PubMed Health⌕ Search

Biomedical subjects

Donald S Burke

Publications and source records attributed to Donald S Burke.

At least 19 recordsLinked to original sources
PubMed2006

Containing a large bioterrorist smallpox attack: a computer simulation approach.

BACKGROUND: A bioterrorist release of smallpox is a constant threat to the population of the USA and other countries. DESIGN: A stochastic simulation model of the spread of smallpox due to a large bioterrorist attack in a structured population was constructed. Disease natural history parameter estimates, time lines of behavioral activities, and control scenarios were based on the literature and on the consensus opinion of a panel of smallpox experts. RESULTS: The authors found that surveillance and containment, i.e., isolation of known cases and vaccination of their close contacts, would be sufficient to effectively contain a large intentional smallpox release. Given that surveillance and containment measures are in place, preemptive vaccination of hospital workers would further reduce the number of smallpox cases and deaths but would require large numbers of prevaccinations. High levels of reactive mass vaccination after the outbreak begins would further reduce smallpox cases and deaths to a minimum, but would require even larger numbers of vaccinations. Reactive closure of schools would have a minimal effect. CONCLUSION: A rapid and well-organized response to a bioterrorist attack would be necessary for effective surveillance and containment to control spread. Preemptive vaccination of hospital workers and reactive vaccination of the target population would further limit spread, but at a cost of many more vaccinated. This cost in resources and potential harm due to vaccination will have to be weighed against the potential benefits should an attack occur. Prevaccination of the general population is not necessary.

Bioterrorism↗
PubMed2006

Protective immunity provided by HLA-A2 epitopes for fusion and hemagglutinin proteins of measles virus.

Natural infection and vaccination with a live-attenuated measles virus (MV) induce CD8(+) T-cell-mediated immune responses that may play a central role in controlling MV infection. In this study, we show that newly identified human HLA-A2 epitopes from MV hemagglutinin (H) and fusion (F) proteins induced protective immunity in HLA-A2 transgenic mice challenged with recombinant vaccinia viruses expressing F or H protein. HLA-A2 epitopes were predicted and synthesized. Five and four peptides from H and F, respectively, bound to HLA-A2 molecules in a T2-binding assay, and four from H and two from F could induce peptide-specific CD8+ T cell responses in HLA-A2 transgenic mice. Further experiments proved that three peptides from H (H9-567, H10-250, and H10-516) and one from F protein (F9-57) were endogenously processed and presented on HLA-A2 molecules. All peptides tested in this study are common to 5 different strains of MV including Edmonston. In both A2K(b) and HHD-2 mice, the identified peptide epitopes induced protective immunity against recombinant vaccinia viruses expressing H or F. Because F and H proteins induce neutralizing antibodies, they are major components of new vaccine strategies, and therefore data from this study will contribute to the development of new vaccines against MV infection.

Amino Acid Sequence↗
PubMed2006

Strategies for mitigating an influenza pandemic.

Development of strategies for mitigating the severity of a new influenza pandemic is now a top global public health priority. Influenza prevention and containment strategies can be considered under the broad categories of antiviral, vaccine and non-pharmaceutical (case isolation, household quarantine, school or workplace closure, restrictions on travel) measures. Mathematical models are powerful tools for exploring this complex landscape of intervention strategies and quantifying the potential costs and benefits of different options. Here we use a large-scale epidemic simulation to examine intervention options should initial containment of a novel influenza outbreak fail, using Great Britain and the United States as examples. We find that border restrictions and/or internal travel restrictions are unlikely to delay spread by more than 2-3 weeks unless more than 99% effective. School closure during the peak of a pandemic can reduce peak attack rates by up to 40%, but has little impact on overall attack rates, whereas case isolation or household quarantine could have a significant impact, if feasible. Treatment of clinical cases can reduce transmission, but only if antivirals are given within a day of symptoms starting. Given enough drugs for 50% of the population, household-based prophylaxis coupled with reactive school closure could reduce clinical attack rates by 40-50%. More widespread prophylaxis would be even more logistically challenging but might reduce attack rates by over 75%. Vaccine stockpiled in advance of a pandemic could significantly reduce attack rates even if of low efficacy. Estimates of policy effectiveness will change if the characteristics of a future pandemic strain differ substantially from those seen in past pandemics.

Antiviral Agents↗
PubMed2006

Common and divergent immune response signaling pathways discovered in peripheral blood mononuclear cell gene expression patterns in presymptomatic and clinically apparent malaria.

