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Biomedical subjects

M P Alpers

Publications and source records attributed to M P Alpers.

At least 19 recordsLinked to original sources
PubMed2001

Ecologic and biologic determinants of filarial antigenemia in bancroftian filariasis in Papua New Guinea.

The relationship between filarial antigenemia and lymphatic pathology was investigated in residents of 11 villages in an area of Papua New Guinea where Wuchereria bancrofti is endemic. Antigenemia was determined in 1322 persons by means of the Og4C3 antibody capture assay. Prevalence of antigenemia by village ranged from 61.7% to 98.2% and did not vary by sex. Antigen level increased with transmission potential among the 4 villages with measured transmission potential (r(2)=.945; P=.028). Antigenemia was associated positively with age in villages with the lowest annual transmission potentials (45 and 404 infective larvae/year; P<.001), but was distributed evenly across age groups in villages with increased transmission (1485 and 2518 infective larvae/year). These data suggest that children and adults have similar worm burdens in areas of high transmission, whereas worm burdens in areas of lower transmission increase with age. These results may be useful in the design and evaluation of programs aimed at eliminating lymphatic filariasis.

Adolescent↗
PubMed2001

Transmission intensity determines lymphocyte responsiveness and cytokine bias in human lymphatic filariasis.

Humans living in areas where filariasis is endemic vary greatly in their exposure to mosquito-borne infective third-stage larvae (L3) of these parasitic helminths. Because the intensity of exposure to Ags affects T cell differentiation and susceptibility to parasitic infections in murine models, we compared T cell and cytokine responses in 97 residents of two villages in Papua New Guinea, where transmission intensity of Wuchereria bancrofti differed by 63-fold (37 vs 2355 L3 per person per year). Residents of the high transmission village had 4- to 11-fold lower proliferation and IFN-gamma responses to filarial Ags, nonparasite Ag, and PHA by PBMC compared with the low transmission village (p < 0.01) even when subjects were matched for intensity of infection. In contrast, filarial Ag-driven IL-5 production was 5.5-fold greater (p < 0.001), and plasma IL-4 and TGF-beta levels were 4-fold and 34% higher, respectively, in residents of the high transmission village. IL-4 and IL-10 responses by PBMC differed little according to village, and increased production of the counterregulatory cytokines IL-10 or TGF-beta by PBMC did not correlate with weak proliferation and IFN-gamma responses. Plasma IL-5, IFN-gamma, and IL-10 levels were similar in the two villages. These data demonstrate that the intensity of exposure to L3 affects lymphocyte responsiveness and cytokine bias possibly by a mechanism that alters APC function.

Adolescent↗
PubMed2000

Increased susceptibility to Kuru of carriers of the PRNP 129 methionine/methionine genotype.

Kuru reached epidemic proportions by the mid-twentieth century among the Fore people of New Guinea and disappeared after the abolition of cannibalistic rituals. To determine susceptibility to kuru and its role in the spread and elimination of the epidemic, we analyzed the PRNP gene coding sequences in 5 kuru patients; no germline mutations were found. Analysis of the PRNP 129 methionine (M)/valine (V) polymorphism in 80 patients and 95 unaffected controls demonstrated that the kuru epidemic preferentially affected individuals with the M/M genotype. A higher representation of M/M carriers was observed among the affected young Fore males entering the age of risk, whereas a lower frequency of M/M homozygotes was found among the survivors. M/V and V/V genotypes predisposed to a lower risk of disease development and longer incubation times. These findings are relevant to the current outbreak of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom, because all vCJD patients tested thus far have been M/M carriers.

Amyloid↗
PubMed2000

Safety and immunogenicity of a three-component blood-stage malaria vaccine in adults living in an endemic area of Papua New Guinea.

