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The intestinal epithelium is perpetually renewed from a stem cell niche in the base of crypts to maintain a healthy bowel mucosa. Exit from this niche and maturation of epithelial cells requires tightly controlled gradients in BMP signalling, progressing from low BMP signalling at the crypt base to high signalling at the luminal surface. The BMP antagonist gremlin 1 (Grem1) is highly expressed by subepithelial myofibroblasts adjacent to the intestinal crypts but its role in regulating the stem cell niche and epithelial renewal in vivo has not been explored. To explore the effects of Grem1 loss in adulthood following normal growth and development, we bred mice (ROSA26CreER-Grem1 flx/flx ) in which Grem1 could be deleted by tamoxifen administration. While Grem1 remained intact, these mice were healthy, grew normally, and reproduced successfully. Following Grem1 depletion, the mice became unwell and were euthanised (at 7-13 days). Post-mortem examination revealed extensive mucosal abnormalities throughout the small and large intestines with failure of epithelial cell replication and maturation, villous atrophy, and features of malabsorption. Bone marrow hypoplasia was also observed with associated early haematopoietic failure. These results demonstrate an essential homeostatic role for gremlin 1 in maintaining normal bowel epithelial function in adulthood, suggesting that abnormalities in gremlin 1 expression can contribute to enteropathies. We also identified a previously unsuspected requirement for gremlin 1 in normal haematopoiesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Genomic imprinting occurs in therian mammals and is a phenomenon whereby the two alleles of a gene are differentially expressed, based on the sex of the parent from whom the alleles were inherited. The allelic differences in expression are the consequence of different epigenetic modifications that are established in the sperm or oocyte during gametogenesis and transmitted at fertilization to offspring. A small minority of genes is regulated in this way but they have important biological functions, and aberrant regulation of imprinted genes contributes to disease aetiology in humans and other animals. The factors driving the evolution of imprinted genes are also of considerable interest, as these genes appear to forego the benefits of diploidy. To broaden the phylogenetic analysis of genomic imprinting, we began a study of imprinted genes in the domestic dog, Canis familiaris. In this report, we show that canine IGF2 and H19 are imprinted, with parent-of origin-dependent monoallelic expression patterns in neonatal umbilical cord. We identify a putative imprint control region associated with the genes, and provide evidence for differential methylation of this region in a somatic tissue (umbilical cord) and for its hypermethylation in the male germline. Canis familiaris is fast becoming a highly informative system for elucidating disease processes and evolution, and the study of imprinted genes in this species may help in understanding how these genes contribute to the generation of morphological and behavioral diversity.

This chapter examines the historical context of Kant’s opposition to suicide in the Groundwork of the Metaphysics of Morals. I argue for an interpretation of his argument – generally thought unsuccessful – whereby Kant is assuming a premise that claims that the mathematical calculations of life’s anticipated pleasures and pains always produces a negative result. I claim that Kant’s broader rhetorical aim to counteract a cultural movement in 18th Century European society that promoted appeal to the passions as the justificatory grounds for moral actions.

Synthetic cathinones, often marketed as ‘bath salts’, have been reported to induce an excited delirium syndrome with characteristic symptoms such as paranoid, hallucination and even aggression. 3,4-Methylenedioxypyrovalerone (MDPV), a norepinephrine-dopamine reuptake inhibitor (NDRI), is one of the psychoactive ingredients in bath salts. The present study utilized cortical EEG and brain microdialysis in rats to compare the effects of MDPV (0.25, 1 and 2 mg/kg, i.p.) with the hallucinogenic drugs MK-801 (0.05, 0.1 and 0.5 mg/kg, i.p.) and ketamine (5, 15 and 25 mg/kg, i.p.). Results revealed that MDPV similar to MK-801 and ketamine caused a dose-dependent increase in the cortical EEG synchronization. In addition, all three drugs produced an increase in DA efflux in the prefrontal cortex (FCx). However, there existed difference between the three drugs. In contrast to MDPV, MK-801 and ketamine had only moderate or little effects on DA efflux in the nucleus accumbens (NAcc). Except for ketamine, the effects of MDPV and MK-801 on EEG synchronization were blocked by the D1 receptor antagonist SCH23990 (0.1 mg/kg, i.p.) and D2 receptor antagonist sulpiride (100 mg/kg, i.p.). SCH23990 or sulpiride had no effect on ketamine-induced increases in EEG synchronization. In summary, the present comparative studies suggest that DA in the FCx, but unlikely the NAcc, exerts a critical role in increasing EEG synchronization associated with the excited delirium syndrome. Neural circuits consisting of glutamatergic and GABAergic neurons responsible for the hallucinogenic effect are discussed in the context of hyperdopamine and dysconnection theories for hallucinatory behaviors.