Using genome-wide expression profiles from persons either experimentally challenged with malaria-infected mosquitoes or naturally infected with Plasmodium falciparum malaria, we present details of the transcriptional changes that occur with infection and that either are commonly shared between subjects with presymptomatic and clinically apparent malaria or distinguish these two groups. Toll-like receptor signaling through NF-kappaB pathways was significantly upregulated in both groups, as were downstream genes that function in phagocytosis and inflammation, including the cytokines tumor necrosis factor alpha, gamma interferon (IFN-gamma), and interleukin-1beta (IL-1beta). The molecular program derived from these signatures illuminates the closely orchestrated interactions that regulate gene expression by transcription factors such as IRF-1 in the IFN-gamma signal transduction pathway. Modulation of transcripts in heat shock and glycolytic enzyme genes paralleled the intensity of infection. Major histocompatibility complex class I molecules and genes involved in class II antigen presentation are significantly induced in 90% of malaria-infected persons regardless of group. Differences between early presymptomatic infection and natural infection involved genes that regulate the induction of apoptosis through mitogen-activated protein (MAP) kinases and signaling pathways through the endogenous pyrogen IL-1beta, a major inducer of fever. The induction of apoptosis in peripheral blood mononuclear cells from patients with naturally acquired infection impacted the mitochondrial control of apoptosis and the activation of MAP kinase pathways centered around MAPK14 (p38alpha and p38beta). Our findings confirm and extend findings regarding aspects of the earliest responses to malaria infection at the molecular level, which may be informative in elucidating how innate and adaptive immune responses may be modulated in different stages of infection.

Adult↗
PubMed2006

Ancient origin and molecular features of the novel human T-lymphotropic virus type 3 revealed by complete genome analysis.

Human T-lymphotropic virus type 3 (HTLV-3) is a new virus recently identified in two primate hunters in Central Africa. Limited sequence analysis shows that HTLV-3 is distinct from HTLV-1 and HTLV-2 but is genetically similar to simian T-lymphotropic virus type 3 (STLV-3). We report here the first complete HTLV-3 sequence obtained by PCR-based genome walking using uncultured peripheral blood lymphocytes from an HTLV-3-infected person. The HTLV-3(2026ND) genome is 8,917 bp long and is genetically equidistant from HTLV-1 and HTLV-2, sharing about 62% identity. Phylogenetic analysis of all gene regions confirms this relationship and shows that HTLV-3 falls within the diversity of STLV-3, suggesting a primate origin. However, HTLV-3(2026ND) is unique, sharing only 87% to 92% sequence identity with STLV-3. SimPlot and phylogenetic analysis did not reveal any evidence of genetic recombination with either HTLV-1, HTLV-2, or STLV-3. Molecular dating estimates that the ancestor of HTLV-3 is as old as HTLV-1 and HTLV-2, with an inferred divergence time of 36,087 to 54,067 years ago. HTLV-3 has a prototypic genomic structure, with all enzymatic, regulatory, and structural proteins preserved. Like STLV-3, HTLV-3 is missing a third 21-bp transcription element found in the long terminal repeats of HTLV-1 and HTLV-2 but instead contains a unique activator protein-1 transcription factor upstream of the 21-bp repeat elements. A PDZ motif, like that in HTLV-1, which is important for cellular signal transduction and transformation, is present in the C terminus of the HTLV-3 Tax protein. A basic leucine zipper region located in the antisense strand of HTLV-1, believed to play a role in viral replication and oncogenesis, was also found in the complementary strand of HTLV-3. The ancient origin of HTLV-3, the broad distribution of STLV-3 in Africa, and the propensity of STLVs to cross species into humans all suggest that HTLV-3 may be prevalent and support the need for expanded surveillance for this virus.

Amino Acid Sequence↗
PubMed2006

Individual-based computational modeling of smallpox epidemic control strategies.

In response to concerns about possible bioterrorism, the authors developed an individual-based (or "agent-based") computational model of smallpox epidemic transmission and control. The model explicitly represents an "artificial society" of individual human beings, each implemented as a distinct object, or data structure in a computer program. These agents interact locally with one another in code-represented social units such as homes, workplaces, schools, and hospitals. Over many iterations, these microinteractions generate large-scale macroscopic phenomena of fundamental interest such as the course of an epidemic in space and time. Model variables (incubation periods, clinical disease expression, contagiousness, and physical mobility) were assigned following realistic values agreed on by an advisory group of experts on smallpox. Eight response scenarios were evaluated at two epidemic scales, one being an introduction of ten smallpox cases into a 6,000-person town and the other an introduction of 500 smallpox cases into a 50,000-person town. The modeling exercise showed that contact tracing and vaccination of household, workplace, and school contacts, along with prompt reactive vaccination of hospital workers and isolation of diagnosed cases, could contain smallpox at both epidemic scales examined.

