Effect of Nonzero Solid Permittivity on the Electrical Repulsion between Charged Surfaces.

The electrical repulsion between two charged solid surfaces separated by an electrolyte is studied as a function of the permittivity ϵs of the solid in the limit in which potentials are small, and the gap between the plane solid surfaces is small compared to the Debye length κ-1 within the electrolyte. The solid surfaces are uniformly charged in a central region |x|< L outside which they are uncharged. When ϵs = 0, ions from the charge cloud between the charged surfaces spill out into regions of length O(κ-1) beyond x = ± L, thereby reducing the pressure between the surfaces from that predicted by Derjaguin-Landau-Verwey-Overbeek theory for infinite, uniformly charged surfaces. When ϵs>0, ions spill out over much larger O(L) regions, thereby reducing still further both the electrical potential between the solid surfaces and the repulsive force between them. However, this reduction becomes smaller as κL becomes large.

Cases of Eastern equine encephalitis in humans associated with Aedes canadensis, Coquillettidia perturbans and Culiseta melanura mosquitoes with the virus in New York State from 1971 to 2012 by analysis of aggregated published data.

From 1971 to 2012, in New York State, years with human Eastern equine encephalitis (EEE) were more strongly associated with the presence of Aedes canadensis, Coquillettidia perturbans and Culiseta melanura mosquitoes infected with the EEE virus (Fisher's exact test, one-sided P = 0.005, 0.03, 0.03) than with Culiseta morsitans, Aedes vexans, Culex pipiens-restuans, Anopheles quadrimaculatus or Anopheles punctipennis (P = 0.05, 0.40, 0.33, 1.00, 1.00). The estimated relative risk of a case in a year in which the virus was detected vs. not detected was 14.67 for Ae. canadensis, 6.38 for Cq. perturbans and 5.50 for Cs. morsitans. In all 5 years with a case, Cs. melanura with the virus was detected. In no year was there a case in the absence of Cs. melanura with the virus. There were 18 years with no case in the presence of Cs. melanura with the virus. Such observations may identify the time of increased risk, and when the methods may be used to prevent or reduce exposure to vector mosquito species in this geographic region.

Incarcerated aboriginal women's experiences of accessing healthcare and the limitations of the 'equal treatment' principle.

BACKGROUND: Colonization continues in Australia, sustained through institutional and systemic racism. Targeted discrimination and intergenerational trauma have undermined the health and wellbeing of Australia's Aboriginal and Torres Strait Islander population, leading to significantly poorer health status, social impoverishment and inequity resulting in the over-representation of Aboriginal people in Australian prisons. Despite adoption of the 'equal treatment' principle, on entering prison in Australia entitlements to the national universal healthcare system are revoked and Aboriginal people lose access to health services modelled on Aboriginal concepts of culturally safe healthcare available in the community. Incarcerated Aboriginal women experience poorer health outcomes than incarcerated non-Indigenous women and Aboriginal men, yet little is known about their experiences of accessing healthcare. We report the findings of the largest qualitative study with incarcerated Aboriginal women in New South Wales (NSW) Australia in over 15 years. METHODS: We employed a decolonizing research methodology, 'community collaborative participatory action research', involving consultation with Aboriginal communities prior to the study and establishment of a Project Advisory Group (PAG) of community expert Aboriginal women to guide the project. Forty-three semi-structured interviews were conducted in 2013 with Aboriginal women in urban and regional prisons in NSW. We applied a grounded theory approach for the data analysis with guidance from the PAG. RESULTS: Whilst Aboriginal women reported positive and negative experiences of prison healthcare, the custodial system created numerous barriers to accessing healthcare. Aboriginal women experienced institutional racism and discrimination in the form of not being listened to, stereotyping, and inequitable healthcare compared with non-Indigenous women in prison and the community. CONCLUSIONS: 'Equal treatment' is an inappropriate strategy for providing equitable healthcare, which is required because incarcerated Aboriginal women experience significantly poorer health. Taking a decolonizing approach, we unpack and demonstrate the systems level changes needed to make health and justice agencies culturally relevant and safe. This requires further acknowledgment of the oppressive transgenerational effects of ongoing colonial policy, a true embracing of diversity of worldviews, and critically the integration of Aboriginal concepts of health at all organizational levels to uphold Aboriginal women's rights to culturally safe healthcare in prison and the community.

