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At least 1,711 records · Page 95Linked to original sources

PubMed2006

Single-nucleotide repeat analysis for subtyping Bacillus anthracis isolates.

Single-nucleotide repeats (SNRs) are variable-number tandem repeats that display very high mutation rates. In an outbreak situation, the use of a marker system that exploits regions with very high mutation rates, such as SNRs, allows the differentiation of isolates with extremely low levels of genetic diversity. This report describes the identification and analysis of SNR loci of Bacillus anthracis. SNR loci were selected in silico, and the loci with the highest diversity were used to design and test locus-specific primers against a number of B. anthracis strains with the same multilocus variable-number tandem repeat analysis (MLVA) genotype. SNR markers that allowed strains with the same MLVA genotype to be differentiated from each other were identified. The resulting SNR marker system can be used as a molecular epidemiological tool in a natural outbreak or bioterrorism event, offering the best chance of distinguishing very closely related isolates.

Animals↗

PubMed2006

Use of various common isolation media to evaluate the new VITEK 2 colorimetric GN Card for identification of Burkholderia pseudomallei.

The use of automated systems in the modern microbiology laboratory is becoming commonplace as the pressure of cost containment impacts on staff resources. With increased international travel and threats of bioterrorism, recognition and accurate identification of organisms such as Burkholderia pseudomallei is important. In areas where this organism is endemic, identification is not usually problematic. This study evaluates the performance of the new VITEK 2 colorimetric GN card for the identification of this organism. A total of 103 previously identified clinical isolates were tested with the new card with isolates taken from MacConkey agar, Columbia horse blood agar, Columbia sheep blood agar, and Trypticase soy agar in order to determine identification performance and to see if there was any variability in results due to the agar. Columbia horse blood agar produced the highest rates of identification (81%), followed by Trypticase soy agar (78%), Columbia sheep blood agar (75%), and MacConkey agar (63%). There was considerable variability in some of the reactions obtained. Seven isolates failed to identify from any of the agars used. This study highlights issues with the identification of this organism with the new VITEK 2 GN card. Enhancements of the algorithm parameters for the GN card are warranted and are in progress. Laboratory personnel need to be aware of the current limitations with this GN card and the software (version 4.02 or older for the VITEK 2 60/XL and version 1.02 or older for VITEK 2 Compact) and rely on clinical history, a high index of suspicion, and basic microbiology tests to confirm the identification of this organism.

Agar↗

PubMed2006

Follow-up on diagnostic proficiency of laboratories equipped to perform orthopoxvirus detection and quantification by PCR: the second international external quality assurance study.

Two years after the first external quality assurance study on bioterrorism-relevant viruses, we have conducted a follow-up study on orthopoxvirus detection by PCR. Thirty-three laboratories (27 European, 4 Austral-Asian, and 2 American) participated. Samples contained 0 to 40,000,000 DNA copies of lyophilized monkeypox, cowpox, and vaccinia virus per ml. Laboratories achieved a >80% detection chance above 56,234 copies per ml. Global sensitivity was not significantly improved over that of the first study. Twenty-seven and 9 participants, respectively, were able to genotype and quantify virus. Four of 27 genotyping results were incorrect. Quantification accuracy was significantly better for vaccinia virus than for the other viruses. False-positive results occurred in 22 (11.8%) of all 186 tests on negative samples, but 18 of these were contributed by only five laboratories. Fifty-five percent of laboratories could appropriately detect PCR inhibition. The use of either real-time PCR or commercial diagnostic kits had significant positive influence on laboratory performance.

Clinical Laboratory Techniques↗

PubMed2006

Inhibition of hendra virus fusion.

Hendra virus (HeV) is a recently identified paramyxovirus that is fatal in humans and could be used as an agent of bioterrorism. The HeV receptor-binding protein (G) is required in order for the fusion protein (F) to mediate fusion, and analysis of the triggering/activation of HeV F by G should lead to strategies for interfering with this key step in viral entry. HeV F, once triggered by the receptor-bound G, by analogy with other paramyxovirus F proteins, undergoes multistep conformational changes leading to a six-helix bundle (6HB) structure that accomplishes fusion of the viral and cellular membranes. The ectodomain of paramyxovirus F proteins contains two conserved heptad repeat regions (HRN and HRC) near the fusion peptide and the transmembrane domains, respectively. Peptides derived from the HRN and HRC regions of F are proposed to inhibit fusion by preventing F, after the initial triggering step, from forming the 6HB structure that is required for fusion. HeV peptides have previously been found to be effective at inhibiting HeV fusion. However, we found that a human parainfluenza virus 3 F-peptide is more effective at inhibiting HeV fusion than the comparable HeV-derived peptide.

Amino Acid Sequence↗

PubMed2004

NSs protein of Rift Valley fever virus blocks interferon production by inhibiting host gene transcription.

