Development and evaluation of a vaginal ring device for sustained delivery of HIV microbicides to non-human primate

Background There is considerable interest in developing coitally indepen- dent, sustained release formulations for long-term administration of HIV microbicides. Vaginal ring devices are at the forefront of this formulation strategy. Methods Non-medicated silicone elastomer vaginal rings were prepared having a range of appropriate dimensions for testing vaginal ?t in pig- tailed and Chinese rhesus macaques. Cervicovaginal proin?ammatory markers were evaluated. Compression testing was performed to compare the relative ?exibility of various macaque and commercial human rings. Results All rings remained in place during the study period and no tissue irritation or signi?cant induction of cervicovaginal proin?ammatory mark- ers or signs of physical discomfort were observed during the 8-week study period. Conclusions Qualitative evaluation suggests that the 25 · 5-mm ring pro- vided optimal ?t in both macaque species. Based on the results presented here, low-consistency silicone elastomers do not cause irritation in maca-

Recurrent lower gastrointestinal bleeding secondary to cytomegalovirus-associated colonic ulcer in a non human immunodeficiency virus infected patient:Timely diagnosis and treatment averted surgery

Mr C, a 68-year-old Chinese male with diabetes mellitus, previous stroke and ischaemic cardiomyopathy on clopidogrel, presented with haematochezia. Colonoscopy showed a sigmoid ulcer, which was treated endoscopically. Histology of the biopsy from the ulcer revealed non-specific changes. However, he presented with recurrent bleeding from this non-healing sigmoid ulcer. A review of the histologic specimen revealed CMV intranuclear inclusion bodies. He was treated with intravenous ganciclovir, with no further hematochezia.

Keywords Hematochezia, cytomegalovirus, ulcer

Early target cells of measles virus after aerosol infection of non-human primates

Measles virus (MV) is highly infectious, and has long been thought to enter the host by infecting epithelial cells of the respiratory tract. However, epithelial cells do not express signaling lymphocyte activation molecule (CD150), which is the high-affinity cellular receptor for wild-type MV strains. We have generated a new recombinant MV strain expressing enhanced green fluorescent protein (EGFP), based on a wild-type genotype B3 virus isolate from Khartoum, Sudan (KS). Cynomolgus macaques were infected with a high dose of rMV(KS)EGFP by aerosol inhalation to ensure that the virus could reach the full range of potential target cells throughout the entire respiratory tract. Animals were euthanized 2, 3, 4 or 5 days post-infection (d.p.i., n?=?3 per time point) and infected (EGFP(+)) cells were identified at all four time points, albeit at low levels 2 and 3 d.p.i. At these earliest time points, MV-infected cells were exclusively detected in the lungs by fluorescence microscopy, histopathology and/or virus isolation from broncho-alveolar lavage cells. On 2 d.p.i., EGFP(+) cells were phenotypically typed as large mononuclear cells present in the alveolar lumen or lining the alveolar epithelium. One to two days later, larger clusters of MV-infected cells were detected in bronchus-associated lymphoid tissue (BALT) and in the tracheo-bronchial lymph nodes. From 4 d.p.i. onward, MV-infected cells were detected in peripheral blood and various lymphoid tissues. In spite of the possibility for the aerosolized virus to infect cells and lymphoid tissues of the upper respiratory tract, MV-infected cells were not detected in either the tonsils or the adenoids until after onset of viremia. These data strongly suggest that in our model MV entered the host at the alveolar level by infecting macrophages or dendritic cells, which traffic the virus to BALT or regional lymph nodes, resulting in local amplification and subsequent systemic dissemination by viremia.

Monkey and humans exhibit similar motion-processing mechanisms

Single cell recording studies have resulted in a detailed understanding of motion-sensitive neurons in non-human primate visual cortex. However, it is not known to what extent response properties of motion-sensitive neurons in the non-human primate brain mirror response characteristics of motion-sensitive neurons in the human brain. Using a motion adaptation paradigm, the direction aftereffect, we show that changes in the activity of human motion-sensitive neurons to moving dot patterns that differ in dot density bear a strong resemblance to data from macaque monkey. We also show a division-like inhibition between neural populations tuned to opposite directions, which also mirrors neural-inhibitory behaviour in macaque. These findings strongly suggest that motion-sensitive neurons in human and non-human primates share common response and inhibitory characteristics.

