Evacuation and Sheltering of People with Medical Dependencies: Knowledge Gaps and Barriers to National Preparedness

This article appeared in Homeland Security Affairs (February 2013), v.9, article 2Emergency plans are mandated by a number of federal regulations, often with conflicting definitions, to incorporate people with medical dependencies. However targeted planning for this segment is presently hampered by substantial knowledge deficits defining this population and the potential resource requirements in a disaster. These gaps prevent the development of evidence-based best practices for locating, communicating with, transporting, sheltering, and ensuring the safe recovery of those with medical dependencies. The authors discuss the knowledge gaps in preparing for this population and propose solutions to fill these gaps in order to facilitate enhanced preparedness for people with medical dependencies

Survey of Cyanophages: A Study of the Bacteriophages associated with Pacific Northwest Cyanobacterial blooms

Cyanobacterial blooms are a growing concern in the Pacific Northwest because of their threat to watershed health and drinking water supplies. Bacteriophages are pathogens of bacteria and may contribute to the growth and decline of seasonal blooms. Bacteriophage S-CRM01, a lytic T4-type myophage, has been isolated from a freshwater strain of Synechococcus (Dreher et al., 2011). This phage was isolated from a cyanobacterial bloom of primarily toxic Microcystis aeruginosa, but an endemic Synechococcus lineage, that was a minor constituent of the bloom, is the actual host for this phage. This survey was conducted to assess the distribution of phage S-CRM01 in Oregon and Northern California in bodies of water with cyanobacterial blooms. On the basis of PCR identification of plaques on LC16 cyanobacteria plates, S-CRM01 was present across a length of about 250 km along the Klamath River valley, from the Williamson River Delta at the northern end of Upper Klamath Lake as far downstream as Seiad Valley in 2009. Although this phage has not been shown to infect toxic cyanobacteria, it is still valuable in the freshwater phage community where few genomes have been sequenced

Survey of Cyanophages: A Study of the Bacteriophages associated with Pacific

Cyanobacterial blooms are a growing concern in the Pacific Northwest because of their threat to watershed health and drinking water supplies. Bacteriophages are pathogens of bacteria and may contribute to the growth and decline of seasonal blooms. Bacteriophage S-CRM01, a lytic T4-type myophage, has been isolated from a freshwater strain of Synechococcus (Dreher et al., 2011). This phage was isolated from a cyanobacterial bloom of primarily toxic Microcystis aeruginosa, but an endemic Synechococcus lineage, that was a minor constituent of the bloom, is the actual host for this phage. This survey was conducted to assess the distribution of phage S-CRM01 in Oregon and Northern California in bodies of water with cyanobacterial blooms. On the basis of PCR identification of plaques on LC16 cyanobacteria plates, S-CRM01 was present across a length of about 250 km along the Klamath River valley, from the Williamson River Delta at the northern end of Upper Klamath Lake as far downstream as Seiad Valley in 2009. Although this phage has not been shown to infect toxic cyanobacteria, it is still valuable in the freshwater phage community where few genomes have been sequenced

Novel Endochin-Like Quinolones Exhibit Potent In Vitro Activity against Plasmodium knowlesi but Do Not Synergize with Proguanil.

Quinolones, such as the antimalarial atovaquone, are inhibitors of the malarial mitochondrial cytochrome bc1 complex, a target critical to the survival of both liver- and blood-stage parasites, making these drugs useful as both prophylaxis and treatment. Recently, several derivatives of endochin have been optimized to produce novel quinolones that are active in vitro and in animal models. While these quinolones exhibit potent ex vivo activity against Plasmodium falciparum and Plasmodium vivax, their activity against the zoonotic agent Plasmodium knowlesi is unknown. We screened several of these novel endochin-like quinolones (ELQs) for their activity against P. knowlesiin vitro and compared this with their activity against P. falciparum tested under identical conditions. We demonstrated that ELQs are potent against P. knowlesi (50% effective concentration, <117?nM) and equally effective against P. falciparum We then screened selected quinolones and partner drugs using a longer exposure (2.5 life cycles) and found that proguanil is 10-fold less potent against P. knowlesi than P. falciparum, while the quinolones demonstrate similar potency. Finally, we used isobologram analysis to compare combinations of the ELQs with either proguanil or atovaquone. We show that all quinolone combinations with proguanil are synergistic against P. falciparum However, against P. knowlesi, no evidence of synergy between proguanil and the quinolones was found. Importantly, the combination of the novel quinolone ELQ-300 with atovaquone was synergistic against both species. Our data identify potentially important species differences in proguanil susceptibility and in the interaction of proguanil with quinolones and support the ongoing development of novel quinolones as potent antimalarials that target multiple species

