Multi-Study Assessment of Vaginal Cytokines and Microflora in the Safety Evaluation of Intravaginal Rings in Pig-Tailed Macaques

BACKGROUND: HIV microbicide trials have emphasized the need to evaluate the safety of topical microbicides and delivery platforms in an animal model prior to conducting clinical efficacy trials. An ideal delivery device should provide sustainable and sufficient concentrations of effective products to prevent HIV transmission while not increasing transmission risk by either local mucosal inflammation and/or disruption of the normal vaginal microflora.

METHODS: Safety analyses of macaque-sized elastomeric silicone and polyurethane intravaginal rings (IVRs) loaded with candidate antiretroviral (ARV) drugs were tested in four studies ranging in duration from 49 to 73 days with retention of the IVR being 28 days in each study. Macaques were assigned to 3 groups; blank IVR, ARV-loaded IVR, and naïve. In sequential studies, the same macaques were used but rotated into different groups. Mucosal and systemic levels of cytokines were measured from vaginal fluids and plasma, respectively, using multiplex technology. Changes in vaginal microflora were also monitored. Statistical analysis (Mann-Whitney test) was used to compare data between two groups of unpaired samples (with and without IVR, and IVR with and without ARV) for the groups collectively, and also for individual macaques.

RESULTS: There were few statistically significant differences in mucosal and systemic cytokine levels measured longitudinally when the ring was present or absent, with or without ARVs. Of the 8 proinflammatory cytokines assayed a significant increase (p = 0.015) was only observed for IL8 in plasma with the blank and ARV loaded IVR (median of 9.2 vs. 5.7 pg/ml in the absence of IVR). There were no significant differences in the prevalence of H2O2-producing lactobacilli or viridans streptococci, or other microorganisms indicative of healthy vaginal microflora. However, there was an increase in the number of anaerobic gram negative rods in the presence of the IVR (p= < 0.0001).

CONCLUSIONS: IVRs with or without ARVs neither significantly induce the majority of potentially harmful proinflammatory cytokines locally or systemically, nor alter the lactobacillus or G. vaginalis levels. The increase in anaerobic gram negative rods alone suggests minimal disruption of normal vaginal microflora. The use of IVRs as a long-term sustained delivery device for ARVs is promising and preclinical studies to demonstrate the prevention of transmission in the HIV/SHIV nonhuman primate model should continue.

A distributed contention-vector division multiple access (D-CVDMA) protocol for wireless networks

Traditional Time Division Multiple Access (TDMA) protocol provides deterministic periodic collision free data transmissions. However, TDMA lacks flexibility and exhibits low efficiency in dynamic environments such as wireless LANs. On the other hand contention-based MAC protocols such as the IEEE 802.11 DCF are adaptive to network dynamics but are generally inefficient in heavily loaded or large networks. To take advantage of the both types of protocols, a D-CVDMA protocol is proposed. It is based on the k-round elimination contention (k-EC) scheme, which provides fast contention resolution for Wireless LANs. D-CVDMA uses a contention mechanism to achieve TDMA-like collision-free data transmissions, which does not need to reserve time slots for forthcoming transmissions. These features make the D-CVDMA robust and adaptive to network dynamics such as node leaving and joining, changes in packet size and arrival rate, which in turn make it suitable for the delivery of hybrid traffic including multimedia and data content. Analyses and simulations demonstrate that D-CVDMA outperforms the IEEE 802.11 DCF and k-EC in terms of network throughput, delay, jitter, and fairness.

Promoting mental health in Northern Ireland: addressing division, inequality and stigma

This article provides an overview of the literature on the impact of ‘the Troubles’ on mental health in Nor thern Ireland. It identifies three main phases of professional and policy response from concerns about the effects of the violence in the early 1970s, through many years of collective denial and neglect, until acknowledgment, following the Good Friday Agreement in 1998 (Nor thern Ireland Office, 1998), of high levels of trauma and unmet need. The issues of inequality and stigma are also considered and it is argued that peace is necessary but insufficient for promoting mental health. The development of mental health services in Nor thern Ireland and the relatively recent focus on promoting mental health are also outlined and examined. It is suggested that attempts to address the needs arising as a result of ‘the Troubles’ and more general mental health promotion strategies have, to some extent, developed in parallel and that it may be impor tant to integrate these effor ts. The relative under-development of mental health services, the comprehensive Bamford Review of Mental Health and Learning Disability (2005; 2006) and the positive approach of the Public Health Agency mean that, even in the current economic climate, there are great oppor tunities for progress. Routine screening, in primary care and mental health services for trauma, including Troubles-related trauma, is recommended to identify and address these issues on an individual level. It is also argued, however, that more substantial political change is needed to effectively address societal division, inequality and stigma to the benefit of all.

