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1.
Am J Hum Genet ; 111(4): 668-679, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38508194

RESUMO

Populations of the Eastern Highlands of Papua New Guinea (EHPNG, area 11,157 km2) lived in relative isolation from the rest of the world until the mid-20th century, and the region contains a wealth of linguistic and cultural diversity. Notably, several populations of EHPNG were devastated by an epidemic prion disease, kuru, which at its peak in the mid-twentieth century led to some villages being almost depleted of adult women. Until now, population genetic analyses to learn about genetic diversity, migration, admixture, and the impact of the kuru epidemic have been restricted to a small number of variants or samples. Here, we present a population genetic analysis of the region based on genome-wide genotype data of 943 individuals from 21 linguistic groups and 68 villages in EHPNG, including 34 villages in the South Fore linguistic group, the group most affected by kuru. We find a striking degree of genetic population structure in the relatively small region (average FST between linguistic groups 0.024). The genetic population structure correlates well with linguistic grouping, with some noticeable exceptions that reflect the clan system of community organization that has historically existed in EHPNG. We also detect the presence of migrant individuals within the EHPNG region and observe a significant excess of females among migrants compared to among non-migrants in areas of high kuru exposure (p = 0.0145, chi-squared test). This likely reflects the continued practice of patrilocality despite documented fears and strains placed on communities as a result of kuru and its associated skew in female incidence.


Assuntos
Kuru , Príons , Adulto , Feminino , Humanos , Kuru/epidemiologia , Kuru/genética , Kuru/história , Papua Nova Guiné/epidemiologia , Príons/genética , Genótipo , Aprendizagem
2.
Omega (Westport) ; : 302228241239210, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38458237

RESUMO

In this paper we examine the traditional mortuary rites of the South Fore people of Papua New Guinea using Robert Hertz's theory of secondary burial and the three mechanisms of mourning identified by Daniel Lagache. The ethnographic data that we obtained on South Fore interpretations of their own mortuary rites showed that all forms of corpse handling achieved the same end results through the process of secondary burial. Furthermore, the three mechanisms of mourning applied equally to all forms of corpse disposal and we found no evidence to support psychosexual interpretations of mortuary anthropophagy which emphasise aggression. South Fore interpretations of mortuary anthropophagy show that the dead were eaten out of love, and to protect the mourners from the painful emotion of witnessing the decomposition of the corpse. These findings affirm the relevance of the concepts of Hertz and Lagache to the universal human experiences of death and mourning.

3.
Nature ; 522(7557): 478-81, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-26061765

RESUMO

Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.


Assuntos
Polimorfismo Genético/genética , Doenças Priônicas/genética , Doenças Priônicas/prevenção & controle , Príons/genética , Príons/metabolismo , Alelos , Substituição de Aminoácidos/genética , Animais , Bovinos , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/prevenção & controle , Encefalopatia Espongiforme Bovina/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Kuru/epidemiologia , Kuru/genética , Kuru/prevenção & controle , Camundongos , Camundongos Transgênicos , Papua Nova Guiné/epidemiologia , Proteínas PrPSc/química , Proteínas PrPSc/genética , Proteínas PrPSc/metabolismo , Doenças Priônicas/epidemiologia , Doenças Priônicas/transmissão , Príons/química , Príons/farmacologia
4.
Hum Mol Genet ; 21(8): 1897-906, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22210626

RESUMO

Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt-Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38-RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 × 10(-8); OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 × 10(-7); odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10(-5); two at PRNP, three at ZBTB38-RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only strong risk factors that act universally across human prion diseases. Our data are most consistent with several other risk loci of modest overall effects which will require further genetic association studies to provide definitive evidence.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Doenças Priônicas/genética , Príons/genética , Estudos de Casos e Controles , Síndrome de Creutzfeldt-Jakob/genética , Resistência à Doença , Encefalopatia Espongiforme Bovina/genética , Feminino , Humanos , Kuru/genética , Proteínas de Neoplasias/genética , Proteínas Priônicas , Fatores de Risco , Proteínas Ativadoras de ras GTPase/genética
5.
N Engl J Med ; 361(21): 2056-65, 2009 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-19923577

