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Biomedical subjects

A Saul

Publications and source records attributed to A Saul.

At least 73 records · Page 4Linked to original sources
PubMed1997

Field epidemiological studies on malaria in a low endemic area in the Philippines.

Field epidemiological studies were conducted to examine factors affecting endemicity in an area with a low prevalence of malaria. Two annual cross sectional surveys were done to estimate parasite prevalence rates at two periods in time, to determine the distribution of the parasitemic population and to describe the serological status of the population. A longitudinal study of a sample of infected people was used to measure reinfection rates and antibody dynamics. A 2 year passive case detection was done to estimate the number and distribution of people with symptomatic infections. Malaria was found in all age groups, with marked clustering of cases. Active and passive case detection and serological surveys all gave a similar pattern of malaria distribution: generally low prevalence with small foci of relatively high endemicity. The infection frequencies were generally similar in all age groups, measured by both active and passive case detection. There was a high frequency of P. falciparum gametocytemic infections in the asymptomatic cases found through active case detection. Twenty to 39 year old males had the highest frequency of infection by active case detection, and 10-19 year old males by passive case detection. These two groups were also more likely to be gametocyte positive than their female counterparts, suggesting that in this community, this portion of the population acts as the main reservoir of infection.

Adolescent↗
PubMed1997

Risk factors for infection with malaria in a low endemic community in Bataan, the Philippines.

The patterns of malaria morbidity and mortality can vary with the level of malaria transmission in a given area. We carried out two annual cross-sectional surveys in the hypoendemic malarious community of Morong, the Philippines, to examine epidemiologic and sociobehavioural risk factors for infection. In both surveys, the greatest risk of having malaria was associated with place of residence. For example, in the first survey, living in an area where more than 50% of the community had a high IFAT titer had an adjusted odds ratio (OR) of 33.7. A range of activities thought to be associated with risk were examined, but in the first survey, only frequent nocturnal visits to the forest were found to be a significant risk factor overall (adjusted OR; 2.65; 95% CI 1.48, 4.73), but this phenomenon was primarily observed among individuals residing in the lowest prevalence areas. In the second survey, where only the area with a relatively high prevalence of malaria was sampled, no association with activities was found. In this survey, significant factors associated with malarial infection were: being a migrant (adjusted OR 1.97; 95% CI 1.33, 2.92), being male (adjusted OR 1.63; 95% CI 1.10, 2.43) and age 30 years or less (adjusted OR 0.29 for age > 30 years; 95% CI 0.16, 0.52). The data suggest that in low-endemic communities like Morong, Bataan, control efforts should be primarily directed to focal areas identified by serology, particularly among migrants and among male young adults.

Adult↗
PubMed1997

Stability of malaria in a community in Bataan, the Philippines: prospects for control.

Malaria in Morong, Bataan, The Philippines, a municipality with relatively low level, but stable malaria is associated with small foci of relatively high endemicity. Although there is little association between age and symptomatic malaria, there is a reservoir of asymptomatic cases which are present throughout the year. Risk analysis suggests that the greatest risk factor in acquiring malaria depends on place of residence and not on occupation, including those associated with forest activities such as charcoal making. Foci of infection and the timing of symptomatic cases is closely correlated with breeding sites and abundance of adult Anopheles flavirostris. In spite of this close association, widely held views in the community that malaria is not related to mosquito transmission are likely to make better malaria control based on vector control difficult to sustain. Observation of treatment practices in the community and estimates of the number of apparently asymptomatic carriers from active case detection illustrate the importance of delayed treatment in providing a continuing reservoir of infection. These results highlight the need for improved early case detection and treatment.

Antibodies, Protozoan↗
PubMed1997

Mapping of conformational B cell epitopes within alpha-helical coiled coil proteins.

An approach to mapping antigenic B cell epitopes within alpha-helical coiled coil proteins has been developed and applied to two proteins: Streptococcal M protein and C. elegans paramyosin protein UNC-15. Overlapping peptides derived from an alpha-helical coiled coil conformational epitope were embedded between helical flanking peptides derived from the completely unrelated GCN4 leucine zipper peptide. The resulting chimeric peptides exhibited helical propensity. Chimeric peptides were tested for antigenicity (recognition by antibody) or immunogenicity (production of appropriate antibody response). A conformational epitope within the Streptococcal M protein recognised by three mAbs spanned 12 residues. Analysis of chimeric peptides based on C. elegans UNC-15 has enabled fine mapping of the minimal B cell epitope recognised by monoclonal antibody NE1-6B2 to seven non-contiguous residues (spanning 15 residues); the footprint of contact residues involved in antibody recognition being restricted to the hydrophilic face of the helix and covering five helical turns. This chimeric peptide epitope when coupled to diphtheria toxoid was highly immunogenic in mice and antisera recognised the conformationally dependent native peptide epitope. This approach has the potential to map conformational epitopes and design minimal epitopes for use as vaccine candidates.

