, however, be affected by other immunity-altering factors, such as HIV and vaccination status, and this needs to be borne in mind during vaccine trials.

Nzila A, Ward SA, Marsh K, Sims PFG, Hyde JE. 2005. Comparative folate metabolism in humans and malaria parasites (part I): pointers for malaria treatment from cancer chemotherapy. Trends Parasitol, 21 (6), pp. 292-298. | Citations: 69 (Scopus) | Show Abstract | Read more

New inhibitors are urgently needed to overcome the burgeoning problem of drug resistance in the treatment of Plasmodium falciparum infection. Targeting the folate pathway has proved to be a powerful strategy for drug development against rapidly multiplying systems such as cancer cells and microorganisms. Antifolates have long been used for malaria treatment but, despite their success, much less is known about parasite folate metabolism than about that of the human host. In this article, we focus on folate enzymes used clinically as anticancer drug targets, in addition to those that have potential to be used as drug targets, for which there are inhibitors at various stages of development. We discuss how this information could lead to the identification of new targets in malaria parasites.

Barnes KI, White NJ. 2005. Population biology and antimalarial resistance: The transmission of antimalarial drug resistance in Plasmodium falciparum. Acta Trop, 94 (3), pp. 230-240. | Citations: 73 (Scopus) | Show Abstract | Read more

Malaria morbidity and mortality continue to increase across sub-Saharan Africa. This is largely as a result of the continued use of chloroquine and sulfadoxine-pyrimethamine, despite widespread resistance. Although eliminating the asexual stages of Plasmodium falciparum is the focus of treatment of individual symptomatic patients, at a population level, reducing the carriage of gametocytes - the sexual stage responsible for infection of the mosquito vector - is necessary to limit the transmission of malaria parasites and the spread of antimalarial resistance. The probability of a mosquito being infected depends on the prevalence, duration and density of viable gametocyte carriage in the human host, although additional humoral and leukocyte factors also affect transmissibility. There is a log-sigmoid relationship between gametocyte density in the patients' blood and infectivity to the mosquito. The infectivity and thus transmission potential associated with a particular antimalarial treatment can be characterised as a function of blood gametocyte density and time, summing these over the acute and all subsequent recrudescences of that infection. Gametocyte carriage and infectivity to mosquitoes is consistently higher in patients infected with drug resistant compared with drug sensitive malaria parasites. It is the ratio of transmission potential in drug resistant versus sensitive infections that drives the spread of resistance. Early access to highly effective antimalarial treatment reduces the risk of disease progression and limits gametocyte carriage. The remarkable spread of sulfadoxine-pyrimethamine (SP) resistance across vast regions results from the very high post-treatment prevalence and density of gametocyte carriage following SP treatment. In areas of low intensity malaria transmission, the gametocyte-reducing effect of widespread use of artemisinin-based combination therapy has resulted in a sustained decrease in malaria transmission and a decrease in the spread of resistance. Malaria treatment policy should be based primarily on therapeutic efficacy against asexual stages, but should also consider transmission reduction potential. Artemisinin-based combination therapies are the only antimalarials currently available which rapidly reduce both asexual and gametocyte stages of the P. falciparum lifecycle.

Gutiérrez JM, Rojas E, Quesada L, León G, Núñez J, Laing GD, Sasa M, Renjifo JM, Nasidi A, Warrell DA et al. 2005. Pan-African polyspecific antivenom produced by caprylic acid purification of horse IgG: an alternative to the antivenom crisis in Africa. Trans R Soc Trop Med Hyg, 99 (6), pp. 468-475. | Citations: 67 (Scopus) | Show Abstract | Read more

A polyspecific Pan-African antivenom has been produced from the plasma of horses immunized with a mixture of the venoms of Echis ocellatus, Bitis arietans and Naja nigricollis, the three most medically important snakes in sub-Saharan Africa. The antivenom is a whole IgG preparation, obtained by caprylic acid precipitation of non-IgG plasma proteins. The antivenom effectively neutralizes the most important toxic activities of the three venoms used in the immunization in standard assays involving preincubation of venom and antivenom before testing. This antivenom compares favourably with other antivenoms designed for use in Africa with respect to neutralization of the toxins present in the venom of E. ocellatus. Caprylic acid fractionation of horse hyperimmune plasma is a simple, convenient and cheap protocol for the manufacture of high quality whole IgG antivenoms. It constitutes a potentially valuable technology for the alleviation of the critical shortage of antivenom in Africa.

Wertheim HFL, Vos MC. 2005. Can mupirocin prevent methicillin-resistant Staphylococcus aureus infections? Crit Care, 9 (3), pp. 257-258. | Citations: 7 (Scopus) | Show Abstract | Read more

In a retrospective study, Dr Muller and colleagues have assessed the efficacy of mupirocin nasal ointment alongside hygienic measures in methicillin-resistant Staphylococcus aureus (MRSA)-positive patients admitted to the intensive care unit (ICU). Their findings, which suggest that intranasal mupirocin can prevent ICU-related MRSA infections, need confirmation in a well-designed clinical trial. In general: early identification, isolation and treatment of all MRSA carriers, including health care workers, and disinfection of contaminated environments, are the main 'ingredients' of an effective MRSA 'search and destroy' program.

Mwangi TW, Mohammed M, Dayo H, Snow RW, Marsh K. 2005. Clinical algorithms for malaria diagnosis lack utility among people of different age groups. Trop Med Int Health, 10 (6), pp. 530-536. | Citations: 57 (Scopus) | Show Abstract | Read more

We conducted a study to determine whether clinical algorithms would be useful in malaria diagnosis among people living in an area of moderate malaria transmission within Kilifi District in Kenya. A total of 1602 people of all age groups participated. We took smears and recorded clinical signs and symptoms (prompted or spontaneous) of all those presenting to the study clinic with a history of fever. A malaria case was defined as a person presenting to the clinic with a history of fever and concurrent parasitaemia. A set of clinical signs and symptoms (algorithms) with the highest sensitivity and specificity for diagnosing a malaria case was selected for the age groups </=5 years, 6-14 years and >/=15 years. These age-optimized derived algorithms were able to identify about 66% of the cases among those <15 years of age but only 23% of cases among adults. Were these algorithms to be used as a basis for a decision on treatment among those presenting to the clinic, 16% of children </=5 years, 44% of those 6-14 years of age and 66% of the adults who had a history of fever and parasitaemia >/=5000 parasites/microl of blood would be sent home without treatment. Clinical algorithms therefore appear to have little utility in malaria diagnosis, performing even worse in the older age groups, where avoiding unnecessary use of anti-malarials would make more drugs available to the really needy population of children under 5 years of age.

Scott S, Cumberland P, Shulman CE, Cousens S, Cohen BJ, Brown DWG, Bulmer JN, Dorman EK, Kawuondo K, Marsh K, Cutts F. 2005. Neonatal measles immunity in rural Kenya: the influence of HIV and placental malaria infections on placental transfer of antibodies and levels of antibody in maternal and cord serum samples. J Infect Dis, 191 (11), pp. 1854-1860. | Citations: 67 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: Young infants are protected from measles infection by maternal measles antibodies. The level of these antibodies at birth depends on the level of antibodies in the mother and the extent of placental transfer. We investigated predictors of levels of measles antibodies in newborns in rural Kenya. METHODS: A total of 747 paired maternal-cord serum samples (91 from human immunodeficiency virus [HIV]-infected and 656 from HIV-uninfected mothers) were tested for measles immunoglobulin G antibodies. Placental malaria infection was determined by biopsy. Data on pregnancy history, gestational age, and anthropometric and socioeconomic status were collected. RESULTS: Infants born to HIV-infected mothers were more likely (odds ratio, 4.6 [95% confidence interval {CI}, 2.2-9.7]) to be seronegative and had 35.1% (95% CI, 9.8%-53.2%) lower levels of measles antibodies than did those born to HIV-uninfected mothers. Preterm delivery, early maternal age, and ethnic group were also associated with reduced levels of measles antibodies. There was little evidence that placental malaria infection was associated with levels of measles antibodies in newborns. CONCLUSION: Our results suggest that maternal HIV infection may reduce levels of measles antibodies in newborns. Low levels of measles antibodies at birth render children susceptible to measles infection at an early age. This is of concern in sub-Saharan African countries, where not only is the prevalence of HIV high, but measles is the cause of much morbidity and mortality.

Lee H, Kotloff K, Chukaserm P, Samosornsuk S, Chompook P, Deen JL, Von Seidlein L, Clemens JD, Wanpen C. 2005. Shigellosis remains an important problem in children less than 5 years of age in Thailand. Epidemiol Infect, 133 (3), pp. 469-474. | Citations: 14 (Scopus) | Show Abstract | Read more

This is a review of existing data on the burden of shigellosis in Thailand to determine trends, vulnerable groups, predominant species and serotypes, and antimicrobial resistance patterns. Diarrhoea and dysentery morbidity and mortality data from 1991 to 1999 was collected from the routine surveillance system and demographic data from the government census. International and local literature published between 1988 and 2000 was systematically reviewed. Based on the routine surveillance system, the annual incidence of bacillary dysentery decreased from 1.3 to 0.2/10,000 persons per year. The remaining burden is highest in children <5 years of age at 2.7/10,000 persons per year. In comparison, a prospective study utilizing active surveillance found an incidence in children <5 years of age that was more than 100-fold higher at 640/10,000 persons per year. Despite the decrease in morbidity and mortality based on routinely collected data, shigellosis remains an important problem in children <5 years of age in Thailand.

Ansaruzzaman M, Lucas M, Deen JL, Bhuiyan NA, Wang X-Y, Safa A, Sultana M, Chowdhury A, Nair GB, Sack DA et al. 2005. Pandemic serovars (O3:K6 and O4:K68) of Vibrio parahaemolyticus associated with diarrhea in Mozambique: spread of the pandemic into the African continent. J Clin Microbiol, 43 (6), pp. 2559-2562. | Citations: 50 (Scopus) | Show Abstract | Read more

Forty-two episodes of Vibrio parahaemolyticus infections were detected in Beira, Mozambique, from January to May 2004. The majority of the isolates (81%) belonged to the pandemic serovars (O3:K6 and O4:K68) of V. parahaemolyticus. The pandemic serovars were positive by group-specific PCR (GS-PCR) and a PCR specific for open reading frame ORF8 (ORF8-PCR), which are molecular markers of the pandemic clone, and were positive for tdh but negative for trh. The remaining 19% of the strains also possessed the tdh gene but were GS-PCR and ORF8-PCR negative and did not belong to the pandemic serovars. Patients with V. parahaemolyticus infection were older (mean age, 27 years) than patients infected by other diarrheal agents (mean age, 21 years). Ten percent of diarrhea patients from whom no V. parahaemolyticus was cultured were severely dehydrated, but none of the V. parahaemolyticus cases were severely dehydrated. This is the first report of the isolation of pandemic strains of V. parahaemolyticus in sub-Saharan Africa and clearly indicates that the pandemic of V. parahaemolyticus has spread into the African continent.

Griffiths MJ, Shafi MJ, Popper SJ, Hemingway CA, Kortok MM, Wathen A, Rockett KA, Mott R, Levin M, Newton CR et al. 2005. Genomewide analysis of the host response to malaria in Kenyan children. J Infect Dis, 191 (10), pp. 1599-1611. | Citations: 82 (Scopus) | Show Abstract | Read more

Malaria is a global problem, and there is a critical need for further understanding of the disease process. When malarial parasites invade and develop within the bloodstream, they stimulate a profound host response whose main clinical sign is fever. To explore this response, we measured host gene expression in whole blood from Kenyan children hospitalized with either acute malaria or other febrile illnesses. Genomewide analysis of expression identified 2 principal gene-expression profiles related to neutrophil and erythroid activity. In addition to these general acute responses, a third gene-expression profile was associated with host parasitemia; mediators of erythrophagocytosis and cellular stress were notable components of this response. The delineation of subjects on the basis of patterns of gene expression provides a molecular perspective of the host response to malaria and further functional insight into the underlying processes of pathogenesis.

Dorfman JR, Bejon P, Ndungu FM, Langhorne J, Kortok MM, Lowe BS, Mwangi TW, Williams TN, Marsh K. 2005. B cell memory to 3 Plasmodium falciparum blood-stage antigens in a malaria-endemic area. J Infect Dis, 191 (10), pp. 1623-1630. | Citations: 70 (Scopus) | Show Abstract | Read more

To gain insight into why antibody responses to malarial antigens tend to be short lived, we studied antigen-specific memory B cells from donors in an area where malaria is endemic. We compared antibody and memory B cell responses to tetanus toxoid with those to 3 Plasmodium falciparum candidate vaccine antigens: the C-terminal portion of merozoite surface protein 1 (MSP1(19)), apical membrane antigen 1 (AMA1), and the cysteine-rich interdomain region 1 alpha (CIDR1 alpha ) of a protein from the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. These data are the first to be generated on memory B cells in children who are in the process of acquiring antimalarial immunity, and they reveal defects in B cell memory to P. falciparum antigens. Compared with the results for tetanus toxoid, more donors who were positive for antibody to AMA1 and CIDR1 alpha were negative for memory B cells. These data imply that some exposures to malaria do not result in the establishment of stable populations of circulating antigen-specific memory B cells, suggesting possible mechanisms for the short-lived nature of many anti-malarial antibody responses.

Wilson J, Rowlands K, Rockett K, Moore C, Lockhart E, Sharland M, Kwiatkowski D, Hull J. 2005. Genetic variation at the IL10 gene locus is associated with severity of respiratory syncytial virus bronchiolitis. J Infect Dis, 191 (10), pp. 1705-1709. | Citations: 57 (Scopus) | Show Abstract | Read more

The intense airway inflammatory response associated with respiratory syncytial virus (RSV) infection may be an important determinant in the severity of the disease. Interleukin (IL)-10 is a key regulatory cytokine known to be secreted during this infection. We investigated the role that IL-10 plays in RSV disease by studying the effects that variation in the IL10 gene has on the outcome of the disease. Eight single nucleotide polymorphisms (SNPs) spanning the IL10 gene were selected, and haplotypes were constructed. SNPs that efficiently tagged these haplotypes were then typed in 580 infants with severe RSV bronchiolitis and in 580 control subjects. None of the SNPs or haplotypes was associated with RSV bronchiolitis. In a subgroup analysis, 2 SNPs (IL10-1117 and IL10-3585) were associated (odds ratio, 1.7; P=.004) with the need for mechanical ventilation. These data are consistent with the theory that IL10 plays a role in the severity of RSV infection in infants.

Kivelä PS, Krol A, Salminen MO, Geskus RB, Suni JI, Anttila V-J, Liitsola K, Zetterberg V, Miedema F, Berkhout B et al. 2005. High plasma HIV load in the CRF01-AE outbreak among injecting drug users in Finland. Scand J Infect Dis, 37 (4), pp. 276-283. | Citations: 12 (Scopus) | Show Abstract | Read more

An explosive outbreak of HIV-1 caused by the recombinant subtype AE (CRF01-AE) was detected in 1998 among Finnish injecting drug users (IDUs). These IDUs were compared with IDUs from the Amsterdam Cohort Study (ACS) infected with subtype B, to detect possible differences between 2 western IDU cohorts infected with different subtypes. Markers for progression (viral load and CD4+lymphocyte count) were compared between 93 IDUs with CRF01-AE and 63 IDUs with subtype B. Only persons with a seroconversion interval =2 y were included. During 48 months of follow-up, both cohorts were similar in CD4+ cell decline, but the Finnish IDUs had 0.34-0.94 log10 copies/ml higher viral loads. The Amsterdam IDUs had a low viral load (<1000 copies/ml) significantly more often than the Finnish IDUs. The difference could not be explained by the use of antiretrovirals. The higher viral load may have contributed to the rapid spread of the recombinant virus in the Finnish outbreak.