Advances in microbicide vaginal rings

Vaginal ring devices capable of providing sustained/controlled release of incorporated actives are already marketed for steroidal contraception and estrogen replacement therapy. In recent years, there has been considerable interest in developing similar ring devices for the administration of microbicidal compounds to prevent vaginal HIV transmission. Intended to be worn continuously, such coitally independent micro- bicide rings are being developed to maintain effective vaginal microbicide concentrations over many weeks or months, thereby overcoming issues around timing of product application, user compliance and acceptability associated with more conventional semi-solid formulations. In this article, an overview of vaginal ring technologies is presented, followed by a review of recent advances and issues pertaining to their application for the delivery of HIV microbicides. This article forms part of a special supplement on presentations covering intravaginal rings, based on the symposium “Trends in Microbicide Formulations”, held on 25 and 26 January 2010, Arlington, VA.

Sexual division of antibacterial resource defence in breeding burying beetles, Nicrophorus vespilloides

A key component of parental care involves defending resources destined for offspring from a diverse array of potential interspecific competitors, such as social parasites, fungi and bacteria. 2. Just as with other aspects of parental care, such as offspring provisioning or brood defence, sexual conflict between parents may arise over how to share the costs of this form of care. There has been little previous work, however, to investigate how this particular burden might be shared. 3. Here, we describe a hitherto uncharacterized form of parental care in burying beetles Nicrophorus vespilloides, a species which prepares carrion for its young and faces competition from microbes for this resource. We found that parents defend the carcass with antibacterial anal exudates, and that the antibacterial activity of these exudates is only upregulated following the discovery of a corpse. At the same time, phenoloxidase activity in the anal exudates is downregulated, indicating parallels with the internal insect immune system. 4. In unmanipulated breeding pairs, females had higher antibacterial activity in their anal exudates than males, suggesting sex-specific roles in this aspect of parental care. 5. When we experimentally widowed males, we found that they increased levels of antibacterial activity in their anal exudates. Experimentally widowing females, however, led them to decrease levels of antibacterial activity in their anal exudates. Widowed beetles of each sex thus produced anal exudates of comparable antibacterial activity. We suggest that this flexible division of antibacterial activity may be coordinated by Juvenile Hormone. © 2009 British Ecological Society.

SK1 of graded division algebras

The reduced Whitehead group $\SK$ of a graded division algebra graded by a torsion-free abelian group is studied. It is observed that the computations here are much more straightforward than in the non-graded setting. Bridges to the ungraded case are then established by the following two theorems: It is proved that $\SK$ of a tame valued division algebra over a henselian field coincides with $\SK$ of its associated graded division algebra. Furthermore, it is shown that $\SK$ of a graded division algebra is isomorphic to $\SK$ of its quotient division algebra. The first theorem gives the established formulas for the reduced Whitehead group of certain valued division algebras in a unified manner, whereas the latter theorem covers the stability of reduced Whitehead groups, and also describes $\SK$ for generic abelian crossed products.

Unitary SK1 of unitary and graded division algebras

The reduced unitary Whitehead group $\SK$ of a graded division algebra equipped with a unitary involution (i.e., an involution of the second kind) and graded by a torsion-free abelian group is studied. It is shown that calculations in the graded setting are much simpler than their nongraded counterparts. The bridge to the non-graded case is established by proving that the unitary $\SK$ of a tame valued division algebra wih a unitary involution over a henselian field coincides with the unitary $\SK$ of its associated graded division algebra. As a consequence, the graded approach allows us not only to recover results available in the literature with substantially easier proofs, but also to calculate the unitary $\SK$ for much wider classes of division algebras over henselian fields.