Osteoarthritis year in review 2018: biology.

This Year in Review highlights a selection of articles published between the 2017 and 2018 Osteoarthritis Research Society International (OARSI) World Congress meetings within the field of osteoarthritis biology, presented at OARSI 2018. Selected articles were obtained from a PubMed search covering cartilage, subchondral bone, inflammation, ageing, pain and animal models. Studies focused on biomechanics, biomarkers, genetics and epigenetics, imaging and clinical studies were excluded due to their coverage in other articles within the OARSI Year in Review series. Significant themes including the role of progenitor cells in cartilage homeostasis and repair, novel signalling mechanisms controlling chondrocyte phenotypic stability and the influence of disrupted or senescent chondrocytes were identified and are discussed in this review. Overarching conclusions derived from these study areas indicate that promising avenues of intervention are on the horizon, however further understanding is required in order to target therapeutic treatments to suitable patient subgroups and disease stages.

Genetic and environmental factors influence Listeria monocytogenes nisin resistance.

AIMS: Listeria monocytogenes nisin resistance increases when first exposed to NaCl and other stresses, such as low pH. In addition to environmental stressors, specific genomic elements can confer nisin resistance, such as the stress survival islet (SSI-1). As SSI-1 is variably present among L. monocytogenes strains, we wanted to determine if SSI-1 was associated with salt-induced nisin resistance. METHODS AND RESULTS: The presence of SSI-1 was determined using PCR for 48 strains of L. monocytogenes. When combined with multilocus sequence typing data, we found that the distribution of SSI-1 is clonal, where strains from clonal complexes (CC) 2, 6 and 11 do not have SSI-1, while strains from CCs 3, 5, 7 and 9 contain SSI-1. The impact of SSI-1 on salt-induced nisin resistance was dependent on CC. The average log decrease after 24 h of exposure to nisin at 7°C under salt-inducing conditions was 2·6 ± 1·1 for CC 9 strains and 2·3 ± 0·7 for CC 11 strains, which had significantly lower survival compared to the other CCs, such as 1·3 ± 0·3 for CC 6. Deletion of SSI-1 from a CC 7 strain demonstrated the role SSI-1 plays in salt-induced nisin resistance, as the deletion mutant had lower resistance compared to the parent strain. CONCLUSIONS: These data suggest that inducible nisin resistance in L. monocytogenes can be influenced by environmental conditions as well as the genetic composition of the strain, which should be considered when selecting control measures for ready-to-eat foods. SIGNIFICANCE AND IMPACT OF THE STUDY: The foodborne pathogen L. monocytogenes can grow in suboptimal conditions, including low temperature and high osmolarity, which makes it a safety concern for ready-to-eat foods. When using antimicrobial peptide inhibitors such as nisin, it is important to understand how food components can impact antimicrobial resistance across the genetic diversity of L. monocytogenes.

Comparison of immunomagnetic separation beads for detection of six non-O157 Shiga toxin-producing Escherichia coli serogroups in different matrices.