Rift Valley fever virus (RVFV) is an important cause of epizootics and epidemics in Africa and a potential agent of bioterrorism. A better understanding of the factors that govern RVFV virulence and pathogenicity is required, given the urgent need for antiviral therapies and safe vaccines. We have previously shown that RVFV strains with mutations in the NSs gene are excellent inducers of alpha/beta interferon (IFN-alpha/beta) and are highly attenuated in mice. Here, we demonstrate that NSs is sufficient to block IFN-beta gene expression at the transcriptional level. In cells transiently expressing NSs, IFN-beta transcripts were not inducible by viral infection or by transfection of poly(I:C). NSs with anti-IFN activity accumulated in the nucleus. In contrast, mutant forms of NSs that had lost their IFN-inhibiting activity remained in the cytoplasm, indicating that nuclear localization plays a role. IFN synthesis is regulated by specific transcription factors, including interferon regulatory factor (IRF-3), NF-kappaB, and AP-1. In the presence of NSs, IRF-3 was still activated and moved to the nucleus. Likewise, NF-kappaB and AP-1 were activated normally, as shown in electrophoretic mobility shift assays. Moreover, NSs was found to inhibit transcriptional activity of a constitutive promoter, in agreement with recent findings showing that NSs targets the basal cellular transcription factor TFIIH. The present results suggest that NSs, unlike other viral IFN antagonists, does not inhibit IFN-specific transcription factors but blocks IFN gene expression at a subsequent step.

Amino Acid Sequence↗

PubMed2004

Induction of potent humoral and cell-mediated immune responses by attenuated vaccinia virus vectors with deleted serpin genes.

Vaccinia virus (VV) has been effectively utilized as a live vaccine against smallpox as well as a vector for vaccine development and immunotherapy. Increasingly there is a need for a new generation of highly attenuated and efficacious VV vaccines, especially in light of the AIDS pandemic and the threat of global bioterrorism. We therefore developed recombinant VV (rVV) vaccines that are significantly attenuated and yet elicit potent humoral and cell-mediated immune responses. B13R (SPI-2) and B22R (SPI-1) are two VV immunomodulating genes with sequence homology to serine protease inhibitors (serpins) that possess antiapoptotic and anti-inflammatory properties. We constructed and characterized rVVs that have the B13R or B22R gene insertionally inactivated (vDeltaB13R and vDeltaB22R) and coexpress the vesicular stomatitis virus glycoprotein (v50DeltaB13R and v50DeltaB22R). Virulence studies with immunocompromised BALB/cBy nude mice indicated that B13R or B22R gene deletion decreases viral replication and significantly extends time of survival. Viral pathogenesis studies in immunocompetent CB6F(1) mice further demonstrated that B13R or B22R gene inactivation diminishes VV virulence, as measured by decreased levels of weight loss and limited viral spread. Finally, rVVs with B13R and B22R deleted elicited potent humoral, T-helper, and cytotoxic T-cell immune responses, revealing that the observed attenuation did not reduce immunogenicity. Therefore, inactivation of immunomodulating genes such as B13R or B22R represents a general method for enhancing the safety of rVV vaccines while maintaining a high level of immunogenicity. Such rVVs could serve as effective vectors for vaccine development and immunotherapy.

Animals↗

PubMed2004

Cells expressing the RING finger Z protein are resistant to arenavirus infection.

Arenaviruses include Lassa fever virus (LFV) and the South American hemorrhagic fever viruses. These viruses cause severe human disease, and they pose a threat as agents of bioterrorism. Arenaviruses are enveloped viruses with a bisegmented negative-strand RNA genome whose proteomic capability is limited to four polypeptides: nucleoprotein (NP); surface glycoprotein (GP), which is proteolytically processed into GP1 and GP2; polymerase (L); and a small (11-kDa) RING finger protein (Z). Our investigators have previously shown that Z has a strong inhibitory activity on RNA synthesis mediated by the polymerase of the prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV). In this report we show that cells transduced with a replication-deficient recombinant adenovirus expressing Z (rAd-Z) are resistant to LCMV and LFV infection. Virus cell entry mediated by LCMV or LFV GP was not affected in rAd-Z-transduced cells, but both virus transcription and replication were strongly and specifically inhibited, which resulted in a dramatic reduction in production of infectious virus. These findings open new avenues for developing antiviral strategies to combat the highly pathogenic human arenaviruses, including LFV.

Adenoviridae↗

PubMed2004

Smallpox DNA vaccine protects nonhuman primates against lethal monkeypox.