Limmathurotsakul D, Wuthiekanun V, Chierakul W, Cheng AC, Maharjan B, Chaowagul W, White NJ, Day NPJ, Peacock SJ. 2005. Role and significance of quantitative urine cultures in diagnosis of melioidosis. J Clin Microbiol, 43 (5), pp. 2274-2276. | Citations: 24 (Scopus) | Show Abstract | Read more

Melioidosis is associated with significant mortality in countries in which it is endemic. Previous studies have demonstrated that quantitative Burkholderia pseudomallei counts in blood are predictive of mortality. Here we examine the relationship between outcomes and quantitative B. pseudomallei counts in urine. A total of 755 patients presenting to Sappasithiprasong Hospital, Ubon Ratchathani, northeast Thailand (in the northeast part of the country), with melioidosis between July 1993 and October 2003 had quantitative urine cultures performed within 72 h of admission. Urine culture results were divided into the following groups: (i) no growth of B. pseudomallei from a neat sample or pellet, (ii) positive result from a centrifuged pellet only (< 10(3) CFU/ml), (iii) detection of between 10(3) CFU/ml and 10(5) CFU/ml from a neat sample, or (iv) detection of > or = 10(5) CFU/ml from a neat sample. The overall in-hospital mortality rate was 45%. Patients with negative urine cultures had the lowest death rate (39%). Mortality rates rose with increasing B. pseudomallei counts in urine, from 58% for those with positive spun pellets only to 61% for those with between 10(3) CFU/ml and 10(5) CFU/ml and 71% for those with > or = 10(5) CFU/ml. This was independent of age, presence of bacteremia, known risk factors for melioidosis such as diabetes, and the prior administration of antibiotics. The presence of B. pseudomallei in urine during systemic infection is associated with a poor prognosis.

Simmons CP, Dong T, Chau NV, Dung NTP, Chau TNB, Thao LTT, Dung NT, Hien TT, Rowland-Jones S, Farrar J. 2005. Early T-cell responses to dengue virus epitopes in Vietnamese adults with secondary dengue virus infections. J Virol, 79 (9), pp. 5665-5675. | Citations: 100 (Web of Science Lite) | Show Abstract | Read more

T-cell responses to dengue viruses may be important in both protective immunity and pathogenesis. This study of 48 Vietnamese adults with secondary dengue virus infections defined the breadth and magnitude of peripheral T-cell responses to 260 overlapping peptide antigens derived from a dengue virus serotype 2 (DV2) isolate. Forty-seven different peptides evoked significant gamma interferon enzyme-linked immunospot (ELISPOT) assay responses in 39 patients; of these, 34 peptides contained potentially novel T-cell epitopes. NS3 and particularly NS3200-324 were important T-cell targets. The breadth and magnitude of ELISPOT responses to DV2 peptides were independent of the infecting dengue virus serotype, suggesting that cross-reactive T cells dominate the acute response during secondary infection. Acute ELISPOT responses were weakly correlated with the extent of hemoconcentration in individual patients but not with the nadir of thrombocytopenia or overall clinical disease grade. NS3556-564 and Env414-422 were identified as novel HLA-A*24 and B*07-restricted CD8+ T-cell epitopes, respectively. Acute T-cell responses to natural variants of Env414-422 and NS3556-564 were largely cross-reactive and peaked during disease convalescence. The results highlight the importance of NS3 and cross-reactive T cells during acute secondary infection but suggest that the overall breadth and magnitude of the T-cell response is not significantly related to clinical disease grade.

Ogutu BR, Nzila AM, Ochong E, Mithwani S, Wamola B, Olola CHO, Lowe B, Kokwaro GO, Marsh K, Newton CRJC. 2005. The role of sequential administration of sulphadoxine/pyrimethamine following quinine in the treatment of severe falciparum malaria in children. Trop Med Int Health, 10 (5), pp. 484-488. | Citations: 8 (Scopus) | Show Abstract | Read more

Sulphadoxine/pyrimethamine (SP) is often administered with quinine in the treatment of severe falciparum malaria to shorten the course of quinine. The efficacy of SP alone in the treatment of non-severe malaria has been declining rapidly in East Africa, raising concerns of the usefulness of a shortened course of quinine followed SP. We audited the efficacy of quinine/SP in the treatment of severe malaria in Kenyan children. Children with severe falciparum malaria were treated with parenteral quinine followed by a single oral dose of SP. A clinical evaluation was performed 3 weeks later in which a blood sample was obtained for full haemogram, blood slide and analysis of the parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) codons, mutations of which are associated with resistance to SP. A total of 452 children were enrolled, of whom 374 completed the study. Fifty-two (13.9%) children were parasitaemic by 3 weeks of whom 17 (4.5%) had fever as well. The treatment failure group had a significantly higher parasitaemia (129 061 vs. 43 339; P<0.001) and haemoglobin on admission, but only admission parasitaemia independently predicted treatment failure. Those with treatment failure had a significantly lower rise in haemoglobin at 3 weeks compared with treatment successes (9.0 vs. 10.0 g/dl). Of the 76 parasite isolates collected before treatment, 40 (53%) were triple mutant DHFR-double DHPS (Tp-Db), the genotype most associated with SP resistance. Three weeks after SP treatment, the proportion of Tp-Db increased to 72% (31/43). The high treatment failure rate and proportion of parasites with Tp-Db negate the use of SP to shorten the course of quinine treatment in East Africa.

Nzila A, Ochong E, Nduati E, Gilbert K, Winstanley P, Ward S, Marsh K. 2005. Why has the dihydrofolate reductase 164 mutation not consistently been found in Africa yet? Trans R Soc Trop Med Hyg, 99 (5), pp. 341-346. | Citations: 37 (Scopus) | Show Abstract | Read more

Resistance to the antifolate sulfadoxine-pyrimethamine (SP), the current mass-treatment antimalarial drug, is associated with selection of point mutations in dihydrofolate reductase and dihydropteroate synthase. Among these mutations, the leucine 164 dihydrofolate reductase mutation (Leu-164) is associated with higher levels of SP resistance; this mutation is also associated with a decrease in the efficacy of chlorproguanil/dapsone, a newly developed antifolate antimalarial drug. Leu-164 has been detected in Southeast Asia and South America, regions where SP is no longer effective. Surprisingly, this mutation has not yet been detected in Africa, using the standard protocol based on PCR-RFLP, despite high SP resistance. In this paper, we discuss briefly the reasons why Leu-164 has not yet been selected in Africa and we propose a means that may slow down the selection of this mutation.

Williams TN, Mwangi TW, Roberts DJ, Alexander ND, Weatherall DJ, Wambua S, Kortok M, Snow RW, Marsh K. 2005. An immune basis for malaria protection by the sickle cell trait. PLoS Med, 2 (5), pp. e128. | Citations: 115 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Malaria resistance by the sickle cell trait (genotype HbAS) has served as the prime example of genetic selection for over half a century. Nevertheless, the mechanism of this resistance remains the subject of considerable debate. While it probably involves innate factors such as the reduced ability of Plasmodium falciparum parasites to grow and multiply in HbAS erythrocytes, recent observations suggest that it might also involve the accelerated acquisition of malaria-specific immunity. METHODS AND FINDINGS: We studied the age-specific protection afforded by HbAS against clinical malaria in children living on the coast of Kenya. We found that protection increased with age from only 20% in the first 2 y of life to a maximum of 56% by the age of 10 y, returning thereafter to 30% in participants greater than 10 y old. CONCLUSIONS: Our observations suggest that malaria protection by HbAS involves the enhancement of not only innate but also of acquired immunity to the parasite. A better understanding of the underlying mechanisms might yield important insights into both these processes.

Ross A, English M. 2005. Early infant growth monitoring--time well spent? Trop Med Int Health, 10 (5), pp. 404-411. | Citations: 5 (Scopus) | Show Abstract | Read more

BACKGROUND: In sub-Saharan Africa, growth monitoring for every infant consumes time and resources with no evidence of any benefits. We consider an alternative pragmatic approach which provides scheduled monitoring for low birth weight infants only, and takes advantage of non-routine clinic visits for normal birth weight infants. We investigate the implications for the number of weighing episodes and performance as a screening tool using data from a cohort study of infants followed-up from birth to 98 days. METHODS: Babies delivered in a Kenyan district hospital and enrolled in a birth cohort were weighed at birth and at follow-up visits coinciding with their immunizations at 6, 10 and 14 weeks. Episodes of illness resulting in clinic visits, hospital admissions or death were identified and recorded. RESULTS: Four-fifths (81%) of the 2210 babies weighed 2500 g or more at birth, of whom 133 (7%) were admitted to hospital or died before 14 weeks of age. 85% of the deaths and 67% of admissions occurred within 3 weeks of birth. Most babies weighing 2500 g or more and who had weight measurements grew well. Only 4% of infants were exclusively breastfed at 14 weeks of age. Neither universal nor pragmatic growth monitoring was a good screening tool among this group of infants for episodes of illness in the short-term. Pragmatic monitoring would involve 72% fewer weighing episodes. CONCLUSIONS: A pragmatic approach in early infancy would not represent a major change in policy, would appear to have no disadvantages and would probably increase the time available for implementing interventions of greater benefit such as breastfeeding promotion.

Berkley JA, Maitland K, Mwangi I, Ngetsa C, Mwarumba S, Lowe BS, Newton CRJC, Marsh K, Scott JAG, English M. 2005. Use of clinical syndromes to target antibiotic prescribing in seriously ill children in malaria endemic area: observational study. BMJ, 330 (7498), pp. 995. | Citations: 103 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: To determine how well antibiotic treatment is targeted by simple clinical syndromes and to what extent drug resistance threatens affordable antibiotics. DESIGN: Observational study involving a priori definition of a hierarchy of syndromic indications for antibiotic therapy derived from World Health Organization integrated management of childhood illness and inpatient guidelines and application of these rules to a prospectively collected dataset. SETTING: Kilifi District Hospital, Kenya. PARTICIPANTS: 11,847 acute paediatric admissions. MAIN OUTCOME MEASURES: Presence of invasive bacterial infection (bacteraemia or meningitis) or Plasmodium falciparum parasitaemia; antimicrobial sensitivities of isolated bacteria. RESULTS: 6254 (53%) admissions met criteria for syndromes requiring antibiotics (sick young infants; meningitis/encephalopathy; severe malnutrition; very severe, severe, or mild pneumonia; skin or soft tissue infection): 672 (11%) had an invasive bacterial infection (80% of all invasive bacterial infections identified), and 753 (12%) died (93% of all inpatient deaths). Among P falciparum infected children with a syndromic indication for parenteral antibiotics, an invasive bacterial infection was detected in 4.0-8.8%. For the syndrome of meningitis/encephalopathy, 96/123 (76%) isolates were fully sensitive in vitro to penicillin or chloramphenicol. CONCLUSIONS: Simple clinical syndromes effectively target children admitted with invasive bacterial infection and those at risk of death. Malaria parasitaemia does not justify withholding empirical parenteral antibiotics. Lumbar puncture is critical to the rational use of antibiotics.

Lindegårdh N, Annerberg A, Blessborn D, Bergqvist Y, Day N, White NJ. 2005. Development and validation of a bioanalytical method using automated solid-phase extraction and LC-UV for the simultaneous determination of lumefantrine and its desbutyl metabolite in plasma. J Pharm Biomed Anal, 37 (5), pp. 1081-1088. | Citations: 37 (Scopus) | Show Abstract | Read more

A bioanalytical method for the determination of lumefantrine (LF) and its metabolite desbutyl-lumefantrine (DLF) in plasma by solid-phase extraction (SPE) and liquid chromatography has been developed. Plasma proteins were precipitated with acetonitrile:acetic acid (99:1, v/v) containing a DLF analogue internal standard before being loaded onto a octylsilica (3 M Empore) SPE column. Two different DLF analogues were evaluated as internal standards. The compounds were analysed by liquid chromatography UV detection on a SB-CN (250 mm x 4.6 mm) column with a mobile phase containing acetonitrile-sodium phosphate buffer pH (2.0; 0.1 M) (55:45, v/v) and sodium perchlorate 0.05 M. Different SPE columns were evaluated during method development to optimise reproducibility and recovery for LF, DLF and the two different DLF analogues. The within-day precisions for LF were 6.6 and 2.1% at 0.042 and 8.02 microg/mL, respectively, and for DLF 4.5 and 1.5% at 0.039 and 0.777 microg/mL, respectively. The between-day precisions for LF were 12.0 and 2.9% at 0.042 and 8.02 microg/mL, respectively, while for DLF 0.7 and 1.2% at 0.039 and 0.777 microg/mL, respectively. The limit of quantification was 0.024 and 0.021 microg/mL for LF and DLF, respectively. Different amounts of lipids in plasma did not affect the absolute recovery of LF or DLF.

Imwong M, Pukrittayakamee S, Grüner AC, Rénia L, Letourneur F, Looareesuwan S, White NJ, Snounou G. 2005. Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1. Malar J, 4 pp. 20. | Citations: 93 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium vivax is the second most prevalent malaria parasite affecting more than 75 million people each year, mostly in South America and Asia. In addition to major morbidity this parasite is associated with relapses and a reduction in birthweight. The emergence and spread of drug resistance in Plasmodium falciparum is a major factor in the resurgence of this parasite. P. vivax resistance to drugs has more recently emerged and monitoring the situation would be helped, as for P. falciparum, by molecular methods that can be used to characterize parasites in field studies and drug efficacy trials. METHODS: Practical PCR genotyping protocols based on polymorphic loci present in two P. vivax genetic markers, Pvcs and Pvmsp1, were developed. The methodology was evaluated using 100 P. vivax isolates collected in Thailand. RESULTS AND DISCUSSION: Analysis revealed that P. vivax populations in Thailand are highly diverse genetically, with mixed genotype infections found in 26 % of the samples (average multiplicity of infection = 1.29). A large number of distinguishable alleles were found for the two markers, 23 for Pvcs and 36 for Pvmsp1. These were generally randomly distributed amongst the isolates. A total of 68 distinct genotypes could be enumerated in the 74 isolates with a multiplicity of infection of 1. CONCLUSION: These results indicate that the genotyping protocols presented can be useful in the assessment of in vivo drug efficacy clinical trials conducted in endemic areas and for epidemiological studies of P. vivax infections.

Baird JK. 2005. Effectiveness of antimalarial drugs. N Engl J Med, 352 (15), pp. 1565-1577. | Citations: 191 (Web of Science Lite) | Read more

Basnyat B. 2005. The physiologic basis of high-altitude diseases. Ann Intern Med, 142 (7), pp. 591. | Read more

Wuthiekanun V, Desakorn V, Wongsuvan G, Amornchai P, Cheng AC, Maharjan B, Limmathurotsakul D, Chierakul W, White NJ, Day NPJ, Peacock SJ. 2005. Rapid immunofluorescence microscopy for diagnosis of melioidosis. Clin Diagn Lab Immunol, 12 (4), pp. 555-556. | Citations: 46 (Scopus) | Show Abstract | Read more

An immunofluorescent (IF) method that detects Burkholderia pseudomallei in clinical specimens within 10 min was devised. The results of this rapid method and those of an existing IF method were prospectively compared with the culture results for 776 specimens from patients with suspected melioidosis. The sensitivities of both IF tests were 66%, and the specificities were 99.5 and 99.4%, respectively.

Newton PN, Chaulet J-F, Brockman A, Chierakul W, Dondorp A, Ruangveerayuth R, Looareesuwan S, Mounier C, White NJ. 2005. Pharmacokinetics of oral doxycycline during combination treatment of severe falciparum malaria. Antimicrob Agents Chemother, 49 (4), pp. 1622-1625. | Citations: 26 (Web of Science Lite) | Show Abstract | Read more

The pharmacokinetics of oral doxycycline administered at 200 mg every 24 h were investigated in 17 patients recovering from severe Plasmodium falciparum malaria. The data suggest that the doses of doxycycline currently recommended (circa 3.5 mg/kg of body weight daily) may not be optimal.

Nacher M, McGready R, Lermoo C, Wichiponpiboon J, Nosten F. 2005. Photoallergy to quinine. Trop Doct, 35 (2), pp. 117-118. | Citations: 1 (Web of Science Lite) | Read more

Cockburn R, Newton PN, Agyarko EK, Akunyili D, White NJ. 2005. The global threat of counterfeit drugs: Why industry and governments must communicate the dangers PLOS MEDICINE, 2 (4), pp. 302-308. | Citations: 72 (Web of Science Lite) | Read more

Urban BC, Hien TT, Day NP, Phu NH, Roberts R, Pongponratn E, Jones M, Mai NTH, Bethell D, Turner GDH et al. 2005. Fatal Plasmodium falciparum malaria causes specific patterns of splenic architectural disorganization. Infect Immun, 73 (4), pp. 1986-1994. | Citations: 61 (Scopus) | Show Abstract | Read more

The spleen is critical for host defense against pathogens, including Plasmodium falciparum. It has a dual role, not only removing aged or antigenically altered erythrocytes from the blood but also as the major lymphoid organ for blood-borne or systemic infections. The human malaria parasite P. falciparum replicates within erythrocytes during asexual blood stages and causes repeated infections that can be associated with severe disease. In spite of the crucial role of the spleen in the innate and acquired immune response to malaria, there is little information on the pathology of the spleen in human malaria. We performed a histological and quantitative immunohistochemical study of spleen sections from Vietnamese adults dying from severe falciparum malaria and compared the findings with the findings for spleen sections from control patients and patients dying from systemic bacterial sepsis. Here we report that the white pulp in the spleens of patients dying from malaria showed a marked architectural disorganization. We observed a marked dissolution of the marginal zones with relative loss of B cells. Furthermore, we found strong HLA-DR expression on sinusoidal lining cells but downregulation on cordal macrophages. P. falciparum infection results in alterations in splenic leukocytes, many of which are not seen in sepsis.