Immunomagnetic separation used with culture based methods has been a useful technique in the detection of pathogens. However, previous studies have not answered many of the necessary questions for real world applications. The objective of this study was to assess the efficacy of different immunomagnetic separation (IMS) bead types in recovery of the correct serogroup from a mixture of big six non-O157 Shiga toxin-producing Escherichia coli strains. To determine the impact of different matrices on recovery, samples of sterile phosphate buffered saline (PBS), sterile and non-sterile cattle faeces, ground beef and lettuce were inoculated with 10 CFU per ml mixture of isolates representing the six serogroups. After a 6 h incubation at 37°C, samples were mixed with IMS beads from three different commercial sources and plated on eosin methylene blue agar (EMB). Three suspect E. coli colonies were selected from each EMB plate and multiplex polymerase chain reaction was used to determine the serogroup. The rate of correct identification varied with the serogroup, IMS bead manufacturer and matrix. Overall, recovery of the correct serogroup became less likely with increase in matrix complexity, with enrichments containing lettuce having the greatest number of bead types with significantly lower likelihood of correct recovery compared to recovery in PBS. SIGNIFICANCE AND IMPACT OF THE STUDY: The need to accurately and efficiently detect Shiga toxin-producing Escherichia coli (STEC) O26, O45, O103, O111, O121 and O145, which have caused outbreaks on numerous occasions, is a major public health and food safety concern in the United States. Detecting these STEC serogroups can be challenging because methods to detect non-O157 serogroups have not been refined as compared to those for O157. Immunomagnetic separation (IMS) has the potential to isolate STEC from a mixture in complex matrices. Our results highlight the need for optimization of IMS-based detection of STEC to effectively recover the targeted serogroup from a variety of sample matrices.

An assessment of the doses received by members of the public in Japan following the nuclear accident at Fukushima Daiichi nuclear power plant.

The earthquake and tsunami on 11 March 2011, centred off the east coast of Japan, caused considerable destruction and substantial loss of life along large swathes of the Japanese coastline. The tsunami damaged the Fukushima Daiichi nuclear power plant (NPP), resulting in prolonged releases of radioactive material into the environment. This paper assesses the doses received by members of the public in Japan. The assessment is based on an estimated source term and atmospheric dispersion modelling rather than monitoring data. It is evident from this assessment that across the majority of Japan the estimates of dose are very low, for example they are estimated to be less than the annual average dose from natural background radiation in Japan. Even in the regions local to Fukushima Daiichi NPP (and not affected by any form of evacuation) the maximum lifetime effective dose is estimated to be well below the cumulative natural background dose over the same period. The impact of the urgent countermeasures on the estimates of dose was considered. And the relative contribution to dose from the range of exposure pathways and radionuclides were evaluated. Analysis of estimated doses focused on the geographic irregularity and the impact of the meteorological conditions. For example the dose to an infant's thyroid received over the first year was estimated to be greater in Hirono than in the non-evacuated region of Naraha, despite Hirono being further from the release location. A number of factors were identified and thought to contribute towards this outcome, including the local wind pattern which resulted in the recirculation of part of the release. The non-uniform nature of dose estimates strengthens the case for evaluations based on dispersion modelling.

Electroosmosis in a finite cylindrical pore: simple models of end effects.

A theoretical model of electroosmosis through a circular pore of radius a that traverses a membrane of thickness h is investigated. Both the cylindrical surface of the pore and the outer surfaces of the membrane are charged. When h ≫ a, end effects are negligible, and the results of full numerical computations of electroosmosis in an infinite pore agree with theory. When h = 0, end effects dominate, and computations again agree with analysis. For intermediate values of h/a, an approximate analysis that combines these two limiting cases captures the main features of computational results when the Debye length κ(-1) is small compared with the pore radius a. However, the approximate analysis fails when κ(-1) ≫ a, when the charge cloud due to the charged cylindrical walls of the pore spills out of the ends of the pore, and the electroosmotic flow is reduced. When this spilling out is included in the analysis, agreement with computation is restored.

Decreased levels of nucleotide pyrophosphatase phosphodiesterase 1 are associated with cartilage calcification in osteoarthritis and trigger osteoarthritic changes in mice.