Two decades after a worldwide vaccination campaign was used to successfully eradicate naturally occurring smallpox, the threat of bioterrorism has led to renewed vaccination programs. In addition, sporadic outbreaks of human monkeypox in Africa and a recent outbreak of human monkeypox in the U.S. have made it clear that naturally occurring zoonotic orthopoxvirus diseases remain a public health concern. Much of the threat posed by orthopoxviruses could be eliminated by vaccination; however, because the smallpox vaccine is a live orthopoxvirus vaccine (vaccinia virus) administered to the skin, the vaccine itself can pose a serious health risk. Here, we demonstrate that rhesus macaques vaccinated with a DNA vaccine consisting of four vaccinia virus genes (L1R, A27L, A33R, and B5R) were protected from severe disease after an otherwise lethal challenge with monkeypox virus. Animals vaccinated with a single gene (L1R) which encodes a target of neutralizing antibodies developed severe disease but survived. This is the first demonstration that a subunit vaccine approach to smallpox-monkeypox immunization is feasible.

Animals↗

PubMed2005

T-bet is required for protection against vaccinia virus infection.

The transcription factor T-bet regulates the differentiation of CD4(+) T-helper type 1 (Th1) cells and represses Th2 lineage commitment. Since Th1 cells are crucial in the defense against pathogens, several studies addressed the role of T-bet in immunity to infection using T-bet knockout (T-bet(-/-)) mice. Nevertheless, it is still unclear whether T-bet is required for defense. Although vaccinia virus (VV) has extensively been used as an expression vector and the smallpox vaccine, there is only limited knowledge about immunity to VV infection. The urgency to understand the immune responses has been increased because of concerns about bioterrorism. Here, we show that T-bet is critical in the defense against VV infection as follows: (i) the survival rate of T-bet(-/-) mice was lower than that of control littermates postinfection; (ii) T-bet(-/-) mice lost more weight postinfection; and (iii) control mice cleared VV faster than T-bet(-/-) mice. As expected, a significant Th2 shift was observed in CD4(+) T cells of T-bet(-/-) mice. Furthermore, absence of T-bet impaired VV-specific CD8(+) cytotoxic T-lymphocyte (CTL) function, including cytolytic activity, antiviral cytokine production, and proliferation. Cytolytic capacity of natural killer (NK) cells was also diminished in T-bet(-/-) mice, whereas anti-VV antibody production was not impaired. These data reveal that the enhanced susceptibility to VV infection in T-bet(-/-) mice was at least partially due to the Th2 shift of CD4(+) T cells and the diminished function of VV-specific CTLs and NK cells but not due to downregulation of antibody production.

Animals↗

PubMed2005

Emerging zoonotic epidemics in the interconnected global community.

The rate at which epidemics of zoonotic disease in humans have surfaced over the past 25 years has shaken--some would say shattered--the assumption that zoonotic diseases are under control, says Paul Gibbs. In this review he analyses the global factors that have led to the increased emergence of zoonotic diseases, sketches several recent epidemics (and where relevant, their relationship to bioterrorism), discusses the lessons learned, and concludes by outlining an agenda for action.

Animals↗

PubMed2006

Francisella tularensis: taxonomy, genetics, and Immunopathogenesis of a potential agent of biowarfare.

Tularemia is a zoonosis of humans caused by infection with the facultative intracellular bacterium Francisella tularensis. Interest in F. tularensis has increased markedly in the past few years because of its potential use as an agent of bioterrorism. Five subspecies of this organism are found in the Northern hemisphere, but only F. tularensis subsp. tularensis and subsp. holarctica cause disease in humans. This review summarizes what is known about the pathogenesis of tularemia with a focus on bacterial surface components such as lipopolysaccharide and capsule as well as information obtained from the F. tularensis subsp. tularensis SCHU S4 genome. In particular, the mechanisms of action of recently identified virulence factors are discussed in the context of bacterial replication in macrophages and manipulation of the host inflammatory response. Throughout this report, shared and unique features of F. tularensis subsp. tularensis, subsp. holarctica, and subsp. novicida are discussed.

Animals↗

PubMed2005

The public health infrastructure and our nation's health.

Threats to Americans' health-including chronic disease, emerging infectious disease, and bioterrorism-are present and growing, and the public health system is responsible for addressing these challenges. Public health systems in the United States are built on an infrastructure of workforce, information systems, and organizational capacity; in each of these areas, however, serious deficits have been well documented. Here we draw on two 2003 Institute of Medicine reports and present evidence for current threats and the weakness of our public health infrastructure. We describe major initiatives to systematically assess, invest in, rebuild, and evaluate workforce competency, information systems, and organizational capacity through public policy making, practical initiatives, and practice-oriented research. These initiatives are based on applied science and a shared federal-state approach to public accountability. We conclude that a newly strengthened public health infrastructure must be sustained in the future through a balancing of the values inherent in the federal system.

Accreditation↗

PubMed2002

Bioethics after the terror.

