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Biomedical subjects

E Michael

Publications and source records attributed to E Michael.

At least 19 recordsLinked to original sources
PubMed2006

Colposcopic management of high-grade referral smears: a retrospective audit supporting 'see and treat'?

OBJECTIVE: The National Health Service Cervical Screening Programme monitors the quality of colposcopy services through the annual KC65 returns. The 2002 returns demonstrated that Standard 7c, which specifies a biopsy rate > or = 90% at first colposcopy visit for high-grade referrals, was not met in the assessed 3-month period. This was investigated along with the other standards. METHODS: Retrospective colposcopy records were accessed for the 597 new referrals, excluding 10 pregnant patients, seen at the colposcopy clinic at the Royal Victoria Infirmary between 1 July 2001 and 31 December 2002, following an abnormal high-grade smear. Cytology and histopathology computer records were checked for confirmation. The results were assessed against the colposcopy standards applicable at that time and the revised standards (2004). RESULTS: Biopsies were taken from 94.47% (Standard > or = 90%) of women at index colposcopy visit including wire loop excision biopsies from 66.16% (87.97% of high-grade colposcopic appearances). Cervical intraepithelial neoplasia (CIN) on histology was found in 91.79% in the study group (Standard > or = 85%) and in 96.71% of index visit biopsies (Standard > or = 90%), meeting the applicable colposcopy standards. The revised 2004 standards specify a biopsy in > or = 95% of high-grade referrals and excision biopsies in 95% if colposcopic appearances are also high-grade, if colposcopy is low grade but the smear is severely dyskaryotic, or when the lesion extends into the canal. The positive predictive value of high-grade cytology for this entire group was 75.54% with CIN present in 90.95%. CONCLUSION: From this study it appears that high-grade cytology in this centre reliably indicates high-grade CIN. Therefore, in women referred for colposcopy following a high-grade smear, excision biopsies should be performed in a higher proportion at the first visit to comply with the revised standards.

Biopsy↗
PubMed2006

Transmission dynamics of lymphatic filariasis: vector-specific density dependence in the development of Wuchereria bancrofti infective larvae in mosquitoes.

The principles of meta-analysis developed in a previous study were extended to investigate the process of Wuchereria bancrofti (Cobbold) (Filarioidea: Onchocercidae) infection in mosquito (Diptera: Culicidae) hosts, focusing specifically on the functional forms and strength of density dependence in the development of ingested microfilariae (mf) to infective (third instar) larvae (L3). Mathematical models describing observed mf-L3 functional responses for each of the major three parasite-transmitting vector genera, Aedes, Culex and Anopheles mosquitoes, were fitted to paired mf-L3 data collated from all available studies in the published literature. Model parameters were estimated and compared by deriving and applying a data synthetic framework, based on applying a non-linear weighted regression model for fitting mathematical models to multistudy data. The results confirm previous findings of the existence of significant between-genera differences in the mf-L3 development relationship, particularly with regard to the occurrence of limitation in Culex mosquitoes and facilitation in Aedes and Anopheles mosquitoes. New and unexpected findings regarding L3 development from ingested mf were discovered as follows: (1) for Culex, overcompensation in L3 development at higher intensities of mf (or a peaked mf-L3 functional response) was detected; (2) for Aedes mosquitoes, facilitation (with an apparent asymptotic constraint on L3 development at high mf densities) was shown to be the major process governing L3 development, and (3) for Anopheles, a stronger facilitation type of response with no apparent saturation in L3 development appears to govern L3 output from ingested mf. These results yield major new insights regarding filarial vector infection dynamics and their potential impacts on parasite control, and demonstrate the efficacy of employing a data synthetic approach to reveal and estimate parasitic infection processes in host populations.

Aedes↗
PubMed2005

Immuno-epidemiology of Ascaris lumbricoides infection in a high transmission community: antibody responses and their impact on current and future infection intensity.