OBJECTIVE: To analyse the function of nucleotide pyrophosphatase phosphodiesterase (NPP1), a member of the pyrophosphate pathway, in osteoarthritis (OA). METHODS: mRNA expression of NPP1, ANK ankylosing protein and tissue non-specific alkaline phosphatase was assessed by quantitative PCR. NPP1 protein levels were analysed in mouse and human cartilage samples. Bone metabolism was analysed by F18-positron emission tomography-scanning and µCT in ttw/ttw mice. Ttw/ttw mice are mice carrying a loss-of-function mutation in NPP1. Calcification of articular cartilage was assessed using von Kossa staining and OA severity using the Mankin score. Cartilage remodelling was investigated by type X collagen immunohistochemistry. RESULTS: Expression of NPP1, but not the other members of this pathway, inversely correlated with cartilage calcification and OA severity in mouse and humans. Proinflammatory cytokines downregulated the expression of NPP1, demonstrating an influence of inflammation on matrix calcification. Ttw/ttw mutant mice, carrying a loss-of-function mutation in NPP1, exhibit increased bone formation process in joints compared with wild types. Ttw/ttw mice also developed spontaneous OA-like changes, evaluated by histological analysis and in vivo imaging. Ectopic calcifications were associated with increased expression of collagen X in the cartilage. CONCLUSION: The authors conclude that OA is characterised by the reactivation of molecular signalling cascades involving proinflammatory cytokines, thereby regulating the pyrophosphate pathway which consequently leads to cartilage ossification, at least in part resembling endochondral ossification.

Packing a flexible fiber into a cavity.

The insertion of an elastic rod or fiber into a confining cavity is studied. Such an insertion is a feature of a variety of problems, including packing and unpacking of DNA in viral capsids and the insertion of catheters during surgery. We consider a simplified geometry in which the container is a smooth (frictionless) circular cylinder of radius a. The fiber is pushed through a hole in the curved surface of the cylinder and is then assumed to stay in a cross-sectional plane perpendicular to the cylinder axis. A solution is found for the fiber shape in which most of the fiber lies against the curved interior surface of the cylinder, apart from the final end section of the fiber, of length 2.0888a, which crosses the interior of the cylinder before ending at the opposite side, which it meets at an angle 1.15 rad to the normal. The force required to push the fiber into the cylinder is EI/2a^{2}, where E is the fiber's Young's modulus and I its cross-sectional moment of inertia. The shape of the final end section of the fiber is confirmed by experiment.

Source attributed case-control study of campylobacteriosis in New Zealand.

BACKGROUND: Following an initial reduction in human campylobacteriosis in New Zealand after the implementation of poultry food chain-focused interventions during 2006-2008, further decline has been relatively small. We report a year-long study of notified campylobacteriosis cases, incorporating a case control study combined with a source attribution study. The purpose was to generate up-to-date evidence on the relative contributions of different sources of campylobacteriosis in New Zealand. METHODS: The study approach included: • A case-control study of notified cases (aged six months or more) sampled in a major urban centre (Auckland, every second case) and a mixed urban/rural area (Manawatu/Whanganui, every case), between 12 March 2018 and 11 March 2019. • Source attribution of human campylobacteriosis cases sampled from these two regions over the study period by modelling of multilocus sequence typing data of Campylobacter jejuni and C. coli isolates from faecal samples of notified human cases and relevant sources (poultry, cattle, sheep). RESULTS: Most cases (84%) were infected with strains attributed to a poultry source, while 14% were attributed to a cattle source. Approximately 90% of urban campylobacteriosis cases were attributed to poultry sources, compared to almost 75% of rural cases. Poultry consumption per se was not identified as a significant risk factor. However specific risk factors related to poultry meat preparation and consumption did result in statistically significantly elevated odds ratios. CONCLUSIONS: The overall findings combining source attribution and analysis of specific risk factors indicate that poultry meat remains a dominant pathway for exposure and infection.

Plant pathogen forensics: capabilities, needs, and recommendations.