Amino Acid Sequence↗
PubMed1997

A putative Plasmodium falciparum exported serine/threonine protein kinase.

An 8kb gene coding for a putative serine/threonine protein kinase from Plasmodium falciparum has been cloned and sequenced. It is arranged in two exons: exon I is 2 kb and exon II is 5.6 kb. The gene codes for a large protein of 2510 amino acids. Antibodies raised against a fusion protein were used to localize the putative kinase. By immunofluorescence microscopy, it was found in the cytoplasm of infected red cells. By immunoelectron microscopy it was associated with membranous structures in the red cell and with the red cell membrane, particularly at parasite-induced knobs. This is the first putative protein kinase of P. falciparum to be exported from the parasite into its host cell.

Amino Acid Sequence↗
PubMed1997

Phase I trial in humans of an oil-based adjuvant SEPPIC MONTANIDE ISA 720.

Seppic MONTANIDE ISA 720 is a metabolizable oil adjuvant that has given good results in animals with recombinant malarial antigens. Twelve human volunteers were given increasing intramuscular doses of MONTANIDE ISA 720, ranging from 0.6 to 1.8 ml. The adjuvant was well tolerated with only minor local effects, including tenderness, local swelling and discomfort on use. MONTANIDE ISA 720 may prove to be an acceptable and effective adjuvant for use in people.

Adjuvants, Immunologic↗
PubMed1997

Selection of an adjuvant for vaccination with the malaria antigen, MSA-2.

Various formulations of the Plasmodium falciparum merozoite surface antigen, MSA-2, were made and tested in animals in order to select one for use in human vaccine trials. Recombinant constructs representing both major allelic forms of MSA-2 were formulated with a range of adjuvants and used to immunize rabbits, mice and sheep. After immunization, antibody responses obtained with the most potent adjuvants were at least tenfold greater than responses obtained with the least potent adjuvant Alhydrogel, which was used as the reference standard, although its lower potency indicated against its further use in clinical trials. Based on broadly similar results obtained with the three animal species, several adjuvants, including the water-in-oil adjuvant Montanide ISA 720, the oil-in-water adjuvant SAF-1, and liposomes containing lipid A formulated with Alhydrogel were demonstrated to be potent and potentially suitable for the clinical evaluation of MSA-2 as a candidate malaria vaccine antigen. Of these, ISA 720 was selected for further trial.

Adjuvants, Immunologic↗
PubMed1997

Mapping the minimal murine T cell and B cell epitopes within a peptide vaccine candidate from the conserved region of the M protein of group A streptococcus.

The highly conserved C-terminus of the M protein of group A streptococcus (GAS) is a promising vaccine candidate. An epitope within the conserved C-terminus of the M protein, peptide 145 (a 20-mer with the sequence: LRRDLDASREAKKQVEKALE), has been defined which is the target of opsonic antibodies in both humans and mice, and is recognized by the sera of most adults living in areas of high streptococcal exposure. However, due to potential cross-reactivity between T cells stimulated by this region of the M protein and host cardiac myosin, it is critical to define precisely the minimal protective epitopes within p145. Studies have shown that the immunodominant epitope expressed by p145 is conformational, occurring as an alpha-helical coiled-coil. To enable us to map the murine minimal B cell and T cell epitopes within p145, we have used a novel strategy that allowed us to present shorter sequences of p145 in a native-like conformation. The minimal B cell epitope was found to be contained within residues 7-20 of the p145 sequence, and we have shown that mice immunized with this region are able to generate antibodies that bind to and also opsonize the organism GAS. The T cell epitope is located at the N-terminal region of the p145 sequence, residues 3-14. We have managed, therefore, to define a vaccine candidate--a minimal opsonic B cell epitope within the p145 sequence--that does not incorporate a potentially deleterious T cell epitope.

Amino Acid Sequence↗
PubMed1997

Instrument performance in bone density testing at five Australian centres.