The role of the humoral immune system in human infection with Ascaris lumbricoides remains unclear. This study documents an epidemiological investigation in a highly endemic community in Vietnam, whereby serum antibody levels were assessed before treatment and after a 6-month reinfection period. These data were examined by correlation with infection status using an age-structured approach in an attempt to help shed light on the role of the humoral immune response. The first part of this study characterized levels of all serum antibody isotypes from the community in response to antigens of both adult and larval A. lumbricoides. Data were assessed in terms of their relation to host age and infection intensity with the aim to provide a broadly detailed account of immune responses to the parasite. In the second part, antibody responses to both life-stages of A. lumbricoides in serum samples collected before anthelmintic chemotherapy were analysed in relation to intensity of re-infection with the parasite 6 months following treatment. The results suggest that antibody responses may not confer protection from current infection or re-infection with A. lumbricoides and may not serve as reliable indicators of future infection intensity. Our results thereby lend support to the theory that immunity to A. lumbricoides may not be based on the humoral immune system.

Adolescent↗
PubMed2005

Bancroftian filariasis: patterns of vector abundance and transmission in two East African communities with different levels of endemicity.

Intensive monitoring of Wuchereria bancrofti vector abundance and transmission intensity was carried out in two communities, one with high-level endemicity for bancroftian filariasis (Masaika, Tanzania) and the other with low-level (Kingwede, Kenya), on the East African coast. Mosquitoes were collected in light traps, from 50 randomly selected households in each community, once weekly for 1 year. They were identified, dissected and checked for parity and filarial larvae. Anopheles gambiae s. l., An. funestus and Culex quinquefasciatus transmitted W. bancrofti in the two communities but the importance of each of these taxa differed between the communities and by season. The overall vector densities and transmission intensities were significantly higher in Masaika than in Kingwede (the annual biting rate by 3.7 times and the annual transmission potential by 14.6 times), primarily because of differences in the available breeding sites for the vectors and in the vectorial capacity of the predominant vector species. A marked seasonal variation in vector abundance and transmission potential contributed to the complex transmission pattern in the communities. Generally, these indices were higher during and shortly after the rainy seasons than at other times of the year. Considerable differences in W. bancrofti transmission were thus observed between communities within a relatively small geographical area (mainly because of environmentally-determined differences in vector habitats), and these were reflected in the marked differences in infection level in the human populations. The variation in vector abundance, vector composition and transmission intensity in the two communities is discussed in respect to its cause, its effects, and its significance to those attempting to control bancroftian filariasis.

Animals↗
PubMed2004

BMP controls nitric oxide-mediated regulation of cell numbers in the developing neural tube.

Balanced cell proliferation and cell death determines neural precursor cell numbers in early stages of neural tube (NT) development. We have previously shown that nitric oxide (NO) regulates cell numbers locally in the NT of eight to 12 somite embryos. Here, we demonstrate that bone morphogenetic protein-4 (BMP-4), which is expressed in the ectoderm and dorsal NT at these developmental stages, induces programmed cell death (PCD) and promotes entry into the S-phase, via nitric oxide synthase (NOS) activity. These effects can be reversed by BMP-4 antagonists, such as follistatin and noggin, or by specific NOS inhibitors, resulting in low NO levels that facilitate mitosis and reduce PCD. Ectopic BMP-4 induction of PCD is restricted to the dorsal NT, whereas promotion of the S-phase is evenly observed across the dorsal-ventral (D-V) axis. Prolonged exposure to either BMP-4 or NOS inhibitors, which results in high or low NO levels, respectively, causes NT defects. The results presented here throw new light on the BMP signaling pathway. The local presence of BMP-4 helps to regulate cell numbers in the developing NT by a NO-mediated pathway, which is essential for normal NT formation.

Animals↗
PubMed2002

Sequence variation in the Trichuris trichiura beta-tubulin locus: implications for the development of benzimidazole resistance.

