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Biomedical subjects

M Alpers

Publications and source records attributed to M Alpers.

At least 19 recordsLinked to original sources
PubMed1999

Maternal immunization.

Maternal immunization can enhance passive immunity of infants to pathogens that cause life-threatening illnesses. In most instances, immunization during pregnancy will provide important protection for the woman as well as for her offspring. The tetanus toxoid and influenza vaccines are examples of vaccines that provide a double benefit. Other vaccines under evaluation include those for respiratory syncytial virus, pneumococci, group B streptococci, and Haemophilus influenzae type b. Although most IgG antibody crosses the placenta in the third trimester, the process is time-dependent, dictating that immunization should be accomplished ideally at least 6 weeks prior to delivery. IgG1 antibodies are transferred preferentially. Maternal immunization has not interfered with active immunization of the infant. Inactivated vaccines administered in the third trimester of pregnancy pose no known risk to the woman or to her fetus.

Bacterial Capsules↗
PubMed1999

Association of the ICAM-1Kilifi mutation with protection against severe malaria in Lambaréné, Gabon.

The intercellular adhesion molecule-1 (ICAM-1) is thought to be a receptor that mediates binding of Plasmodium falciparum-infected erythrocytes. Especially in vital organs, the binding of parasitized cells to the endothelium via ICAM-1 may lead to severe disease and death. Recently, a mutation in the coding region of ICAM-1, termed ICAM-1Kilifi, was described, causing a change from Lys to Met in the loop that interacts with rhinoviruses, lymphocytes, and parasitized red blood cells. Surprisingly, this mutation was shown to increase susceptibility of Kenyan children to severe malaria in one study. When we compared the distribution of ICAM-1Kilifi in two groups of Gabonese children enrolled in a case-control, matched-pair study who presented with either mild or severe malaria, we found that 55% of the patients with mild malaria were carriers whereas only 39% of those with severe malaria were carriers. The difference in the distribution of ICAM-1Kilifi homozygous pairs between the groups, as well as the distribution of ICAM-1Kilifi carriers, was statistically highly significant (P = 0.027 and P = 0.012, by the McNemar test). In a group of healthy school children from the same region, a distribution of 52% ICAM-1Kilifi carriers to 48% wild-type individuals was found. In a survey for the ICAM-1Kilifi in other malaria-endemic regions, this allele was also found in Nigeria and Papua New Guinea, but not in Thailand.

Animals↗
PubMed1996

Plasmodium vivax: favored gene frequencies of the merozoite surface protein-1 and the multiplicity of infection in a malaria endemic region.

In this study, we present an analysis of the Plasmodium vivax MSP-1 polymorphic region 5 and identify a new recombinant gene element. In clinical isolates from Papua New Guinea (PNG), the P. vivax MSP-1 gene type was characterized by restriction fragment length polymorphisms and by Southern blot oligonucleotide hybridizations using probes to type-specific sequences. There were three pairs of dimorphic gene elements in the MSP-1 polymorphic region 5; four of the eight potential different combinations of sequence elements for this region have been identified. The center gene segment was the most polymorphic, especially for the glutamine (Q) repeat element with virtually every gene containing a different length of Q repeats, a finding consistent with database sequence information. The frequencies of all of the polymorphic MSP-1 gene elements were approximately equal except for the first segment, which was biased 10:1 for the Type II (Sal-1 type) versus Type I (Belem type) gene segment. In fact, only one combination (I/Q/S) of the genetic elements containing the type I gene segment for polymorphic region 5 was identified, a finding consistent with sequences reported to gene data banks. Considering only the multiplicity of MSP-1 gene types, 38% of the patients were identified as having multiple infections; when correlated with the circumsporozoite protein and the Duffy antigen binding protein gene types, the multiple infection rate increased to 65% of 23 isolates characterized. Increased age was the only clinical parameter that positively correlated with multiclonal infections and there was no other apparent bias or linkage of gene types among the three loci. These data identify multiple clonal populations of P. vivax in the PNG population and potentially a high rate of concurrent infections in clinical cases. The extreme polymorphism of the MSP-1 polymorphic region 5 suggests that frequent recombination occurs within this gene. The bias in frequency for one recombinant gene motif indicates that intrinsic host or parasite factors may engender increased frequency of one genetic element over another. Failure to identify this type of discrete clonal marker as well as reliance on a single marker can mask the true multiclonal nature of an infection and lead to underestimation of the multiplicity of infection.

