Laboratory-acquired infections due to a variety of bacteria, viruses, parasites, and fungi have been described over the last century, and laboratory workers are at risk of exposure to these ...infectious agents. However, reporting laboratory-associated infections has been largely voluntary, and there is no way to determine the real number of people involved or to know the precise risks for workers. In this study, an international survey based on volunteering was conducted in biosafety level 3 and 4 laboratories to determine the number of laboratory-acquired infections and the possible underlying causes of these contaminations. The analysis of the survey reveals that laboratory-acquired infections have been infrequent and even rare in recent years, and human errors represent a very high percentage of the cases. Today, most risks from biological hazards can be reduced through the use of appropriate procedures and techniques, containment devices and facilities, and the training of personnel.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Research on highly pathogenic microorganisms in biosafety level 3 and 4 laboratories is very important for human public health, as it provides opportunities for the development of vaccines and novel ...therapeutics as well as diagnostic methods to prevent epidemics. However, in recent years, after the anthrax and World Trade Center attacks in 2001 in the USA, the threat of bioterrorism has grown for both the public and the authorities. As a result, technical and physical containment measures and biosafety and biosecurity practices have been implemented in laboratories handling these dangerous pathogens. Working with selected biological agents and toxins is now highly regulated, owing to their potential to pose a threat to public health and safety, despite the fact that the anthrax attack was found to be the result of a lack of security at a US Army laboratory. Thus, these added regulations have been associated with a large amount of fruitless investment. Herein, we describe the limitations of research in these facilities, and the multiple consequences of the increased regulations. These limitations have seriously negatively impacted on the number of collaborations, the size of research projects, and, more generally, scientific research on microbial pathogens. Clearly, the actual number of known victims and fatalities caused by the intentional use of microorganisms has been negligible as compared with those caused by naturally acquired human infections.
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BFBNIB, DOBA, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UKNU, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
French military surveillance identified an increase in Plasmodium ovale attacks among soldiers in Ivory Coast. This emergence and the low sensitivity of biological tests raise the question of a ...possible role of P. ovale variant species.
Epidemiological data about P. ovale attacks from 1993 to 2012 were studied; the species diagnosis was based on a thin blood smear and/or a quick diagnostic test. Clinical and biological features in soldiers hospitalized in 2 French military hospitals were also reviewed. Malaria polymerase chain reaction followed by genotyping was performed when available.
French military physicians declared 328 P. ovale attacks over the 20-year study. A peak of incidence occurred in 2005. Among patients with positive blood smears, the quick diagnostic test was positive in 33 of 101 tests performed. The hospital study showed that symptoms and biological changes were not specific, which made diagnosis challenging: fever, anemia, and thrombocytopenia were not present in 20%, 71%, and 23% of the 45 confirmed cases, respectively. It was possible to perform molecular investigations on 19 clinical isolates: 18 were classic haplotypes with additional polymorphism and 1 was variant.
This emergence of P. ovale malaria enabled a good description to be made in nonimmune patients. The lack of sensitivity of both clinical features and quick diagnostic tests suggests an underestimation. Reasons for this outbreak are especially intense exposure to the vectors and the insufficient efficacy of doxycycline against P. ovale. The polymorphism of classic haplotypes of P. ovale rather than variant forms could be involved.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Control of the energetics and specificity of DNA binding polyamides is necessary for inhibition of protein-DNA complex formation and gene regulation studies. Typically, solid-phase methods using Boc ...monomers for synthesis have depended on Boc-beta-Ala-PAM resin which affords a beta-alanine-Dp tail at the C-terminus, after cleavage with N,N-dimethylaminopropylamine (Dp). To address the energetic consequences of this tail for DNA minor groove binding, we describe an alternative solid phase method employing the Kaiser oxime resin which allows the synthesis of polyamides with incrementally shortened C-terminal tails. Polyamides without Dp and having methyl amide tails rather than beta-alanine show similar affinity relative to the standard beta-Dp tail. The truncated tail diminishes the A,T base pair energetic preference of the beta-Dp tail which will allow a greater variety of DNA sequences to be targeted by hairpin polyamides.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids are synthetic ligands that have an affinity and specificity for DNA comparable to those of many naturally occurring ...DNA binding proteins. A machine-assisted Fmoc solid phase synthesis of polyamides has been optimized to afford high stepwise coupling yields (>99%). Two monomer building blocks, Fmoc-Py acid and Fmoc-Im acid, were prepared in multigram scale. Cleavage by aminolysis followed by HPLC purification affords up to 200 mg quantities of polyamide with purities and yields greater than or equal to those reported using Boc chemistry. A broader set of reaction conditions will increase the number and complexity of minor groove binding polyamides which may be prepared and help ensure compatibility with many commercially available peptide synthesizers.
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IJS, KILJ, NUK, PNG, UL, UM
The objective of this study was to validate the use of pftetQ and pfmdt genes as molecular markers of decreased in vitro susceptibility to doxycycline in 113 Plasmodium falciparum isolates from ...Dakar, Senegal. The results show that copy numbers of pftetQ and pfmdt, estimated by TaqMan real-time PCR, are not significantly associated with reduced susceptibility to doxycycline in vitro; however, the number of samples with a high doxycycline IC50 was likely to be too low to derive statistically significant results. Thus, no definitive conclusions could be drawn. The markers should be further tested by analysing more isolates.
