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

Isentropic Curves at Magnetic Phase Transitions

Experiments on cold atom systems in which a lattice potential is ramped up on a confined cloud have raised intriguing questions about how the temperature varies along isentropic curves, and how these curves intersect features in the phase diagram. In this paper, we study the isentropic curves of two models of magnetic phase transitions- the classical Blume-Capel Model (BCM) and the Fermi Hubbard Model (FHM). Both Mean Field Theory (MFT) and Monte Carlo (MC) methods are used. The isentropic curves of the BCM generally run parallel to the phase boundary in the Ising regime of low vacancy density, but intersect the phase boundary when the magnetic transition is mainly driven by a proliferation of vacancies. Adiabatic heating occurs in moving away from the phase boundary. The isentropes of the half-filled FHM have a relatively simple structure, running parallel to the temperature axis in the paramagnetic phase, and then curving upwards as the antiferromagnetic transition occurs. However, in the doped case, where two magnetic phase boundaries are crossed, the isentrope topology is considerably more complex

Using monoclonal antibodies to prevent mucosal transmission of epidemic infectious diseases.

Passive immunization with antibodies has been shown to prevent a wide variety of diseases. Recent advances in monoclonal antibody technology are enabling the development of new methods for passive immunization of mucosal surfaces. Human monoclonal antibodies, produced rapidly, inexpensively, and in large quantities, may help prevent respiratory, diarrheal, and sexually transmitted diseases on a public health scale

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

Optical Spectroscopy and Decoherence Studies of Yb3+:YAG at 968 nm

The F7/22↔F5/22 optical transitions of Yb3+ doped into Y3Al5O12 (YAG) were studied for potential quantum information and photonic signal processing applications. Absorption and fluorescence spectroscopy located the energy levels of the ground F7/22 and excited F5/22 manifolds, allowing inconsistencies between previous assignments of crystal field splittings in the literature to be resolved. These measurements reveal an unusually large splitting between the first and second levels in both the ground and excited multiplets, potentially providing for reduced sensitivity to thermally induced decoherence and spin-lattice relaxation. Spectral hole burning through two-level saturation was observed, determining the excited state lifetime to be 860 μs and resolving ambiguities in previous fluorescence measurements that were caused by the large radiation trapping effects in this material. Optical decoherence measurements using two-pulse photon echoes gave a homogeneous linewidth of 18 kHz for an applied magnetic field of 1 T, narrowing to 5 kHz at 2.5 T. The observed decoherence was described by spectral diffusion attributed to Yb3+−Yb3+ magnetic dipole interactions. Laser absorption determined an inhomogeneous linewidth of 3.6 GHz for this transition in this 0.05%-doped crystal, which is narrower than for any other rare-earth-ion transition previously studied in the YAG host. The temperature dependence of the transition energy and linewidth of the lowest F7/22 to lowest F5/22 transition centered at 968.571 nm measured from 4 K to 300 K was well described by phonon scattering at higher temperatures, with an additional anomalous linear temperature-dependent broadening at temperatures below 80 K. Two magnetically inequivalent subgroups of Yb3+ ions were identified when a magnetic field was applied along the ⟨111⟩ axis, as expected for the D2 sites in the cubic symmetry crystal, with ground and excited state effective g-values of gg=3.40 (3.34) and ge=1.04 (2.01), respectively. Together with the convenient diode laser wavelength of this transition, our study suggests that Yb3+:YAG is a promising material system for spectral hole burning and quantum information applications