A Phase I safety and immunogenicity study with a three-component blood-stage malaria vaccine was conducted in adult male subjects living in an endemic area of Papua New Guinea. The preparations were recombinant proteins which corresponded to parts of the two merozoite surface proteins of Plasmodium falciparum (MSP1 and 2), and of the ring-infected erythrocyte surface antigen (RESA). The three proteins were emulsified with the adjuvant Montanide ISA720. Ten subjects were injected twice (four weeks apart) with the vaccine formulation and two with the adjuvant alone. Mild pain at the site of injection was reported by about half of the subjects but no systemic reaction related to the formulation occurred. There was a sharp rise in geometric mean stimulation index after the second dose compared to baseline for MSP1 and RESA, while the rise was small for MSP2. Geometric mean antibody titres increased for MSP1 during the study, whereas they hardly changed for MSP2 and RESA. The vaccine formulation was safe when used in an already immune population. The vaccine induced good cellular responses, especially for MSP1 and RESA. Boosting of humoral responses was weak, probably because of high baseline antibody levels.

Adjuvants, Immunologic↗
PubMed2000

Cross-species interactions between malaria parasites in humans.

The dynamics of multiple Plasmodium infections in asymptomatic children living under intense malaria transmission pressure provide evidence for a density-dependent regulation that transcends species as well as genotype. This regulation, in combination with species- and genotype-specific immune responses, results in nonindependent, sequential episodes of infection with each species.

Adolescent↗
PubMed2000

Human polyomavirus JC variants in Papua New Guinea and Guam reflect ancient population settlement and viral evolution.

The peopling of the Pacific was a complex sequence of events that is best reconstructed by reconciling insights from various disciplines. Here we analyze the human polyomavirus JC (JCV) in Highlanders of Papua New Guinea (PNG), in Austronesian-speaking Tolai people on the island of New Britain, and in nearby non-Austronesian-speaking Baining people. We also characterize JCV from the Chamorro of Guam, a Micronesian population. All JCV strains from PNG and Guam fall within the broad Asian group previously defined in the VP1 gene as Type 2 or Type 7, but the PNG strains were distinct from both genotypes. Among the Chamorro JCV samples, 8 strains (Guam-1) were like the Type 7 strains found in Southeast Asia, while nine strains (Guam-2) were distinct from both the mainland strains and most PNG strains. We identified three JCV variants within Papua New Guinea (PNG-1, PNG-2 and PNG-3), but none of the Southeast Asian (Type 7) strains. PNG-1 strains were present in all three populations (Highlanders and the Baining and Tolai of New Britain), but PNG-2 strains were restricted to the Highlanders. Their relative lack of DNA sequence variation suggests that they arose comparatively recently. The single PNG-3 strain, identified in an Austronesian-speaking Tolai individual, was closely related to the Chamorro variants (Guam-2), consistent with a common Austronesian ancestor. In PNG-2 variants a complex regulatory region mutation inserts a duplication into a nearby deletion, a change reminiscent of those seen in the brains of progressive multifocal leukoencephalopathy patients. This is the first instance of a complex JCV rearrangement circulating in a human population.

Adult↗
PubMed2000

Comparison between anopheline mosquitoes (Diptera: Culicidae) caught using different methods in a malaria endemic area of Papua New Guinea.

The mosquito sampling efficiency of CDC (Centers for Disease Control) miniature light traps hung adjacent to mosquito nets, was compared with that of both indoor and outdoor human-bait collections in ten villages in the Wosera area of Papua New Guinea. The most frequently collected anopheline in the matched indoor and light trap samples was Anopheles koliensis Owen, followed by A. punctulatus Dönitz, A. karwari (James), A. farauti Laveran (sensu lato), A. longirostris Brug and A. bancroftii Giles. All species were much less frequent in the light traps than in landing catches. The hypothesis that the numbers of mosquitoes in light traps are proportional to human landing catches was examined using regression models that allowed for sampling error in both entomological measurements. Light traps under-sampled A. punctulatus and A. farauti s.l. at high densities. The models indicated that the ratio of light trap to landing catch females of A. koliensis and A. karwari increased with increasing mosquito density. Light trap catches of A. longirostris were proportional to indoor landing rates but when outdoor landing rates were high this species was under-sampled by light traps. Numbers of A. bancroftii in light traps were found to be proportional to those in outdoor landing catches, but were negatively related to those attempting to bite indoors. Circumsporozoite positivity rates for both Plasmodium falciparum Welch and P. vivax (Grassi & Feletti) in A. punctulatus and A. farauti s.l. were significantly higher in light trap collections than in either indoor or outdoor landing catches, suggesting that light traps may selectively sample older mosquitoes of these species.