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BFBNIB, DOBA, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UKNU, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A prototype of a novel class of DNA alkylating agents, which combines the DNA crosslinking moiety chlorambucil (Chl) with a sequence‐selective hairpin pyrrole–imidazole polyamide ...ImPy‐β‐ImPy‐γ‐ImPy‐β‐Dp (polyamide 1), was evaluated for its ability to damage DNA and induce biological responses. Polyamide 1‐Chl conjugate (1‐Chl) alkylates and interstrand crosslinks DNA in cell‐free systems. The alkylation occurs predominantly at 5′‐AGCTGCA‐3′ sequence, which represents the polyamide binding site. Conjugate‐induced lesions were first detected on DNA treated for 1 h with 0.1 µM 1‐Chl, indicating that the conjugate is at least 100‐fold more potent than Chl. Prolonged incubation allowed for DNA damage detection even at 0.01 µM concentration. Treatment with 1‐Chl decreased DNA template activity in simian virus 40 (SV40) in vitro replication assays. 1‐Chl inhibited mammalian cell growth, genomic DNA replication and cell cycle progression, and arrested cells in the G2/M phase. Moreover, cellular effects were observed at 1‐Chl concentrations similar to those needed for DNA damage in cell‐free systems. Neither of the parent compounds, unconjugated Chl or polyamide 1, demonstrated any cellular activity in the same concentration range. The conjugate molecule 1‐Chl possesses the sequence‐selectivity of a polyamide and the enhanced DNA reactivity of Chl.
Rapid diagnostic tests (RDTs) are the best alternative for malaria diagnosis where a microscopic examination cannot be performed. We report here the first case of P. falciparum (false-negative) ...misdiagnosis in a soldier stationed in Uganda, associated with a reduced number of repeats in the P. falciparum histidine-rich protein 2 gene (pfhrp2). This gene was subsequently sequenced to determine the reason for the discordance between the RDT results and the later microscopic examination. Ten repeats of the type 2 motif AHHAHHAAD and four repeats of the type 7 motif AHHAAD were found. This isolate belongs to the group of non-sensitive parasites (<43 repeats) that are not detected by HRP2 RDTs. This inappropriate case management could have been fatal for the patient. This case confirms the problem of negative RDT results in isolated situations and of basing a therapeutic strategy on these negative results. Investigations should be conducted in Uganda and other areas of Africa to determine the presence and the geographical spread of parasites with pfhrp2 gene deletion to ensure the best performance of RDTs.
Abstract
Background/Introduction
Dysregulated inflammation following myocardial infarction (MI) can lead to maladaptive infarct healing, myocardial damage and heart failure. Formyl peptide receptor 2 ...(FPR2) plays an important role in the ligand-dependent regulation of inflammation resolution. Stimulation of resolution via FPR2 activation is hypothesized to preserve left ventricular (LV) structure-function relationships thereby preventing pathological cardiac remodeling, and heart failure.
Purpose
We evaluated a selective 4-phenylpyrrolidinone FPR2 agonist in rodent MI models by assessing the impact on LV and infarct scar remodeling and cardiac function.
Methods
The FPR2 agonist was evaluated in phagocytosis, chemotaxis and cytokine response assays. In vivo, following permanent occlusion of the left anterior descending (LAD) artery, C57BL/6 mice or Sprague-Dawley rats were treated with the FPR2 agonist or vehicle; PO gavage, QD. Treatment began 24 hours after occlusion (0.3 and 3 mg/kg) and continued for three days to assess early inflammation or four weeks to evaluate LV and infarct structure and function. Rats subjected to permanent MI were treated 48 hours after occlusion (0.01, 0.1. 1, 10 mg/kg) for six weeks to assess structure-function relationships. A parallel study in rats evaluated compound treatment (0.01, 0.1. 1, 10 mg/kg) following 60 minutes occlusion and reperfusion of the LAD artery.
Results
The FPR2 agonist enhanced cellular phagocytosis and chemotaxis, and stimulated IL-10 and MCP-1 gene expression in isolated human whole blood. In mice, FPR2 agonist treatment improved survival post MI, reduced LV chamber area and infarct size (26% and 55% vs. vehicle, respectively, P<0.05) and preserved infarct wall thickness (59% vs. vehicle, P<0.05). Treatment increased macrophage arginase 1 levels three days post-MI in the infarct border zone and CD206 levels in the whole heart, indicating a shift towards a pro-resolution phenotype. In rats, FPR2 agonist treatment preserved infarct wall thickness (maximal at 10 mg/kg, 96% vs. vehicle, P<0.05) and increased LV ejection fraction at all doses (+9% vs. vehicle, P<0.05). Following occlusion and reperfusion of the LAD artery, treatment preserved viable myocardium across the infarct wall at multiple doses (25–41%, P<0.05) resulting in increased ejection fraction (14% and 19% vs vehicle at 0.01 and 1 mg/kg, respectively, P<0.05).
Conclusion(s)
Improvements in cardiac structure-function versus vehicle treated animals support the concept that agonism of FPR2 improves post-MI wound healing, limiting adverse post-MI LV remodeling, thereby preserving cardiac function. These preclinical results suggest targeting FPR2 may present an innovative approach towards development of effective drug therapies to prevent heart failure post-MI.
Acknowledgement/Funding
Bristol-Myers Squibb Company
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