RESUMO

BACKGROUND: Kuru is a devastating epidemic prion disease that affected a highly restricted geographic area of the Papua New Guinea highlands; at its peak, it predominantly affected adult women and children of both sexes. Its incidence has steadily declined since the cessation of its route of transmission, endocannibalism. METHODS: We performed genetic and selected clinical and genealogic assessments of more than 3000 persons from Eastern Highland populations, including 709 who participated in cannibalistic mortuary feasts, 152 of whom subsequently died of kuru. RESULTS: Persons who were exposed to kuru and survived the epidemic in Papua New Guinea are predominantly heterozygotes at the known resistance factor at codon 129 of the prion protein gene (PRNP). We now report a novel PRNP variant--G127V--that was found exclusively in people who lived in the region in which kuru was prevalent and that was present in half of the otherwise susceptible women from the region of highest exposure who were homozygous for methionine at PRNP codon 129. Although this allele is common in the area with the highest incidence of kuru, it is not found in patients with kuru and in unexposed population groups worldwide. Genealogic analysis reveals a significantly lower incidence of kuru in pedigrees that harbor the protective allele than in geographically matched control families. CONCLUSIONS: The 127V polymorphism is an acquired prion disease resistance factor selected during the kuru epidemic, rather than a pathogenic mutation that could have triggered the kuru epidemic. Variants at codons 127 and 129 of PRNP demonstrate the population genetic response to an epidemic of prion disease and represent a powerful episode of recent selection in humans.


Assuntos
Predisposição Genética para Doença , Kuru/genética , Polimorfismo Genético , Príons/genética , Adolescente , Adulto , Idoso , Canibalismo , Surtos de Doenças , Feminino , Frequência do Gene , Aptidão Genética , Genótipo , Haplótipos , Humanos , Kuru/epidemiologia , Masculino , Pessoa de Meia-Idade , Papua Nova Guiné/epidemiologia , Proteínas Priônicas , Adulto Jovem
6.
PLoS Genet ; 5(2): e1000383, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19214206

RESUMO

Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice. Further, we report an association between HECTD2 haplotypes and susceptibility to the acquired human prion diseases, vCJD and kuru. We report a genotype-associated differential expression of Hectd2 mRNA in mouse brains and human lymphocytes and a significant up-regulation of transcript in mice at the terminal stage of prion disease. Although the substrate of HECTD2 is unknown, these data highlight the importance of proteosome-directed protein degradation in neurodegeneration. This is the first demonstration of a mouse quantitative trait gene that also influences susceptibility to human prion diseases. Characterisation of such genes is key to understanding human risk and the molecular basis of incubation periods.


Assuntos
Predisposição Genética para Doença , Doenças Priônicas/genética , Doenças Priônicas/veterinária , Doenças dos Roedores/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Animais , Células Cultivadas , Feminino , Expressão Gênica , Humanos , Linfócitos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Doenças Priônicas/metabolismo , Locos de Características Quantitativas , Doenças dos Roedores/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , População Branca/genética , Adulto Jovem
7.
Hum Vaccin ; 6(1): 17-20, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20173407

RESUMO

Despite its small population and isolated location Papua New Guinea (PNG) with a malaria burden comparable to sub-Saharan Africa, its intense transmission of all four human Plasmodium species and an unrivalled combination of environmental and human variation offers unique perspectives on malaria vaccines. Building on a long history of malaria research, in this article we review past achievements, highlight current research and outline future directions in malaria vaccine research. With intensive transmission of all four species of human malaria, a full range of malaria endemicities, well described epidemiology and a demonstrated capacity to evaluate a malaria vaccine, PNG currently has the only field site that is ready to conduct proof-of-principle studies of currently available P. vivax vaccine candidates and future combined P. falciparum / P. vivax vaccines and also offers unique opportunities for P. falciparum vaccine research. PNG is thus ready to contribute significantly in the global malaria vaccine endeavor.