A biological attack on U.S. crops, rangelands, or forests could reduce yield and quality, erode consumer confidence, affect economic health and the environment, and possibly impact human nutrition and international relations. Preparedness for a crop bioterror event requires a strong national security plan that includes steps for microbial forensics and criminal attribution. However, U.S. crop producers, consultants, and agricultural scientists have traditionally focused primarily on strategies for prevention and management of diseases introduced naturally or unintentionally rather than on responding appropriately to an intentional pathogen introduction. We assess currently available information, technologies, and resources that were developed originally to ensure plant health but also could be utilized for postintroduction plant pathogen forensics. Recommendations for prioritization of efforts and resource expenditures needed to enhance our plant pathogen forensics capabilities are presented.

Knob-positive and knob-negative Plasmodium falciparum differ in expression of a strain-specific malarial antigen on the surface of infected erythrocytes.

We have investigated the expression of a strain-specific malarial antigen on the surface of erythrocytes infected with knobless (K-) variants of knob-positive (K+) strains of Plasmodium falciparum. Aotus blood infected with K+ or K- parasites derived from two independent geographical isolates (Malayan camp and Santa Lucia) was surface iodinated by the lactoperoxidase method. Infected and uninfected erythrocytes were then separated by a new procedure involving equilibrium density sedimentation on a Percoll gradient containing sorbitol. Strain-specific antigens were readily identified on the surface of erythrocytes infected with either of the K+ strains by their characteristic size and detergent solubility. These proteins were not detected on the surface of erythrocytes infected with either of the K- variants nor on uninfected erythrocytes isolated from K+- or K- -infected blood. These results are consistent with a role for the strain-specific surface antigen in cytoadherence of P. falciparum-infected erythrocytes. Our findings represent the second biochemical difference (with the knob-associated histidine-rich protein) between K+ and K- P. falciparum.

Repeated therapeutic dosing selects macrolide-resistant Campylobacter spp. in a turkey facility.

AIMS: This study assessed the effects of the therapeutic use of Tylan® in a large-scale turkey production facility on the selection of macrolide-resistant Campylobacter. METHODS AND RESULTS: A flock of production turkeys (c. 30,000 birds) was followed from brooding to slaughter, and the effects of macrolide application was assessed in one half of the flock from finishing stage to final product and compared against the control barn where no macrolide was used. Overall, Campylobacter prevalence in turkeys was almost 100% by 4 weeks of age. When Campylobacter prevalence was assessed in relation to treatment, high levels of macrolide resistance were evident in this group following treatment, with Campylobacter coli becoming the dominant strain type. Over time, and in the absence of a selection agent, the population of resistant strains decreased suggesting that there was a fitness cost associated with macrolide resistance carriage and persistence. Macrolide resistance was detected in the control barn at a very low level (four isolates recovered during the study), suggesting that the creation or selection of macrolide-resistant Campylobacter was correlated with the treatment regime used. Molecular analysis of a selection of macrolide-resistant Campylobacter recovered was assessed using PCR, RFLP and sequence analysis of the 23S rRNA. The majority of isolates displaying high-level macrolide resistance (>256 µg ml(-1)) possessed an A2075G transition mutation in the 23S rRNA and the CmeABC efflux pump. CONCLUSIONS: These studies suggest that macrolide resistance can be promoted through the application of treatment during the grow-out phase and once established in a production facility has the potential to persist and be transferred to final product. SIGNIFICANCE AND IMPACT OF THE STUDY: The study highlights the prudent use of antimicrobials in treatment of disease in poultry. Of significance is the presence of macrolide-resistant Campylobacter in poultry production and finished product as a consequence of macrolide usage.

Platelet thrombospondin mediates attachment and spreading of human melanoma cells.