Electroencephalography (EEG) likely reflects activity of cortical neurocircuits, making it an insightful estimation for mental health in patients with substance use disorder (SUD). EEG signals are recorded as sinusoidal waves, containing spectral amplitudes across several frequency bands with high spatio-temporal resolution. Prior work on EEG signal analysis has been made mainly at individual electrodes. These signals can be evaluated from advanced aspects, including sub-regional and hemispheric analyses. Due to limitation of computational techniques, few studies in earlier work could conduct data analyses from these aspects. Therefore, EEG in patients with SUD is not fully understood. In the present retrospective study, spectral powers from a data house containing opioid (OUD), methamphetamine/stimulants (MUD), and alcohol use disorder (AUD) were extracted, and then converted into five distinct topographic data (i.e., electrode-based, cortical subregion-based, left-right hemispheric, anterior-posterior based, and total cortex-based analyses). We found that data conversion and reorganization in the topographic way had an impact on EEG spectral powers in patients with OUD significantly different from those with MUD or AUD. Differential changes were observed from multiple perspectives, including individual electrodes, subregions, hemispheres, anterior-posterior cortices, and across the cortex as a whole. Understanding the differential changes in EEG signals may be useful for future work with machine learning and artificial intelligence (AI), not only for diagnostic but also for prognostic purposes in patients with SUD.

This study examined the effects of dietary supplementation with laminarin or chitosan on colonic health in pigs challenged with dextran sodium sulphate (DSS). Weaned pigs were assigned to: (1) a basal diet (n = 22), (2) a basal diet + laminarin (n = 10), and (3) a basal diet + chitosan (n = 10). On d35, the basal group was split, creating four groups: (1) the basal diet (control), (2) the basal diet + DSS, (3) the basal diet + laminarin + DSS, and (4) the basal diet + chitosan + DSS. From d39&ndash, 42, the pigs were orally challenged with DSS. On d44, colonic tissue/digesta samples were collected. The basal DSS group had reduced growth, higher pathology score and an increased expression of MMP1, IL13 and IL23 compared with the controls (p &lt, 0.05), these parameters were similar between the DSS-challenged groups (p &gt, 0.05). In the basal DSS group, the relative abundance of beneficial taxa including Prevotella and Roseburia were reduced while Escherichia/Shigella were increased, compared with the controls (p &lt, 0.05). The relative abundance of Escherichia/Shigella was reduced and the molar proportions of acetate were increased in the laminarin DSS group compared with the basal DSS group (p &lt, 0.01), suggesting that laminarin has potential to prevent pathogen proliferation and enhance the volatile fatty acid profile in the colon in a porcine model of colitis.

This is an edited collection devoted to the topic of the role of animals within Kant’s philosophy. It addresses key issues within both his theoretical and practical philosophy. It examines the place of Kant’s model of animal minds in the historical and contemporary contexts. It addresses the question of whether Kant’s philosophy of mind allows for animals to be capable of intentional representations of spatiotemporal objects. It explores how Kant treated the issue of animal nature as it manifests in humans and non-humans alike and questions how Kant’s scientific theory attempted to accommodate animals within his broader Enlightenment worldview. It also addresses traditional worries about the moral status of animals within Kant’s and Kantian moral theory. Kant notoriously denied that we have direct obligations to animals, and the question persists as to whether Kantian moral theory provides the right account of the moral status of non-human animals. Several papers in this collection address the question and whether Kant’s views can be defended or ought to be rejected altogether on this basis alone. The collection considers the relevance of Kantian theory for our understanding of contemporary challenges facing human beings with regard to our relationship to animals.

This chapter discusses the historical context of Kant’s theory of animal minds. The continuity thesis is discussed. This is the claim that, whatever the variations in their mental lives, animal and human minds manifest no differences in kind but rather exhibit the same general type of mental capacities merely exercised with very different degrees of sophistication. Kant is an ardent denier of the continuity thesis in that he claims that human beings are different in kind from animals by virtue of our ability for self-conscious understanding and the opportunities for normative self-determination that this ability affords. The approaches of Montaigne, Descartes, and Bayle are outlined. It is claimed that the relevant cognitive achievement with which Kant was concerned was that of the comparison of representations with each other and the noting of similarity or difference. It is argued that Kant adopted an analogy strategy, which claims that animals possess a capacity for the comparison of representations that is only analogous to human beings’ representational capacity.

Imprinted genes are epigenetically modified in a parent-of-origin dependent manner and as a consequence are differentially expressed, with one allele typically expressed while the other is repressed. In canine, the insulin like growth factor 2 receptor gene (IGF2R) is imprinted with predominant expression of the maternally inherited allele. Because imprinted genes usually occur in clusters, we examined the allelic expression pattern of the gene encoding the canine Mas receptor (MAS1), which is located upstream of IGF2R on canine chromosome 1 and is highly conserved in mammals. In this report we describe monoallelic expression of canine MAS1 in the neonatal umbilical cord of several individuals and we identify the expressed allele as maternally inherited. These data suggest that canine MAS1 is an imprinted gene.

It is well known that at the heart of Kant’s Critical philosophy is the claim that the mind possesses an essentially spontaneous power or capacity (Vermögen). It is also sometimes maintained that Kant’s appeals to this spontaneous power are intimately tied to his recognition of there being a fundamental and irreducible normative dimension to judgement. However, I attempt to complicate this picture by way of appeal to some less appreciated influences upon the development of Kant’s epistemology. A different conception of the role of spontaneity in judgement has clear precedents, I claim, in the works of Cudworth and Rousseau. There the imagined role for the active power of the mind is not to identify criteria that might serve as norms for epistemically responsible judgement. Rather the spontaneous power of the mind is cited as the source of representational contents that secure the truth conditions of our everyday claims to empirical knowledge.

Early diagnosis of endometritis in dairy cattle is currently requires invasive techniques and specialist expertise. The goal of this study is to utilize a gel-free mass-spectrometry based proteomics approach to compare the plasma proteome of dairy cattle with cytological endometritis to those without. Blood samples were collected from cows (N = 112) seven days postpartum (DPP). Plasma samples from a cohort of 20 animals with cytological endometritis (n = 10) and without (n = 10) as classified 21 DPP were selected for proteomic analysis. Differential abundances of proteins between the two animal groups were determined using both fold change (≥1.5 fold change) and statistical significance threshold (p, Journal of Proteomics, 205, ISSN:1874-3919, ISSN:1876-7737

In a recreational use of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”), some but not all users are stricken with a serious serotonin (5-hydroxytryptamine; 5-HT) syndrome. This raises a question as to whether there exist subpopulations that are more susceptible to MDMA intoxication. The hypothesis was tested with hyperthyroid versus euthyroid rats by measuring changes in body-core temperature (T(cor)) and 5-HT in the hypothalamus. In the euthyroid rats, injection of MDMA at a recreationally relevant dose had no serious effect on T(cor). In contrast, the same dose was sufficient to evoke life-threatening hyperthermia in hyperthyroid rats. Neurochemical studies revealed that there was greater 5-HT efflux in the hyperthyroid than the euthyroid rats. These effects were blocked by pretreatment with M100907, a 5-HT(2A) receptor antagonist. In summary, our data support the hypothesis that individuals with hyperthyroidism are more susceptible to having a serious serotonin syndrome following MDMA administration.

Background MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. Methods Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. Results Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. Conclusion Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification. Electronic supplementary material The online version of this article (10.1186/s40360-019-0326-6) contains supplementary material, which is available to authorized users.

I argue that Kant’s transcendental idealism and Strawson’s descriptive metaphysics are both examples of what I call methodological conservativism. Methodological conservativism involves the claim that a subset of common first-order beliefs is immune to revision. I argue that there are striking differences between their respective commitments to this position, however. For Kant, his conservativism is based upon a commitment to the reliability of particular results of the sciences of his day. For Strawson, in contrast, his conservativism is based upon his attempted liberation of arguments for the necessity of a certain conceptual scheme from any particular scientific commitments. In fact, for Strawson, no change in scientific commitments could displace the conceptual scheme employed to navigate the manifest world of ordinary perceptual experience. Each approach brings with it challenges with regard to how to accommodate potential scientific theory change.

We describe histopathologic abnormalities in the kidneys of small Indian mongoose (Herpestes auropunctatus) on the Caribbean island of Saint Kitts. The lesions observed in moderate to severe cases were suggestive of a chronic nephropathy. Further investigation is needed to explore the magnitude of the problem, potential causes, and predisposing factors.

Ecstasy is a recreational drug containing 3,4-methylenedioxymethamphetamine (MDMA). In the U.S., there are several millions of lifetime users, and millions each year added to the list as new users. Only several thousand every year show signs of severe toxicity and require emergency intervention. The illness is known as serotonin (5-HT) syndrome, which can be mild, moderate or severe. The relationship between mild, moderate and severe syndromes appears to be interchangeable, but the severe syndrome is life-threatening. The serotonergic mechanisms of how the mild or moderate syndrome becomes severe and life-threatening have attracted considerable attention in the last few years as an effort to explore new treatments potentially to manage illness and prevent death of patients. High levels of extracellular 5-HT in the brain produced by large doses of MDMA are not always necessary to cause a severe serotonin syndrome. Additional mechanisms may be more important. Recent research has demonstrated that environmental conditions (i.e., non-drug factors) are more critical in determining the severity of MDMA-induced serotonin syndrome than the drug dose. The purpose of the current article was to review available evidence regarding the effect of non-drug factors on serotonergic extrasynaptic receptor responsivity and the severity of MDMA-induced serotonin syndrome.

Leptospiral pulmonary haemorrhage syndrome (LPHS) is a severe form of leptospirosis. Pathogenic mechanisms are poorly understood. Lung tissues from 26 dogs with LPHS, 5 dogs with pulmonary haemorrhage due to other causes and 6 healthy lungs were labelled for IgG (n=26), IgM (n=25) and leptospiral antigens (n=26). Three general staining patterns for IgG/IgM were observed in lungs of dogs with LPHS with most tissues showing more than one staining pattern: (1) alveolar septal wall staining, (2) staining favouring alveolar surfaces and (3) staining of intra-alveolar fluid. Healthy control lung showed no staining, whereas haemorrhagic lung from dogs not infected with Leptospira showed staining of intra-alveolar fluid and occasionally alveolar septa. Leptospiral antigens were not detected. We conclude that deposition of IgG/IgM is demonstrable in the majority of canine lungs with naturally occurring LPHS, similar to what has been described in other species. Our findings suggest involvement of the host humoral immunity in the pathogenesis of LPHS and provide further evidence to support the dog as a natural disease model for human LPHS.

Leptospiral pulmonary haemorrhage syndrome (LPHS) is a particularly severe form of leptospirosis. LPHS is increasingly recognized in both humans and animals and is characterized by rapidly progressive intra-alveolar haemorrhage leading to high mortality. The pathogenic mechanisms of LPHS are poorly understood which hampers the application of effective treatment regimes. In this study a 2-D guinea pig proteome lung map was created and used to investigate the pathogenic mechanisms of LPHS. Comparison of lung proteomes from infected and non-infected guinea pigs via differential in-gel electrophoresis revealed highly significant differences in abundance of proteins contained in 130 spots. Acute phase proteins were the largest functional group amongst proteins with increased abundance in LPHS lung tissue, and likely reflect a local and/or systemic host response to infection. The observed decrease in abundance of proteins involved in cytoskeletal and cellular organization in LPHS lung tissue further suggests that infection with pathogenic Leptospira induces changes in the abundance of host proteins involved in cellular architecture and adhesion contributing to the dramatically increased alveolar septal wall permeability seen in LPHS. Biological significance The recent completion of the complete genome sequence of the guinea pig (Cavia porcellus) provides innovative opportunities to apply proteomic technologies to an important animal model of disease. In this study, the comparative proteomic analysis of lung tissue from experimentally infected guinea pigs with leptospiral pulmonary haemorrhage syndrome (LPHS) revealed a decrease in abundance of proteins involved in cellular architecture and adhesion, suggesting that loss or down-regulation of cytoskeletal and adhesion molecules plays an important role in the pathogenesis of LPHS. A publically available guinea pig lung proteome map was constructed to facilitate future pulmonary proteomics in this species.