Benzimidazole resistance has evolved in a variety of organisms and typically results from mutations in the beta-tubulin locus at specific amino acid sites. Despite widespread treatment of human intestinal nematodes with benzimidazole drugs, there have been no unambiguous reports of resistance. However, since beta-tubulin mutations conferring resistance are generally recessive, frequencies of resistance alleles less than 30% would be difficult to detect on the basis of drug treatment failures. Here we investigate sequence variation in a 1079 bp segment of the beta-tubulin locus in the human whipworm Trichuris trichiura from 72 individual nematodes from seven countries. We did not observe any alleles with amino acid mutations indicative of resistance, and of 40 point mutations there were only four non-synonymous mutations all of which were singletons. Estimated effective population sizes are an order of magnitude lower than those from another nematode species in which benzimidazole resistance has developed (Haemonchus contortus). Both the lower diversity and reduced population sizes suggest that benzimidazole resistance is likely to evolve less rapidly in Trichuris than in trichostrongyle parasites of livestock. We observed moderate levels of population subdivision (Phi(ST)=0.26) comparable with that previously observed in Ascaris lumbricoides, and identical alleles were frequently found in parasites from different continents, suggestive of recent admixture. A particularly interesting feature of the data is the high nucleotide diversities observed in nematodes from the Caribbean. This genetic complexity may be a direct result of extensive admixture and complex history of human populations in this region of the world. These data should encourage (but not make complacent) those involved in large-scale benzimidazole treatment of human intestinal nematodes.

Animals↗
PubMed2002

Impact of untreated bednets on prevalence of Wuchereria bancrofti transmitted by Anopheles farauti in Papua New Guinea.

Despite the growing evidence that insecticide-treated mosquito nets reduce malaria morbidity and mortality in a variety of epidemiological conditions, their value against lymphatic filariasis infection and disease is yet to be established. The impact of untreated bednets on the prevalence of Wuchereria bancrofti (Cobbold) (Nematoda: Filarioidea) infection and disease was investigated on Bagabag island in Papua New Guinea, where both malaria and filariasis are transmitted by the same vector mosquitoes of the Anopheles punctulatus Dönitz group (Diptera: Culicidae). Community-wide surveys were conducted recording demographic characteristics including bednet usage. Physical examinations for hydrocoele and lymphoedema were performed and blood samples assessed for filarial and malaria parasites. Mosquitoes were sampled using the all-night landing catch method and individually dissected to determine W. bancrofti infection and infective rates. Bednet usage among residents was 61% and the mean age of users (25.6 years) was similar to non-users (22.5 years). Anopheles farauti Laveran was the only species were found to contain filarial larvae: 2.7% infected (all stages), 0.5% infective (L3). The overall W. bancrofti microfilaraemia and antigenaemia rates were 28.5% and 53.1%, respectively. Bednet users had lower prevalence of W. bancrofti microfilaraemia, antigenaemia and hydrocoele rates than non-users. In comparison, untreated bednets had no effect on the prevalence and intensity of Plasmodium falciparum and P. vivax infections. The impact of bednet usage on rates of microfilaraemia and antigenaemia remained significant even when confounding factors such as age, location and sex were taken into account, suggesting that untreated bednets protect against W. bancrofti infection.

Adult↗
PubMed2002

Transmission dynamics of lymphatic filariasis: density-dependence in the uptake of Wuchereria bancrofti microfilariae by vector mosquitoes.

Gaining a better understanding of parasite infection dynamics in the vector mosquito (Diptera: Culicidae) population is central to improving knowledge regarding the transmission, persistence and hence control of lymphatic filariasis. Here, we use data on mosquito feeding experiments collated from the published literature to examine the available evidence regarding the functional form of the first component of this parasite-vector relationship for Wuchereria bancrofti (Filarioidea: Onchocercidae) causing Bancroftian filariasis, i.e. the rate of microfilariae (mf) uptake from the blood of infected humans by the feeding mosquito vector. Using a simple logarithmic regression model for describing the observed relationships between the mean numbers of mf ingested per mosquito and parasite load in humans in each study, and a linear mixed-effects meta-analytical framework for synthesizing the observed regressions across studies, we show here for the first time clear evidence for the existence of density-dependence in this process for all the three major filariasis transmitting mosquito vectors. An important finding of this study is that this regulation of mf uptake also varies significantly between the vector genera, being weakest in Culex, comparatively stronger in Aedes and most severe and occurring at significantly lower human mf loads in Anopheles mosquitoes. The analysis of the corresponding mf uptake prevalence data has further highlighted how density-dependence in mf uptake may influence the observed distributions of mf in vector populations. These results show that whereas strong regulation of mf uptake, especially when it leads to saturation in uptake at low human parasite intensities, can lead to static distributions of mf per mosquito with host parasite intensity, a weaker regulation of mf ingestion can give rise to changes in both mean mf loads and in the frequency distribution of parasites/mosquito with increasing human parasite intensity. These findings highlight the importance of considering local vector infection dynamics when attempting to predict the impacts of community-based filariasis control. They also emphasize the value of developing and applying robust meta-analytic methods for estimating functional relationships regarding parasitic infection from population ecological data.