Assuntos
Vacinas Antimaláricas/imunologia , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária Vivax/epidemiologia , Malária Vivax/prevenção & controle , Pesquisa Biomédica/tendências , Ensaios Clínicos como Assunto , Humanos , Papua Nova Guiné/epidemiologia , Plasmodium falciparum/imunologia , Plasmodium vivax/imunologia
8.
Theranostics ; 10(21): 9620-9643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32863950

RESUMO

Long non-coding RNAs (lncRNAs) have emerged as integral components of E2F1-regulated gene regulatory networks (GRNs), but their implication in advanced or treatment-refractory malignancy is unknown. Methods: We combined high-throughput transcriptomic approaches with bioinformatics and structure modeling to search for lncRNAs that participate in E2F1-activated prometastatic GRNs and their phenotypic targets in the highly-relevant case of E2F1-driven aggressive bladder cancer (BC). RNA immunoprecipitation was performed to verify RNA-protein interactions. Functional analyses including qRT-PCR, immunoblotting, luciferase assays and measurement of extracellular fluxes were conducted to validate expression and target gene regulation. Results: We identified E2F1-responsive lncRNA-SLC16A1-AS1 and its associated neighboring protein-coding gene, SLC16A1/MCT1, which both promote cancer invasiveness. Mechanistically, upon E2F1-mediated co-transactivation of the gene pair, SLC16A1-AS1 associates with E2F1 in a structure-dependent manner and forms an RNA-protein complex that enhances SLC16A1/MCT1 expression through binding to a composite SLC16A1-AS1:E2F1-responsive promoter element. Moreover, SLC16A1-AS1 increases aerobic glycolysis and mitochondrial respiration and fuels ATP production by fatty acid ß-oxidation. These metabolic changes are accompanied by alterations in the expression of the SLC16A1-AS1:E2F1-responsive gene PPARA, a key mediator of fatty acid ß-oxidation. Conclusions: Our results unveil a new gene regulatory program by which E2F1-induced lncRNA-SLC16A1-AS1 forms a complex with its transcription factor that promotes cancer metabolic reprogramming towards the acquisition of a hybrid oxidative phosphorylation/glycolysis cell phenotype favoring BC invasiveness.


Assuntos
Reprogramação Celular/fisiologia , Fator de Transcrição E2F1/genética , Transportadores de Ácidos Monocarboxílicos/genética , RNA Longo não Codificante/genética , Simportadores/genética , Neoplasias da Bexiga Urinária/genética , Trifosfato de Adenosina/genética , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Glicólise/genética , Humanos , Mitocôndrias/genética , Oxirredução , Regiões Promotoras Genéticas/genética , Ativação Transcricional/genética , Neoplasias da Bexiga Urinária/patologia
9.
Lancet Neurol ; 8(1): 57-66, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19081515

RESUMO

BACKGROUND: Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD). METHODS: We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection. FINDINGS: The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2.5 x 10(-17); best haplotypic association in vCJD p=1 x 10(-24)). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1.9 x 10(-7)). A similar association was found in a small sample of patients with iatrogenic CJD (p=0.030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5.6 x 10(-5)), kuru incubation time (p=0.017), and resistance to kuru (p=2.5 x 10(-4)), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease. INTERPRETATION: The polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease.


Assuntos
Síndrome de Creutzfeldt-Jakob/epidemiologia , Síndrome de Creutzfeldt-Jakob/genética , Adulto , Idade de Início , Idoso , Alelos , Cromossomos Humanos/genética , DNA/genética , Interpretação Estatística de Dados , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Kuru/epidemiologia , Desequilíbrio de Ligação/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Papua Nova Guiné/epidemiologia , Polimorfismo de Nucleotídeo Único , Vigilância da População , Proteínas Priônicas , Príons/genética , Controle de Qualidade , Fatores de Risco , Estatmina , Reino Unido/epidemiologia
10.
Malar J ; 8: 158, 2009 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-19602275