Human platelet thrombospondin adsorbed on plastic promotes attachment and spreading of human G361 melanoma cells. Attachment is rapid, and spreading is maximal by 90 min with 60-90% of the attached cells spread. In contrast, thrombospondin promotes attachment but not spreading of human C32 melanoma cells, which attach and spread only on laminin substrates. The specificity of these interactions and the regions of the thrombospondin molecule involved in attachment and spreading were examined using proteolytic fragments of thrombospondin and by inhibition studies. The sulfated fucan, fucoidan, and monoclonal antibody A2.5, which is directed against the heparin-binding domain of thrombospondin, selectively inhibit spreading but only weakly inhibit attachment. Monoclonal antibodies against some other domains of thrombospondin, however, are potent inhibitors of attachment. The amino-terminal heparin-binding domain of thrombospondin does not promote attachment. Large fragments lacking the heparin-binding domain support attachment but not spreading of G361 cells. Attachment activity is lost following removal of the 18-kD carboxyl-terminal domain. These results suggest that at least two melanoma ligands are involved in cell attachment and spreading on thrombospondin. The carboxyl-terminal region and perhaps other regions of the molecule bind to receptor(s) on the melanoma surface that promote initial attachment but not cell spreading. Interaction of the heparin-binding domain with sulfated glycoconjugates on melanoma surface proteoglycans and/or sulfated glycolipids mediates spreading. Monoclonal antibodies A2.5 and C6.7 also reverse spreading of G361 cells growing on glass culture substrates, suggesting that binding to thrombospondin mediates attachment of these melanoma cells in culture.

Transport of an Mr approximately 300,000 Plasmodium falciparum protein (Pf EMP 2) from the intraerythrocytic asexual parasite to the cytoplasmic face of the host cell membrane.

The profound changes in the morphology, antigenicity, and functional properties of the host erythrocyte membrane induced by intraerythrocytic parasites of the human malaria Plasmodium falciparum are poorly understood at the molecular level. We have used mouse mAbs to identify a very large malarial protein (Mr approximately 300,000) that is exported from the parasite and deposited on the cytoplasmic face of the erythrocyte membrane. This protein is denoted P. falciparum erythrocyte membrane protein 2 (Pf EMP 2). The mAbs did not react with the surface of intact infected erythrocytes, nor was Pf EMP 2 accessible to exogenous proteases or lactoperoxidase-catalyzed radioiodination of intact cells. The mAbs also had no effect on in vitro cytoadherence of infected cells to the C32 amelanotic melanoma cell line. These properties distinguish Pf EMP 2 from Pf EMP 1, the cell surface malarial protein of similar size that is associated with the cytoadherent property of P. falciparum-infected erythrocytes. The mAbs did not react with Pf EMP 1. In one strain of parasite there was a significant difference in relative mobility of the 125I-surface-labeled Pf EMP 1 and the biosynthetically labeled Pf EMP 2, further distinguishing these proteins. By cryo-thin-section immunoelectron microscopy we identified organelles involved in the transit of Pf EMP through the erythrocyte cytoplasm to the internal face of the erythrocyte membrane where the protein is associated with electron-dense material under knobs. These results show that the intraerythrocytic malaria parasite has evolved a novel system for transporting malarial proteins beyond its own plasma membrane, through a vacuolar membrane and the host erythrocyte cytoplasm to the erythrocyte membrane, where they become membrane bound and presumably alter the properties of this membrane to the parasite's advantage.

Development and validation of a hemangiosarcoma likelihood prediction model in dogs presenting with spontaneous hemoabdomen: The HeLP score.