Amino Acid Sequence↗
PubMed1996

Transmission dynamics of Wuchereria bancrofti in East Sepik Province, Papua New Guinea.

Bancroftian filariasis is endemic in many areas of Papua New Guinea. This study describes the entomologic indices of transmission near Dreikikir in East Sepik Province, Papua New Guinea. A total of 1,735 culicine mosquitoes, including Culex and Mansonia species, were dissected, but none were infected with filarial larvae. In contrast, Anopheles punctulatus and An. koliensis were found to be potential vectors: 7.3% of Anopheles were infected and the mean number of first- to third-stage larvae per infected mosquito was 2.7. Transmission indices varied significantly in five villages located within a 50-km radius of each other. Annual biting rates ranged from 4,789 to 48,020 bites/person/year; annual infective biting rates from 15 to 836/person/year; and annual transmission potential from 31 to 2,340 third-stage larvae/person/year. Monthly transmission potential and monthly infective biting rate varied significantly in each village, with the highest indices of transmission observed in villages nearest sites where puddles formed in river beds during the dry season. These data indicate that there is small area variation in the intensity and temporal pattern of filariasis transmission and that culicine mosquitoes are not important vectors of W. bancrofti in this area.

Animals↗
PubMed1995

Plasmodium falciparum: malaria morbidity is associated with specific merozoite surface antigen 2 genotypes.

Plasmodium falciparum merozoite surface antigen 2 (MSA2) is considered a vaccine candidate in a subunit vaccine against blood stage malaria. In order to test if a specific genotype of the highly polymorphic MSA2 is associated with disease, we conducted a case-control study in a malaria endemic area of Papua New Guinea involving 227 individuals, mostly children under the age of 10 years. All cases and controls were genotyped by polymerase chain reaction for their respective MSA2 genotypes. We report that at the time of the study parasites carrying the FC27-like genotype were twice as likely to be found in symptomatic malaria cases than in asymptomatic controls. Mixed genotype infections were significantly less frequent in symptomatic malaria infections. One individual allele (WOS10) of the FC27 family was found only in cases. This may be a form of P. falciparum infrequently encountered and may cause morbidity due to lack of immunity to it. This study provides evidence that MSA2 is involved in the morbidity of malaria and supports the inclusion of MSA2 in a subunit vaccine.

Adolescent↗
PubMed1995

Humoral and cell-mediated immunity to the Plasmodium falciparum ring-infected erythrocyte surface antigen in an adult population exposed to highly endemic malaria.

A parasitological and immunological survey was carried out in an area in Papua New Guinea highly endemic for malaria. Two hundred fourteen adult individuals were selected for studies to assess their immune responses against the malaria vaccine candidate ring-infected erythrocyte surface antigen (RESA). Total immunoglobulin G (IgG) antibodies directed against RESA as well as specific IgG1, IgG2, and IgG3 antibodies were determined. Humoral responses directed against RESA were frequent in all IgG subclasses. Only IgG3 responses were found to be age dependent. Total anti-RESA IgG antibodies were not correlated with protection against malaria as measured by parasite prevalence, parasite density, or health center attendance. In contrast, cytophilic antibodies (IgG1 and IgG3) were associated with reduced Plasmodium falciparum prevalence and reduced health center attendance. T-cell proliferation in general was low and very infrequent. No correlation between humoral and cellular immune responses could be found. Parasite density, parasite prevalence, and health center visits tended to be reduced in individuals with good humoral and cell-mediated immune responses.

Animals↗
PubMed1995

Evidence of HLA class II association with antibody response against the malaria vaccine SPF66 in a naturally exposed population.