Animals↗
PubMed2002

A geostatistical analysis of the geographic distribution of lymphatic filariasis prevalence in southern India.

Gaining a better understanding of the spatial population structure of infectious agents is increasingly recognized as being key to their more effective mapping and to improving knowledge of their overall population dynamics and control. Here, we investigate the spatial structure of bancroftian filariasis distribution using geostatistical methods in an endemic region in Southern India. Analysis of a parasite antigenemia prevalence dataset assembled by sampling 79 villages selected using a World Health Organization (WHO) proposed 25 x 25 km grid sampling procedure in a 225 x 225 km area within this region was compared with that of a corresponding microfilaraemia prevalence dataset assembled by sampling 119 randomly selected villages from a smaller subregion located within the main study area. A major finding from the analysis was that once large-scale spatial trends were removed, the antigenemia data did not show evidence for the existence of any small-scale dependency at the study sampling interval of 25 km. By contrast, analysis of the randomly sampled microfilaraemia data indicated strong spatial contagion in prevalence up to a distance of approximately 6.6 kms, suggesting the likely existence of small spatial patches or foci of transmission in the study area occurring below the sampling scale used for sampling the antigenemia data. While this could indicate differences in parasite spatial population dynamics based on antigenemia versus microfilaraemia data, the result may also suggest that the WHO recommended 25 x 25 km sampling grid for rapid filariasis mapping could have been too coarse a scale to capture and describe the likely local variation in filariasis infection in this endemic location and highlights the need for caution when applying uniform sampling schemes in diverse endemic regions for investigating the spatial pattern of this parasitic infection. The present results, on the other hand, imply that both small-scale spatial processes and large-scale factors may characterize the observed distribution of filariasis in the study region. Our preliminary analysis of a mountain range associated large-scale trend in the antigenemia data suggested that a nonlinear relationship of infection prevalence with elevation might be a factor behind such observed global spatial patterns. We conclude that geostatistic methods can provide a powerful framework for carrying out the empirical investigation and analysis of parasite spatial population structure. This study shows that their successful application, however, will crucially depend on our gaining a more thorough understanding of the appropriate geographic scales at which spatial studies should be carried out.

Adult↗
PubMed2001

A simple and quick method for enhanced detection of specific IgE in serum from lymphatic filariasis patients.

A new simple and quick technique, using a suspension of protein A agarose beads to absorb IgG4 from sera prior to determination of filarial-specific IgE in ELISA, is presented. The optimal ratio between serum and absorbant was determined by absorbing fixed volumes of sera from individuals from a Wuchereria bancrofti endemic area with different volumes of the protein A agarose bead suspension and testing supernatants for filaria-specific IgG4 and IgE. The effect of absorption on measured IgG4 and IgE intensities in sera from various categories of individuals from the endemic area was thereafter examined. Overall, absorption resulted in a 96.5% decrease in mean ELISA OD values for IgG4 and a 41.6% increase in mean ELISA OD values for IgE. Higher increases in IgE measurements were seen with sera from circulating filarial antigen (CFA) negative individuals (64.7%), microfilaria (mf) negative individuals (56.1%) and individuals with chronic filarial disease (62.7%) than with sera from individuals who were CFA positive (23.4%), mf positive (10.0%), or without chronic disease (36.5%). These differences indicate that the degree to which IgE detection in unabsorbed serum is blocked by IgG4 varies with infection and disease status. Absorption of IgG4 from serum with a protein A agarose bead suspension prior to measurement of specific IgE is a useful alternative to conventional gel column absorption methods, particularly when processing many samples.