OBJECTIVE: To calculate a risk prediction model for hemangiosarcoma (HSA) diagnosis in dogs presenting with nontraumatic hemoabdomen. DESIGN: Retrospective multicenter observational cohort study enrolling dogs presented 2003-2016. SETTING: Five academic veterinary medical centers. ANIMALS: A total of 406 dogs with nontraumatic hemoabdomen as the presenting complaint that underwent surgical exploration or necropsy and received a histological diagnosis. Overall, 219 dogs from 3 centers provided the data for model construction, and 187 dogs from 2 centers provided the population for external validation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The risk score was modeled on 4 predictors: bodyweight (P = 0.01), total plasma protein (P < 0.01), platelet count (P < 0.01), and thoracic radiograph findings (P = 0.02). The incidence of HSA diagnosis was 36%, 76%, and 96% in the low risk (≤40), medium risk (41-55), and high risk (>55) score groups, respectively. The risk score AUROC was 0.85 (95% CI 0.79-0.90) on the construction population, and 0.77 (95% CI 0.70-0.84) on the validation population. CONCLUSIONS: The risk of HSA diagnosis in dogs presenting with nontraumatic hemoabdomen could be predicted using a simple risk score, which could aid in identification and treatment of dogs at lower risk for this diagnosis.

Cell models for the primary electroviscous effect.

The primary electroviscous effect in a nondilute suspension of charged spherical particles is studied by means of cell models. The governing equations are derived, and then analytic results are obtained by restricting attention to the limit of thin double layers, small Hartmann and Peclet numbers, and small potentials. Previous work has assumed that the velocity at the outer boundary of the cell is identical to the imposed flow, as proposed by Simha (J. Appl. Phys. 1952, 23, 1020). Results with this boundary condition are compared against those predicted when the tangential shear stress on the outer boundary is assumed to be unperturbed, as proposed by Happel (J. Appl. Phys. 1957, 28, 1288). Both the hydrodynamic and electroviscous contributions to the effective viscosity are smaller with the Happel boundary condition, showing that such cell models offer a range of predictions and should be used with caution.

Topical antibody delivery systems produce sustained levels in mucosal tissue and blood.

Immunity at mucosal surfaces, which are ports of entry for many pathogens, is essential in preventing infections. But most current strategies for passive immunization involve injection of antibodies for systemic, not mucosal, protection. We measured mucosal and systemic antibody levels after controlled topical delivery to the vagina. Poly(ethylene-co-vinyl acetate) disks containing 125I-labeled monoclonal IgG or anti-lactate dehydrogenase-C4 antibodies were placed in the vaginas of mice. High antibody levels (0.26-12 micrograms/ml) were maintained at the mucosal surface for 7 days after disk insertion. Antibody molecules also penetrated into the vaginal epithelium, presumably by diffusing through the extracellular space, and entered the circulation. Biologically active antibodies were detected in the blood. The antibody concentration in the blood was approximately 1% of the concentration in the vagina. Although the permeability of the epithelium to macro-molecules is low, high concentrations were maintained at the luminal surface for an extended period, permitting substantial systemic uptake of antibody.

Controlled release of antibodies for long-term topical passive immunoprotection of female mice against genital herpes.

Current methods for sexually transmitted diseases (STD) prophylaxis, which can be disruptive and inconvenient, must be used before each act of sexual intercourse, so a method that provides protection over the course of many acts is desirable. We used a mouse model of vaginally-transmitted herpes simplex virus 2 (HSV-2) infection to test polymeric controlled-release devices for sustained passive immunoprotection. Vaginal disks were prepared by dispersing a monoclonal antibody to HSV-2 (III-174) within a matrix of poly(ethylene-co-vinyl acetate); these disks released 2 to 40 micrograms/day of antibody into buffered water. When disks were placed in the vagina, large amounts of III-174 (5 to 3,000 ng) were recovered from the vaginal fluid over the next 8 days. Mice were vaginally challenged with 10 ID50 of HSV-2 either 3 or 7 days after disk placement; no mice receiving III-174 disks became infected, while 65% of control mice receiving identical disks with nonspecific IgG did. Controlled-release disks with III-174 provided significant protection against HSV-2 infection (p < 0.005). This new technology for long-term STD prophylaxis should increase user compliance, a factor limiting the efficacy of current methods.