Animals↗
PubMed2000

Age- and species-specific duration of infection in asymptomatic malaria infections in Papua New Guinea.

The burden and duration of asymptomatic malaria infections were measured in residents of the malaria endemic village of Gonoa, Madang Province, Papua New Guinea. Plasmodium falciparum, P. vivax and P. malariae infections in people aged 4 years to adulthood were compared. Frequent sampling at 3-day intervals for up to 61 days allowed assessment of individual episodes of infection. Statistical assessment of P. falciparum detection revealed a periodicity consistent with synchronous replication of this species over periods up to 27 days. The duration of P. falciparum episodes was longer across all age groups than that of P. vivax and P. malariae. A trend for decreasing duration with age was also noted in data from each species. This was most prominent in P. falciparum infections: median duration in 4-year-olds was > 48 days compared with a median between 9 and 15 days in older children and adults. The results are consistent with the slow acquisition of immunity to antigenically diverse Plasmodium populations and suggest a faster rate of acquisition to P. vivax and P. malariae than to P. falciparum.

Adolescent↗
PubMed2000

Genetic diversity and dynamics of plasmodium falciparum and P. vivax populations in multiply infected children with asymptomatic malaria infections in Papua New Guinea.

We describe the dynamics of co-infections of Plasmodium falciparum and P. vivax in 28 asymptomatic children by genotyping these species using the polymorphic loci Msp2 and Msp3alpha, respectively. The total number of Plasmodium spp. infections detected using 3 day sampling over 61 days varied between 1 and 14 (mean 6.6). The dynamics of P. falciparum and P. vivax genotypes varied greatly both within and amongst children. Periodicity in the detection of P. falciparum infections is consistent with the synchronous replication of individual genotypes. Replication synchrony of multiple co-infecting genotypes was not detected. In 4-year-old children P. falciparum genotype complexity was reduced and episodes lasted significantly longer (median duration > 60 days) when compared to children aged 5-14 years (median duration 9 days). P. vivax genotype complexity was not correlated with age but the episode duration was also longer for this species in 4-year-olds than in older children but was not as long as P. falciparum episodes. Recurrence of P. falciparum and P. vivax genotypes over weeks was observed. We interpret these major fluctuations in the density of genotypes over time as the result of the mechanism of antigenic variation thought to be present in these Plasmodium species.

Adolescent↗
PubMed2000

Genetic analysis of IgG subclass responses against RESA and MSP2 of Plasmodium falciparum in adults in Papua New Guinea.

Contributions of environmental and genetic factors to IgG subclass responses against Plasmodium falciparum antigens RESA and MSP2 were investigated among adults in a highly endemic area of Papua New Guinea. Heritabilities were estimated using variance component analysis. Familial aggregation of several responses was found, including IgG1, IgG2 and IgG3 responses against RESA, IgG1 and IgG3 responses against the 3D7 form of MSP2 and IgG1, IgG2 responses against the FC27 form of MSP2. Allowance for sharing of houses explained some of the non-genetic variance but not the familial aggregation. The variance of IgG3 responses against RESA and IgG1, IgG2 against MSP2 (FC27) was partly explained by sharing of HLA class II genotypes, although heritability was low. Segregation analyses indicated that any genetic regulation was more complex than governed by a single major gene. Such host genetic variation in responses to specific malaria antigens has implications for immuno-epidemiology and vaccine development.

Adolescent↗
PubMed2000

Influence of age and HLA type on interferon-gamma (IFN-gamma) responses to a naturally occurring polymorphic epitope of Plasmodium falciparum liver stage antigen-1 (LSA-1).

Antigenic polymorphism and HLA restriction may limit the immunogenicity of a subunit vaccine against liver-stage Plasmodium falciparum. We examined 59 clinical isolates and five laboratory clones of P. falciparum for polymorphism in the N- and C-terminal regions of LSA-1, evaluated binding of the corresponding peptides to selected HLA class I alleles, and measured IFN-gamma responses in residents of a malaria-endemic area of Papua New Guinea where HLA-A*1101, -24, -B13, and -B40 are the most common class I alleles. LSA-1 polymorphism was limited to a single non-synonymous mutation encoding serine (S), proline (P), or threonine (T) at amino acid 85. Nine-mer 84-92 peptides with S, T, or P at the primary anchor position bound differentially to HLA-A11, -A2, and -B7. IFN-gamma ELISPOT responses increased with age in malaria-exposed subjects: 14-16% and 30-36% of 2-5- and 6-54-year-olds, respectively, had > or =10 IFN-gamma-secreting cells/106 peripheral blood mononuclear cells when stimulated with at least one peptide variant (P<0.05). IFN-gamma responses to all three peptides were also greater for older than younger individuals. No children < 3 years old had lymphocytes that responded to all three 84-92 peptides, whereas 45% of adults (mean age 48 years) had aggregated IFN-gamma responses. These data support the notion that age-related cumulative exposure to P. falciparum increases the frequency of IFN-gamma responses to polymorphic epitopes of liver-stage antigens such as LSA-1.

Adolescent↗
PubMed2000

Bacterial, viral and parasitic aetiology of paediatric diarrhoea in the highlands of Papua New Guinea.

Enteropathogens and clinical features associated with diarrhoea were investigated in 1526 children admitted over a 5-year period to the paediatric ward of a hospital in the highlands of Papua New Guinea. Overall, a recognized pathogen was isolated from 39 per cent of the children admitted with diarrhoea. The most commonly isolated agents were rotavirus (23 per cent), Shigella spp. (13 per cent), Campylobacter spp. (12 per cent), Cryptosporidium parvum (10 per cent) and enteropathogenic Escherichia coli (8 per cent). The clearest clinical associations were rotavirus with vomiting, and Shigella with blood and pus in the stool. A control series of children admitted with other complaints was also included, and the odds ratios for diarrhoea for the above five pathogens were 18.2, 9.6, 3.7, 2.2, and 1.6, respectively.

Bacterial Infections↗
PubMed2000

Random distribution of mixed species malaria infections in Papua New Guinea.

Plasmodium falciparum (Pf), P. vivax (Pv), P. malariae (Pm), and P. ovale (Po) infections are endemic in coastal areas of Papua New Guinea. Here 2,162 individuals living near Dreikikir, East Sepik Province, have been analyzed for complexity of malaria infection by blood smear and polymerase chain reaction (PCR) diagnoses. According to blood smear, the overall prevalence of Plasmodium infection was 0.320. Most individuals (0.283) were infected with a single species only. The prevalence of mixed species infections was low (0.037). Further analysis of a 173-sample subset by nested PCR of small subunit ribosomal DNA resulted in an overall 3.0-fold increase in prevalence of infection, with a 17.5-fold increase in the frequency of mixed species infections. Among mixed species infections detected by PCR, the frequency of double species was 0.364, and that of triple species was 0.237. Nine individuals (0.052) were infected with all 4 species. To determine if infection status (uninfected, single, and multiple infections) deviates from an independent random distribution (null hypothesis), observed versus expected frequencies of all combinations of Plasmodium species infections, or assemblages (Pf-, Pv-, Pm-, Po-, to Pf+, Pv+, Pm+, Po+), were compared using a multiple-kind lottery model. All 4 species were randomly distributed whether diagnosed by blood smear or PCR in the overall population and when divided into age group categories. These findings suggest that mixed species malaria infections are common, and that Plasmodium species appear to establish infection independent of one another.

Animals↗
PubMed2000

Application of a polymerase chain reaction-ELISA to detect Wuchereria bancrofti in pools of wild-caught Anopheles punctulatus in a filariasis control area in Papua New Guinea.