(E)-2-(4-Arylbut-1-en-3-yn-1-yl)chromones as synthons for the synthesis of xanthone-1,2,3-triazole dyads

Xanthone-1,2,3-triazole dyads have been synthesized by two different approaches, both starting from novel (E)-2-(4-arylbut-1-en-3-yn-1-yl)chromones, prepared through a base-catalyzed aldol reaction of 2-methylchromone and arylpropargyl aldehydes. In the first method, the xanthone moiety is built by Diels-Alder reaction of the referred unsaturated chromones with N-methylmaleimide under microwave irradiation, followed by oxidation of the obtained adducts with DDQ, whereas the 1,2,3-triazole ring results from the cycloaddition reaction of the acetylene moiety with sodium azide. The second strategy first involves the cycloaddition reaction with sodium azide to provide the 1,2,3-triazole ring, followed by methylation of the triazole NH group prior to Diels-Alder reaction with N-methylmaleimide. The last step in this synthesis of novel xanthone-1,2,3-triazole dyads entails oxidation of the cycloadducts with DDQ

Mathematical modelling of polyamine metabolism in bloodstream-form trypanosoma brucei: An application to drug target identification

© 2013 Gu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis article has been made available through the Brunel Open Access Publishing Fund.We present the first computational kinetic model of polyamine metabolism in bloodstream-form Trypanosoma brucei, the causative agent of human African trypanosomiasis. We systematically extracted the polyamine pathway from the complete metabolic network while still maintaining the predictive capability of the pathway. The kinetic model is constructed on the basis of information gleaned from the experimental biology literature and defined as a set of ordinary differential equations. We applied Michaelis-Menten kinetics featuring regulatory factors to describe enzymatic activities that are well defined. Uncharacterised enzyme kinetics were approximated and justified with available physiological properties of the system. Optimisation-based dynamic simulations were performed to train the model with experimental data and inconsistent predictions prompted an iterative procedure of model refinement. Good agreement between simulation results and measured data reported in various experimental conditions shows that the model has good applicability in spite of there being gaps in the required data. With this kinetic model, the relative importance of the individual pathway enzymes was assessed. We observed that, at low-to-moderate levels of inhibition, enzymes catalysing reactions of de novo AdoMet (MAT) and ornithine production (OrnPt) have more efficient inhibitory effect on total trypanothione content in comparison to other enzymes in the pathway. In our model, prozyme and TSHSyn (the production catalyst of total trypanothione) were also found to exhibit potent control on total trypanothione content but only when they were strongly inhibited. Different chemotherapeutic strategies against T. brucei were investigated using this model and interruption of polyamine synthesis via joint inhibition of MAT or OrnPt together with other polyamine enzymes was identified as an optimal therapeutic strategy.The work was carried out under a PhD programme partly funded by Prof. Ray Welland, School of Computing Science, University of Glasgo

Comparative efficacy of buparvaquone and imidocarb in inhibiting the in vitro growth of Babesia bovis