Adult↗
PubMed2006

Seroprevalence and distribution of Flaviviridae, Togaviridae, and Bunyaviridae arboviral infections in rural Cameroonian adults.

Arboviruses from the families Flaviviridae, Togaviridae, and Bunyaviridae are suspected to cause widespread morbidity in sub-Saharan African populations, but little research been done to document the burden and distribution of these pathogens. We tested serum samples from 256 Cameroonian adults from nine rural villages for the presence of Dengue-2 (DEN-2), West Nile (WN), Yellow fever (YF), Chikungunya (CHIK), O'nyong-nyong (ONN), Sindbis (SIN), and Tahyna (TAH) infection using standard plaque-reduction neutralization tests (PRNT). Of these samples, 12.5% were DEN-2 positive, 6.6% were WN positive, 26.9% were YF positive, 46.5% were CHIK seropositive, 47.7% were ONN positive, 7.8% were SIN positive, and 36.3% were TAH positive. DEN-2, YF, and CHIK seroprevalence rates were lower among individuals living in dwellings with grass or thatched roofs versus corrugated tin and in villages isolated from urban centers. Seroprevalence rates of YF and CHIK increased with age. These results suggest that inter-epidemic arboviral infection is common in central African populations.

Adolescent↗
PubMed2005

Chaotic desynchronization of multistrain diseases.

Multistrain diseases are diseases that consist of several strains, or serotypes. The serotypes may interact by antibody-dependent enhancement (ADE), in which infection with a single serotype is asymptomatic, but infection with a second serotype leads to serious illness accompanied by greater infectivity. It has been observed from serotype data of dengue hemorrhagic fever that outbreaks of the four serotypes occur asynchronously. Both autonomous and seasonally driven outbreaks were studied in a model containing ADE. For sufficiently small ADE, the number of infectives of each serotype synchronizes, with outbreaks occurring in phase. When the ADE increases past a threshold, the system becomes chaotic, and infectives of each serotype desynchronize. However, certain groupings of the primary and secondary infectives remain synchronized even in the chaotic regime.

Animals↗
PubMed2005

Improved measles surveillance in Cameroon reveals two major dynamic patterns of incidence.

OBJECTIVE: To characterize the province-specific incidence patterns of measles in Cameroon and determine if an increase in measles incidence during the period January 2000-June 2001 is consistent with coincident epidemics in several regions with different inter-epidemic periods. METHOD: Periodic behavior of the monthly measles incidence time-series from each province of Cameroon was analyzed using time-series analysis and cluster techniques. Cumulative incidence in each province of Cameroon over a five-year period was associated with birth rates, and vaccination coverage. RESULTS: Distinct patterns of measles incidence were found in two different areas of Cameroon. The three northern-most provinces experience major epidemics every year. Seven southern provinces show evidence of experiencing major epidemics every third year. In January 2000, Cameroon experienced coincident peaks in these two cycles and thus an increase in measles incidence countrywide over the previous year. Higher cumulative province-specific incidence rates were associated with higher birth rates and lower routine vaccination coverage rates. CONCLUSION: Within one country, two dramatically different dynamic patterns of measles incidence were observed. Long-term surveillance data is crucial to the evaluation of measles immunization campaigns. The availability of a five-year record of measles incidence in Cameroon reveals an interesting dynamic pattern of measles incidence that accounts for the increase in countrywide incidence in 2000-2001.

Cameroon↗
PubMed2005

Dynamic effects of antibody-dependent enhancement on the fitness of viruses.

Antibody-dependent enhancement (ADE), a phenomenon in which viral replication is increased rather than decreased by immune sera, has been observed in vitro for a large number of viruses of public health importance, including flaviviruses, coronaviruses, and retroviruses. The most striking in vivo example of ADE in humans is dengue hemorrhagic fever, a disease in which ADE is thought to increase the severity of clinical manifestations of dengue virus infection by increasing virus replication. We examine the epidemiological impact of ADE on the prevalence and persistence of viral serotypes. Using a dynamical system model of n cocirculating dengue serotypes, we find that ADE may provide a competitive advantage to those serotypes that undergo enhancement compared with those that do not, and that this advantage increases with increasing numbers of cocirculating serotypes. Paradoxically, there are limits to the selective advantage provided by increasing levels of ADE, because greater levels of enhancement induce large amplitude oscillations in incidence of all dengue virus infections, threatening the persistence of both the enhanced and nonenhanced serotypes. Although the models presented here are specifically designed for dengue, our results are applicable to any epidemiological system in which partial immunity increases pathogen replication rates. Our results suggest that enhancement is most advantageous in settings where multiple serotypes circulate and where a large host population is available to support pathogen persistence during the deep troughs of ADE-induced large amplitude oscillations of virus replication.