AIMS: To assess the in vitro precision and accuracy of bone mineral densitometry (BMD) within and between locations at five Australian centres. METHODS: Using a multicentre reliability study the accuracy and short- and long-term precision of dual-energy X-ray absorptiometry (DXA) in vitro was compared on five instruments. Measures were performed using pencil beam mode on four Hologic QDR-2000 densitometers and one Hologic QDR-1000/W (Hologic Inc, Waltham, MA). RESULTS: Short-term precision of bone mineral density measurement was less than 0.5% for spine phantoms (n = 10 for each centre, mean intrasite coefficient of variation [CV] 0.39 +/- 0.09% [SD]) and for hip phantoms (n = 10 for each centre, mean intrasite coefficient of variation [CV] 0.34 +/- 0.10% [SD]). Between-centre measurement (n = 10 for each phantom) of a single spine phantom and a single hip phantom (specified mineral contents-58.5 g and 38.6 g, respectively) revealed ranges of bone mineral content of 57.7-58.1 g (all-point CV = 0.52%) and 37.1-37.8 g (all-point CV = 0.70%), respectively. When results from pairs of machines were compared there were statistically different mean BMD results for the majority of the ten possible pairings for both spine and hip measurements. Each study centre measured in vitro stability of phantom BMD measurements over a one year period (n = 45-283, median 157 for spine; and n = 0-262, median 38, for hip); CVs ranged from 0.38 to 0.53% for the spine measurements and from 0.38 to 0.54% for the hip measurements. The mean all-point accuracy of the spine phantom measurements was 99.1% and the hip phantom measurements was 96.7%. CONCLUSIONS: Across a number of instruments DXA demonstrates in vitro all-point precision of 0.5% for the spine phantom and 0.7% for the hip phantom. The instrument demonstrates accuracy of greater than 99% at the spine and 96% at the hip. This finding has clinical, research and quality control implications.

Absorptiometry, Photon↗
PubMed1997

Assessment of the humoral immune response against Plasmodium falciparum rhoptry-associated proteins 1 and 2.

Naturally occurring antibody responses to Plasmodium falciparum rhoptry-associated proteins 1 and 2 (RAP-1 and RAP-2) were measured with recombinant and parasite-derived forms of the antigens. For comparative purposes, responses to multiple forms of three other malarial antigens were also examined. The sera of 100 Papua New Guineans were screened for antibodies. Eighty-six and 82% of individuals over 30 years of age had antibodies that recognized parasite-derived RAP-1 and RAP-2, respectively. Importantly, we found that recombinant and native antigens share linear epitopes seen by the human immune system; thus, the recombinant proteins may be adequate human immunogens. However, antibodies affinity purified on recombinant RAP-1 reacted with other antigens in addition to parasite-derived RAP-1. Thus, the antigenicity of RAP-1 may have been overestimated previously. The recognition of RAP-1 and RAP-2 correlated with age and with the recognition of recombinant forms of the ring-infected erythrocyte surface antigen, merozoite surface protein 1, and merozoite surface antigen 2 (MSA2) antigens. Antibodies to these antigens appear to be generated in response to the total exposure to malaria of the host. Antibodies to conserved regions of MSA2 had stronger correlations with both age and the recognition of other antigens than did the full-length recombinant MSA2 molecule. In contrast to results with the other antigens, there was no significant difference in the ages of individuals with a certain antibody titer to the full-length recombinant or parasite-derived MSA2 molecule, but antibodies to these two antigens did correlate with parasitemia. For all antigens tested, antibody levels after two infections can approach the peak levels of antibodies obtained in immune individuals.

Adolescent↗
PubMed1997

Measurement of Plasmodium falciparum growth rates in vivo: a test of malaria vaccines.

Several prototype vaccines against the asexual blood stage of malaria are undergoing preclinical and phase I testing. Although these vaccines have been chosen for their ability to elicit an anti-parasite response, no practical and sensitive clinical trial procedure has been available for measuring their impact on parasite growth. We describe a system that allows parasite growth rates to be measured in volunteers through the incubation period. Two necessary elements of this system are developed: suitable blood-stage Plasmodium falciparum inocula, and a highly sensitive and quantitative assay to measure parasite growth during the incubation period. We infected five nonimmune volunteers with an inoculum as small as 300 parasites and demonstrated that the resultant in vivo asexual parasite growth rates were reproducible at 12-15-fold per cycle. The system allowed the infection to be followed for eight days before treatment without symptoms developing. These findings suggest that it is feasible to directly measure the anti-parasite efficacy of a prototype malaria vaccine in human volunteers without subjecting them to the risk of disease.

Adult↗
PubMed1997

Macromolecular transport in malaria--does the duct exist?