Dunstan SJ, Hawn TR, Hue NT, Parry CP, Ho VA, Vinh H, Diep TS, House D, Wain J, Aderem A et al. 2005. Host susceptibility and clinical outcomes in toll-like receptor 5-deficient patients with typhoid fever in Vietnam. J Infect Dis, 191 (7), pp. 1068-1071. | Citations: 45 (Scopus) | Show Abstract | Read more

Toll-like receptor 5 (TLR5) mediates innate immune responses to bacterial pathogens by binding to flagellin. A polymorphism in the TLR5 gene introduces a premature stop codon (TLR5(392STOP)) that is associated with susceptibility to legionnaires disease. Here we investigated whether TLR5(392STOP) was associated with typhoid fever. The frequency of TLR5(392STOP) was not significantly different in 565 patients with typhoid fever and 281 ethnically matched control subjects. Furthermore, TLR5 deficiency had no measurable effect on a number of clinical parameters associated with typhoid fever, including fever clearance time, pathogen burden, disease severity, or age at acquisition of disease. TLR5 may not play an important role in TLR-stimulated innate immune responses to human infection with Salmonella enterica serovar Typhi. Initiation of these responses may rely on other TLRs that recognize different bacterial ligands.

de Fost M, Chierakul W, Pimda K, Dondorp AM, White NJ, Van der Poll T. 2005. Activation of cytotoxic lymphocytes in patients with scrub typhus. Am J Trop Med Hyg, 72 (4), pp. 465-467. | Citations: 22 (Scopus) | Show Abstract

Thai patients with scrub typhus caused by the intracellular pathogen Orientia tsutsugamushi displayed elevated plasma concentrations of granzymes A and B, interferon-gamma (IFN)-gamma-inducible protein 10, and monokine induced by IFN-gamma. These data suggest that activation of cytotoxic lymphocytes is part of the early host response to scrub typhus.

Omodeo-Salè F, Motti A, Dondorp A, White NJ, Taramelli D. 2005. Destabilisation and subsequent lysis of human erythrocytes induced by Plasmodium falciparum haem products. Eur J Haematol, 74 (4), pp. 324-332. | Citations: 50 (Scopus) | Show Abstract | Read more

In falciparum malaria, both infected and uninfected red cells have structural and functional alterations. To investigate the mechanisms of these modifications, we studied the effects of two Plasmodium falciparum haem products (haematin and malaria pigment in the synthetic form beta-haematin) on isolated human red blood cells (RBCs) and purified RBC ghosts. A dose- and time-dependent incorporation of haematin into RBC ghosts and intact cells was observed, which was in proportion to the extent of haematin- induced haemolysis. RBCs pre-incubated with haematin were more sensitive to haemolysis induced by hypotonic shock, low pH, H2O2 or haematin itself. Haemolysis was not related to membrane lipid peroxidation and only partially to oxidation of protein sulphydryl groups and it could not be prevented by scavengers of lipid peroxidation or hydroperoxide groups. N-acetylcysteine partly protected the oxidation of SH groups and significantly reduced haemolysis. In contrast, beta-haematin was neither haemolytic nor oxidative towards protein sulphydryl groups. Beta-haematin did destabilise the RBC membrane, but to a lesser extent than haematin, inducing increased susceptibility to lysis caused by hypotonic medium, H2O2 or haematin. This study suggests that the destabilising effect of haematin and, to a much less extent, beta-haematin on the RBC membrane does not result from oxidative damage of membrane lipids but from direct binding or incorporation which may affect the reciprocal interactions between the membrane and cytoskeleton proteins. These changes could contribute to the reduced red cell deformability associated with severe malaria.

Bishop AL, Baker S, Jenks S, Fookes M, Gaora PO, Pickard D, Anjum M, Farrar J, Hien TT, Ivens A, Dougan G. 2005. Analysis of the hypervariable region of the Salmonella enterica genome associated with tRNA(leuX). J Bacteriol, 187 (7), pp. 2469-2482. | Citations: 30 (Web of Science Lite) | Show Abstract | Read more

The divergence of Salmonella enterica and Escherichia coli is estimated to have occurred approximately 140 million years ago. Despite this evolutionary distance, the genomes of these two species still share extensive synteny and homology. However, there are significant differences between the two species in terms of genes putatively acquired via various horizontal transfer events. Here we report on the composition and distribution across the Salmonella genus of a chromosomal region designated SPI-10 in Salmonella enterica serovar Typhi and located adjacent to tRNA(leuX). We find that across the Salmonella genus the tRNA(leuX) region is a hypervariable hot spot for horizontal gene transfer; different isolates from the same S. enterica serovar can exhibit significant variation in this region. Many P4 phage, plasmid, and transposable element-associated genes are found adjacent to tRNA(leuX) in both Salmonella and E. coli, suggesting that these mobile genetic elements have played a major role in driving the variability of this region.

Zurovac D, Ochola SA, Midia B, Snow RW. 2005. The quality of sulfadoxine-pyrimethamine prescriptions, counselling and drug-dispensing practices, for children in Kenya. Ann Trop Med Parasitol, 99 (3), pp. 321-324. | Citations: 8 (Web of Science Lite) | Read more

Isbister GK, White J, Currie BJ, Bush SP, Vetter RS, Warrell DA. 2005. Spider bites: addressing mythology and poor evidence. Am J Trop Med Hyg, 72 (4), pp. 361-364. | Citations: 10 (Scopus)

Wertheim HFL, Verveer J, Boelens HAM, van Belkum A, Verbrugh HA, Vos MC. 2005. Effect of mupirocin treatment on nasal, pharyngeal, and perineal carriage of Staphylococcus aureus in healthy adults. Antimicrob Agents Chemother, 49 (4), pp. 1465-1467. | Citations: 62 (Scopus) | Show Abstract | Read more

Nasal carriage of Staphylococcus aureus is an important risk factor for S. aureus infections. Mupirocin nasal ointment is presently the treatment of choice for decolonizing the anterior nares. However, recent clinical trials show limited benefit from mupirocin prophylaxis in preventing nosocomial S. aureus infections, probably due to (re)colonization from extranasal carriage sites. Therefore, we studied the effectiveness of mupirocin nasal ointment treatment on the dynamics of S. aureus nasal and extranasal carriage. Twenty noncarriers, 26 intermittent carriers, and 16 persistent carriers had nasal, throat, and perineum samples taken 1 day before and 5 weeks after mupirocin treatment (twice daily for 5 days) and assessed for growth of S. aureus. The identities of cultured strains were assessed by restriction fragment length polymorphisms of the coagulase and protein A genes. The overall carriage rate (either nasal, pharyngeal, or perineal carrier or a combination) was significantly reduced after mupirocin treatment from 30 to 17 carriers (P = 0.003). Of the 17 carriers, 10 (60%) were still colonized with their old strain, 6 (35%) were colonized with an exogenous strain, and 1 (5%) was colonized with both. Two noncarriers became carriers after treatment. The acquisition of exogenous strains after mupirocin treatment is a common phenomenon. The finding warrants the use of mupirocin only in proven carriers for decolonization purposes. Mupirocin is effective overall in decolonizing nasal carriers but less effective in decolonizing extranasal sites.

Horby P, Macintyre CR, McIntyre PB, Gilbert GL, Staff M, Hanlon M, Heron LG, Cagney M, Bennett C. 2005. A boarding school outbreak of pertussis in adolescents: value of laboratory diagnostic methods. Epidemiol Infect, 133 (2), pp. 229-236. | Citations: 25 (Web of Science Lite) | Show Abstract | Read more

Culture for Bordetella pertussis (B. pertussis) is the traditional gold standard for laboratory diagnosis of pertussis but is insensitive, especially later in the course of illness and in vaccinated persons. Interpretation of serology is limited by the lack of an appropriate reference standard. An outbreak of pertussis in a crowded boarding-school dormitory allowed evaluation of laboratory correlates of infection. Questionnaires, serum samples and throat swabs were collected from members of the exposed group. Serum samples from unexposed controls of a similar age group were used for comparison. B. pertussis PCR was performed on throat swabs, and sera were tested for IgA antibodies against whole-cell (WC) B. pertussis antigen and IgG antibodies to pertussis toxin (PT). The Centers for Disease Control and Prevention definition for pertussis was used to define clinical cases. We evaluated the use of a previously published cut-off for PT IgG of 125 EIA units (EU)/ml. Completed questionnaires were obtained from 115 students, of whom 85 (74%) reported coughing symptoms, including 32 (28%) who met the clinical case definition for pertussis. B. pertussis was detected by PCR in 17 (15%) and WC IgA in 22 (19%) students; neither correlated with symptoms, but dormitory of residence strongly predicted PCR status. The mean PT IgG geometric mean concentration, in this situation of high pertussis exposure, correlated with severity of symptoms and was significantly higher in both symptomatic and asymptomatic children exposed during the outbreak (P < 0.001) than in control children. A cut-off for PT IgG of 125 EU/ml was too high in an outbreak situation to be sensitive enough to identify pertussis cases. A case of pertussis in a crowded boarding-school dormitory resulted rapidly in an outbreak. Serology and PCR were useful in identifying the outbreak and commencing disease control measures. The use of serology has mostly been evaluated in community serosurveys, where it is not possible to determine if immunity reflects vaccination, asymptomatic disease or symptomatic disease. This outbreak gave us the opportunity to evaluate the value of serology and PCR in the presence of confirmed exposure to pertussis.

Buckling A, Neilson J, Lindsay J, ffrench-Constant R, Enright M, Day N, Massey RC. 2005. Clonal distribution and phase-variable expression of a major histocompatibility complex analogue protein in Staphylococcus aureus. J Bacteriol, 187 (8), pp. 2917-2919. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

The mapW gene of Staphylococcus aureus strain N315 contains a poly(A) tract which truncates translation of the protein. This study demonstrates that mapW is an allelic variant of the map/eap genes found in other strains and that the variation in the length of this poly(A) tract suggests that it is a contingency locus.

Sá JM, Nomura T, Neves JD, Baird JK, Wellems TE, del Portillo HA. 2005. Plasmodium vivax: allele variants of the mdr1 gene do not associate with chloroquine resistance among isolates from Brazil, Papua, and monkey-adapted strains. Exp Parasitol, 109 (4), pp. 256-259. | Citations: 51 (Web of Science Lite) | Show Abstract | Read more

We describe here the sequence of the Plasmodium vivax mdr1 gene from 10 different isolates differing in chloroquine sensitivity. The deduced amino acid sequence of PvMDR1 shares more than 70% similarity with other malarial MDR proteins and it displays consensus motifs of an ABC family transporter including two transmembrane domains and two ATP binding cassettes. Similarity and dendrogram analyses revealed that sequences could be grouped according to their geographical origin. Within each geographical group however, no correlation was found between chloroquine resistance and specific mutations.

Nyakeriga AM, Williams TN, Marsh K, Wambua S, Perlmann H, Perlmann P, Grandien A, Troye-Blomberg M. 2005. Cytokine mRNA expression and iron status in children living in a malaria endemic area. Scand J Immunol, 61 (4), pp. 370-375. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

Iron deficiency has been reported to affect both malaria pathogenesis and cell-mediated immune responses; however, it is unclear whether the protection afforded by iron deficiency is mediated through direct effects on the parasite, through immune effector functions or through both. We have determined cytokine mRNA expression levels in 59 children living in a malaria endemic area on the coast of Kenya who we selected on the basis of their biochemical iron status. Real-time quantitative reverse transcriptase polymerase chain reaction analysis of cytokine mRNA levels of peripheral blood mononuclear cells (PBMC) obtained from these children showed an association between interleukin-4 (IL-4) mRNA levels and all the biochemical indices of iron that we measured. Furthermore, IL-10 mRNA was higher in parasite blood smear-positive children than in blood smear-negative children irrespective of their iron status. This study suggests that IL-4 expression by PBMC may be affected by iron status.

White LJ, Waris M, Cane PA, Nokes DJ, Medley GF. 2005. The transmission dynamics of groups A and B human respiratory syncytial virus (hRSV) in England & Wales and Finland: seasonality and cross-protection. Epidemiol Infect, 133 (2), pp. 279-289. | Citations: 62 (Scopus) | Show Abstract | Read more

Human respiratory syncytial virus (hRSV) transmission dynamics are inherently cyclical, and the observed genetic diversity (between groups A and B) also appears to have a repeating pattern. A key unknown is the extent to which genetic variants interact immunologically, and thus impact on epidemiology. We developed a novel mathematical model for hRSV transmission including seasonal forcing of incidence and temporary intra- and inter-group partial immunity. Simultaneous model fits to data from two locations (England & Wales, UK, and Turku, Finland) successfully reproduced the contrasting infection dynamics and group A/B dominance patterns. Parameter estimates are consistent with direct estimates. Differences in the magnitude and seasonal variation in contact rate between the two populations alone could account for the variation in dynamics between these populations. The A/B group dominance patterns are explained by reductions in susceptibility to and infectiousness of secondary homologous and heterologous infections. The consequences of the observed dynamic complexity are discussed.

Evans ND, White LJ, Chapman MJ, Godfrey KR, Chappell MJ. 2005. The structural identifiability of the susceptible infected recovered model with seasonal forcing MATHEMATICAL BIOSCIENCES, 194 (2), pp. 175-197. | Citations: 14 (Web of Science Lite) | Read more

Evans ND, White LJ, Chapman MJ, Godfrey KR, Chappell MJ. 2005. The structural identifiability of the susceptible infected recovered model with seasonal forcing. Math Biosci, 194 (2), pp. 175-197. | Citations: 15 (Scopus) | Show Abstract | Read more

In this paper, it is shown that the SIR epidemic model, with the force of infection subject to seasonal variation, and a proportion of either the prevalence or the incidence measured, is unidentifiable unless certain key system parameters are known, or measurable. This means that an uncountable number of different parameter vectors can, theoretically, give rise to the same idealised output data. Any subsequent parameter estimation from real data must be viewed with little confidence as a result. The approach adopted for the structural identifiability analysis utilises the existence of an infinitely differentiable transformation that connects the state trajectories corresponding to parameter vectors that give rise to identical output data. When this approach proves computationally intractable, it is possible to use the converse idea that the existence of a coordinate transformation between states for particular parameter vectors implies indistinguishability between these vectors from the corresponding model outputs.

Basnyat B, Pandit A, Pun M, West JB. 2005. The physiologic basis of high-altitude diseases [3] (multiple letters) Annals of Internal Medicine, 142 (7), pp. 591-592. | Citations: 2 (Scopus)

Berkley JA, Lowe BS, Scott JAG. 2005. Bacteremia among Kenyan children - Reply NEW ENGLAND JOURNAL OF MEDICINE, 352 (13), pp. 1380-1381. | Citations: 1 (Web of Science Lite)

Zimmermann O, de Ciman R, Gross U. 2005. Bacteremia among Kenyan Children. N Engl J Med, 352 (13), pp. 1379-1381. | Citations: 4 (Scopus) | Read more

Webster DP, Dunachie S, Vuola JM, Berthoud T, Keating S, Laidlaw SM, McConkey SJ, Poulton I, Andrews L, Andersen RF et al. 2005. Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara. Proc Natl Acad Sci U S A, 102 (13), pp. 4836-4841. | Citations: 194 (Scopus) | Show Abstract | Read more

Malaria is a major global health problem for which an effective vaccine is required urgently. Prime-boost vaccination regimes involving plasmid DNA and recombinant modified vaccinia virus Ankara-encoding liver-stage malaria antigens have been shown to be powerfully immunogenic for T cells and capable of inducing partial protection against experimental malaria challenge in humans, manifested as a delay in time to patent parasitemia. Here, we report that substitution of plasmid DNA as the priming vector with a specific attenuated recombinant fowlpox virus, FP9, vaccine in such prime-boost regimes can elicit complete sterile protection that can last for 20 months. Protection at 20 months was associated with persisting memory but not effector T cell responses. The protective efficacy of various immunization regimes correlated with the magnitude of induced immune responses, supporting the strategy of maximizing durable T cell immunogenicity to develop more effective liver-stage vaccines against Plasmodium falciparum malaria.