Animals↗
PubMed2005

Strategies for containing an emerging influenza pandemic in Southeast Asia.

Highly pathogenic H5N1 influenza A viruses are now endemic in avian populations in Southeast Asia, and human cases continue to accumulate. Although currently incapable of sustained human-to-human transmission, H5N1 represents a serious pandemic threat owing to the risk of a mutation or reassortment generating a virus with increased transmissibility. Identifying public health interventions that might be able to halt a pandemic in its earliest stages is therefore a priority. Here we use a simulation model of influenza transmission in Southeast Asia to evaluate the potential effectiveness of targeted mass prophylactic use of antiviral drugs as a containment strategy. Other interventions aimed at reducing population contact rates are also examined as reinforcements to an antiviral-based containment policy. We show that elimination of a nascent pandemic may be feasible using a combination of geographically targeted prophylaxis and social distancing measures, if the basic reproduction number of the new virus is below 1.8. We predict that a stockpile of 3 million courses of antiviral drugs should be sufficient for elimination. Policy effectiveness depends critically on how quickly clinical cases are diagnosed and the speed with which antiviral drugs can be distributed.

Age Distribution↗
PubMed2005

Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters.

The human T-lymphotropic viruses (HTLVs) types 1 and 2 originated independently and are related to distinct lineages of simian T-lymphotropic viruses (STLV-1 and STLV-2, respectively). These facts, along with the finding that HTLV-1 diversity appears to have resulted from multiple cross-species transmissions of STLV-1, suggest that contact between humans and infected nonhuman primates (NHPs) may result in HTLV emergence. We investigated the diversity of HTLV among central Africans reporting contact with NHP blood and body fluids through hunting, butchering, and keeping primate pets. We show that this population is infected with a wide variety of HTLVs, including two previously unknown retroviruses: HTLV-4 is a member of a phylogenetic lineage that is distinct from all known HTLVs and STLVs; HTLV-3 falls within the phylogenetic diversity of STLV-3, a group not previously seen in humans. We also document human infection with multiple STLV-1-like viruses. These results demonstrate greater HTLV diversity than previously recognized and suggest that NHP exposure contributes to HTLV emergence. Our discovery of unique and divergent HTLVs has implications for HTLV diagnosis, blood screening, and potential disease development in infected persons. The findings also indicate that cross-species transmission is not the rate-limiting step in pandemic retrovirus emergence and suggest that it may be possible to predict and prevent disease emergence by surveillance of populations exposed to animal reservoirs and interventions to decrease risk factors, such as primate hunting.

Base Sequence↗
PubMed2005

Cutaneous onchocerciasis in an American traveler.

A case report of cutaneous onchocercias acquired during travels to Africa is presented. The salient epidemiologic, clinical, diagnostic, and therapeutic aspects are reviewed. Clinical and laboratory differences between onchocerciasis patients who are inhabitants of endemic areas and those who are occasional visitors to such areas are discussed. Parasitic infections, including onchocerciasis, should be considered in the differential diagnosis of pruritic eruptions in patients with a history of foreign travel to Africa, Central and South America.

Africa↗
PubMed2005

Bushmeat hunting, deforestation, and prediction of zoonoses emergence.

Understanding the emergence of new zoonotic agents requires knowledge of pathogen biodiversity in wildlife, human-wildlife interactions, anthropogenic pressures on wildlife populations, and changes in society and human behavior. We discuss an interdisciplinary approach combining virology, wildlife biology, disease ecology, and anthropology that enables better understanding of how deforestation and associated hunting leads to the emergence of novel zoonotic pathogens.

Animals↗
PubMed2005

Central African hunters exposed to simian immunodeficiency virus.

HIV-seronegative Cameroonians with exposure to nonhuman primates were tested for simian immunodeficiency virus (SIV) infection. Seroreactivity was correlated with exposure risk (p<0.001). One person had strong humoral and weak cellular immune reactivity to SIVcol peptides. Humans are exposed to and possibly infected with SIV, which has major public health implications.

Animals↗