A Topical Microbicide Gel Formulation of CCR5 Antagonist Maraviroc Prevents HIV-1 Vaginal Transmission in Humanized RAG-hu Mice

For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field

Oral Pre-Exposure Prophylaxis by Anti-Retrovirals Raltegravir and Maraviroc Protects against HIV-1 Vaginal Transmission in a Humanized Mouse Model

Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP). Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs

Role of salt intake in prevention of cardiovascular disease: controversies and challenges.

Strong evidence indicates that reduction of salt intake lowers blood pressure and reduces the risk of cardiovascular disease (CVD). The WHO has set a global target of reducing the population salt intake from the current level of approximately 10 g daily to 85 categories of food; many other developed countries are following the UK's lead. In developing countries where most of the salt is added by consumers, public health campaigns have a major role. Every country should adopt a coherent, workable strategy. Even a modest reduction in salt intake across the whole population can lead to a major improvement in public health and cost savings

Optimal foraging and community structure: implications for a guild of generalist grassland herbivores

A particular linear programming model is constructed to predict the diets of each of 14 species of generalist herbivores at the National Bison Range, Montana. The herbivores have body masses ranging over seven orders of magnitude and belonging to two major taxa: insects and mammals. The linear programming model has three feeding constraints: digestive capacity, feeding time and energy requirements. A foraging strategy that maximizes daily energy intake agrees very well with the observed diets. Body size appears to be an underlying determinant of the foraging parameters leading to diet selection. Species that possess digestive capacity and feeding time constraints which approach each other in magnitude have the most generalized diets. The degree that the linear programming models change their diet predictions with a given percent change in parameter values (sensitivity) may reflect the observed ability of the species to vary their diets. In particular, the species which show the most diet variability are those whose diets tend to be balanced between monocots and dicots. The community-ecological parameters of herbivore body-size ranges and species number can possibly be related to foraging behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47765/1/442_2004_Article_BF00377109.pd

Anomalous right subclavian artery and coarctation-related aneurysm repaired with bilateral subclavian-to-carotid transposition and exclusion stent-grafting

AbstractIntroductionAortic arch anomalies are common; however, the presence of concomitant pathology may present a complex management problem.ReportA 42 year old lady with anomalous right subclavian artery was found to have recurrent coarctation of the aorta and an aneurysm related to the previous repair. Management of the aneurysm was complicated by the proximity of subclavian artery origins. Bilateral subclavian-to-carotid transposition was undertaken to preserve antegrade vertebral artery flow, with subsequent exclusion stent-grafting of the aneurysm and coarctation.DiscussionThis case illustrates combined surgical and interventional radiological repair to deal with a complex thoracic aortic clinical problem

The impact of antimalarial resistance on the genetic structure of Plasmodium falciparum in the DRC.

The Democratic Republic of the Congo (DRC) harbors 11% of global malaria cases, yet little is known about the spatial and genetic structure of the parasite population in that country. We sequence 2537 Plasmodium falciparum infections, including a nationally representative population sample from DRC and samples from surrounding countries, using molecular inversion probes - a high-throughput genotyping tool. We identify an east-west divide in haplotypes known to confer resistance to chloroquine and sulfadoxine-pyrimethamine. Furthermore, we identify highly related parasites over large geographic distances, indicative of gene flow and migration. Our results are consistent with a background of isolation by distance combined with the effects of selection for antimalarial drug resistance. This study provides a high-resolution view of parasite genetic structure across a large country in Africa and provides a baseline to study how implementation programs may impact parasite populations