Absorption↗
PubMed2001

Transmission intensity and the immunoepidemiology of bancroftian filariasis in East Africa.

Previous attempts to determine the interactions between filariasis transmission intensity, infection and chronic disease have been limited by a lack of a theoretical framework that allows the explicit examination of mechanisms that may link these variables at the community level. Here, we show how deterministic mathematical models, in conjunction with analyses of standardized field data from communities with varying parasite transmission intensities, can provide a particularly powerful framework for investigating this topic. These models were based on adult worm population dynamics, worm initiated chronic disease and two major forms of acquired immunity (larval- versus adult-worm generated) explicitly linked to community transmission intensity as measured by the Annual Transmission Potential (ATP). They were then fitted to data from low, moderate and moderately high transmission communities from East Africa to determine the mechanistic relationships between transmission, infection and observed filarial morbidity. The results indicate a profound effect of transmission intensity on patent infection and chronic disease, and on the generation and impact of immunity on these variables. For infection, the analysis indicates that in areas of higher parasite transmission, community-specific microfilarial rates may increase proportionately with transmission intensity until moderated by the generation of herd immunity. This supports recent suggestions that acquired immunity in filariasis is transmission driven and may be significant only in areas of high transmission. In East Africa, this transmission threshold is likely to be higher than an ATP of at least 100. A new finding from the analysis of the disease data is that per capita worm pathogenicity could increase with transmission intensity such that the prevalences of both hydrocele and lymphoedema, even without immunopathological involvement, may increase disproportionately with transmission intensity. For lymphoedema, this rise may be further accelerated with the onset of immunopathology. An intriguing finding is that there may be at least two types of immunity operating in filariasis: one implicated in anti-infection immunity and generated by past experience of adult worms, the other involved in immune-mediated pathology and based on cumulative experience of infective larvae. If confirmed, these findings have important implications for the new global initiative to achieve control of this disease.

Age Distribution↗
PubMed2001

Wuchereria bancrofti in a community with seasonal transmission: stability of microfilaraemia, antigenaemia and filarial-specific antibody concentrations.

The effect of seasonal transmission on microfilaraemia, antigenaemia and filarial-specific antibody levels in individuals infected with Wuchereria bancrofti was investigated in a follow-up study in an endemic community in north-eastern Tanzania. The subjects were 37 adult male residents who were found to be positive for circulating filarial antigen (CFA) at the beginning of the study (26 of whom were also found microfilaraemic with W. bancrofti at this time). Blood samples were collected from each subject in July 1998, January 1999 and July 1999, during the seasons when transmission intensity was high, low and high, respectively. The mean intensities of microfilaraemia and the mean concentrations of CFA were each slightly higher during the low-transmission season than during the two high-transmission seasons but the differences were not statistically significant (P > 0.05). Similarly, the mean levels of filarial-specific IgG1, IgG2, IgG3, IgG4 or IgE did not differ to a statistically significant degree between the three examination times. Microfilaraemias and the levels of CFA and filarial-specific antibodies all therefore appeared to be remarkably stable and largely unaffected by the seasonal variation in transmission. That no variation in the mean IgG4/IgE ratio was observed over the study period may indicate that the level of resistance to W. bancrofti infection in the study subjects was also unaffected by the transmission season.

Adult↗
PubMed2001

Quantifying mosquito biting patterns on humans by DNA fingerprinting of bloodmeals.

A major debate in infectious disease epidemiology concerns the relative importance of exposure and host factors, such as sex and acquired immunity, in determining observed age patterns of parasitic infection in endemic communities. Nonhomogeneous contact between hosts and vectors is also expected to increase the reproductive rate, and hence transmission, of mosquito-borne infections. Resolution of these questions for human parasitic diseases has been frustrated by the lack of a quantitative tool for quantifying the exposure rate of people in communities. Here, we show that the polymerase chain reaction (PCR) technique for amplifying and fingerprinting human DNA from mosquito bloodmeals can address this problem for mosquito-borne diseases. Analysis of parallel human and mosquito (resting Culex quinquefasciatus) samples from the same households in an urban endemic focus for bancroftian filariasis in South India demonstrates that a 9-locus radioactive short-tandem repeat system is able to identify the source of human DNA within the bloodmeals of nearly 80% of mosquitoes. The results show that a person's exposure rate, and hence the age and sex patterns of exposure to bites in an endemic community, can be successfully quantified by this method. Out of 276 bloodmeal PCR fingerprints, we also found that on average, 27% of the mosquitoes caught resting within individual households had fed on people outside the household. Additionally, 13% of mosquitoes biting within households contained blood from at least 2 people, with the rate of multiple feeding depending on the density of humans in the household. These complex vector feeding behaviors may partly account for the discrepancies in estimates of the infection rates of mosquito-borne diseases calculated parasitologically and entomologically, and they underline the potential of this tool for investigating the transmission dynamics of infection.