Introduction:B. bovis is an apicomplexan parasite responsible for bovine babesiosis, a tick-borne disease with a worldwide impact. The disease remains inefficiently controlled, and few effective drugs, including imidocarb dipropionate (ID), are currently available in endemic areas. The objective of this study was to evaluate whether buparvaquone (BPQ), a drug currently used to treat cattle infected with the Babesia-related Theileria spp. parasites, could be active against Babesia parasites. Herein, we compared the effect of ID and BPQ on B. bovis growth in vitro erythrocyte culture.Methods:We compared the effect of ID and BPQ on the culture-adapted Texas T2Bo strain of B. bovis. In vitro cultured parasites were incubated with ID and BPQ at two starting parasitemia levels (PPE), 0.2% and 1%. In vitro cultured parasites were treated with ID or BPQ at concentrations ranging from 10 to 300 nM, during 4 consecutive days. Parasitemia levels were daily evaluated using microscopic examination. Data was compared using the independent Student’s t-test.Results and discussion:Both ID and BPQ significantly inhibited (p &lt; 0.05) the growth of B. bovis, regardless of the initial parasitemia used. At 1% parasitemia, BPQ had lower calculated inhibitory concentration 50 (IC50: 50.01) values than ID (IC50: 117.3). No parasites were found in wells with 0.2% starting parasitemia, treated previously with 50 nM of BPQ or ID, after 2 days of culture without drugs. At 1% parasitemia, no parasite survival was detected at 150 nM of BPQ or 300 nM of ID, suggesting that both drugs acted as babesiacidals.Conclusion:Overall, the data suggests that BPQ is effective against B. bovis and shows a residual effect that seems superior to ID, which is currently the first-line drug for treating bovine babesiosis globally

Endochin-Like Quinolones Exhibit Promising Efficacy Against Neospora Caninum in vitro and in Experimentally Infected Pregnant Mice

We report on the efficacy of selected endochin-like quinolones (ELQs) against N. caninum tachyzoites grown in human foreskin fibroblasts (HFF), and in a pregnant BALB/c mouse model. Fourteen ELQs were screened against transgenic N. caninum tachyzoites expressing β-galactosidase (Nc-βgal). Drugs were added concomitantly to infection and the values for 50% proliferation inhibition (IC50) were determined after 3 days. Three compounds exhibited IC50 values below 0.1 nM, 3 ELQs had IC50s between 0.1 and 1 nM, for 7 compounds values between 1 and 10 nM were noted, and one compound had an IC50 of 22.4 nM. Two compounds, namely ELQ-316 and its prodrug ELQ-334 with IC50s of 0.66 and 3.33 nM, respectively, were previously shown to display promising activities against experimental toxoplasmosis and babesiosis caused by Babesia microti in mice, and were thus further studied. They were assessed in long-term treatment assays by exposure of infected HFF to ELQs at 0.5 μM concentration, starting 3 h after infection and lasting for up to 17 days followed by release of drug pressure. Results showed that the compounds substantially delayed parasite proliferation, but did not exert parasiticidal activities. TEM of drug treated parasites detected distinct alterations within the parasite mitochondria, but not in other parasite organelles. Assessment of safety of ELQ-334 in the pregnant mouse model showed that the compound did not interfere in fertility or pregnancy outcome. In N. caninum infected pregnant mice treated with ELQ-334 at 10 mg/kg/day for 5 days, neonatal mortality (within 2 days post partum) was found in 7 of 44 pups (15.9%), but no postnatal mortality was noted, and vertical transmission was reduced by 49% compared to the placebo group, which exhibited 100% vertical transmission, neonatal mortality in 15 of 34 pups (44%), and postnatal mortality for 18 of the residual 19 pups during the 4 weeks follow-up. These findings encourage more research on the use of ELQs for therapeutic options against N. caninum infection

Methylthioadenosine reverses brain autoimmune disease

OBJECTIVE: To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune encephalomyelitis (EAE) and in patients with multiple sclerosis. METHODS: We studied the effect of intraperitoneal MTA in the acute and chronic EAE model by quantifying clinical and histological scores and by performing immunohistochemistry stains of the brain. We studied the immunomodulatory effect of MTA in lymphocytes from EAE animals and in peripheral blood mononuclear cells from healthy control subjects and multiple sclerosis patients by assessing cell proliferation and cytokine gene expression, by real-time polymerase chain reaction, and by nuclear factor-kappaB modulation by Western blot. RESULTS: We found that MTA prevents acute EAE and, more importantly, reverses chronic-relapsing EAE. MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T-cell activation in vivo and in vitro, likely through a blockade in T-cell signaling resulting in the prevention of inhibitor of kappa B (IkappaB-alpha) degradation and in the impaired activation transcription factor nuclear factor-kappaB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10). INTERPRETATION: MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases