Vaginal Microbicides: Detecting Toxicities in Vivo that Paradoxically Increase Pathogen Transmission

BACKGROUND: Microbicides must protect against STD pathogens without causing unacceptable toxic effects. Microbicides based on nonoxynol-9 (N9) and other detergents disrupt sperm, HSV and HIV membranes, and these agents are effective contraceptives. But paradoxically N9 fails to protect women against HIV and other STD pathogens, most likely because it causes toxic effects that increase susceptibility. The mouse HSV-2 vaginal transmission model reported here: (a) Directly tests for toxic effects that increase susceptibility to HSV-2, (b) Determines in vivo whether a microbicide can protect against HSV-2 transmission without causing toxicities that increase susceptibility, and (c) Identifies those toxic effects that best correlate with the increased HSV susceptibility. METHODS: Susceptibility was evaluated in progestin-treated mice by delivering a low-dose viral inoculum (0.1 ID50) at various times after delivering the candidate microbicide to detect whether the candidate increased the fraction of mice infected. Ten agents were tested – five detergents: nonionic (N9), cationic (benzalkonium chloride, BZK), anionic (sodium dodecylsulfate, SDS), the pair of detergents in C31G (C14AO and C16B); one surface active agent (chlorhexidine); two non-detergents (BufferGel®, and sulfonated polystyrene, SPS); and HEC placebo gel (hydroxyethylcellulose). Toxic effects were evaluated by histology, uptake of a 'dead cell' dye, colposcopy, enumeration of vaginal macrophages, and measurement of inflammatory cytokines. RESULTS: A single dose of N9 protected against HSV-2 for a few minutes but then rapidly increased susceptibility, which reached maximum at 12 hours. When applied at the minimal concentration needed for brief partial protection, all five detergents caused a subsequent increase in susceptibility at 12 hours of ~20–30-fold. Surprisingly, colposcopy failed to detect visible sign of the N9 toxic effect that increased susceptibility at 12 hours. Toxic effects that occurred contemporaneously with increased susceptibility were rapid exfoliation and re-growth of epithelial cell layers, entry of macrophages into the vaginal lumen, and release of one or more inflammatory cytokines (Il-1β, KC, MIP 1α, RANTES). The non-detergent microbicides and HEC placebo caused no significant increase in susceptibility or toxic effects. CONCLUSION: This mouse HSV-2 model provides a sensitive method to detect microbicide-induced toxicities that increase susceptibility to infection. In this model, there was no concentration at which detergents provided protection without significantly increasing susceptibility.JHU Woodrow Wilson Fellowship; National Institutes of Health (Program Project A1 45967

Education Program for Improved Water Quality in Copano Bay Final Report

The Copano Bay watershed covers approximately 1.4 million acres encompassing portions of Karnes, Bee, Goliad, Refugio, San Patricio and Aransas counties. Copano Bay and its main tributaries, the Mission and Aransas rivers, were placed on the Texas Commission on Environmental Quality (TCEQ) 303(d) list in 1998 due to levels of bacteria that exceed water quality standards established to protect oyster waters use. A Total Maximum Daily Load (TMDL) program was initiated in September 2003 to identify and assess sources of these bacteria. The Center for Research in Water Resources at the University of Texas at Austin (UT CRWR) was funded by TCEQ to conduct computer-based modeling to determine the bacterial loading and reductions necessary to attain water quality standards. Subsequently Texas A&M University-Corpus Christi (TAMU-CC) conducted bacterial source tracking (BST) with funding from Texas General Land Office (TGLO) and the Coastal Bend Bays and Estuaries Program (CBBEP) to determine actual sources of bacteria. Due to the findings of the initial efforts of the TMDL and concerns voiced by stakeholders in the watershed, Texas AgriLife Extension Service was awarded a Clean Water Act § 319(h) Nonpoint Source Grant from the Texas State Soil and Water Conservation Board (TSSWCB) and the U.S. Environmental Protection Agency. The overall goal of this project was to improve water quality in Copano Bay and its tributaries by increasing awareness of water quality issues throughout the watershed. This increased awareness was to be accomplished by providing education and demonstrations for land and livestock owners in the watershed on best management practices (BMPs) to decrease or prevent bacteria from entering waterways. Through creation of a project website, 52 educational programs, and nine one-on-one consultations over the span of the project, we have reached 5,408 residents in and around the Copano Bay watershed. Additionally, through this project all data collected for the initial TMDL efforts was re-evaluated and findings were presented in the “Task 2 Report.” Project members developed a curriculum for horse owners, “A Guide to Good Horsekeeping” that addressed BMPs specific to horse operations. Land and livestock owners who had already implemented BMPs or were interested in implementing BMPs were given a participation certificate

Cervicovaginal fluid and semen block the microbicidal activity of hydrogen peroxide produced by vaginal lactobacilli