RESUMO

BACKGROUND: In areas where malaria endemicity is high, many people harbour blood stage parasites without acute febrile illness, complicating the estimation of disease burden from infection data. For Plasmodium falciparum the density of parasitaemia that can be tolerated is low in the youngest children, but reaches a maximum in the age groups at highest risk of infection. There is little data on the age dependence of tolerance in other species of human malaria. METHODS: Parasite densities measured in 24,386 presumptive malaria cases at two local health centres in the Wosera area of Papua New Guinea were compared with the distributions of parasite densities recorded in community surveys in the same area. We then analyse the proportions of cases attributable to each of Plasmodium falciparum, P. vivax, and P. malariae as functions of parasite density and age using a latent class model. These attributable fractions are then used to compute the incidence of attributable disease. RESULTS: Overall 33.3%, 6.1%, and 0.1% of the presumptive cases were attributable to P. falciparum, P. vivax, and P. malariae respectively. The incidence of attributable disease and parasite density broadly follow similar age patterns. The logarithm of the incidence of acute illness is approximately proportion to the logarithm of the parasite density for all three malaria species, with little age variation in the relationship for P. vivax or P. malariae. P. falciparum shows more age variation in disease incidence at given levels of parasitaemia than the other species. CONCLUSION: The similarities between Plasmodium species in the relationships between parasite density and risk of attributable disease are compatible with the hypothesis that pan-specific mechanisms may regulate tolerance to different human Plasmodia. A straightforward mathematical expression might be used to project disease burden from parasite density distributions assessed in community-based parasitological surveys.


Assuntos
Tolerância Imunológica/imunologia , Malária/epidemiologia , Parasitemia/epidemiologia , Plasmodium/isolamento & purificação , Adolescente , Adulto , Distribuição por Idade , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Humanos , Incidência , Malária/sangue , Malária/parasitologia , Modelos Biológicos , Papua Nova Guiné/epidemiologia , Parasitemia/parasitologia , Plasmodium/classificação , Vigilância da População , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
11.
Ethn Health ; 14(2): 147-68, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19280444

RESUMO

BACKGROUND: In Papua New Guinea (PNG) there continues to be considerable interest in developing a health system that incorporates both traditional and western medicine. A policy on traditional medicine has recently been endorsed. Simultaneously, there is limited information about the traditional beliefs and practices that influence treatment-seeking behaviour. AIM OF THE STUDY: A case study among the Nasioi people of Bougainville was conducted to gather information that could help to inform the implementation of the National Policy on Traditional Medicine for PNG. RESEARCH OBJECTIVES: The main objective of the case study was to describe how health knowledge and belief systems influence treatment-seeking behaviour, specifically in relation to the use of traditional and western health care systems. The study also sought to develop an explanatory model for decision-making responses to febrile illnesses and skin conditions. METHODOLOGY: By using a non-experimental, cross-sectional study design and focused ethnographic approach, a sample of 200 Nasioi community members were interviewed by Nasioi-speaking research assistants. RESULTS: The study found that people in the sample group subscribe to both traditional and western medical paradigms. Western medical concepts have been assimilated but have not displaced traditional understanding of illness. There was congruence between beliefs about causes of illness, treatment-seeking responses to illness and stated or hypothetical preferences for traditional or western medicine. Data obtained in each of these domains reflect concepts of illness derived from both medical paradigms and demonstrate participants' confidence in the efficacy of both traditional and western medicine. CONCLUSIONS: It is proposed that a health system that incorporates traditional medicine may be better aligned with people's concepts of illness than the current system. Because it is more consistent with Nasioi concepts of illness, an incorporated health system may lead to more appropriate health service utilisation and, ultimately, to improvements in population health status.


Assuntos
Medicina Clínica , Conhecimentos, Atitudes e Prática em Saúde , Medicina Tradicional , Aceitação pelo Paciente de Cuidados de Saúde/etnologia , Estudos Transversais , Tomada de Decisões , Países em Desenvolvimento , Feminino , Comportamentos Relacionados com a Saúde/etnologia , Humanos , Masculino , Avaliação das Necessidades , Papua Nova Guiné , Satisfação do Paciente , Medição de Risco , Estudos de Amostragem , Ocidente
13.
PLoS Med ; 5(3): e56, 2008 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-18351796

RESUMO

BACKGROUND: The heritable haemoglobinopathy alpha(+)-thalassaemia is caused by the reduced synthesis of alpha-globin chains that form part of normal adult haemoglobin (Hb). Individuals homozygous for alpha(+)-thalassaemia have microcytosis and an increased erythrocyte count. Alpha(+)-thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA) (Hb concentration < 50 g/l), but does not influence parasite count. We tested the hypothesis that the erythrocyte indices associated with alpha(+)-thalassaemia homozygosity provide a haematological benefit during acute malaria. METHODS AND FINDINGS: Data from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by alpha(+)-thalassaemia against severe malaria were reanalysed to assess the genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease. We observed a reduction in median erythrocyte count of approximately 1.5 x 10(12)/l in all children with acute falciparum malaria relative to values in community children (p < 0.001). We developed a simple mathematical model of the linear relationship between Hb concentration and erythrocyte count. This model predicted that children homozygous for alpha(+)-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 x 10(12)/l as a result of the reduced mean cell Hb in homozygous alpha(+)-thalassaemia. In addition, children homozygous for alpha(+)-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hb concentration to fall to 50 g/l, the cutoff for SMA. We estimated that the haematological profile in children homozygous for alpha(+)-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24-1.12, p = 0.09). CONCLUSIONS: The increased erythrocyte count and microcytosis in children homozygous for alpha(+)-thalassaemia may contribute substantially to their protection against SMA. A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum. This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia. Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage.


Assuntos
Anemia Hipocrômica/sangue , Anemia Hipocrômica/prevenção & controle , Contagem de Eritrócitos , Malária Falciparum/prevenção & controle , Talassemia alfa/sangue , Estudos de Casos e Controles , Pré-Escolar , Eritrócitos/parasitologia , Feminino , Hemoglobinas/metabolismo , Homozigoto , Humanos , Lactente , Malária Falciparum/sangue , Masculino , Papua Nova Guiné , Talassemia alfa/genética
14.
PLoS Med ; 5(6): e127, 2008 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-18563961

RESUMO

BACKGROUND: Severe malaria (SM) is classically associated with Plasmodium falciparum infection. Little information is available on the contribution of P. vivax to severe disease. There are some epidemiological indications that P. vivax or mixed infections protect against complications and deaths. A large morbidity surveillance conducted in an area where the four species coexist allowed us to estimate rates of SM among patients infected with one or several species. METHODS AND FINDINGS: This was a prospective cohort study conducted within the framework of the Malaria Vaccine Epidemiology and Evaluation Project. All presumptive malaria cases presenting at two rural health facilities over an 8-y period were investigated with history taking, clinical examination, and laboratory assessment. Case definition of SM was based on the World Health Organization (WHO) criteria adapted for the setting (i.e., clinical diagnosis of malaria associated with asexual blood stage parasitaemia and recent history of fits, or coma, or respiratory distress, or anaemia [haemoglobin < 5 g/dl]). Out of 17,201 presumptive malaria cases, 9,537 (55%) had a confirmed Plasmodium parasitaemia. Among those, 6.2% (95% confidence interval [CI] 5.7%-6.8%) fulfilled the case definition of SM, most of them in children <5 y. In this age group, the proportion of SM was 11.7% (10.4%-13.2%) for P. falciparum, 8.8% (7.1%-10.7%) for P. vivax, and 17.3% (11.7%-24.2%) for mixed P. falciparum and P. vivax infections. P. vivax SM presented more often with respiratory distress than did P. falciparum (60% versus 41%, p = 0.002), but less often with anaemia (19% versus 41%, p = 0.0001). CONCLUSION: P. vivax monoinfections as well as mixed Plasmodium infections are associated with SM. There is no indication that mixed infections protected against SM. Interventions targeted toward P. falciparum only might be insufficient to eliminate the overall malaria burden, and especially severe disease, in areas where P. falciparum and P. vivax coexist.


Assuntos
Malária/epidemiologia , Malária/etiologia , Plasmodium falciparum/fisiologia , Plasmodium vivax/fisiologia , Animais , Criança , Pré-Escolar , Estudos de Coortes , Humanos , Malária/diagnóstico , Malária/parasitologia , Morbidade , Papua Nova Guiné/epidemiologia , Vigilância da População , Prevalência , Estudos Prospectivos , Índice de Gravidade de Doença
15.
Am J Trop Med Hyg ; 78(2): 289-93, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18256431

RESUMO

Laboratory tools to monitor infection burden are important to evaluate progress and determine endpoints in programs to eliminate lymphatic filariasis. We evaluated changes in Wuchereria bancrofti microfilaria, filarial antigen and Bm14 antibody in individuals who participated in a five-year mass drug administration trial in Papua New Guinea. Comparing values before treatment and one year after four annual treatments, the proportion of microfilaria positive individuals declined to the greatest degree, with less marked change in antibody and antigen rates. Considering children as sentinel groups who reflect recent transmission intensity, children surveyed before the trial were more frequently microfilaria and antibody positive than those examined one year after the trial stopped. In contrast, antigen positive rates were similar in the two groups. All infection indicators continued to decline five years after cessation of mass drug administration; Bm14 antibody persisted in the greatest proportion of individuals. These data suggest that Bm14 antibody may be a sensitive test to monitor continuing transmission during and after mass drug administration aimed at eliminating transmission of lymphatic filariasis.


Assuntos
Anticorpos Anti-Helmínticos/sangue , Antígenos de Helmintos/sangue , Antiparasitários/uso terapêutico , Filariose Linfática/prevenção & controle , Wuchereria bancrofti/imunologia , Animais , Antiparasitários/administração & dosagem , Criança , Pré-Escolar , Dietilcarbamazina/uso terapêutico , Quimioterapia Combinada , Filariose Linfática/tratamento farmacológico , Filariose Linfática/epidemiologia , Filariose Linfática/imunologia , Seguimentos , Humanos , Lactente , Ivermectina/administração & dosagem , Ivermectina/uso terapêutico , Papua Nova Guiné/epidemiologia , Wuchereria bancrofti/isolamento & purificação
16.
P N G Med J ; 51(3-4): 120-30, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-21061943

RESUMO

Malnutrition is a significant risk factor for childhood infectious diseases in developing countries, including Papua New Guinea (PNG). Whilst the mechanisms are not fully understood there is little doubt that impairment of immune function is a major contributing factor in enhancing disease susceptibility in malnourished children. This susceptibility has been clearly shown for pneumonia in PNG. The aim of this study was to examine the effect of undernutrition on the humoral immune profile in children less than 60 months of age with pneumonia. The study was cross-sectional with measurements of nutritional status and parameters of the immune response being assessed simultaneously. The children were grouped according to age for the purpose of comparative analysis. The children were from the Goroka region of the Eastern Highlands Province of PNG and had been admitted to hospital with moderate-severe pneumonia. They were classified as undernourished (less than 80% weight for age) or nourished (greater than or equal to 80% weight for age). Serum albumin, IgG, IgA and IgM and salivary albumin and IgA were measured. Antibodies to nontypeable Haemophilus influenzae outer membrane protein and Escherichia coli O antigen were also determined in serum and saliva. Undernourished children aged less than 49 months had lower levels of serum albumin than nourished children throughout this age range. Lower values of salivary IgA were observed in infants (less than 13 months of age) than in older children, with a larger proportion of younger children having no detectable IgA. The age-related immunological profile was similar in undernourished and nourished children. At different age intervals the concentration of immunoglobulins in serum and saliva from undernourished children was generally found to be less than or the same as that from nourished children. In most cases undernourished children had lower levels of specific antibodies than nourished children but for some antibodies in some age groups the levels in the undernourished were higher. In conclusion, undernutrition was associated with hypoalbuminaemia and reduced humoral immune responses in children with pneumonia but its immunological effects varied with age in an unpredictable way.


Assuntos
Imunidade Humoral , Desnutrição , Pneumonia/imunologia , Albuminas/análise , Pré-Escolar , Estudos Transversais , Suscetibilidade a Doenças , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/análise , Imunoglobulina M/imunologia , Lactente , Masculino , Estado Nutricional , Papua Nova Guiné/epidemiologia , Pneumonia/epidemiologia , Fatores de Risco
17.
Lancet ; 367(9528): 2068-74, 2006 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-16798390

RESUMO

BACKGROUND: Kuru provides the principal experience of epidemic human prion disease. Its incidence has steadily fallen after the abrupt cessation of its route of transmission (endocannibalism) in Papua New Guinea in the 1950s. The onset of variant Creutzfeldt-Jakob disease (vCJD), and the unknown prevalence of infection after the extensive dietary exposure to bovine spongiform encephalopathy (BSE) prions in the UK, has led to renewed interest in kuru. We investigated possible incubation periods, pathogenesis, and genetic susceptibility factors in kuru patients in Papua New Guinea. METHODS: We strengthened active kuru surveillance in 1996 with an expanded field team to investigate all suspected patients. Detailed histories of residence and exposure to mortuary feasts were obtained together with serial neurological examination, if possible. FINDINGS: We identified 11 patients with kuru from July, 1996, to June, 2004, all living in the South Fore. All patients were born before the cessation of cannibalism in the late 1950s. The minimum estimated incubation periods ranged from 34 to 41 years. However, likely incubation periods in men ranged from 39 to 56 years and could have been up to 7 years longer. PRNP analysis showed that most patients with kuru were heterozygous at polymorphic codon 129, a genotype associated with extended incubation periods and resistance to prion disease. INTERPRETATION: Incubation periods of infection with human prions can exceed 50 years. In human infection with BSE prions, species-barrier effects, which are characteristic of cross-species transmission, would be expected to further increase the mean and range of incubation periods, compared with recycling of prions within species. These data should inform attempts to model variant CJD epidemiology.


Assuntos
Amiloide/genética , Kuru/genética , Vigilância da População/métodos , Precursores de Proteínas/genética , Idoso , Criança , Feminino , Rituais Fúnebres , Humanos , Kuru/transmissão , Masculino , Pessoa de Meia-Idade , Nova Guiné , Polimorfismo Genético , Proteínas Priônicas , Príons , Fatores de Tempo
18.
N Engl J Med ; 347(23): 1841-8, 2002 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-12466508

RESUMO

BACKGROUND: The global initiative to eradicate bancroftian filariasis currently relies on mass treatment with four to six annual doses of antifilarial drugs. The goal is to reduce the reservoir of microfilariae in the blood to a level that is insufficient to maintain transmission by the mosquito vector. METHODS: In nearly 2500 residents of Papua New Guinea, we prospectively assessed the effects of four annual treatments with a single dose of diethylcarbamazine plus ivermectin or diethylcarbamazine alone on the incidence of microfilariae-positive infections, the severity of lymphatic disease, and the rate of transmission of Wuchereria bancrofti by mosquitoes. Random assignment to treatment regimens was carried out according to the village of residence, and villages were categorized as having moderate or high rates of transmission. RESULTS: The four annual treatments with either drug regimen were taken by 77 to 86 percent of the members of the population who were at least five years old; treatments were well tolerated. The proportion with microfilariae-positive infections decreased by 86 to 98 percent, with a greater reduction in areas with a moderate rate of transmission than in those with a high rate. The respective aggregate frequencies of hydrocele and leg lymphedema were 15 percent and 5 percent before the trial began, and 5 percent (P<0.001) and 4 percent (P=0.04) after five years. Hydrocele and leg lymphedema were eliminated in 87 percent and 69 percent, respectively, of those who had these conditions at the outset. The rate of transmission by mosquitoes decreased substantially, and new microfilariae-positive infections in children were almost completely prevented over the five-year study period. CONCLUSIONS: Annual mass treatment with drugs such as diethylcarbamazine can virtually eliminate the reservoir of microfilariae and greatly reduce the frequency of clinical lymphatic abnormalities due to bancroftian filariasis. Eradication may be possible in areas with moderate rates of transmission, but longer periods of treatment or additional control measures may be necessary in areas with high rates of transmission.