Torok ME, Day JN, Hien TT, Farrar JJ. 2005. Immediate or deferred antiretroviral therapy for central nervous system opportunistic infections? AIDS, 19 (5), pp. 535-536. | Citations: 3 (Scopus) | Read more

Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. 2005. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature, 434 (7030), pp. 214-217. | Citations: 1911 (Scopus) | Show Abstract | Read more

Interest in mapping the global distribution of malaria is motivated by a need to define populations at risk for appropriate resource allocation and to provide a robust framework for evaluating its global economic impact. Comparison of older and more recent malaria maps shows how the disease has been geographically restricted, but it remains entrenched in poor areas of the world with climates suitable for transmission. Here we provide an empirical approach to estimating the number of clinical events caused by Plasmodium falciparum worldwide, by using a combination of epidemiological, geographical and demographic data. We estimate that there were 515 (range 300-660) million episodes of clinical P. falciparum malaria in 2002. These global estimates are up to 50% higher than those reported by the World Health Organization (WHO) and 200% higher for areas outside Africa, reflecting the WHO's reliance upon passive national reporting for these countries. Without an informed understanding of the cartography of malaria risk, the global extent of clinical disease caused by P. falciparum will continue to be underestimated.

Fowler VG, Justice A, Moore C, Benjamin DK, Woods CW, Campbell S, Reller LB, Corey GR, Day NPJ, Peacock SJ. 2005. Risk factors for hematogenous complications of intravascular catheter-associated Staphylococcus aureus bacteremia. Clin Infect Dis, 40 (5), pp. 695-703. | Citations: 151 (Scopus) | Show Abstract | Read more

BACKGROUND: The role of both host and pathogen characteristics in hematogenous seeding following Staphylococcus aureus bacteremia is incompletely understood. METHODS: Consecutive patients with intravascular catheter-associated Staphylococcus aureus bacteremia were prospectively recruited over a 91-month period. The corresponding bloodstream isolates were examined for the presence of 35 putative virulence determinants. Patient and bacterial characteristics associated with the development of hematogenous complications (HCs) (i.e., septic arthritis, vertebral osteomyelitis, or endocarditis) were defined. RESULTS: HC occurred in 42 (13%) of 324 patients. Patient characteristics at diagnosis that were associated with HC included community onset (relative risk [RR], 2.25; 95% confidence interval [CI], 1.24-4.07; P=.007), increased symptom duration (odds ratio for each day, 1.14; 95% CI, 1.06-1.2; P<.001), presence of a long-term intravascular catheter or noncatheter prosthesis (RR, 4.02; 95% CI, 1.74-9.27; P<.001), hemodialysis dependence (RR, 3.84; 95% CI, 2.08-7.10; P<.001), and higher APACHE II score (P=.02). Bacterial characteristics included sea (RR, 2.03; 95% CI, 1.16-3.55; P=.011) and methicillin-resistant S. aureus (MRSA) (RR, 2.09; 95% CI, 1.19-3.67; P=.015). Subsequent failure to remove a catheter was also associated with HC (RR, 2.28; 95% CI, 1.22-4.27; P=.011). On multivariable analysis, symptom duration, hemodialysis dependence, presence of a long-term intravascular catheter or a noncatheter device, and infection with MRSA remained significantly associated with HC. CONCLUSIONS: This investigation identifies 4 host- and pathogen-related risk factors for hematogenous bacterial seeding and reaffirms the importance of prompt catheter removal.

Guerin PJ, Vold L, Aavitsland P. 2005. Communicable disease control in a migrant seasonal workers population: a case study in Norway. Euro Surveill, 10 (3), pp. 48-50. | Citations: 7 (Scopus) | Show Abstract

Reliable data on the health status of migrant seasonal workers in Europe is scarce. Access to public health care for this population depends on national regulations, and their legal status in host countries. In this manuscript we describe a case study of a salmonellosis outbreak that occurred in Norway, and highlight the difficulties encountered in applying control measures in a population of seasonal migrant farm workers. Surveillance and control of infectious diseases need to be supported by legislation which makes implementation of control measures possible. Efforts have been made to improve the rights for migrants in Europe with regard to healthcare, but seasonal migrant workers still remain largely outsiders where these measures are concerned. Special attention should be given to this disadvantaged group in terms of social rights and healthcare. Preparedness plans should be improved to deal with contagious pathogens involving the seasonal migrant population.

Abuye C, Tsegaye A, West CE, Versloot P, Sanders EJ, Wolday D, Hamann D, De Wit TFR, Fontanet AL. 2005. Determinants of CD4 counts among HIV-negative Ethiopians: role of body mass index, gender, cigarette smoking, khat (Catha Edulis) chewing, and possibly altitude? J Clin Immunol, 25 (2), pp. 127-133. | Citations: 20 (Web of Science Lite) | Show Abstract | Read more

To study the determinants of CD4% and CD4 counts among HIV-negative Ethiopians, and to identify factors susceptible to explain the low CD4 counts observed among Ethiopian subjects. Cohort studies among factory workers in Akaki and Wonji, Ethiopia. Clinical and laboratory examinations, including determination of HIV serological status and T-cell subsets, were performed during follow-up visits every six months. In addition, micronutrients (retinol, carotenoids, tocopherol, transferrin receptor, and selenium) plasma concentrations were determined in a subset of 38 HIV-positive and 121 HIV-negative participants. HIV-negative participants with at least one CD4 count measurement were 157 females in Akaki, 203 males in Akaki, and 712 males in Wonji. CD4 counts were independently and positively associated with body mass index (through an increase in lymphocyte counts), female gender (through an increase in CD4%), cigarette smoking (through an increase in CD4%), khat chewing (through an increase in both lymphocyte counts and CD4%), and Akaki study site (through a large increase in lymphocyte counts compensating a decrease in CD4%). Intestinal parasitic infections were not associated with CD4% or CD4 counts. Retinol, carotenoids, and alpha-tocopherol plasma concentrations decreased with HIV infection and advancing immunosuppression, but were not associated with CD4 counts among HIV-negative subjects. Low body mass index among Ethiopians may have contributed to their overall low CD4 counts. Other factors remain to be elucidated.

Wain J, House D, Zafar A, Baker S, Nair S, Kidgell C, Bhutta Z, Dougan G, Hasan R. 2005. Vi antigen expression in Salmonella enterica serovar Typhi clinical isolates from Pakistan. J Clin Microbiol, 43 (3), pp. 1158-1165. | Citations: 41 (Web of Science Lite) | Show Abstract | Read more

The accurate identification of Salmonella enterica subsp. enterica serovar Typhi variants that fail to express the capsular polysaccharide, Vi, is an important and much discussed issue for medical microbiology. We have tested a multiplex PCR method which shows the presence or absence of the genetic locus required for Vi expression. Of 2,222 Salmonella serovar Typhi clinical isolates collected from patients' blood over a 4-year period in a region of Pakistan where typhoid is endemic, 12 tested negative for Vi expression by serological agglutination. However, only 1 of these 12 was Vi negative by the multiplex PCR method. This result was confirmed by immunofluorescence, the most sensitive method for Vi characterization in Salmonella serovar Typhi. The multiplex PCR described therefore represents a simple and accurate method for surveillance for Vi-negative variants of Salmonella serovar Typhi in Pakistan. Testing of clinical isolates of Salmonella serovar Typhi, before subculture, from other regions where Vi-negative Salmonella serovar Typhi has been described should be carried out so that the impact of vaccination with purified Vi antigen on the levels of Vi-negative Salmonella serovar Typhi in bacterial populations can be assessed.

Bryant JE, Vasconcelos PFC, Rijnbrand RCA, Mutebi JP, Higgs S, Barrett ADT. 2005. Size heterogeneity in the 3' noncoding region of South American isolates of yellow fever virus. J Virol, 79 (6), pp. 3807-3821. | Citations: 37 (Scopus) | Show Abstract | Read more

The 3' noncoding region (3' NCR) of flaviviruses contains secondary and tertiary structures essential for virus replication. Previous studies of yellow fever virus (YFV) and dengue virus have found that modifications to the 3' NCR are sometimes associated with attenuation in vertebrate and/or mosquito hosts. The 3' NCRs of 117 isolates of South American YFV have been examined, and major deletions and/or duplications of conserved RNA structures have been identified in several wild-type isolates. Nineteen isolates (designated YF-XL isolates) from Brazil, Trinidad, and Venezuela, dating from 1973 to 2001, exhibited a 216-nucleotide (nt) duplication, yielding a tandem repeat of conserved hairpin, stem-loop, dumbbell, and pseudoknot structures. YF-XL isolates were found exclusively within one subclade of South American genotype I YFV. One Brazilian isolate exhibited, in addition to the 216-nt duplication, a deletion of a 40-nt repeated hairpin (RYF) motif (YF-XL-DeltaRYF). To investigate the biological significance of these 3' NCR rearrangements, YF-XL-DeltaRYF and YF-XL isolates, as well as other South American YFV isolates, were evaluated for three phenotypes: growth kinetics in cell culture, neuroinvasiveness in suckling mice, and ability to replicate and produce disseminated infections in Aedes aegypti mosquitoes. YF-XL-DeltaRYF and YF-XL isolates showed growth kinetics and neuroinvasive characteristics comparable to those of typical South American YFV isolates, and mosquito infectivity trials demonstrated that both types of 3' NCR variants were capable of replication and dissemination in a laboratory-adapted colony of A. aegypti.

Van der Bij AK, Kloosterboer N, Prins M, Boeser-Nunnink B, Geskus RB, Lange JMA, Coutinho RA, Schuitemaker H. 2005. GB virus C coinfection and HIV-1 disease progression: The Amsterdam Cohort Study. J Infect Dis, 191 (5), pp. 678-685. | Citations: 74 (Scopus) | Show Abstract | Read more

BACKGROUND: The effect that GB virus C (GBV-C) coinfection has on human immunodeficiency virus type 1 (HIV-1) disease progression is controversial and therefore was studied in 326 homosexual men from the prospective Amsterdam Cohort Studies who had an accurately estimated date of HIV-1 seroconversion and were followed up for a median period of 8 years. METHODS: A first plasma sample, obtained shortly after HIV-1 seroconversion, and a last plasma sample, obtained before 1996, were tested for GBV-C RNA and envelope protein-2 antibodies. The effect that GBV-C has on HIV-1 disease progression was studied by use of time-dependent Cox proportional-hazards models with adjustment for baseline variables and time-updated HIV-1 RNA and CD4(+) cell count. RESULTS: Men who lost GBV-C RNA between collection of the first sample and collection of the last sample had a nearly 3-fold-higher risk of HIV-1 disease progression than did men who had never had GBV-C RNA. This effect became much smaller after adjustment for time-updated CD4(+) cell count. CONCLUSION: Rather than a positive effect of GBV-C RNA presence, a negative effect of GBV-C RNA loss on HIV-1 disease progression was found, which disappeared after adjustment for time-updated CD4(+) cell count. We therefore hypothesize that GBV-C RNA persistence depends on the presence of a sufficient number of CD4(+) cells--and that the CD4(+) cell decrease associated with HIV-1 disease progression is a cause, not a consequence, of GBV-C RNA loss.

van der Lugt JCT, Geskus RB, Rozing PM. 2005. Primary Souter-Strathclyde total elbow prosthesis in rheumatoid arthritis. Surgical technique. J Bone Joint Surg Am, 87 Suppl 1 (Pt 1), pp. 67-77. | Citations: 7 (Scopus) | Show Abstract | Read more

BACKGROUND: Total elbow arthroplasty is a well-established treatment for the painful elbow joint in patients with rheumatoid arthritis. We present the results of what we believe to be the first prospective study of the Souter-Strathclyde total elbow prosthesis. METHODS: Between June 1982 and December 2000, 204 primary total elbow prostheses were inserted in 166 patients who had rheumatoid arthritis. No patient was lost to follow-up. The mean duration of follow-up was 6.4 years. All patients were examined preoperatively, at one and two years postoperatively, and at regular intervals thereafter. RESULTS: Six of the 204 elbows had pain at rest at the time of the latest follow-up. Ten patients (ten elbows) without previous neurological symptoms had development of paresthesias in the distribution of the ulnar nerve postoperatively. Patients who had pain at rest or at night and those who had ulnar nerve symptoms preoperatively were found to have a significant chance of having the same complaints postoperatively. Pain at rest or at night and a decrease in function during the follow-up period were associated with humeral loosening. Twenty-four elbows had revision of the total elbow prosthesis because of loosening of the humeral component (ten), loosening after fracture (six), dislocation (four), infection (two), restricted range of motion (one), or fracture of the middle part of the humeral shaft, proximal to the prosthesis (one). One prosthesis was removed because of humeral loosening, and eight were removed because of deep infection. Another five prostheses were radiographically loose at the time of the latest follow-up. The rate of implant survival, according to the method of Kaplan-Meier, was 77.4% after ten years and 65.2% after eighteen years. CONCLUSIONS: Total elbow replacement is associated with a high complication rate and therefore may be warranted only for seriously disabled patients. Currently, the results associated with the Souter-Strathclyde total elbow prosthesis are comparable with the results associated with other prostheses, but loosening of the humeral component remains a concern.

Cheng AC, Dance DA, Currie BJ. 2005. Bioterrorism, Glanders and melioidosis. Euro Surveill, 10 (3), pp. 11-12. | Show Abstract | Read more

We note with interest the recently published guidelines for management of melioidosis and glanders. We are clinicians with extensive experience with melioidosis in Australia and Thailand and would like to express our concern at a number of inaccuracies in these guidelines.

Lucas MES, Deen JL, von Seidlein L, Wang X-Y, Ampuero J, Puri M, Ali M, Ansaruzzaman M, Amos J, Macuamule A et al. 2005. Effectiveness of mass oral cholera vaccination in Beira, Mozambique. N Engl J Med, 352 (8), pp. 757-767. | Citations: 180 (Scopus) | Show Abstract | Read more

BACKGROUND: New-generation, orally administered cholera vaccines offer the promise of improved control of cholera in sub-Saharan Africa. However, the high prevalence of human immunodeficiency virus (HIV) infection in many cholera-affected African populations has raised doubts about the level of protection possible with vaccination. We evaluated a mass immunization program with recombinant cholera-toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in Beira, Mozambique, a city where the seroprevalence of HIV is 20 to 30 percent. METHODS: From December 2003 to January 2004, we undertook mass immunization of nonpregnant persons at least two years of age, using a two-dose regimen of rBS-WC vaccine in Esturro, Beira (population 21,818). We then assessed vaccine protection in a case-control study during an outbreak of El Tor Ogawa cholera in Beira between January and May 2004. To estimate the level of vaccine protection, antecedent rates of vaccination were compared between persons with culture-confirmed cholera severe enough to have prompted them to seek treatment and age- and sex-matched neighborhood controls without treated diarrhea. RESULTS: We assessed the effectiveness of the vaccine in 43 persons with cholera and 172 controls. Receipt of one or more doses of rBS-WC vaccine was associated with 78 percent protection (95 percent confidence interval, 39 to 92 percent; P=0.004). The vaccine was equally effective in children younger than five years of age and in older persons. A concurrently conducted case-control study designed to detect bias compared persons with treated, noncholeraic diarrhea and controls without diarrhea in the same population and found no protection associated with receipt of the rBS-WC vaccine. CONCLUSIONS: The rBS-WC vaccine was highly effective against clinically significant cholera in an urban sub-Saharan African population with a high prevalence of HIV infection.