The antibody response against the malaria vaccine SPf66 and against circumsporozoite (CS) protein has been tested in immune adults from a malaria endemic area in Papua New Guinea. All individuals were genotyped for the HLA class II DQB1 and DRB1 loci, and the humoral response was analyzed with respect to the identified class II alleles. At each locus, only three alleles were frequent, namely DRB1*11, *15, and *16, and DQB1*0301, *0502, and *0601. Antibodies against SPf66 and CS protein were found in 84% and 79% of the individuals, respectively. A strong negative association was detected between the humoral response against SPf66 and DRB1*15 and DQB1*0601. A positive association of the response was observed with DRB1*11 and DQB1*0301. After analysis with a multiple regression model in which all alleles were included simultaneously, only DRB1*15 remained significantly associated with low antibody responses. This suggests that nonresponders may be expected after immunization with SPf66 in certain populations.

Adolescent↗
PubMed1995

The use of the polymerase chain reaction for more sensitive detection of Plasmodium falciparum.

The prevalence of Plasmodium falciparum in children and adults living in a malaria-endemic area in Papua New Guinea was determined by microscopy and by polymerase chain reaction (PCR). The sensitivity of detecting P. falciparum infections increased two-fold with PCR. Undetected infections by microscopy were more frequent in adults (including adolescents) than in children. Detecting this subpatent parasitaemia by PCR resulted in an equal P. falciparum prevalence in children and adults; in children the parasitaemia rate increased from 32% to 48% and in adults from 23% to 47%. In more than 50% of all blood samples positive for P. vivax and P. malariae an underlying P. falciparum infection remained undetected by microscopy. The introduction of PCR has opened up new possibilities in malaria diagnosis and research.

Adolescent↗
PubMed1994

Altitude, language, and class I HLA allele frequencies in Papua New Guinea.

Class I HLA gene frequencies show considerable variation over short geographical distances in Papua New Guinea. Hypothesis to account for this invoke natural selection, population structure, the pattern of population movement, or past demographic changes. To determine the role of the various factors in shaping this distribution, we have studied correlations between HLA-based genetic distances, geographical distances, altitude, and linguistic differences in Papua New Guinea. Linguistic differences at the family or stock level within the Trans-New Guinea Phylum generally correspond to genetic differences. However, on the basis of their HLA gene frequencies, speakers of Austronesian (AN) languages do not form a distinct group of populations. Linguistic variation and spatial autocorrelation do not fully account for the altitudinal cline differences noted in gene frequencies, particularly at the HLA-A locus. We propose that the distribution of HLA gene frequencies in Papua New Guinea is partially under the control of selection operating differentially along the altitude gradient.

Alleles↗
PubMed1994

Plasmodium falciparum: extensive polymorphism in merozoite surface antigen 2 alleles in an area with endemic malaria in Papua New Guinea.

Plasmodium falciparum: Extensive polymorphism in merozoite surface antigen 2 alleles in an area with endemic malaria in Papua New Guinea. Experimental Parasitology 79, 106-116. The prevalence of Plasmodium falciparum in 304 individuals from two villages in Papua New Guinea has been determined by PCR amplification of the gene encoding the merozoite surface antigen 2 (MSA2). Forty-seven percent of the blood samples were positive for P. falciparum. The MSA2 alleles of this parasite population were characterized by PCR-RFLP genotyping. In 144 P. falciparum infections 38 different MSA2 alleles were found. The most common allele (22%) was a variant of FC27. Further alleles, found in the study area, were IC1, KF1916, and MAD71. In addition to these previously described alleles, 33 novel variant forms of MSA2 were detected, most of which were represented at very low frequency in the study population. MSA2 genotyping of a local P. falciparum population revealed an unexpected amount of genetic heterogeneity. The diversity is mostly due to variation in the repeat region resulting in length polymorphism that can be easily detected by PCR-RFLP.

Adolescent↗
PubMed1994

Relationships between Plasmodium falciparum infection and morbidity in a highly endemic area.

A total of 736 outpatients diagnosed as having malaria using clinical criteria at a health centre in a highly endemic area of Papua New Guinea were investigated parasitologically. Plasmodium falciparum-attributable fractions were determined using a logistic regression model to compare parasite densities in cases with those of healthy individuals in community surveys. Thirty-seven percent of presumptive cases were found to have raised P. falciparum parasitaemia. This corresponds to an average reporting rate for the population of 0.53 attributable episodes per annum. Whilst the maximum prevalence of parasitaemia in the community was in children aged 5-9 years, the maximum age-specific incidence of attributable cases at the outpatient clinic was 2 cases per annum in the 2- to 4-year-old age group. The procedure for estimating attributable fractions makes it possible to compare morbidity rates between age groups, and to examine how the relationship between morbidity risk and parasite density changes with age, without diagnosing individual episodes. The average tolerance of parasites in an age group was measured by considering the level of parasitaemia associated with a given risk of malaria-attributable morbidity. In contrast to anti-parasite immunity, tolerance of parasites declines with age since at parasite isodensity the probability of being symptomatic increases with age.