BACKGROUND: H(2)O(2 )produced by vaginal lactobacilli is believed to protect against infection, and H(2)O(2)-producing lactobacilli inactivate pathogens in vitro in protein-free salt solution. However, cervicovaginal fluid (CVF) and semen have significant H(2)O(2)-blocking activity. METHODS: We measured the H(2)O(2 )concentration of CVF and the H(2)O(2)-blocking activity of CVF and semen using fluorescence and in vitro bacterial-exposure experiments. RESULTS: The mean H(2)O(2 )measured in fully aerobic CVF was 23 ± 5 μM; however, 50 μM H(2)O(2 )in salt solution showed no in vitro inactivation of HSV-2, Neisseria gonorrhoeae, Hemophilus ducreyii, or any of six BV-associated bacteria. CVF reduced 1 mM added H(2)O(2 )to an undetectable level, while semen reduced 10 mM added H(2)O(2 )to undetectable. Moreover, the addition of just 1% CVF supernatant abolished in vitro pathogen-inactivation by H(2)O(2)-producing lactobacilli. CONCLUSIONS: Given the H(2)O(2)-blocking activity of CVF and semen, it is implausible that H(2)O(2)-production by vaginal lactobacilli is a significant mechanism of protection in vivo

Slug Testing in Wells With Finite-Thickness Skin

We present an analysis of the slug test in a well surrounded by an annulus of altered material, which is treated as a skin of finite thickness. By assuming the skin has a thickness, the storage capacity of the altered material is included in the analysis. The problem is solved in the Laplace domain. The solution is found in terms of well-bore storage and the thickness, hydraulic conductivity, and specific storage of the skin. Type curves are generated by numerical inversion of the Laplace transform solution. We find that standard methods of analysis, involving a skin of infinitesimal thickness, are adequate for open-well or drill-stem tests. However, for pressurized tests the response may differ markedly from standard slug-test solutions

Comparison of the collagen haemostat Sangustop(R) versus a carrier-bound fibrin sealant during liver resection; ESSCALIVER-study

Background: Haemostasis in liver surgery remains a challenge despite improved resection techniques. Oozing from blood vessels too small to be ligated necessitate a treatment with haemostats in order to prevent complications attributed to bleeding. There is good evidence from randomised trials for the efficacy of fibrin sealants, on their own or in combination with a carrier material. A new haemostatic device is Sangustop(R). It is a collagen based material without any coagulation factors. Pre-clinical data for Sangustop(R) showed superior haemostatic effect. This present study aims to show that in the clinical situation Sangustop(R) is not inferior to a carrier-bound fibrin sealant (Tachosil(R)) as a haemostatic treatment in hepatic resection. Methods: This is a multi-centre, patient-blinded, intra-operatively randomised controlled trial. A total of 126 patients planned for an elective liver resection will be enrolled in eight surgical centres. The primary objective of this study is to show the non-inferiority of Sangustop(R) versus a carrier-bound fibrin sealant (Tachosil(R)) in achieving haemostasis after hepatic resection. The surgical intervention is standardised with regard to devices and techniques used for resection and primary haemostasis. Patients will be followed-up for three months for complications and adverse events. Discussion: This randomised controlled trial (ESSCALIVER) aims to compare the new collagen haemostat Sangustop(R) with a carrier-bound fibrin sealant which can be seen as a "gold standard" in hepatic and other visceral organ surgery. If non-inferiority is shown other criteria than the haemostatic efficacy (e.g. costs, adverse events rate) may be considered for the choice of the most appropriate treatment. Trial Registration: NCT0091861

Silylation of titanium-containing amorphous silica catalyst: effect on the alkenes epoxidation with H2O2

The surface of a Ti/SiO2 catalyst was silylated using hexamethyldisilazane (HMDS) and tetramethyldisilazane (TMDS) as silylating reagents in vapor phase. The silylation of silanol (Si–OH) on the catalysts was confirmed by diffuse reflectance UV-Vis, DRIFT spectroscopy and solid-state 29Si MAS NMR techniques. Silylation with TMDS improves the catalytic performance of Ti/SiO2 catalyst more significantly than with HMDS and this is mainly due to the steric bulk effects of trimethylsilyl groups from HMDS as compared to dimethylsilyl groups from TMDS. The silylation degree with TMDS was found to be higher than with HMDS and no changes in the silylation degree with TMDS was observed for silylation times longer than 2 h. Despite the silylation route employed, the silylated surface is hydrophobic which enhances not only in hydrogen peroxide efficiency but also and in selectivity to epoxide in the epoxidation of alkenes with H2O2. These effects are more evident when the hydrogen peroxide concentration is higher and particularly for the catalyst modified with TMDS.Peer reviewe

Effect of volcanic dykes on coastal groundwater flow and saltwater intrusion : a field-scale multiphysics approach and parameter evaluation

Acknowledgments This research was primarily based on research grant‐aided by the Irish Department of Communications, Energy and Natural Resources under the National Geoscience Programme 2007–2013. It also benefited from complementary funding from the Scottish Alliance for Geoscience, Environment and Society (SAGES). We acknowledge the contribution in data acquisition of the MSc students in Environmental Engineering at Queen's University Belfast, the landowner for access to the inland fields and the Department of Geography, Archaeology and Paleoecology at QUB for provision of the tidal model of Belfast Lough. The data used are listed in the references, tables, and figures and are available from the corresponding author upon demand. We acknowledge the constructive comments by the Associate Editor and three reviewers, which helped in improving the final manuscript.Peer reviewedPublisher PD