More-than-human histories and the failure of grand state schemes: sylviculture in the New Forest, England

As James Scott’s Seeing Like a State attests, forests played a central role in the rise of the modern state, specifically as test spaces for evolving methods of managing state resources at a distance, and as the location for grand state schemes. Together, such ambitions necessitated both the elimination of local understandings of forest management – to be replaced by centrally controlled scientific precision – and a narrowing of state vision. Forests thus began to be conflated with trees (and their timber) alone. All other aspects of the forest, both human and non-human, were ignored. Through the lens of the 18th and early 19th century New Forest in southern England, this paper examines the impact of government attempts to shift the focus of state forests from being remnant medieval hunting spaces to spaces of income generation through the creation of vast sylvicultural plantations. This state scheme not only reworked the relationship between the metropole and the provinces – something effected through systematic surveys and novel bureaucratic procedures – but also dramatically impacted upon the biophysical and cultural geographies of the forest. By equating forest space with trees alone, the British state failed to legislate for the actions of both local commoners and non-human others in resisting their schemes. Indeed, subsequent oppositions proved not only the tenacity of commoners in protecting their livelihoods but also the destructive power of non-human actants, specifically rabbits and mice. The paper concludes that grand state schemes necessarily fail due to their own internal illogic: the narrowing of state vision creates blind spots in which human and non-human lives assert their own visions.

A comparison of monkey and human motion processing mechanisms

Single-cell recording studies have provided vision scientists with a detailed understanding of motion processing at the neuronal level in non-human primates. However, despite the development of brain imaging techniques, it is not known to what extent the response characteristics of motion-sensitive neurons in monkey brain mirror those of human motion sensitive neurons. Using a motion adaptation paradigm, the direction aftereffect, we recently provided evidence of a strong resemblance in the response functions of motion-sensitive neurons in monkey and human to moving dot patterns differing in dot density. Here we describe a series of experiments in which measurements of the direction aftereffect are used to infer the response characteristics of human motion-sensitive neurons when viewing transparent motion and moving patterns that differ in their signal-to-noise ratio (motion coherence). In the case of transparent motion stimuli, our data suggest suppressed activity of motion-sensitive neurons similar to that reported for macaque monkey. In the case of motion coherence, our results are indicative of a linear relationship between signal intensity (coherence) and neural activity; a pattern of activity which also bears a striking similarity to macaque neural activity. These findings strongly suggest that monkey and human motionsensitive neurons exhibit similar response and inhibitory characteristics.

Small RNAs from plants, bacteria and fungi within the order Hypocreales are ubiquitous in human plasma

Background

The human microbiome plays a significant role in maintaining normal physiology. Changes in its composition have been associated with bowel disease, metabolic disorders and atherosclerosis. Sequences of microbial origin have been observed within small RNA sequencing data obtained from blood samples. The aim of this study was to characterise the microbiome from which these sequences are derived.

Abundant non-human small RNA sequences were identified in plasma and plasma exosomal samples. Assembly of these short sequences into longer contigs was the pivotal novel step in ascertaining their origin by BLAST searches. Most reads mapped to rRNA sequences. The taxonomic profiles of the microbes detected were very consistent between individuals but distinct from microbiomes reported at other sites. The majority of bacterial reads were from the phylum Proteobacteria, whilst for 5 of 6 individuals over 90% of the more abundant fungal reads were from the phylum Ascomycota; of these over 90% were from the order Hypocreales. Many contigs were from plants, presumably of dietary origin.  In addition, extremely abundant small RNAs derived from human Y RNAs were detected.

A characteristic profile of a subset of the human microbiome can be obtained by sequencing small RNAs present in the blood. The source and functions of these molecules remain to be determined, but the specific profiles are likely to reflect health status. The potential to provide biomarkers of diet and for the diagnosis and prognosis of human disease is immense.

Protest practice and (tree) cultures of conflict: understanding the spaces of ‘tree maiming’ in eighteenth- and early nineteenth-century England

Developing understandings of protest and cultures of resistance has been a central theme of the 'new' cultural geography of the 1990s and 2000s. But whilst geographers of the here and now have been highly sensitive to the importance of acts of protest which occur outside of the context of broader social movements, geographers concerned with past protests have tended to focus overwhelmingly upon either understanding the development of social movements or highly specific place-based studies. Through a focus upon the hitherto ignored practice of 'tree maiming', this paper demonstrates not only the value of examining specific protest practices in helping to better understand the complexity of conflict, but also how in periods of acute socio-economic change the evolving relationship between humans and the non-human – in this case trees – is a central discourse to the protest practices of the poor. Such attacks often involved complex cultural understandings about the ways in which trees should – and should not – be socially enrolled.