Adolescent↗
PubMed1994

Natural variation within the principal adhesion domain of the Plasmodium vivax duffy binding protein.

The blood-stage development of malaria parasites is initiated by the invasion of merozoites into susceptible erythrocytes. Specific receptor-ligand interactions must occur for the merozoites to first attach to and then invade erythrocytes. Because the invasion process is essential for the parasite's survival and the merozoite adhesion molecules are exposed on the merozoite surface during invasion, these adhesion molecules are candidates for antibody-dependent malaria vaccines. The Duffy binding protein of Plasmodium vivax belongs to a family of erythrocyte-binding proteins that contain functionally conserved cysteine-rich regions. The amino cysteine-rich regions of these homologous erythrocyte-binding proteins were recently identified for P. vivax, Plasmodium knowlesi, and Plasmodium falciparum as the principal erythrocyte-binding domains (C. Chitnis and L. H. Miller, J. Exp. Med. 180:497-506, 1994, and B. K. L. Sim, C. E. Chitnis, K. Wasniowska, T. J. Hadley, and L. H. Miller, Science 264:1941-1944, 1994). We report that amino acids in this critical ligand domain of the P. vivax Duffy binding protein are hypervariable, but this variability is limited. Hypervariability of the erythrocyte-binding domain suggests that this domain is the target of an effective immune response, but conservation of amino acid substitutions indicates that functional constraints limit this variation. In addition, the amino cysteine-rich region and part of the hydrophilic region immediately following it were the site of repeated homologous recombinations as represented by tandem repeat sequence polymorphisms. Similar polymorphisms have been identified in the same region of the homologous genes of P. falciparum and P. knowlesi, suggesting that there is a common mechanism of recombination or gene conversion that occurs in these Plasmodium genes.

Amino Acid Sequence↗
PubMed1994

Assessment of the humoral and cell-mediated immunity against the Plasmodium falciparum vaccine candidates circumsporozoite protein and SPf66 in adults living in highly endemic malarious areas of Papua New Guinea.

To assess natural immunity against the circumsporozoite (CS) protein and the synthetic vaccine SPf66, immunologic studies were carried out in a highly endemic malarious area of Papua New Guinea. Antibody prevalence, antibody titers, and T cell proliferation against both antigens were measured in 214 adults. Immunologic data were analyzed with respect to longitudinal malariologic and morbidity data. Evidence of genetic traits such as glucose-6-phosphate dehydrogenase deficiency and ovalocytosis was analyzed. Antibody prevalence was high, with 79% and 84% for CS protein and SPf66, respectively, while T cell proliferation was infrequent and low, with 14% and 12% responders, respectively. Anti-CS protein antibodies increased with age but showed no association to malaria indices or morbidity. No protective value was observed with T cell responses or with humoral response to SPf66. These results provide a first description of naturally developed immunity against SPf66 and suggest further studies in to fully understand the mechanism of immunity against this antigen.

Adolescent↗
PubMed1993

Comparison of single-dose diethylcarbamazine and ivermectin for treatment of bancroftian filariasis in Papua New Guinea.