The proposal that a parasitophorous 'duct' traverses the malaria-infected erythrocyte cytoplasm and is responsible for the unusual molecular uptake kinetics observed in malaria, has created considerable debate on the nature of macromolecular transport in this parasite. The existence of a 'duct' has important implications for the immunobiology of this parasite, particularly the possibility that antibodies may have access to 'internal' antigens in malaria. The most compelling evidence that there is a direct connection between the parasite and the surrounding media comes from the experiment of Pouvelle et al. (Nature 353, 73-75 (1991)) using small highly fluorescent latex spheres. However, we have found that fluorescent labeling of the parasite and tubular structures that extend from the parasite is due to the release of dye from the latex spheres during the incubation and is not due to the uptake of the spheres themselves. The inability of malaria-infected erythrocytes to take up latex beads down to 14 nm diameter establishes that an 'open' channel connecting the parasite with the surrounding media does not exist. This finding has important implications for establishing the unusual nature of macromolecular transport across the infected erythrocyte cytoplasm in malaria.

Animals↗
PubMed1996

A peptide derived from a B cell epitope of Plasmodium falciparum rhoptry associated protein 2 specifically raises antibodies to rhoptry associated protein 1.

Mice immunised with a recombinant form of malarial antigen rhoptry-associated protein 2 (RAP2) produce antisera which recognise the native protein by indirect immunofluorescence and immunoblotting. Purified IgG components of the antisera partially inhibit erythrocyte invasion in vitro. This response was obtained only if the recombinant immunogen was presented to the mice in the presence of reducing and denaturing agents. An 8-mer epitope in RAP2 was recognised by antibodies in three of the antisera: E25TEFSKLY32. Immunisation with this octapeptide raised antibodies which strongly recognised reduced RAP2 in seven out of eight mice. However, this antisera either failed to recognise (five out of eight mice), or only weakly (three out of eight mice) recognised nonreduced RAP2. Examination of disulphide bonds in native RAP2 showed that the 4 cysteines of RAP2 form two disulphide bridges: Cys24-Cys88, and Cys277-Cys376. One of these (Cys24-Cys88) is adjacent to the octapeptide in the native protein. Surprisingly, seven out of eight mice immunised with the octapeptide also raised antibodies against native rhoptry-associated protein 1 (RAP1). The raising of antibodies which recognise RAP1 was induced specifically by the RAP2 octapeptide rather than the carrier protein used for immunisation. The epitope in RAP1 recognised by the antibodies was identified and shown not to be the result of any shared contiguous homologous sequence between the two proteins, but to shared homologous amino acids in critical positions within the epitope. Purified IgG components from the antisera of mice immunised with the octapeptide gave partial inhibition of erythrocyte invasion in vitro.

Amino Acid Sequence↗
PubMed1996

Retired elite female ballet dancers and nonathletic controls have similar bone mineral density at weightbearing sites.

Elite female ballet dancers exhibit several risk factors for osteoporosis during their performing years. To study the long-term effect of this lifestyle, we compared the bone mineral density (BMD) of 101 retired elite female ballet dancers (mean age 51 years, SD = 14 years) and 101 normal controls, derived from a twin study, matched hierarchically for age, height, weight, and menopausal status. The dancers, who had been retired for a mean of 25.6 years (range 1-53 years) reported a greater prevalence of previous menstrual disturbance, greater lifetime alcohol intake and smoking, and a lower dietary milk intake in adolescence than controls (all p < 0.05). However, current exercise in the dancers was twice that of the controls (p < 0.01). The BMD of retired dancers did not differ from that of the controls at weightbearing sites. The mean +/- SE difference in BMD (dancers minus controls) was 0.009 +/- 0.013 at the total body, -0.009 +/- 0.018 at the total hip, 0.005 +/- 0.017 at the femoral neck, 0.014 +/- 0.018 at the femoral trochanter, 0.036 +/- 0.022 at the femoral intertrochanter and -0.017 +/- 0.021 at the lumbar spine. Retired dancers had lower mean (+/- SE) BMD at the nonweightbearing sites: ultradistal radius (-0.029 +/- 0.008) (p < 0.01) and at the midthird radius (-0.019 +/- 0.011) (p < 0.05). There was no difference in the proportion in each of the World Health Organization (WHO) categories of osteopenia (t score -1.0 to -2.5) and osteoporosis (t score < -2.5) at any of the measured sites. Regression analysis revealed that menstrual disturbance was negatively associated with BMD at the lumbar spine and the ultradistal radial sites, but not at the weightbearing femoral sites. This sample of retired elite ballet dancers who had multiple historical risk factors does not appear to have an increased risk for future hip or vertebral fracture based on WHO standards.

Absorptiometry, Photon↗
PubMed1996

A model for predicting the transmission rate of malaria from serological data.

A model is developed to estimate the duration for which malaria antibody levels in the blood remain high in a closed population. This estimate can be used to calculate the transmission rate within a region, in conjunction with the serological information contained in the population. The model is used on data obtained from a study of malaria in the Philippines and shows excellent agreement. It is subsequently utilised for predictions and seems to be an appropriate vehicle for this purpose.

Animals↗