Optical Spectroscopy and Decoherence Studies of Yb3+:YAG at 968 nm

The F7/22↔F5/22 optical transitions of Yb3+ doped into Y3Al5O12 (YAG) were studied for potential quantum information and photonic signal processing applications. Absorption and fluorescence spectroscopy located the energy levels of the ground F7/22 and excited F5/22 manifolds, allowing inconsistencies between previous assignments of crystal field splittings in the literature to be resolved. These measurements reveal an unusually large splitting between the first and second levels in both the ground and excited multiplets, potentially providing for reduced sensitivity to thermally induced decoherence and spin-lattice relaxation. Spectral hole burning through two-level saturation was observed, determining the excited state lifetime to be 860 μs and resolving ambiguities in previous fluorescence measurements that were caused by the large radiation trapping effects in this material. Optical decoherence measurements using two-pulse photon echoes gave a homogeneous linewidth of 18 kHz for an applied magnetic field of 1 T, narrowing to 5 kHz at 2.5 T. The observed decoherence was described by spectral diffusion attributed to Yb3+−Yb3+ magnetic dipole interactions. Laser absorption determined an inhomogeneous linewidth of 3.6 GHz for this transition in this 0.05%-doped crystal, which is narrower than for any other rare-earth-ion transition previously studied in the YAG host. The temperature dependence of the transition energy and linewidth of the lowest F7/22 to lowest F5/22 transition centered at 968.571 nm measured from 4 K to 300 K was well described by phonon scattering at higher temperatures, with an additional anomalous linear temperature-dependent broadening at temperatures below 80 K. Two magnetically inequivalent subgroups of Yb3+ ions were identified when a magnetic field was applied along the ⟨111⟩ axis, as expected for the D2 sites in the cubic symmetry crystal, with ground and excited state effective g-values of gg=3.40 (3.34) and ge=1.04 (2.01), respectively. Together with the convenient diode laser wavelength of this transition, our study suggests that Yb3+:YAG is a promising material system for spectral hole burning and quantum information applications

Narrow inhomogeneous and homogeneous optical linewidths in a rare earth doped transparent ceramic

Inhomogeneous and homogeneous linewidth are reported in a Eu3+ doped transparent Y2O3 ceramic for the 7F 0-5D0 transition, using high-resolution coherent spectroscopy. The 8.7-GHz inhomogeneous linewidth is close to that of single crystals, as is the 59-kHz homogeneous linewidth at 3 K (T2 = 5.4 μs). The homogeneous linewidth exhibits a temperature dependence that is typical of a crystalline environment, and additional dephasing observed in the ceramic is attributed to magnetic impurities or defects introduced during the synthesis process. The absence of Eu3+segregation at the grain boundaries, evidenced through confocal microfluorescence, further indicates that the majority of Eu3+ions in the ceramic experience an environment comparable to a single crystal. The obtained results suggest that ceramic materials can be competitive with single crystals for applications in quantum information and spectral hole burning devices, beyond their current applications in lasers and scintillatorsThis work was supported by National Science Foundation under award No. PHY-1212462, the European Union FP7 project QuRep (247743), the Spanish Ministry of Economy and Competitiveness (MAT2010-17443) and Comunidad de Madrid (S-2009/MAT-1756

Asthma among Staten Island fresh kills landfill and barge workers following the September 11, 2001 World Trade Center terrorist attacks

Background: Although airborne respiratory irritants at the World Trade Center (WTC) site have been associated with asthma among WTC Ground Zero workers, little is known about asthma associated with work at the Staten Island landfill or barges. Methods: To evaluate the risk of asthma first diagnosed among Staten Island landfill and barge workers, we conducted a survey and multivariable logistic regression analysis regarding the association between Staten Island landfill and barge-related work exposures and the onset of post-9/11 asthma. Results: Asthma newly diagnosed between September 11, 2001 and December 31, 2004 was reported by 100/1,836 (5.4%) enrollees. Jobs involving sifting, digging, welding, and steel cutting, enrollees with high landfill/barge exposure index scores or who were police and sanitation workers, and enrollees with probable posttraumatic stress disorder all had increased odds ratios for new-onset asthma. Conclusions: Post-9/11 asthma cumulative incidence among Staten Island landfill/barge workers was similar to that of other WTC disaster rescue and recovery workers