Assuntos
Dietilcarbamazina/uso terapêutico , Filariose Linfática/tratamento farmacológico , Filaricidas/uso terapêutico , Ivermectina/uso terapêutico , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Culicidae/parasitologia , Dietilcarbamazina/administração & dosagem , Dietilcarbamazina/efeitos adversos , Reservatórios de Doenças , Esquema de Medicação , Quimioterapia Combinada , Filariose Linfática/epidemiologia , Filariose Linfática/prevenção & controle , Filariose Linfática/transmissão , Filaricidas/administração & dosagem , Filaricidas/efeitos adversos , Humanos , Ivermectina/efeitos adversos , Linfedema/tratamento farmacológico , Linfedema/etiologia , Masculino , Papua Nova Guiné/epidemiologia , Estudos Prospectivos , Hidrocele Testicular/tratamento farmacológico , Hidrocele Testicular/etiologia , Wuchereria bancrofti/isolamento & purificação
19.
Infect Genet Evol ; 7(1): 44-51, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16647307

RESUMO

Extensive genetic polymorphism is generally found in Plasmodium falciparum surface antigens. This poses a considerable obstacle to the development of a malaria vaccine. In order to assess possible effects of a polymorphic vaccine, we have analyzed the genetic diversity of parasites collected in the course of a phase 2b field trial of the blood stage vaccine Combination B in Papua New Guinea. The full-length 3D7 allele of the merozoite surface protein 2 (MSP2) was included in Combination B as one of three subunits. Vaccinees had a lower prevalence of parasites carrying a 3D7-type allele (corresponding to that in the vaccine) and selection appeared to favour the alternative FC27-type alleles resulting in a higher incidence of morbid episodes associated with FC27-type parasites. We sequenced MSP2 alleles detected in study participants after vaccination to identify breakthrough genotypes. Extensive genetic diversity of MSP2 was observed in both the repetitive and family-specific domains, but alleles occurring in vaccine recipients were no different from those found in placebo recipients. A phylogenetic analysis showed no clustering of 3D7-type breakthrough infections from vaccine recipients. The repeat unit present in the vaccine molecule occurred in a number of alleles from the trial area and was also observed in vaccinated individuals. Thus the anti-repeat immune response did not lead to elimination of parasites carrying the same repeat unit. We conclude that the conserved epitopes in the family-specific domain were the most important determinants of the vaccine effect against new 3D7-type infections and that the hypervariable domains were not subject to selective effects of the vaccine.


Assuntos
Antígenos de Protozoários/genética , Variação Genética/efeitos dos fármacos , Vacinas Antimaláricas/administração & dosagem , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/genética , Animais , Antígenos de Protozoários/química , Criança , Pré-Escolar , Estudos Transversais , Humanos , Vacinas Antimaláricas/imunologia , Malária Falciparum/epidemiologia , Malária Falciparum/imunologia , Filogenia , Plasmodium falciparum/genética , Plasmodium falciparum/imunologia , Proteínas de Protozoários/química , Análise de Sequência de DNA , Vacinas Sintéticas/imunologia
20.
Am J Trop Med Hyg ; 76(1): 62-6, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17255231

RESUMO

The efficacy of diethylcarbamazine alone was compared with diethylcarbamazine plus albendazole in residents of an island in Papua New Guinea endemic for Wuchereria bancrofti. There was no statistically significant difference between the two drug regimens in decreasing the microfilaria positive rate at 12 and 24 months after a single-dose treatment with either regimen, e.g., 50.0% clearance of microfilaria at 24 months for diethylcarbamazine alone versus 65.7% clearance of microfilaria for diethylcarbamazine plus albendazole (P > 0.05). In contrast, diethylcarbamazine plus albendazole resulted in a significant decrease in Og4C3 antigen prevalence (17%; P = 0.003) at 24 months whereas diethylcarbamazine did not (10%; P = 0.564). These data showed no statistically significant difference in the efficacy of the two drug regimens in lowering the microfilaria reservoir, but they support the use of diethylcarbamazine combined with albendazole in mass treatment programs on the basis of greater activity against adult worms.


Assuntos
Albendazol/administração & dosagem , Albendazol/uso terapêutico , Dietilcarbamazina/administração & dosagem , Dietilcarbamazina/uso terapêutico , Filariose/tratamento farmacológico , Adulto , Animais , Feminino , Humanos , Masculino , Wuchereria bancrofti/isolamento & purificação
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