The European red squirrel (Sciurus vulgaris) has suffered a 20 % decline in range in Ireland since the introduction of the eastern grey squirrel (Sciurus carolinensis) in 1911. In the UK, squirrelpox virus (SQPV) has been identified as being a major contributor to the decline of red squirrel populations but has only recently been confirmed in a red squirrel from Wicklow in Ireland with anecdotal references to a previous outbreak in the Shankill area of south County Dublin and a case in Kilmacanogue, north County Wicklow. The current study examined a sample of grey squirrels from these areas for SQPV seroprevalence. Enzyme-linked immunosorbent assay (ELISA) tests were carried out on sera from 51 grey squirrels culled from two sites in south County Dublin, areas A and B, and a third site in north County Wicklow, area C. The results indicated declining SQPV seroprevalence rates moving northwards from Wicklow, 55 % in area C, 50 % in area B and 11 % in area A. The low levels of seropositivity in Killiney (A) suggest that this is the wave-front of grey squirrel expansion from Wicklow and that the population may not yet have reached the threshold density for SQPV transmission to the red squirrel population to occur. The results of this study indicate that there is potential overlap between seropositive grey squirrel populations and susceptible red squirrel populations with obvious implications for conservation and management. National Parks and Wildlife Service

In his winning submission for the 1763 Berlin Academy prize essay competition, Moses Mendelssohn explained how necessary truths are grasped. All such propositions, in both mathematics and metaphysi...

Trichomonosis is an endemic disease in cattle that are reared under extensive conditions and bred by natural mating. It causes profound economic losses to the producers by increasing calving interval, increasing embryo losses, and decreasing pregnancy rates. The aim of this study was to determine whether Tritrichomonas foetus infections were absent from cattle in St. Kitts. Using the modified hypergeometric method, preputial samples from bulls (n = 78) were tested using the InPouch™ culture for presence of T. foetus. Results highlighted an absence of trichomoniasis in bulls on St. Kitts with a 95% confidence.

Background A uterine neoplasm was observed, as an incidental finding, during post-mortem examination of a 26-year-old female multiparous African green monkey (Chlorocebus aethiops sabaeus). The intramural, expansile, 2 to 3 cm well-demarcated, dark-red, nodular neoplasm was located on the anterior uterine body (corpus) wall. Methods The mass was examined by light microscopy and by immunohistochemistry. Results The mass was confirmed as a cavernous uterine angioleiomyoma (syn. vascular leiomyoma) characterized by abundant intratumoural vasculature lined by Factor VIII-positive endothelial cells and surrounded by smooth muscle actin-positive cell proliferations. Conclusion Angioleiomyoma sharing the characteristics of intramural human cavernous uterine angioleiomyoma should be considered in the differential diagnosis of uterine tumours in non-human primates.

The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm’s canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system.

Computer models allow the mechanistically detailed study of tumour proliferation and its dependency on nutrients. However, the computational study of large vascular tumours requires detailed information on the 3-dimensional vessel network and rather high computation times due to complex geometries. This study puts forward the idea of partitioning vascularised tissue into connected avascular elements that can exchange cells and nutrients between each other. Our method is able to rapidly calculate the evolution of proliferating as well as dead and quiescent cells, and hence a proliferative index, from a given amount and distribution of vascularisation of arbitrary complexity. Applying our model, we found that a heterogeneous vessel distribution provoked a higher proliferative index, suggesting increased malignancy, and increased the amount of dead cells compared to a more static tumour environment when a homogenous vessel distribution was assumed. We subsequently demonstrated that under certain amounts of vascularisation, cell proliferation may even increase when vessel density decreases, followed by a subsequent decrease of proliferation. This effect was due to a trade-off between an increase in compensatory proliferation for replacing dead cells and a decrease of cell population due to lack of oxygen supply in lowly vascularised tumours. Findings were illustrated by an ectopic colorectal cancer mouse xenograft model. Our presented approach can be in the future applied to study the effect of cytostatic, cytotoxic and anti-angiogenic chemotherapy and is ideally suited for translational systems biology, where rapid interaction between theory and experiment is essential. ispartof: Journal of Theoretical Biology vol:402 pages:129-143 ispartof: location:England status: published