Folkbiology doesn’t come from Folkpsychology: evidence from Yukatek Maya in cross-cultural perspective

Nearly all psychological research on basic cognitive processes of category formation and reasoning uses sample populations associated with large research institutions in technologically-advanced societies. Lopsided attention to a select participant pool risks biasing interpretation, no matter how large the sample or how statistically reliable the results. The experiments in this article address this limitation. Earlier research with urban-USA children suggests that biological concepts are (1) thoroughly enmeshed with their notions of naive psychology, and (2) strikingly human-centered. Thus, if children are to develop a causally appropriate model of biology, in which humans are seen as simply one animal among many, they must undergo fundamental conceptual change. Such change supposedly occurs between 7 and 10 years of age, when the human-centered view is discarded. The experiments reported here with Yukatek Maya speakers challenge the empirical generality and theoretical importance of these claims. Part 1 shows that young Maya children do not anthropocentrically interpret the biological world. The anthropocentric bias of American children appears to owe to a lack of cultural familiarity with non-human biological kinds, not to initial causal understanding of folkbiology as such. Part 2 shows that by age of 4-5 (the earliest age tested in this regard) Yukatek Maya children employ a concept of innate species potential or underlying essence much as urban American children seem to, namely, as an inferential framework for understanding the affiliation of an organism to a biological species, and for projecting known and unknown biological properties to organisms in the face of uncertainty. Together, these experiments indicate that folkpsychology cannot be the initial source of folkbiology. They also underscore the possibility of a species-wide and domain-specific basis for acquiring knowledge about the living world that is constrained and modified but not caused or created by prior nonbiological thinking and subsequent cultural experience.

Animal maiming, intimacy and the politics of shared life: the bestial and the beastly in eighteenth- and early nineteenth-century England

The everyday lives of many farm workers in eighteenth- and early nineteenth-century England were intricately and often intimately bound with the lives of animals, the ebb and flow of human life being inseparable from that of animal life. Farmyards, fields, folds as well as barns and stables were all spaces where animals transcended being the mere instruments of capital to instead being obvious co-constituents of the rhythms of existence. Living and working in such close proximity meant that the ‘species barrier’ was crossed and intimacies developed in everyday agricultural practices. Still, the relationship was based upon, if not reducible to, the workings of capital: the animal enrolled as a form of embodied capital, the labourer engaged by the farmer to act upon the animal. And in such relationships intimacies are mirrored by violences: the keeping captive, slaughter, and – occasionally – abuse. In this formative period in which the discourses and policies that continue to inform animal welfare were first formulated, the declining economic and material fortunes of farm workers when juxtaposed to farm animals’ fortune as increasingly ‘cosseted capital’ gave a particular charge to these abuses. Farm animals, and especially horses and cattle, so it is shown, were subjected to a series of violences. Many cases of animal maiming parodied tenderness in their brutality, whilst other attacks on the sexual organs of animals represented complex statements about the ways in which agrarian capitalism regulated all culture. Analysing the changing relationship between humans and animals therefore also helps us to better understand how capitalism mediates – and is mediated by – the non-human as well as the human, and how it defines cultural relations.

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P <5 × 10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r(2) > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r(2) > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

Measles immune suppression:lessons from the Macaque Model

Measles remains a significant childhood disease, and is associated with a transient immune suppression. Paradoxically, measles virus (MV) infection also induces robust MV-specific immune responses. Current hypotheses for the mechanism underlying measles immune suppression focus on functional impairment of lymphocytes or antigen-presenting cells, caused by infection with or exposure to MV. We have generated stable recombinant MVs that express enhanced green fluorescent protein, and remain virulent in non-human primates. By performing a comprehensive study of virological, immunological, hematological and histopathological observations made in animals euthanized at different time points after MV infection, we developed a model explaining measles immune suppression which fits with the "measles paradox". Here we show that MV preferentially infects CD45RA - memory T-lymphocytes and follicular B-lymphocytes, resulting in high infection levels in these populations. After the peak of viremia MV-infected lymphocytes were cleared within days, followed by immune activation and lymph node enlargement. During this period tuberculin-specific T-lymphocyte responses disappeared, whilst strong MV-specific T-lymphocyte responses emerged. Histopathological analysis of lymphoid tissues showed lymphocyte depletion in the B- and T-cell areas in the absence of apoptotic cells, paralleled by infiltration of T-lymphocytes into B-cell follicles and reappearance of proliferating cells. Our findings indicate an immune-mediated clearance of MV-infected CD45RA - memory T-lymphocytes and follicular B-lymphocytes, which causes temporary immunological amnesia. The rapid oligoclonal expansion of MV-specific lymphocytes and bystander cells masks this depletion, explaining the short duration of measles lymphopenia yet long duration of immune suppression. © 2012 de Vries et al.