Chemotherapy-based eradication programs are aimed at stopping transmission of Wuchereria bancrofti by its obligatory mosquito vector. This study compares one year post-treatment W. bancrofti infection rates of Anopheles punctulatus, the main vector of lymphatic filariasis in Papua New Guinea, using traditional dissection techniques and a polymerase chain reaction (PCR)-based ELISA of a parasite-specific Ssp I repeat. A total of 633 mosquitoes in 35 batches were dissected. Six batches contained W. bancrofti-infected mosquitoes, giving a minimum infection rate of 0.9%. This value was not different than the actual infection rate, which was 9 (1.4%) of 633 mosquitoes (P = 0.48). The DNA was extracted from 47 pools containing a mean of 13.2 mosquitoes per pool. A total of 621 mosquitoes were processed for the PCR-ELISA, including 486 caught by human bait and 135 by light trap, which included both dead and live mosquitoes. Of 23 pools of alcohol-preserved human-bait mosquitoes, seven were positive by the PCR-ELISA, giving an infection rate identical to that obtained by dissection of individual mosquitoes (1.4%). The minimum infection rates for pools of light-trap mosquitoes found dead and alive were 2.7% (2 of 74) and 4.9% (3 of 61), respectively. These values did not differ from each other (P = 0.84), but the overall infection rate of light-trap mosquitoes was greater than that of mosquitoes captured by human bait (3.7% versus 1.4%; P = 0.09). These data indicate that the PCR-ELISA of a W. bancrofti Ssp I repeat using pools of mosquitoes is comparable to traditional dissection techniques for monitoring transmission intensity following introduction of mass chemotherapy. This approach may also be useful for rapid and cost-effective assessment of transmission in endemic areas where the frequency of overt lymphatic pathology is low.

Animals↗
PubMed2000

The influence of zinc supplementation on morbidity due to Plasmodium falciparum: a randomized trial in preschool children in Papua New Guinea.

Zinc is crucial for normal immune function and can reduce morbidity from multiple infectious diseases. To determine the influence of zinc on malaria morbidity we conducted a randomized placebo-controlled trial of daily zinc supplementation in children residing in a malaria endemic region of Papua New Guinea. A total of 274 preschool children aged 6 to 60 months were given 10 mg elemental zinc (n = 136) or placebo (n = 138) for 6 days a week for 46 weeks. Slide-confirmed malaria episodes were detected by surveillance of cases self-reporting to a local health center. Cross-sectional surveys were conducted at the beginning, middle, and end of the study to assess infection rates, parasite density, spleen enlargement, and hemoglobin levels. Zinc supplementation resulted in a 38% (95% CI 3-60, P = 0.037) reduction in Plasmodium falciparum health center-based episodes, defined as parasitemia > or = 9200 parasites/microl with axial temperature > or = 37.5 degreesC or reported fever. Episodes accompanied by any parasitemia were also reduced by 38% (95% CI 5-60, P = 0.028), and episodes with parasitemia > or = 100,000/microl were reduced by 69% (95% CI 25-87, P = 0.009). There was no evidence of the effects of zinc on Plasmodium vivax morbidity or on health center attendance for causes other than P. falciparum. Zinc had no consistent effect on cross-sectional malariometric indices. Although P. falciparum prevalence tended to be lower at the end of the study in children given the placebo, such changes were absent at the mid-study survey. These results suggest that improved dietary zinc intake may reduce morbidity due to P. falciparum.

Animals↗
PubMed2000

Assessment of different sources of variation in the antibody responses to specific malaria antigens in children in Papua New Guinea.

BACKGROUND: A potential problem for malaria vaccine development and testing is between-host variation in antibody responses to specific malaria antigens. Previous work in adults in an area highly endemic for Plasmodium falciparum in Papua New Guinea found that genetic regulation partly explained heterogeneity in responsiveness. We have now assessed the relative contributions of environmental and genetic factors in total IgG responses to specific malaria antigens in children, and quantified temporal variation within individuals of total IgG responses. METHODS: Total IgG responses against schizont extract, merozoite surface protein-1, merozoite surface protein-2, ring-infected erythrocyte surface antigen, and SPf66 were measured by ELISA. Variance component analysis was used to estimate the variation explained by genetic and environmental factors in these antibody responses. Intra- and inter-class correlations of antibody responses within relative pairs were estimated. We adjusted for age, P. falciparum density, sex and village differences either within or prior to the analysis. RESULTS: For all malaria antigens, temporal variation in the total IgG response was the predominant source of variation. There was substantial familial aggregation of all IgG responses, but it remained unclear how much this clustering was attributable to genetic factors and how much to a common environment in the household. The remaining variance, which could not be explained by either of the above, was very small for most of the antigens. CONCLUSIONS: Temporal variation and clustering of immune responses to specific malaria antigens need to be taken into account when planning, conducting and interpreting immuno-epidemiological and vaccine studies.

Animals↗