Adolescent↗
PubMed2000

Targeted disruption of the epidermal growth factor receptor inhibits development of papillomas and carcinomas from human papillomavirus-immortalized keratinocytes.

The epidermal growth factor receptor (EGF-R) is frequently overexpressed in human papillomavirus (HPV)-associated dysplasias and carcinomas, implying that it is important for the progression of keratinocytes to malignancy. We used mice with a targeted disruption of the EGF-R gene to directly examine its role in cell immortalization and tumor development. Epidermal keratinocytes were cultured from EGF-R knockout, heterozygous, and wild-type mice, infected with retroviruses encoding HPV-16 E6 and E7 oncogenes, and grafted to nude mice. E6/E7 induced immortalization of EGF-R wild-type cells 5-fold more efficiently than null cells. Immortal EGF-R null cells grew more slowly, achieved a lower saturation density, and were more sensitive to apoptosis than the immortalized wild-type or heterozygous cells. Analyses using cDNA expression arrays showed that EGF-R null cells expressed increased levels of RNAs encoding p21waf and insulin-like growth factor-binding protein-2. EGF-R-positive immortal keratinocytes formed papillomas in 17% (15 of 90) of skin grafts, and seven grafts progressed to squamous carcinoma after 6-12 months. EGF-R null keratinocytes did not form papillomas, but 1 of 96 grafts progressed to a squamous carcinoma after 1 year. However, treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate induced tumors in 18 and 35% of grafts containing EGF-R null or EGF-R-positive cells, respectively. Transduction with an activated v-Ha-ras gene, which signals downstream of the EGF-R, induced rapidly growing carcinomas in all grafts regardless of EGF-R genotype. These results directly show that the EGF-R is important, but not essential, for immortalization by HPV and for progression of immortal cells to papillomas and carcinomas.

Animals↗
PubMed2000

The potential of geographical information systems and remote sensing in the epidemiology and control of human helminth infections.

Geographic information systems (GIS) and remote sensing (RS) technologies are being used increasingly to study the spatial and temporal patterns of infectious diseases. For helminth infections, however, such applications have only recently begun despite the recognition that infection distribution patterns in endemic areas may have profound effects on parasite population dynamics and therefore the design and implementation of successful control programmes. Here, we review the early applications of these technologies to the major human helminths (geohelminths, schistosomes and the major lymphatic filarial worms), which demonstrate the potential of these tools to serve as: (1) an effective data capture, mapping and analysis tool for the development of helminth atlases; (2) an environment for modeling the spatial distribution of infection in relation to RS and environmental variables, hence furthering the understanding of the impact of density-independent factors in underlying observed parasite spatial distributions and their effective prediction; and (3) a focal tool in parasite control programming given their abilities to (i) better define endemic areas, (ii) provide more precise estimates of populations-at-risk, (iii) map their distribution in relation to health facilities and (iv) by facilitating the stratification of areas by infection risk probabilities, to aid in the design of optimal drug or health measure delivery systems. These applications suggest a successful role for GIS/RS applications in investigating the spatial epidemiology of the major human helminths. It is evident that further work addressing a range of critical issues include problems of data quality, the need for a better understanding of the population biological impact of environmental factors on critical stages of the parasite life-cycle, the impacts and consequences of spatial scale on these relationships, and the development and use of appropriate spatially-explicit statistical and modeling techniques in data analysis, is required if the true potential of this tool to helminthology is to be fully realized.

Animals↗