Nosten F, McGready R, Ashley E, White NJ. 2005. Malaria misconceptions. Lancet, 365 (9460), pp. 653. | Citations: 4 (Web of Science Lite) | Read more

de Jong MD, Bach VC, Phan TQ, Vo MH, Tran TT, Nguyen BH, Beld M, Le TP, Truong HK, Nguyen VVC et al. 2005. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma. N Engl J Med, 352 (7), pp. 686-691. | Citations: 403 (Scopus) | Show Abstract | Read more

In southern Vietnam, a four-year-old boy presented with severe diarrhea, followed by seizures, coma, and death. The cerebrospinal fluid contained 1 white cell per cubic millimeter, normal glucose levels, and increased levels of protein (0.81 g per liter). The diagnosis of avian influenza A (H5N1) was established by isolation of the virus from cerebrospinal fluid, fecal, throat, and serum specimens. The patient's nine-year-old sister had died from a similar syndrome two weeks earlier. In both siblings, the clinical diagnosis was acute encephalitis. Neither patient had respiratory symptoms at presentation. These cases suggest that the spectrum of influenza H5N1 is wider than previously thought.

de Jong MD, Van Cam B, Qui PT, Hien VM, Thanh TT, Hue NB, Beld M, Phuong LT, Khanh TH, Chau NVV et al. 2005. Brief report: Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma NEW ENGLAND JOURNAL OF MEDICINE, 352 (7), pp. 686-691. | Citations: 340 (Web of Science Lite) | Read more

Bejon P, Andrews L, Andersen RF, Dunachie S, Webster D, Walther M, Gilbert SC, Peto T, Hill AVS. 2005. Calculation of liver-to-blood inocula, parasite growth rates, and preerythrocytic vaccine efficacy, from serial quantitative polymerase chain reaction studies of volunteers challenged with malaria sporozoites. J Infect Dis, 191 (4), pp. 619-626. | Citations: 113 (Scopus) | Show Abstract | Read more

We calculated the number and growth rate of Plasmodium falciparum parasites emerging in recipients of candidate preerythrocytic malaria vaccines and unvaccinated control subjects undergoing mosquito-bite challenge. This was done to measure vaccine efficacy and to distinguish the effects on blood-stage multiplication from those on liver-stage parasites. Real-time polymerase chain reaction measurements of parasite densities were analyzed by nonlinear regression and mixed-effects models. Substantial reductions in numbers of liver parasites resulted from the use of 2 immunization regimens: FP9 boosted by modified virus Ankara (MVA) encoding the malaria epitope-thrombospondin-related adhesion protein insert (92% reduction) and RTS,S/AS02 used in heterologous prime-boost immunization regimens, with MVA encoding the circumsporozoite protein (97% reduction). Forty-eight-hour growth rates in blood from control subjects were not different from those in blood from any vaccination group (mean, 14.4-fold [95% confidence interval, 11-19-fold]).

Maitland K, Pamba A, English M, Peshu N, Marsh K, Newton C, Levin M. 2005. Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Clin Infect Dis, 40 (4), pp. 538-545. | Citations: 118 (Scopus) | Show Abstract | Read more

BACKGROUND: Metabolic acidosis is the best predictor of death in children with severe falciparum malaria; however, its treatment presents a therapeutic dilemma, because acidosis and hypovolemia may coexist with coma, which can be associated with elevated intracranial pressure. We postulated that volume resuscitation with albumin might correct acidosis and hypovolemia with a lower risk of precipitating cerebral edema than crystalloid. In an open-label, randomized, controlled trial, we compared the safety of resuscitation with albumin to saline in Kenyan children with severe malaria. METHODS: We randomly assigned children with severe malaria and metabolic acidosis (base deficit, >8 mmol/L) to receive fluid resuscitation with either 4.5% albumin or normal saline. A control (maintenance only) group was only included for patients with a base deficit of <15 mmol/L. The primary outcome measure was the percentage reduction in base deficit at 8 h. Secondary end points included death, the requirement for rescue therapies, and neurological sequelae in survivors. RESULTS: Of 150 children recruited for the trial, 61 received saline, 56 received albumin, and 33 served as control subjects. There was no significant difference in the resolution of acidosis between the groups; however, the mortality rate was significantly lower among patients who received albumin (3.6% [2 of 56 patients]) than among those who received saline (18% [11 of 61]; relative risk, 5.5; 95% confidence interval, 1.2-24.8; P=.013). CONCLUSIONS: In high-risk children with severe malaria and acidosis, fluid resuscitation with albumin may reduce mortality. Our study design did not enable us to determine whether saline administration is preferable to fluid restriction or whether saline administration is actually hazardous. Further studies are needed to confirm our findings before definitive treatment recommendations can be made.

Thwaites GE, Quy HT, Farrar JJ. 2005. Dexamethasone for tuberculous meningitis - Reply NEW ENGLAND JOURNAL OF MEDICINE, 352 (6), pp. 629-630.

Marras TK. 2005. Dexamethasone for tuberculous meningitis. N Engl J Med, 352 (6), pp. 628-630. | Citations: 4 (Scopus) | Read more

Wuthiekanun V, Mayxay M, Chierakul W, Phetsouvanh R, Cheng AC, White NJ, Day NPJ, Peacock SJ. 2005. Detection of Burkholderia pseudomallei in soil within the Lao People's Democratic Republic. J Clin Microbiol, 43 (2), pp. 923-924. | Citations: 21 (Web of Science Lite) | Show Abstract | Read more

Clinical cases of melioidosis caused by the saprophyte Burkholderia pseudomallei were first noted in the Lao People's Democratic Republic (PDR) in 1999. In this study, 36% of 110 soil samples in northern Lao PDR were positive for B. pseudomallei, providing further evidence for the presence of melioidosis in this country.

Hay SI, Shanks GD, Stern DI, Snow RW, Randolph SE, Rogers DJ. 2005. Climate variability and malaria epidemics in the highlands of East Africa. Trends Parasitol, 21 (2), pp. 52-53. | Citations: 29 (Web of Science Lite) | Show Abstract | Read more

Malaria epidemics in the highlands of East Africa garner significant research attention, due, in part, to their proposed sensitivity to climate change. In a recent article, Zhou et al. claim that increases in climate variance, rather than simple increases in climate mean values, have had an important role in the resurgence of malaria epidemics in the East African highlands since the early 1980s. If proven, this would be an interesting result but we believe that the methods used do not test the hypothesis suggested.

Yeung S, White NJ. 2005. How do patients use antimalarial drugs? A review of the evidence. Trop Med Int Health, 10 (2), pp. 121-138. | Citations: 85 (Web of Science Lite) | Show Abstract | Read more

Patient adherence is a major determinant of the therapeutic response to antimalarial drugs, as most treatments are taken at home without medical supervision. With the introduction of new, effective, but more expensive antimalarials, there is concern that the high levels of efficacy observed in clinical trials may not be translated into effectiveness in the normal context of use. We reviewed available published evidence on adherence to antimalarial drugs and community drug usage; 24 studies were identified of which nine were 'intervention' studies, seven were classified as 'outcome studies', and the remainder were purely descriptive studies of antimalarial adherence. Definitions, methods, and results varied widely. Adherence was generally better when treatments were effective, and was improved by interventions focusing on provider knowledge and behaviour, packaging, and provision of correct dosages. There is insufficient information on this important subject, and current data certainly do not justify extrapolation from results with ineffective drugs to new effective treatments. Research in this area would benefit from of standardization of methodologies and the application of pharmacokinetic modelling.

Hien TT, Davis TME, Chuong LV, Ilett KF, Sinh DXT, Phu NH, Agus C, Chiswell GM, White NJ, Farrar J. 2005. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe Falciparum malaria (vol 11, pg 4234, 2004) ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 49 (2), pp. 871-871. | Citations: 2 (Web of Science Lite) | Read more

Siddiqui AA, Brouwer AE, Wuthiekanun V, Jaffar S, Shattock R, Irving D, Sheldon J, Chierakul W, Peacock S, Day N et al. 2005. IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis. J Immunol, 174 (3), pp. 1746-1750. | Citations: 86 (Scopus) | Show Abstract | Read more

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.

Maitland K, Pamba A, English M, Peshu N, Levin M, Marsh K, Newton CRJC. 2005. Pre-transfusion management of children with severe malarial anaemia: a randomised controlled trial of intravascular volume expansion. Br J Haematol, 128 (3), pp. 393-400. | Citations: 51 (Scopus) | Show Abstract | Read more

Symptomatic severe malarial anaemia (SMA) has a high fatality rate of 30-40%; most deaths occur in children awaiting blood transfusion. Blood transfusion services in most of Africa are not capable of delivering adequate supplies of safe blood in a timely manner to critically ill children with SMA. Contrary to widely held belief, hypovolaemia, rather than heart failure, has emerged as a common complication in such children. We examined the safety of pre-transfusion management (PTM) by volume expansion, aimed at stabilizing children and obviating the urgency for blood transfusion. Kenyan children with severe falciparum anaemia (haemoglobin <5 g/dl) and respiratory distress were randomly assigned to 20 ml/kg of 4.5% albumin or 0.9% saline or maintenance only (control) while awaiting blood transfusion. PTM was apparently safe since it did not lead to the development of pulmonary oedema or other adverse events. There was no significant difference in the primary outcome [mean percentage reduction in base excess between admission and 8 h (95% confidence interval)] between the control group 42% (19-66%) albumin group 44% (32-57%) and saline group 36% (16-57%); adjusted analysis of variance F=0.31, P=0.7. However, the number of children requiring emergency interventions was significantly greater in the control group, four of 18 (22%) than the saline group 0 of 20 (P=0.03). We have established the safety of this PTM in children with SMA whilst awaiting blood transfusion at a hospital with an adequate blood-banking program. The impact on mortality should be assessed where blood transfusion services are unable to supply emergency transfusions.

Krudsood S, Imwong M, Wilairatana P, Pukrittayakamee S, Nonprasert A, Snounou G, White NJ, Looareesuwan S. 2005. Artesunate-dapsone-proguanil treatment of falciparum malaria: genotypic determinants of therapeutic response. Trans R Soc Trop Med Hyg, 99 (2), pp. 142-149. | Citations: 22 (Scopus) | Show Abstract | Read more

The combination of chlorproguanil and dapsone is being considered as an alternative antimalarial to sulfadoxine-pyrimethamine in Africa, because of its greater efficacy against resistant parasites, and its shorter half-lives, which exert less selective pressure for the emergence of resistance. A triple artesunate-chlorproguanil-dapsone combination is under development. In a previous study of relatively low-dose chlorproguanil-dapsone in multidrug-resistant falciparum malaria in Thailand failure rates were high. Proguanil is inexpensive, widely available and very similar to chlorproguanil. The safety and efficacy of artesunate-dapsone-proguanil (artesunate 4 mg/kg, dapsone 2.5mg/kg, proguanil 8 mg/kg daily for three days), was studied prospectively in 48 Thai adult patients with acute falciparum malaria followed daily for 28 days. Eleven of these had a recrudescence of their infection. Genotyping of Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) indicated that the Pfdhfr I164L mutation was the main determinant of therapeutic outcome; all 11 failures carried this mutation (failure rate 11/37; 30%) whereas none of the 11 infections with 'wild type' 164 genotypes failed. The addition of artesunate considerably augments the antimalarial activity of the biguanide-dapsone combination, but this is insufficient for infections with parasites carrying the highly antifol-resistant Pfdhfr I164L mutation.

Kluytmans JAJW, Wertheim HFL. 2005. Nasal carriage of Staphylococcus aureus and prevention of nosocomial infections. Infection, 33 (1), pp. 3-8. | Citations: 186 (Scopus) | Show Abstract | Read more

This review summarizes the clinically relevant aspects of nasal carriage of Staphylococcus aureus. The epidemiology, associated risk, and the effects of eradication are discussed. The main conclusions are that nasal carriage of S. aureus is a well-defined risk factor for subsequent infection in nearly all categories of hospitalized patients that have been studied. However, studies that have been performed to evaluate the effect of eradication of carriage using mupirocin nasal ointment have been inconclusive so far in most subgroups. Only in patients on hemodialysis or chronic ambulatory peritoneal dialysis (CAPD) was a significant reduction of the infection rate found. But prolonged treatment in these groups carries a risk for the development of resistance. In surgical patients two randomized studies have found an effect on the surgical site infection rate in carriers that, when those studies are combined, was close to being statistically significant (p = 0.06). In non-surgical patients a significant delay in the onset of infection was found but the overall infection rate was not significantly different. When the results of all well-designed studies that have been performed are combined, a significant reduction of the nosocomial S. aureus infections in carriers is found (approximately 50% lower). Future studies should focus on treating carriers only and consider other treatment regimens.

Hastings MD, Maguire JD, Bangs MJ, Zimmerman PA, Reeder JC, Baird JK, Sibley CH. 2005. Novel Plasmodium vivax dhfr alleles from the Indonesian Archipelago and Papua New Guinea: association with pyrimethamine resistance determined by a Saccharomyces cerevisiae expression system. Antimicrob Agents Chemother, 49 (2), pp. 733-740. | Citations: 40 (Web of Science Lite) | Show Abstract | Read more

In plasmodia, the dihydrofolate reductase (DHFR) enzyme is the target of the pyrimethamine component of sulfadoxine-pyrimethamine (S/P). Plasmodium vivax infections are not treated intentionally with antifolates. However, outside Africa, coinfections with Plasmodium falciparum and P. vivax are common, and P. vivax infections are often exposed to S/P. Cloning of the P. vivax dhfr gene has allowed molecular comparisons of dhfr alleles from different regions. Examination of the dhfr locus from a few locations has identified a very diverse set of alleles and showed that mutant alleles of the vivax dhfr gene are prevalent in Southeast Asia where S/P has been used extensively. We have surveyed patient isolates from six locations in Indonesia and two locations in Papua New Guinea. We sequenced P. vivax dhfr alleles from 114 patient samples and identified 24 different alleles that differed from the wild type by synonymous and nonsynonymous point mutations, insertions, or deletions. Most importantly, five alleles that carried four or more nonsynonymous mutations were identified. Only one of these highly mutant alleles had been previously observed, and all carried the 57L and 117T mutations. P. vivax cannot be cultured continuously, so we used a yeast assay system to determine in vitro sensitivity to pyrimethamine for a subset of the alleles. Alleles with four nonsynonymous mutations conferred very high levels of resistance to pyrimethamine. This study expands significantly the total number of novel dhfr alleles now identified from P. vivax and provides a foundation for understanding how antifolate resistance arises and spreads in natural P. vivax populations.

Syafruddin D, Asih PBS, Casey GJ, Maguire J, Baird JK, Nagesha HS, Cowman AF, Reeder JC. 2005. Molecular epidemiology of Plasmodium falciparum resistance to antimalarial drugs in Indonesia. Am J Trop Med Hyg, 72 (2), pp. 174-181. | Citations: 17 (Web of Science Lite) | Show Abstract

The extent of gene polymorphisms associated with resistance to chloroquine and sulfadoxine-pyrimethamine was examined in field isolates of Plasmodium falciparum from Indonesia. Eight malaria-endemic areas, representing a broad region of the western and eastern Indonesian Archipelago were surveyed. Blood from 20-50 patients was collected at each site, DNA was isolated, and the sequences of four different genes (dihydrofolate reductase [dhfr], dihydropteroate synthase [dhps], P. falciparum multidrug resistance 1 [pfmdr1], and P. falciparum chloroquine resistance transporter [pfcrt]) were analyzed using polymerase chain reaction and restriction fragment length polymorphisms to detect polymorphisms previously shown to be associated with resistance. This analysis identified polymorphisms in dhfr at 108-Asn/Thr, 16-Val, and 59-Arg. Polymorphisms in dhps were found less frequently, either 437-Gly alone or paired with 540-Glu. The pfcrt 76-Thr polymorphism was fixed in all parasite populations and pfmdr1 86-Tyr polymorphisms in all populations except in the most eastern regions. The pfmdr1 1042-Asp polymorphism occurred less frequently. These findings indicate that polymorphisms in genes associated with drug resistance in P. falciparum are found across a broad region of Indonesia.

Thwaites CL. 2005. Tetanus Current Anaesthesia & Critical Care, 16 (1), pp. 50-57. | Citations: 5 (Scopus) | Show Abstract | Read more

Despite long-standing availability of a vaccine, tetanus continues to cause high morbidity and mortality throughout the world. In the developed world, the elderly have traditionally been most at risk due to decline in protective antibody levels, however recent cases have occurred in younger people, particularly injecting drug users. Much of the management is supportive, although treatment aimed at preventing toxin release and uptake into the central nervous system should be given. Recent studies have focussed on optimizing antitoxin effect and improving control of muscle spasms and cardiovascular instability. This paper reviews these and other current concepts regarding the pathophysiology and management of tetanus. © 2005 Elsevier Ltd. All rights reserved.

Woodrow CJ. 2005. Artemisinins Postgraduate Medical Journal, 81 (952), pp. 71-78. | Read more

Collins NE, Liebenberg J, de Villiers EP, Brayton KA, Louw E, Pretorius A, Faber FE, van Heerden H, Josemans A, van Kleef M et al. 2005. The genome of the heartwater agent Ehrlichia ruminantium contains multiple tandem repeats of actively variable copy number. Proc Natl Acad Sci U S A, 102 (3), pp. 838-843. | Show Abstract | Read more

Heartwater, a tick-borne disease of domestic and wild ruminants, is caused by the intracellular rickettsia Ehrlichia ruminantium (previously known as Cowdria ruminantium). It is a major constraint to livestock production throughout subSaharan Africa, and it threatens to invade the Americas, yet there is no immediate prospect of an effective vaccine. A shotgun genome sequencing project was undertaken in the expectation that access to the complete protein coding repertoire of the organism will facilitate the search for vaccine candidate genes. We report here the complete 1,516,355-bp sequence of the type strain, the stock derived from the South African Welgevonden isolate. Only 62% of the genome is predicted to be coding sequence, encoding 888 proteins and 41 stable RNA species. The most striking feature is the large number of tandemly repeated and duplicated sequences, some of continuously variable copy number, which contributes to the low proportion of coding sequence. These repeats have mediated numerous translocation and inversion events that have resulted in the duplication and truncation of some genes and have also given rise to new genes. There are 32 predicted pseudogenes, most of which are truncated fragments of genes associated with repeats. Rather then being the result of the reductive evolution seen in other intracellular bacteria, these pseudogenes appear to be the product of ongoing sequence duplication events.

Berkley JA, Lowe BS, Mwangi I, Williams T, Bauni E, Mwarumba S, Ngetsa C, Slack MPE, Njenga S, Hart CA et al. 2005. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med, 352 (1), pp. 39-47. | Citations: 505 (Scopus) | Show Abstract | Read more

BACKGROUND: There are few epidemiologic data on invasive bacterial infections among children in sub-Saharan Africa. We studied every acute pediatric admission to a rural district hospital in Kenya to examine the prevalence, incidence, types, and outcome of community-acquired bacteremia. METHODS: Between August 1998 and July 2002, we cultured blood on admission from 19,339 inpatients and calculated the incidence of bacteremia on the basis of the population served by the hospital. RESULTS: Of a total of 1783 infants who were under 60 days old, 228 had bacteremia (12.8 percent), as did 866 of 14,787 children who were 60 or more days of age (5.9 percent). Among infants who were under 60 days old, Escherichia coli and group B streptococci predominated among a broad range of isolates (14 percent and 11 percent, respectively). Among infants who were 60 or more days of age, Streptococcus pneumoniae, nontyphoidal salmonella species, Haemophilus influenzae, and E. coli accounted for more than 70 percent of isolates. The minimal annual incidence of community-acquired bacteremia was estimated at 1457 cases per 100,000 children among infants under a year old, 1080 among children under 2 years, and 505 among children under 5 years. Of all in-hospital deaths, 26 percent were in children with community-acquired bacteremia. Of 308 deaths in children with bacteremia, 103 (33.4 percent) occurred on the day of admission and 217 (70.5 percent) within two days. CONCLUSIONS: Community-acquired bacteremia is a major cause of death among children at a rural sub-Saharan district hospital, a finding that highlights the need for prevention and for overcoming the political and financial barriers to widespread use of existing vaccines for bacterial diseases.

Walther M, Dunachie S, Keating S, Vuola JM, Berthoud T, Schmidt A, Maier C, Andrews L, Andersen RF, Gilbert S et al. 2005. Safety, immunogenicity and efficacy of a pre-erythrocytic malaria candidate vaccine, ICC-1132 formulated in Seppic ISA 720. Vaccine, 23 (7), pp. 857-864. | Citations: 66 (Scopus) | Show Abstract | Read more

ICC-1132, a recombinant virus-like particle comprising of a modified hepatitis B core protein with a B cell (NANP) and two T cell epitopes of Plasmodium falciparum circumsporozoite protein (CSP), was administered i.m. as a single 50 microg dose in Seppic ISA 720 to 11 volunteers. Local reactogenicity and systemic side effects were acceptable with the predominant finding being mild pain at the injection site. This regimen induced anti-NANP antibodies in 10/11 and modest T cell responses. There was no evidence of protection from experimental challenge with P. falciparum sporozoites. Other formulations and/or multi-dose regimens will be required to enhance the immunogenicity and efficacy of ICC-1132.

Cheng AC, Day NPJ, Mayo MJ, Gal D, Currie BJ. 2005. Burkholderia pseudomallei strain type, based on pulsed-field gel electrophoresis, does not determine disease presentation in melioidosis. Microbes Infect, 7 (1), pp. 104-109. | Citations: 11 (Scopus) | Show Abstract | Read more

Melioidosis, the infection due to Burkholderia pseudomallei, may present with a spectrum of severity and may affect any site in the body. Differential strain virulence and tropism suggested by previous studies would have implications for virulence and vaccine work. We explored clinical correlations using pulsed-field gel electrophoresis (PFGE) typing in a well-characterised clinical collection. Two methods of analysis were used based on band-based similarity values: first, a conventional cluster analysis formed by the unweighted paired group mean analysis, and second, an analysis of the distribution of the "within-group" and "between-group" Dice coefficient. Clinical isolates from 114 cases of melioidosis occurring in the Northern Territory, Australia were studied; 71 strain types were defined with a Simpson's index of 0.91. No correlation was found between strain type and disease severity or site of melioidosis on presentation, with no differences in similarity values found when comparing within and between-groups. In particular, isolates from patients with neurological melioidosis were not clustered. There was evidence of geographical localisation. This study suggests that the variation in strain type may not be as important as host and environmental factors in determining the pattern of disease.

Hutagalung R, Paiphun L, Ashley EA, McGready R, Brockman A, Thwai KL, Singhasivanon P, Jelinek T, White NJ, Nosten FH. 2005. A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand. Malar J, 4 pp. 46. | Citations: 65 (Scopus) | Show Abstract | Read more

BACKGROUND: The use of antimalarial drug combinations with artemisinin derivatives is recommended to overcome drug resistance in Plasmodium falciparum. The fixed combination of oral artemether-lumefantrine, an artemisinin combination therapy (ACT) is highly effective and well tolerated. It is the only registered fixed combination containing an artemisinin. The trial presented here was conducted to monitor the efficacy of the six-dose regimen of artemether-lumefantrine (ALN) in an area of multi-drug resistance, along the Thai-Myanmar border. METHODS: The trial was an open-label, two-arm, randomized study comparing artemether-lumefantrine and mefloquine-artesunate for the treatment of uncomplicated falciparum malaria with 42 days of follow up. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish recrudescent from newly acquired P. falciparum infections. The PCR adjusted cure rates were evaluated by survival analysis. RESULTS: In 2001-2002 a total of 490 patients with slide confirmed uncomplicated P. falciparum malaria were randomly assigned to receive artemether-lumefantrine (n = 245) or artesunate and mefloquine (n = 245) and were followed for 42 days. All patients had rapid initial clinical and parasitological responses. In both groups, the PCR adjusted cure rates by day 42 were high: 98.8% (95% CI 96.4, 99.6%) for artemether-lumefantrine and 96.3% (95% CI 93.1, 98.0%) for artesunate-mefloquine. Both regimens were very well tolerated with no serious adverse events observed attributable to either combination. CONCLUSION: Overall, this study confirms that these two artemisinin-based combinations remain highly effective and result in equivalent therapeutic responses in the treatment of highly drug-resistant falciparum malaria.

Nosten F. 2005. [Malaria control in Plasmodium falciparum resistant to multi-therapy: a field opinion]. Med Trop (Mars), 65 (1), pp. 91-92.

Hay SI, Guerra CA, Tatem AJ, Atkinson PM, Snow RW. 2005. Urbanization, malaria transmission and disease burden in Africa. Nat Rev Microbiol, 3 (1), pp. 81-90. | Citations: 277 (Scopus) | Show Abstract | Read more

Many attempts have been made to quantify Africa's malaria burden but none has addressed how urbanization will affect disease transmission and outcome, and therefore mortality and morbidity estimates. In 2003, 39% of Africa's 850 million people lived in urban settings; by 2030, 54% of Africans are expected to do so. We present the results of a series of entomological, parasitological and behavioural meta-analyses of studies that have investigated the effect of urbanization on malaria in Africa. We describe the effect of urbanization on both the impact of malaria transmission and the concomitant improvements in access to preventative and curative measures. Using these data, we have recalculated estimates of populations at risk of malaria and the resulting mortality. We find there were 1,068,505 malaria deaths in Africa in 2000 - a modest 6.7% reduction over previous iterations. The public-health implications of these findings and revised estimates are discussed.

Vuola JM, Keating S, Webster DP, Berthoud T, Dunachie S, Gilbert SC, Hill AVS. 2005. Differential immunogenicity of various heterologous prime-boost vaccine regimens using DNA and viral vectors in healthy volunteers. J Immunol, 174 (1), pp. 449-455. | Citations: 126 (Scopus) | Show Abstract | Read more

Heterologous prime-boost vaccination has been shown to be an efficient way of inducing T cell responses in animals and in humans. We have used three vaccine vectors, naked DNA, modified vaccinia virus Ankara (MVA), and attenuated fowlpox strain, FP9, for prime-boost vaccination approaches against Plasmodium falciparum malaria in humans. In this study, we characterize, using two types of ELISPOT assays and FACS analysis, cell-mediated immune responses induced by different prime-boost combinations where all vectors encode a multiepitope string fused to the pre-erythrocytic Ag thrombospondin-related adhesion protein. We show that these different vectors need to be used in a specific order for an optimal ex vivo IFN-gamma response. From the different combinations, DNA priming followed by MVA boosting and FP9 priming followed by MVA boosting were most immunogenic and in both cases the IFN-gamma response was of broad specificity and cross-reactive against two P. falciparum strains (3D7 and T9/96). Immunization with all three vectors showed no improvement over optimal two vector regimes. Strong ex vivo IFN-gamma responses peaked 1 wk after the booster dose, but cultured ELISPOT assays revealed longer-lasting T cell memory responses for at least 6 mo. In the DNA-primed vaccinees the IFN-gamma response was mainly due to CD4(+) T cells, whereas in the FP9-primed vaccinees it was mainly due to CD4-dependent CD8(+) T cells. This difference may be of importance for the protective efficacy of these vaccination approaches against various diseases.

Miotto O, Tan TW, Brusic V. 2005. Supporting the curation of biological databases with reusable text mining. Genome Inform, 16 (2), pp. 32-44. | Citations: 19 (Scopus) | Show Abstract

Curators of biological databases transfer knowledge from scientific publications, a laborious and expensive manual process. Machine learning algorithms can reduce the workload of curators by filtering relevant biomedical literature, though their widespread adoption will depend on the availability of intuitive tools that can be configured for a variety of tasks. We propose a new method for supporting curators by means of document categorization, and describe the architecture of a curator-oriented tool implementing this method using techniques that require no computational linguistic or programming expertise. To demonstrate the feasibility of this approach, we prototyped an application of this method to support a real curation task: identifying PubMed abstracts that contain allergen cross-reactivity information. We tested the performance of two different classifier algorithms (CART and ANN), applied to both composite and single-word features, using several feature scoring functions. Both classifiers exceeded our performance targets, the ANN classifier yielding the best results. These results show that the method we propose can deliver the level of performance needed to assist database curation.

Bejon P, Mwacharo J, Kai O, Lowe B, Todryk S, Peshu N, Gilbert S, Lang T, Marsh K, Hill A. 2005. Safety, immunogenicity and efficacy studies of candidate malaria vaccines FP9 and MVA encoding ME-TRAP in Kenyan children [MIM-PB-224908] ACTA TROPICA, 95 pp. S84-S84.

Kai O, Mwacharo J, Bejon P, Lowe B, Molyneux S, Peshu N, Marsh K, Hill A. 2005. Safety and immunogenicity of the candidate malaria vaccines FP9 ME-TRAP and MVA METRAP in semi-immune adult males [MIM-OK-87312] ACTA TROPICA, 95 pp. S421-S421.

Shanks GD, Biomndo K, Guyatt HL, Snow RW. 2005. Travel as a risk factor for uncomplicated Plasmodium falciparum malaria in the highlands of western Kenya. Trans R Soc Trop Med Hyg, 99 (1), pp. 71-74. | Citations: 21 (Scopus) | Show Abstract | Read more

In the 1980s, highland malaria returned to the tea estates of western Kenya after an absence of nearly a generation. In order to determine the importance of travel for the spread of malaria in this region, we prospectively collected blood films and travel, demographic and geographic information on well persons and outpatients on tea estates near the western rim of the Rift Valley. Risk factors for malaria asexual parasitaemia included: tribal/ethnic group, home province and home district malaria endemicity. Travel away from the Kericho tea estates within the previous two months showed an odds ratio (OR) for parasitaemia of 1.59 for well persons and 2.38 for outpatients. Sexual stages of malaria parasites (gametocytes) had an OR of 3.14 (well persons) and 2.22 (outpatients) for those who had travelled. Increased risk of malaria parasitaemia with travel was concentrated in children aged <5 years. An increase in population gametocytaemia is possibly due to increased chloroquine resistance and suppressed infections contracted outside of the tea estates.

Omumbo JA, Guerra CA, Hay SI, Snow RW. 2005. The influence of urbanisation on measures of Plasmodium falciparum infection prevalence in East Africa. Acta Trop, 93 (1), pp. 11-21. | Citations: 39 (Scopus) | Show Abstract | Read more

There is a growing interest in the effects of urbanisation in Africa on Plasmodium falciparum risks and disease outcomes. We undertook a review of published and unpublished literature to identify parasite survey data from communities in East Africa. Data were selected to represent the most reliable and contemporary estimates of infection prevalence and were categorised by urban or rural status using a number of approaches. We identified 329 spatially distinct surveys undertaken since 1980 in the sub-region of which 37 were undertaken in urban settlements and 292 in rural settlements. Overall rural settlements reported significantly higher parasite prevalence among children aged 0-14 than urban settlements (on average 10% higher infection rates; p<0.05). No urban settlements recorded parasite prevalence in excess of 75%. In areas of East Africa where climatic conditions are likely to support higher parasite transmission, the rural-urban difference was most marked. There was a significant trend towards documenting higher classes of parasite prevalence in rural compared to urban settlements (p<0.05) and the mean difference between rural and urban samples was 18% (p<0.001). These results further highlight the need to better define urban extents in Africa in order to capture the non-climatic determinants of infection and disease risk and provide a more informed approach to describing the burden of disease across the continent.

White NJ. 2005. Intermittent presumptive treatment for malaria. PLoS Med, 2 (1), pp. e3. | Citations: 126 (Web of Science Lite) | Read more

Vinh H, Duong NM, Phuong LT, Truong NT, Bay PVB, Wain J, Diep TS, Ho VA, White NJ, Day NPJ, Parry CM. 2005. Comparative trial of short-course ofloxacin for uncomplicated typhoid fever in Vietnamese children. Ann Trop Paediatr, 25 (1), pp. 17-22. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

An open, randomised comparison of 2 or 3 days of oral ofloxacin (10 mg/kg/day) for uncomplicated typhoid fever was conducted in 235 Vietnamese children. Multi-drug-resistant Salmonella typhi was isolated from 182/202 (90%) children and 5/166 (3%) tested isolates were nalidixic acid-resistant (Na(R)). Eighty-nine of 116 children randomised to 2 days and 107/119 randomised to 3 days were blood culture-positive and eligible for analysis. There were 12 (13.5%) failures in the 2-day group (six clinical failures, four blood culture-positive post treatment, two relapses) compared with eight (7.5%) failures in the 3-day group (four clinical failures, one blood culture-positive post treatment, three relapses) (OR 1.9, 95% CI 0.7-5.5,p = 0.17). There were no significant differences in the mean (95% confidence interval) fever clearance times (h) [92 (82-102) vs 101 (93-110), p = 0.18] or duration of hospitalisation (d) [7.6 (7.2-8.1) vs 8.0 (7.6-8.4), p = 0.19] between the two groups. There was one failure in the four eligible children infected with an Na(R) isolate of S. typhi. No adverse events were attributable to the ofloxacin. These results extend previous observations on the efficacy of short courses of ofloxacin for children with uncomplicated multi-drug-resistant typhoid fever.

Kombe F, Abuya T, Mutemi W, Molyneux S, Marsh V. 2005. Does injection use influence choice of and satisfaction with private health clinics? A user perspective [MIM-FK-216766] ACTA TROPICA, 95 pp. S246-S247.

Lang T, Hill A. 2005. Developing a deployable vaccine for Africa [MIM-TL-0] ACTA TROPICA, 95 pp. S311-S311.