This double-blind study compared the clinical safety and parasitologic efficacy of single-dose regimens of diethylcarbamazine (DEC) and ivermectin for treatment of bancroftian filariasis in Papua New Guinea. Five groups of 10 men each with mean levels of parasitemia ranging from 2,985 to 5,185 microfilariae (mf)/ml were given DEC (6 mg/kg of body weight one time or 1 mg/kg, then 6 mg/kg four days later) or ivermectin (220 micrograms/kg; 20 micrograms/kg, then 200 micrograms/kg four days later or 20 micrograms/kg, then 400 micrograms/kg four days later). No significant side effects (e.g., acute adenolymphangitis, fever lasting more than eight hours, hypotension) were observed in any of the five treatment groups. The magnitude of reduction in microfilaremia was greater (P < 0.01) for the three ivermectin groups versus the two DEC groups in the first 30 days after drug administration (mf levels < 1% of pretreatment values versus 22.6-41.5%, respectively). At 90 and 180 days, mf levels continued to decrease in the DEC groups whereas they increased in the ivermectin groups given a total dose of 220 micrograms/kg. Eighteen months after drug administration, individuals given DEC or 420 micrograms/kg of ivermectin had the greatest degree of reduction in microfilaremia (86-90% compared with the pretreatment values). Decreases in parasite antigenemia measured by enzyme-linked immunosorbent assay for a secreted 200-kD adult worm antigen were greatest for the single-dose DEC group (39.7% decrease relative to the pretreatment level versus 7.8-15.7% for the ivermectin groups). These results indicate that single-dose DEC and ivermectin are well-tolerated by Wuchereria bancrofti-infected individuals with high levels of microfilaremia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Ineffectiveness of amodiaquine against Plasmodium falciparum malaria in symptomatic young children living in an endemic malarious area of Papua New Guinea.

The standard in vivo 7-day test of drug resistance was conducted on 83 children with symptomatic P. falciparum infection, using a full 3-day course of amodiaquine. All children were living in an endemic malarious area of the East Sepik Province of Papua New Guinea. Analysis of blood amodiaquine levels by an ELISA method showed increased blood amodiaquine concentration with progressive days of treatment. By day 7 of the study period parasites had cleared in 68 (82 per cent) of the children while 15 (18 per cent) had persistence or recrudescence of P. falciparum. Of these 15 resistant cases, four were R1 resistant (early recrudescence), seven were R2, and four were R3. This is a higher proportion of R2/R3 resistance than has usually been reported in Papua New Guinea. In vivo amodiaquine resistance declined significantly with increasing age of the child. Resistance was found to be more common in children with low weight for age: this possible association requires further investigation in the study area, which has one of the highest rates of malnutrition in Papua New Guinea.

Age Factors↗
PubMed1991

Glucose tolerance in Papua New Guinea: comparison of Austronesian and non-Austronesian communities of Karkar Island.

Epidemiological studies in Pacific populations have suggested a relationship between glucose tolerance and proportional Austronesian genetic admixture, with non-Austronesian Melanesians relatively free of glucose intolerance. However, a survey conducted in 1985 demonstrated the apparent emergence of glucose intolerance in a peri-urban non-Austronesian community, casting doubt on this hypothesis. In 1986 glucose tolerance was studied in three village communities on Karkar Island, Papua New Guinea. Two were of Austronesian and one was of non-Austronesian genetic ancestry. Prevalence of diabetes was low in all communities. However, prevalence of impaired glucose tolerance (IGT) was 7% in the more developed Austronesian community, as compared with 2% in the equivalent non-Austronesian group (p less than 0.05). Multiple regression analysis demonstrated not only a highly significant association between 2-h plasma glucose and insulin concentrations (p less than 0.001), but also that for a given value of plasma insulin, 2-h plasma glucose values were lower for non-Austronesian than for Austronesian subjects (males, p less than 0.05, females, p less than 0.01). However, average plasma insulin concentrations were relatively high in the non-Austronesian community, despite lower average plasma glucose concentrations.

Adult↗
PubMed1990

Plasma glucose and insulin responses in young Papua New Guineans (aged 10-19 years).

A study of rural and periurban children aged 10-19 years in the Tolai population of Papua New Guinea has demonstrated a higher average plasma glucose concentration and relative hyperinsulinaemia after an oral glucose challenge in the periurban group. The findings could not be explained by differences in age or adiposity. In the rural children, plasma insulin concentration remained consistently low throughout the range of glucose tolerance, indicating a high degree of insulin sensitivity. In the periurban children there was a marked increase in plasma insulin concentration with increasing plasma glucose concentration, possibly suggesting the development of insulin resistance, or an antecedent state, and incipient glucose intolerance. In view of the potential public health implications of these findings, further ecological studies of insulin response in children and adolescents would appear warranted. These should include appropriate measures of pubertal development, which is a possible confounding factor not addressed in the present study, as well as addressing the role of nutritional factors.

Adolescent↗