Bioethics as a field has been fortunate that its values and concerns have mirrored the values and concerns of society. In light of the September 11th attacks, it is possible that we are witnessing the beginning of a transition in American culture, one fraught with implications for bioethics. The emphasis on autonomy and individual rights may come to be tempered by greater concern over the collective good. Increased emphasis on solidarity over autonomy could greatly alter public response to research abuses aimed at defense from bioterrorism, to privacy of genetic information, and to control of private medical resources to protect the public health.

Bioethics↗

PubMed2005

Host-based antipoxvirus therapeutic strategies: turning the tables.

The potential threat of the smallpox virus as a bioterror weapon has long been recognized, and the need for developing suitable countermeasures has become especially acute following the events of September 2001. Traditional antiviral agents interfere with viral proteins or functions. In a new study, Yang et al. focus instead on host cellular pathways used by the virus. A drug that interferes with the cellular ErbB-1 signal transduction pathway, activated by smallpox growth factor, sheds new light on how the virus replicates in the cell. Drugs that target the ErbB-signaling pathways represent a promising new class of antiviral agents.

Biological Warfare↗

PubMed2002

New millennium antivirals against pandemic and epidemic influenza: the neuraminidase inhibitors.

The mushroom shaped outer spike protein of influenza, neuraminidase, was first discovered nearly 60 years ago. Its importance in viral replication was soon recognised both at the point of viral release from the cell and also enabling passage of virus through nasal fluid to reach the cell. The enzyme active site was identified by x-ray crystallography, allowing an atomic study of interaction of enzyme with the sialic acid substrate. Analogues could then be identified and synthesized and became a focused target for antivirals. With the current threat of bioterrorism and the potential for the emergence of a new pandemic strain in the near future, efforts are underway to develop more potent second-generation anti-neuraminidase inhibitors with enhanced protective and therapeutic effects. Here we review older and newer neuraminidase inhibitors and the role that they will play in the fight against influenza in its epidemic and pandemic face.

Animals↗

PubMed2004

Challenges for the development of ribonucleoside analogues as inducers of error catastrophe.

RNA viruses are responsible for numerous human diseases; some of these viruses are also potential agents of bioterrorism. In general, the replication of RNA viruses results in the incorporation of at least one mutation per round of replication, leading to a heterogeneous population, termed a quasispecies. The antiviral nucleoside ribavirin has been shown to cause an increase in the mutation frequency of RNA viruses. This increase in mutation frequency leads to a loss of viability due to error catastrophe. In this article, we review lethal mutagenesis as an antiviral strategy, emphasizing the challenges remaining for the development of lethal mutagenesis into a practical clinical approach.

Animals↗

PubMed2002

Changing emphases in public health and medical education in health care reform.

Globalisation of economies, diseases and disasters with poverty, emerging infectious diseases, ageing and chronic conditions, violence and terrorism has begun to change the face of public health and medical education. Escalating costs of care and increasing poverty have brought urgency to professional training to improve efficiency, cut costs and maintain gains in life expectancy and morbidity reduction. Technology, genetics research and designer drugs have dramatically changed medical practice. Creatively, educational institutions have adopted the use of: (1) New educational and communication technologies: internet and health informatics; (2) Problem based learning approaches; Integrated Practice and Theory Curricula; Research and Problem Solving methodologies and (3) Partnership and networking of institutions to synergise new trends (e.g. core competencies). Less desirably, changes are inadequate in key areas, e.g., Health Economics, Poverty and Health Development, Disaster Management & Bioterrorism and Ethics. Institutions have begun to adjust and develop new programs of study to meet challenges of emerging diseases, design methodologies to better understand complex social and economic determinants of disease, assess the effects of violence and address cost containment strategies in health. Besides redesigning instruction, professional schools need to conduct research to assess the impact of health reform. Such studies will serve as sentinels for the public's health, and provide key indicators for improvements in training, service provision and policy.

Asia↗

PubMed2002

Future health: coping with change.

WHO's Declaration of the "Health for All" (HFA) goal was pronounced in 1978 in Alma Ata, and it was planned that HFA would be achieved through primary health care programmes and approaches by 2000. However, it is now 2002 and despite the technological advancements in medicine, science, and ICT, Health for All is far from reality. Instead, more and more conflicts are emerging with lethal consequences, such as, bioterrorism, biological agent abuse, global-terrorism, and environmental destruction is occurring at a greater scale that we have witnessed before. We may have the latest technology and knowledge today, but ironically, we are using them to inflict more suffering and pain in the world. In the Asia-Pacific, the past 30 years has seen dramatic advancement and lifestyle changes. We are now paying a high price for such progress in terms of risk factors to the health of the population, such as, ageing diseases, obesity, smoking, diabetes, hypertension, and related conditions. The social, political, economic and environmental factors appeared to have deterred and negated WHO's HFA goal to attain basic human rights and health care for all. The HFA will not be achieved in the future if we do not learn from history and start taking measures now.

Asia, Southeastern↗