Warrell DA. 2005. Rabies on the doorstep. Adv Exp Med Biol, 568 pp. 145-160. | Read more

Newton PN, Day NPJ, White NJ, Franco-Parades C, Dismukes R, Nicolls D, Kozarsky PE. 2005. Misattribution of central nervous system dysfunction to artesunate [4] (multiple letters) Clinical Infectious Diseases, 41 (11), pp. 1687-1689. | Citations: 14 (Scopus)

White NJ, Silamut K, Milner DA, Dzamalala CP, Liomba G, Molyneux ME, Taylor TE. 2005. Postmortem brain smear assessment of fatal malaria [2] (multiple letters) Journal of Infectious Diseases, 192 (3), pp. 547-548. | Citations: 2 (Scopus)

Cockburn R, Newton PN, Agyarko EK, Akunyili D, White NJ. 2005. The global threat of counterfeit drugs: why industry and governments must communicate the dangers. PLoS Med, 2 (4), pp. e100. | Citations: 152 (Scopus) | Read more

Zinderman CE, Wise R, Landow L. 2005. Fluid solutions in dengue shock syndrome. N Engl J Med, 353 (23), pp. 2510-2511. | Citations: 1 (Scopus) | Read more

Anderson TJC, Nair S, Qin H, Singlam S, Brockman A, Paiphun L, Nosten F. 2005. Erratum: Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance? (Antimicrobial Agents and Chemotherapy (2005) 49, 6 (2180-2188)) Antimicrobial Agents and Chemotherapy, 49 (9), pp. 3990. | Citations: 1 (Scopus) | Read more

Nosten F, McGready R, Ashley E, White NJ. 2005. Malaria misconceptions The Lancet, 365 (9460), pp. 653-653. | Citations: 4 (Scopus) | Read more

Nosten F. 2005. Malaria control in Plasmodium falciparum resistant to multi-therapy: a field opinion Médecine tropicale : revue du Corps de santé colonial., 65 (1), pp. 91-92.

Liem NT, Lim W, World Health Organization International Avian Influenza Investigation Team, Vietnam. 2005. Lack of H5N1 avian influenza transmission to hospital employees, Hanoi, 2004. Emerg Infect Dis, 11 (2), pp. 210-215. | Citations: 91 (Scopus) | Show Abstract | Read more

To establish whether human-to-human transmission of influenza A H5N1 occurred in the healthcare setting in Vietnam, we conducted a cross-sectional seroprevalence survey among hospital employees exposed to 4 confirmed and 1 probable H5N1 case-patients or their clinical specimens. Eighty-three (95.4%) of 87 eligible employees completed a questionnaire and provided a serum sample, which was tested for antibodies to influenza A H5N1. Ninety-five percent reported exposure to > or = 1 H5N1 case-patients; 59 (72.0%) reported symptoms, and 2 (2.4%) fulfilled the definition for a possible H5N1 secondary case-patient. No study participants had detectable antibodies to influenza A H5N1. The data suggest that the H5N1 viruses responsible for human cases in Vietnam in January 2004 are not readily transmitted from person to person. However, influenza viruses are genetically variable, and transmissibility is difficult to predict. Therefore, persons providing care for H5N1 patients should continue to take measures to protect themselves.

Horby PW, Williams A, Burgess MA, Wang H. 2005. Prevalence and determinants of influenza vaccination in Australians aged 40 years and over--a national survey. Aust N Z J Public Health, 29 (1), pp. 35-37. | Citations: 21 (Scopus) | Show Abstract | Read more

OBJECTIVES: To determine influenza vaccination coverage in 2001 in Australian adults aged > or = 40 years, assess awareness of and attitudes to influenza vaccine, factors associated with vaccination, and estimate uptake of free vaccine provided to those aged > or = 65 years. METHODS: National computer-assisted telephone interview (CATI) survey in October/November 2001. RESULTS: Interviews were completed with 5,266 people aged > or = 65 and 2,415 aged 40-64 years. Thirty per cent of selected households participated. Overall, 67% of respondents believed that the vaccine was somewhat to very effective in preventing influenza. Seventy-eight per cent of those aged > or = 65 years reported influenza vaccination; 89% had received it free. Independent predictors of vaccination were: belief that influenza vaccine is effective in preventing influenza (OR=13.5, 95% CI 10.6-17.2); and the presence of chronic disease (OR=1.6, 95% CI 1.3-2.0). Overall, 24% of those aged 40-64 years were vaccinated; only 34% of those who met any of the criteria for vaccination (medical risk factor, at-risk occupation, or being Aboriginal or Torres Strait Islander) reported vaccination. CONCLUSIONS: Influenza vaccine coverage was high in those aged > or = 65 years, but coverage of those at-risk aged 40-64 years remained suboptimal. Immunisation against influenza was influenced more by beliefs about the vaccine's effectiveness and existing medical risk factors, rather than socio-demographic factors such as gender and income.

Williams TN, Mwangi TW, Roberts DJ, Alexander ND, Weatherall DJ, Wambua S, Kortok M, Snow RW, Marsh K. 2005. An immune basis for malaria protection by the sickle cell trait PLoS Medicine, 2 (5), pp. 0441-0445. | Citations: 122 (Scopus) | Show Abstract | Read more

Background: Malaria resistance by the sickle cell trait (genotype HbAS) has served as the prime example of genetic selection for over half a century. Nevertheless, the mechanism of this resistance remains the subject of considerable debate. While it probably involves innate factors such as the reduced ability of Plasmodium falciparum parasites to grow and multiply in HbAS erythrocytes, recent observations suggest that it might also involve the accelerated acquisition of malaria-specific immunity. Methods and Findings: We studied the age-specific protection afforded by HbAS against clinical malaria in children living on the coast of Kenya. We found that protection increased with age from only 20% in the first 2 y of life to a maximum of 56% by the age of 10 y, returning thereafter to 30% in participants greater than 10 y old. Conclusions: Our observations suggest that malaria protection by HbAS involves the enhancement of not only innate but also of acquired immunity to the parasite. A better understanding of the underlying mechanisms might yield important insights into both these processes. © 2005 Williams et al.

Maguire GP, Handojo T, Pain MCF, Kenangalem E, Price RN, Tjitra E, Anstey NM. 2005. Lung injury in uncomplicated and severe falciparum malaria: a longitudinal study in papua, Indonesia. J Infect Dis, 192 (11), pp. 1966-1974. | Citations: 51 (Scopus) | Show Abstract | Read more

BACKGROUND: In patients with severe malaria, acute respiratory distress syndrome usually develops after the start of drug treatment and is a major cause of death. Its pathogenesis is not well understood. METHODS: Respiratory symptom, spirometry, and gas transfer analyses were performed longitudinally in adults in Papua, Indonesia, with uncomplicated (n=50) and severe (n=30) falciparum malaria; normal values were derived from 109 control subjects. Gas transfer was partitioned into its alveolar-capillary membrane (D(M)) and pulmonary vascular (Vc) components, to characterize the site of impaired gas transfer. RESULTS: Cough was frequent in both patients with uncomplicated malaria (50%) and those with severe malaria (30%) and resolved by day 14. Reduced midexpiratory flow indicated obstruction of the small airways. Gas transfer was significantly impaired in patients with severe malaria. D(M) was reduced in patients with severe malaria but not in those with uncomplicated malaria and only returned to normal levels after 2 weeks. In patients with uncomplicated malaria, Vc was reduced at presentation but improved thereafter. In patients with severe malaria, Vc decreased with treatment and was lowest at day 7. CONCLUSIONS: Our results suggest that pulmonary vascular occlusion occurs in both patients with uncomplicated malaria and those with severe malaria, likely from sequestration of both red blood cells (RBCs) and white blood cells. There was also impaired alveolar-capillary membrane function in patients with severe malaria but not in those with uncomplicated malaria. Persistent impairment long after clearance of parasitized RBCs suggests prolonged posttreatment inflammatory alveolar-capillary injury.

Wertheim HFL, Vos MC, Ott A, Voss A, Kluytmans JAJW, Vandenbroucke-Grauls CMJE, Meester MHM, Van Keulen PHJ, Verbrugh HA. 2005. Mupirocin prophylaxis for the prevention of nosocomial infections due to nasal carriers of Staphylococcus aureus is of no use in nonsurgical patients as yet Nederlands Tijdschrift voor Geneeskunde, 149 (7), pp. 350-355. | Show Abstract

Objective. To assess the efficacy of mupirocin prophylaxis in preventing nosocomial Staphylococcus aureus infections in nonsurgical patients. Design. Randomised, double-blind, placebo-controlled multicentre trial. Method. In three tertiary-care university hospitals and one peripheral teaching hospital, 1602 culture-proven nasal S. aureus carriers hospitalized on nonsurgical wards were treated with mupirocin 2% nasal ointment (n = 793) or placebo ointment (n = 809), twice daily for 5 days, starting 1 to 3 days after admission. Data collected included nosocomial S. aureus infections according to defined criteria, in-hospital mortality, duration of hospitali sation, and time to nosocomial S. aureus infection. S. aureus isolates were genotyped to assess whether infection was caused by endogenous strains. Results. The mupirocin and placebo groups did not differ statistically significantly in the rates of nosocomial S. aureus infections (mupirocin group: 2.6%; placebo group: 2.8%; risk difference: 0.2% (95% CI: -1.5%-1.9%)), mortality (mupirocin: 3.0%; placebo: 2.8%; risk difference: -0.2% (95% CI: -1.9%-1.5%)), or duration of hospitalisation (median for both groups: 8 days). However, the time to nosocomial S. aureus infection was increased in the mupirocin group from 12 to 25 days (p = 0.28). A total of 77% of S. aureus nosocomial infections were endogenous. Conclusion. Routine culture for nasal carriage of S. aureus at admission and subsequent mupirocin prophylaxis in the carriers did not prevent nosocomial S. aureus infections in nonsurgical patients.

Nahlen BL, Korenromp EL, Miller JM, Shibuya K. 2005. Malaria risk: estimating clinical episodes of malaria. Nature, 437 (7056), pp. E3. | Citations: 13 (Scopus) | Show Abstract | Read more

Estimates of the disease burden caused by malaria are crucial for informing malaria control programmes. Snow and colleagues claim that their estimate of 515 million cases of malaria caused by Plasmodium falciparum globally is up to 50% higher than that reported by the World Health Organization (WHO), and 200% higher for areas outside Africa. However, this comparison refers to the WHO's estimates from 1990 and 1998, and not to the range of 300 million to 500 million that the WHO has used since 2000 (ref. 2). Both groups agree that the burden of malaria disease outside Africa, especially in South Asia, is greater than was estimated in the 1990s.

Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K, Chotivanich K, Newton PN, Pitisuttithum P, Smithyman AM, White NJ, Day NPJ. 2005. Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2 PLoS Medicine, 2 (8), pp. 0788-0797. | Citations: 225 (Scopus) | Show Abstract | Read more

Background: In falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden sequestered parasite load in vivo has not previously been possible. The peripheral blood parasite count measures only the circulating, relatively non-pathogenic parasite numbers. P. falciparum releases a specific histidine-rich protein (PfHRP2) into plasma. Quantitative measurement of plasma PfHRP2 concentrations may reflect the total parasite biomass in falciparum malaria. Methods and Findings: We measured plasma concentrations of PfHRP2, using a quantitative antigen-capture enzyme-linked immunosorbent assay, in 337 adult patients with falcipar um malaria of varying severity hospitalised on the Thai-Burmese border. Based on in vitro production rates, we constructed a model to link this measure to the total parasite burden in the patient. The estimated geometric mean parasite burden was 7 × 10 11 (95% confidence interval [CI] 5.8 × 10 11 to 8.5 × 10 11 ) parasites per body, and was over six times higher in severe malaria (geometric mean 1.7 × 10 12 , 95% CI 1.3 × 10 12 to 2.3 × 10 12 ) than in patients hospitalised without signs of severity (geometric mean 2.8 × 10 11 , 95% CI 2.3 × 10 11 to 3.5 × 10 11 ; p < 0.001). Parasite burden was highest in patients who died (geometric mean 3.4 × 10 12 , 95% CI 1.9 × 10 12 to 6.3 × 10 12 ; p = 0.03). The calculated number of sequestered parasites increased with disease severity and was higher in patients with late developmental stages of P. falciparum present on peripheral blood smears. Comparing model and laboratory estimates of the time of sequestration suggested that admission to hospital with uncomplicated malaria often follows schizogony - but in severe malaria is unrelated to stage of parasite development. Conclusion: Plasma PfHRP2 concentrations may be used to estimate the total body parasite biomass in acute falciparum malaria. Severe malaria results from extensive sequestration of parasitised erythrocytes. © 2005 Dondorp et al.

Fisher MC, Hanage WP, de Hoog S, Johnson E, Smith MD, White NJ, Vanittanakom N. 2005. Low Effective Dispersal of Asexual Genotypes in Heterogeneous Landscapes by the Endemic Pathogen Penicillium marneffei PLoS Pathogens, 1 (2), pp. e20-e20. | Citations: 40 (Scopus) | Show Abstract | Read more

Long-distance dispersal in microbial eukaryotes has been shown to result in the establishment of populations on continental and global scales. Such "ubiquitous dispersal" has been claimed to be a general feature of microbial eukaryotes, homogenising populations over large scales. However, the unprecedented sampling of opportunistic infectious pathogens created by the global AIDS pandemic has revealed that a number of important species exhibit geographic endemicity despite long-distance migration via aerially dispersed spores. One mechanism that might tend to drive such endemicity in the face of aerial dispersal is the evolution of niche-adapted genotypes when sexual reproduction is rare. Dispersal of such asexual physiological "species" will be restricted when natural habitats are heterogeneous, as a consequence of reduced adaptive variation. Using the HIV-associated endemic fungus Penicillium marneffei as our model, we measured the distribution of genetic variation over a variety of spatial scales in two host species, humans and bamboo rats. Our results show that, despite widespread aerial dispersal, isolates of P. marneffei show extensive spatial genetic structure in both host species at local and country-wide scales. We show that the evolution of the P. marneffei genome is overwhelmingly clonal, and that this is perhaps the most asexual fungus yet found. We show that clusters of genotypes are specific to discrete ecological zones and argue that asexuality has led to the evolution of niche-adapted genotypes, and is driving endemicity, by reducing this pathogen's potential to diversify in nature. © 2005 Fisher et al.

White NJ. 2005. Dynamic determinants of the cytoadherence of Plasmodium falciparum-infected erythrocytes. Am J Trop Med Hyg, 72 (6), pp. 658-659.

White NJ. 2005. Intermittent presumptive treatment for malaria: A better understanding of the pharmacodynamics will guide more rational policymaking PLoS Medicine, 2 pp. 0028-0033. | Citations: 132 (Scopus) | Read more

Uren TK, Wijburg OLC, Simmons C, Johansen F-E, Brandtzaeg P, Strugnell RA. 2005. Vaccine-induced protection against gastrointestinal bacterial infections in the absence of secretory antibodies. Eur J Immunol, 35 (1), pp. 180-188. | Citations: 62 (Scopus) | Show Abstract | Read more

Secretory IgA (SIgA) is widely held to be responsible for the defense of the mucosae against pathogenics and other potentially harmful agents. In this study, polymeric Ig receptor (pIgR) knockout mice, which lack secretory antibodies (SAb), were used to investigate the role of vaccine-elicited SAb in protection against gastrointestinal bacterial infections. An essential role for specific SAb in protection against Vibrio cholerae was evident from experiments showing that vaccinated pIgR(-/-) mice, but not vaccinated C57BL/6 mice, were susceptible to cholera toxin challenge. Vaccination of C57BL/6 mice with Salmonella typhimurium elicited strong antigen-specific, mucosal responses, which blocked in vitro invasion of epithelia. However, vaccinated C57BL/6 and pIgR(-/-) mice were equally resistant to challenge infection with virulent S. typhimurium. Finally, we investigated the importance of SIgA in protection against recurrent infections with Citrobacter rodentium. Although higher numbers of bacteria were detected early after challenge infection in feces of vaccinated pIgR(-/-) mice compared with vaccinated C57BL/6 mice, both mouse strains showed complete clearance after 9 days. These results suggested that, in immune animals, SIgA is crucial for the protection of gastrointestinal surfaces against secreted bacterial toxins, may inhibit early colonization by C. rodentium, but is not essential for protection against re-infection with S. typhimurium or C. rodentium.

Zurovac D, Midia B, Snow R. 2005. Effects of microscopy on outpatient malaria case management in Kenya [MIM-DZ-8658] ACTA TROPICA, 95 pp. S269-S269.

Premawardhena A, Fisher CA, Olivieri NF, de Silva S, Arambepola M, Perera W, O'Donnell A, Peto TEA, Viprakasit V, Merson L et al. 2005. Haemoglobin E beta thalassaemia in Sri Lanka. Lancet, 366 (9495), pp. 1467-1470. | Citations: 60 (Scopus) | Show Abstract | Read more

Haemoglobin E beta thalassaemia is the commonest form of severe thalassaemia in many Asian countries, but little is known about its natural history, the reasons for clinical diversity, or its management. We studied 109 Sri Lankan patients with the disorder over 5 years. 25 patients were not receiving transfusion; transfusion was stopped with no deleterious effect in a further 37. We identified several genetic and environmental factors that might contribute to the phenotypic diversity of the disorder, including modifiers of haemoglobin F production, malaria, and age-related changes in adaptive function. Our findings suggest that haemoglobin E beta thalassaemia can be managed without transfusion in many patients, even with low haemoglobin levels. Age-related changes in the pattern of adaptation to anaemia suggest that different and more cost-effective approaches to management should be explored.

Berkley J, Newton C, Mwangi I, Osier F, Shebbe M, Maitland K, Lowe B, Marsh K. 2005. Morbidity and co-morbidity in children with signs of severe malaria [MIM-JB-166260] ACTA TROPICA, 95 pp. S53-S53.

Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K, Chotivanich K, Newton PN, Pitisuttithum P, Smithyman AM, White NJ, Day NPJ. 2005. Correction: Estimation of the Total Parasite Biomass in Acute Falciparum Malaria from Plasma PfHRP2 PLoS Medicine, 2 (10), pp. e390-e390. | Citations: 3 (Scopus) | Read more

Maitland K, Newton C, Marsh K, Levin M. 2005. Volume status in severe malaria: no evidence provided for the degree of filling of the intravascular compartment. PLoS Med, 2 (1), pp. e27. | Citations: 1 (Web of Science Lite) | Read more

Maitland K, Newton C, Marsh K, Levin M, Krishna S, Planche T. 2005. Volume status in severe malaria: No evidence provided for the degree of filling of the intravascular compartment [1] (multiple letters) PLoS Medicine, 2 pp. 0079. | Citations: 1 (Scopus) | Read more

Sur D, Deen JL, Manna B, Niyogi SK, Deb AK, Kanungo S, Sarkar BL, Kim DR, Danovaro-Holliday MC, Holliday K et al. 2005. The burden of cholera in the slums of Kolkata, India: data from a prospective, community based study. Arch Dis Child, 90 (11), pp. 1175-1181. | Citations: 55 (Scopus) | Show Abstract | Read more

AIMS: To conduct a prospective, community based study in an impoverished urban site in Kolkata (formerly Calcutta) in order to measure the burden of cholera, describe its epidemiology, and search for potential risk factors that could be addressed by public health strategies. METHODS: The study population was enumerated at the beginning and end of the study period. Surveillance through five field outposts and two referral hospitals for acute, watery, non-bloody diarrhoea was conducted from 1 May 2003 to 30 April 2004. Data and a stool sample for culture of Vibrio cholerae were collected from each patient. Treatment was provided in accordance with national guidelines. RESULTS: From 62 329 individuals under surveillance, 3284 diarrhoea episodes were detected, of which 3276 (99%) had a stool sample collected and 126 (4%) were culture confirmed cholera. Nineteen (15%) were children less than 2 years of age, 29 (23%) had severe dehydration, and 48 (38%) were hospitalised. Risk factors for cholera included a household member with cholera during the period of surveillance, young age, and lower educational level. CONCLUSIONS: There was a substantial burden of cholera in Kolkata with risk factors not easily amenable to intervention. Young children bear the brunt not only of diarrhoeal diseases in general, but of cholera as well. Mass vaccination could be a potentially useful tool to prevent and control seasonal cholera in this community.

Eziefula A, Mwakisha N, Macharia A, Williams T, Maitland K, Lowe B, Dondorp A, Newton C. 2005. Correlates of red blood cell deformability (RCD) with adverse outcome in severe falciparum malaria: The effect of sequestered parasitized red cells [MIM-AE-70550] ACTA TROPICA, 95 pp. S384-S385.

Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TKT, Nguyen TH, Tran TH et al. 2005. Avian influenza A (H5N1) infection in humans. N Engl J Med, 353 (13), pp. 1374-1385. | Citations: 943 (Scopus) | Read more

Cepeda JA, Whitehouse T, Cooper B, Hails J, Jones K, Kwaku F, Taylor L, Hayman S, Cookson B, Shaw S et al. 2005. Isolation of patients in single rooms or cohorts to reduce spread of MRSA in intensive-care units: prospective two-centre study. Lancet, 365 (9456), pp. 295-304. | Citations: 224 (Scopus) | Show Abstract | Read more

BACKGROUND: Hospital-acquired infection due to meticillin-resistant Staphylococcus aureus (MRSA) is common within intensive-care units. Single room or cohort isolation of infected or colonised patients is used to reduce spread, but its benefit over and above other contact precautions is not known. We aimed to assess the effectiveness of moving versus not moving infected or colonised patients in intensive-care units to prevent transmission of MRSA. METHODS: We undertook a prospective 1-year study in the intensive-care units of two teaching hospitals. Admission and weekly screens were used to ascertain the incidence of MRSA colonisation. In the middle 6 months, MRSA-positive patients were not moved to a single room or cohort nursed unless they were carrying other multiresistant or notifiable pathogens. Standard precautions were practised throughout. Hand hygiene was encouraged and compliance audited. FINDINGS: Patients' characteristics and MRSA acquisition rates were similar in the periods when patients were moved and not moved. The crude (unadjusted) Cox proportional-hazards model showed no evidence of increased transmission during the non-move phase (0.73 [95% CI 0.49-1.10], p=0.94 one-sided). There were no changes in transmission of any particular strain of MRSA nor in handwashing frequency between management phases. INTERPRETATION: Moving MRSA-positive patients into single rooms or cohorted bays does not reduce crossinfection. Because transfer and isolation of critically ill patients in single rooms carries potential risks, our findings suggest that re-evaluation of isolation policies is required in intensive-care units where MRSA is endemic, and that more effective means of preventing spread of MRSA in such settings need to be found.

Bejon P. 2005. Steps towards a malaria vaccine Evidence-based Healthcare and Public Health, 9 (3), pp. 177-178. | Read more

Carrique-Mas J, Andersson Y, Hjertqvist M, Svensson A, Torner A, Giesecke J. 2005. Risk factors for domestic sporadic campylobacteriosis among young children in Sweden. Scand J Infect Dis, 37 (2), pp. 101-110. | Citations: 54 (Scopus) | Show Abstract | Read more

A case-control study was conducted in Sweden to study risk factors for domestically acquired Campylobacter jejuni/coli infections among children aged less than 6 y. A total of 126 cases, reported to the national surveillance system were recruited over 1 y. Controls, selected from the population register, were matched to the cases by age, gender, place of residence and time of infection of the case. Information was gathered by posted questionnaires. Two separate conditional regression models were developed including and excluding 'protective' factors. Two of the factors significantly associated with Campylobacter infection were water-related: having a well in the household (OR=2.6) and drinking water from a lake/river (OR=7.4; 6.0). Other exposures associated with increased risk were: having a dog (OR=8.4; 3.8) and eating grilled meat (OR=5.5; 2.1). Drinking unpasteurized milk was borderline significant in 1 model (OR=3.7). Eating sausage was protective (OR=0.05). Eating chicken was not a significant risk. Exposures such as eating grilled meat and drinking water from a lake or a river were more common in the warm months, a factor that may partly explain the observed seasonality. The authors suggest that differences between risk factors across studies may reflect geographical and age-specific differences in the sources of infection.

Thwaites GE, Tran TH. 2005. Tuberculous meningitis: many questions, too few answers. Lancet Neurol, 4 (3), pp. 160-170. | Citations: 201 (Scopus) | Show Abstract | Read more

Tuberculous meningitis (TM) is difficult to diagnose and treat; clinical features are non-specific, conventional bacteriology is widely regarded as insensitive, and assessment of newer diagnostic methods is not complete. Treatment includes four drugs, which were developed more than 30 years ago, and prevents death or disability in less than half of patients. Mycobacterium tuberculosis resistant to these drugs threatens a return to the prechemotherapeutic era in which all patients with TM died. Research findings suggest that adjunctive treatment with corticosteroids improve survival but probably do not prevent severe disability, although how or why is not known. There are many important unanswered questions about the pathophysiology, diagnosis, and treatment of TM. Here we review the available evidence to answer some of these questions, particularly those on the diagnosis and treatment of TM.

HIEN TTT, HAI TN, PHUONG NT, OGATA HY, WILDER MN. 2005. The effects of dietary lipid sources and lecithin on the production of giant freshwater prawn Macrobrachium rosenbergii larvae in the Mekong Delta region of Vietnam Fisheries Science, 71 (2), pp. 279-286. | Citations: 8 (Scopus) | Show Abstract | Read more

The giant freshwater prawn, Macrobrachium rosenbergii, is cultured widely in the Mekong Delta region of Vietnam but it is often difficult or expensive for hatchery operators to purchase commercial diets used as a feeding supplement to Artemia nauplii. Therefore, in the present study, the effects of lipid sources and lecithin on the growth and survival rate of M. rosenbergii larvae were examined in order to develop suitable hand-prepared larval diets for seed production of M. rosenbergii in this area. Six egg custard diets consisting of various ratios of lipid (originating from soybean oil and squid oil) and lecithin were used for rearing Macrobrachium rosenbergii larvae. Treatments in which larvae were fed diets containing squid oil exhibited the highest body length and survival rates (7.14-7.43 mm and 51.1-68.1%, respectively), and differed significantly from other treatments (P < 0.05). Use of dietary soybean oil yielded the lowest body length and survival rates (6.29-6.75 mm and 22.0-48.7%, respectively). The supplementation of dietary lecithin did not increase final body weight but did improve larval survival rates. The n-3 HUFA content of prawns fed dietary squid oil was higher than those of animals provided with other diets. These results indicated that the most appropriate diet for rearing M. rosenbergii larvae is the diet containing 3% squid oil and 1.5% lecithin.

Hien TT, Davis TME, Chuong LV, Ilett KF, Sinh DXT, Phu NH, Agus C, Chiswell GM, White NJ, Farrar J. 2005. Erratum: Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria (Antimicrobial Agents and Chemotherapy (2004) 48:11 (4234-4239)) Antimicrobial Agents and Chemotherapy, 49 (2), pp. 871. | Read more

Quy HT, Lan NH, Dung NH, Hien TT, Duc NH, Couturaud F, Leroyer C. 2005. A case of avian influenza (H5N1) pulmonary infection with early expansion of lung bulla formations Respiratory Medicine Extra, 1 (3), pp. 61-64. | Show Abstract | Read more

A 22 year old previously healthy male subject was admitted to hospital in Ho Chi Minh City, Vietnam, with fever and severe pneumonia. On interviewing the patient a recent close contact with poultry was revealed and a RT-PCR test for H5 and N1 influenza antigen was found positive following nose and throat swabs. Partial recovery was highlighted by the development of extensive bulla formations in the left lung. We herein report clinical and radiological features in a 22 year old male Vietnamese patient who developed severe acute pneumonia and in whose RT-PCR test for H5 and N1 influenza antigen was found positive following nose and throat swabs. Partial recovery was highlighted by the development of extensive bulla formations in the left lung. © 2005 Elsevier Ltd. All rights reserved.

Meister S, Kanzok SM, Zheng X-L, Luna C, Li T-R, Hoa NT, Clayton JR, White KP, Kafatos FC, Christophides GK, Zheng L. 2005. Immune signaling pathways regulating bacterial and malaria parasite infection of the mosquito Anopheles gambiae. Proc Natl Acad Sci U S A, 102 (32), pp. 11420-11425. | Citations: 144 (Scopus) | Show Abstract | Read more

We show that, in the malaria vector Anopheles gambiae, expression of Cecropin 1 is regulated by REL2, an NF-kappaB-like transcription factor orthologous to Drosophila Relish. Through alternative splicing, REL2 produces a full-length (REL2-F) and a shorter (REL2-S) protein isoform lacking the inhibitory ankyrin repeats and death domain. RNA interference experiments show that, in contrast to Drosophila Relish, which responds solely to Gram-negative bacteria, the Anopheles REL2-F and REL2-S isoforms are involved in defense against the Gram-positive Staphylococcus aureus and the Gram-negative Escherichia coli bacteria, respectively. REL2-F also regulates the intensity of mosquito infection with the malaria parasite, Plasmodium berghei. The adaptor IMD shares the same activities as REL2-F. Microarray analysis identified 10 additional genes regulated by REL2, including CEC3, GAM1, and LRIM1.

Thwaites GE. 2005. Pyrexia of unknown origin. Acute Med, 4 (1), pp. 10-14. | Show Abstract

Classical pyrexia of unknown origin (PUO), defined as fever of >38 °C on several occasions for greater than three weeks despite investigation in hospital (>3 days) or out of hospital (>2 visits), is an uncommon but challenging problem. The incidence and aetiology vary according to the geographic region, the age structure of the population, and the immune status of the patient; alternative definitions of PUO exist for immune compromised individuals. Preliminary investigations should be determined by detailed history and repeated examination. Biopsy of abnormal tissues should be performed early. If uncertainty persists, abdominal computerised tomography (CT), radiolabeled white cell scans, and the Duke endocarditis criteria carry the highest diagnostic yield. Blind bone marrow biopsy is probably only useful in immunocompromised patients.

Evans ND, Cronin DM, White LJ, Chappell MJ, Chapman MJ, Godfrey KR. 2005. CONTROLLING THE TRANSMISSION OF MASTITIS-CAUSING PATHOGENS ACROSS HETEROGENEOUS DAIRY HERDS IFAC Proceedings Volumes, 38 (1), pp. 19-24. | Show Abstract | Read more

Using a mathematical model for the transmission of mastitis-causing pathogens in a dairy herd and parameter estimation, control strategies are derived for a number of different herds. in addition, a single common strategy is derived for control of all of the herds. A key feature of all of the control strategies is that they minimise the combined costs associated with infection and treatment. Only a small decrease in performance results from developing a common strategy. Copyright © 2005 IFAC.

Basnyat B. 2005. The Khumbu cure. High Alt Med Biol, 6 (4), pp. 342-345. | Citations: 2 (Scopus) | Read more

Bishop R, Shah T, Pelle R, Hoyle D, Pearson T, Haines L, Brass A, Hulme H, Graham SP, Taracha ELN et al. 2005. Analysis of the transcriptome of the protozoan Theileria parva using MPSS reveals that the majority of genes are transcriptionally active in the schizont stage. Nucleic Acids Res, 33 (17), pp. 5503-5511. | Citations: 30 (Web of Science Lite) | Show Abstract | Read more

Massively parallel signature sequencing (MPSS) was used to analyze the transcriptome of the intracellular protozoan Theileria parva. In total 1,095,000, 20 bp sequences representing 4371 different signatures were generated from T.parva schizonts. Reproducible signatures were identified within 73% of potentially detectable predicted genes and 83% had signatures in at least one MPSS cycle. A predicted leader peptide was detected on 405 expressed genes. The quantitative range of signatures was 4-52,256 transcripts per million (t.p.m.). Rare transcripts (<50 t.p.m.) were detected from 36% of genes. Sequence signatures approximated a lognormal distribution, as in microarray. Transcripts were widely distributed throughout the genome, although only 47% of 138 telomere-associated open reading frames exhibited signatures. Antisense signatures comprised 13.8% of the total, comparable with Plasmodium. Eighty five predicted genes with antisense signatures lacked a sense signature. Antisense transcripts were independently amplified from schizont cDNA and verified by sequencing. The MPSS transcripts per million for seven genes encoding schizont antigens recognized by bovine CD8 T cells varied 1000-fold. There was concordance between transcription and protein expression for heat shock proteins that were very highly expressed according to MPSS and proteomics. The data suggests a low level of baseline transcription from the majority of protein-coding genes.

Cheng AC, Dance DAB, Currie BJ. 2005. Bioterrorism, Glanders and melioidosis. Euro Surveill, 10 (3), pp. E1-E2. | Citations: 13 (Scopus)

Cooper BS, Stone SR, Kibbler CC, Cookson BD, Roberts JA, Medley GF, Duckworth GJ, Lai R, Ebrahim S. 2005. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: A review of the literature with epidemiological and economic modeling INTERNATIONAL JOURNAL OF TECHNOLOGY ASSESSMENT IN HEALTH CARE, 21 (1), pp. 146-146. | Citations: 1 (Web of Science Lite)

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