In spite of the fact that systemic administration of MDMA elicits serotonin syndrome, direct intracranial administration fails to reproduce the effect. To reconcile these findings, it has been suggested that the cause of serotonin syndrome is attributed mainly to MDMA hepatic metabolites, and less likely to MDMA itself. Recently, however, this explanation has been challenged, and alternative hypotheses need to be explored. Here, we tested the hypothesis that serotonin syndrome is the result of excessive 5HT simultaneously in many brain areas, while MDMA administered intracranially fails to cause serotonin syndrome because it produces only a localized effect at the delivery site and not to other parts of the brain. This hypothesis was examined using adult male Sprague Dawley rats by comparing 5HT responses in the right and left hemispheric frontal cortices, right and left hemispheric diencephalons, and medullar raphe nucleus. Occurrence of serotonin syndrome was confirmed by measuring change in body temperature. Administration routes included intraperitoneal (IP), intracerebroventricular (ICV) and reverse microdialysis. First, we found that IP administration caused excessive 5HT in all five sites investigated and induced hypothermia, suggesting the development of the serotonin syndrome. In contrast, ICV and reverse microdialysis caused excessive 5HT only in regions of delivery sites without changes in body-core temperature, suggesting the absence of the syndrome. Next, chemical dyes were used to trace differences in distribution and diffusion patterns between administration routes. After systemic administration, the dyes were found to be evenly distributed in the brain. However, the dyes administered through ICV or reverse microdialysis injection still remained in the delivery sites, poorly diffusing to the brain. In conclusion, intracranial MDMA administration in one area has no or little effect on other areas, which must be considered a plausible reason for the difference in MDMA-elicited serotonin syndrome between systemic and intracranial administrations.

Case summary This case describes a young non-pregnant cat that presented with uterine prolapse in association with an unusual diffuse, polypoid, fibrosing perimetritis and parametritis. Following ovariohysterectomy the cat recovered fully. No intra-abdominal complications were seen on ultrasound examination 3 months postsurgery. At the time of writing, the cat remains healthy. Relevance and novel information Uterine prolapse in the cat is relatively rare and usually associated with the periparturient period. Inflammatory polypoid perimetritis and parametritis have not previously been documented in cats, and in dogs have only been reported in association with the administration of oestrogenic compounds. The polypoid inflammation affecting the uterus and parametrium may have contributed to increased laxity of the uterine ligaments and predisposed to the development of uterine prolapse.

Chronic nonhealing wounds, particularly those complicated by multidrug resistant infections, represent a major health and economic challenge. Plasma treatment promotes wound repair due to its antimicrobial, angiogenic, and cell modulating properties. This study investigated the efficacy of the kINPen Med system in promoting healing and assessed if efficacy was enhanced by adding collagen or hyaluronic acid (HA). Two 6 mm diameter punch biopsy wounds were created on the lumbar spine of Sprague Dawley rats. Based on the results of a pilot study, operating process conditions involving 30 s plasma/day were selected for the pivotal study. In the pivotal study, six groups of rats (n = 28/group) received either control (1), plasma (2), HA (3), plasma and HA (4), collagen (5), or plasma and collagen (6). Wound measurements were obtained on Days 0, 4, 7, and 14. The mean reduction in wound size was significantly higher in all treatment groups compared to controls on Day 4; group 6 performed best. On Day 7, group 6 still performed significantly better compared to groups 1, 2, 3, and 4. Day 14 results were more comparable between groups. Histology (Day 14) revealed epidermal hyperplasia and serocellular crusts. Neutrophilic infiltrates in group 6 were significantly lower compared to group 2. Mononuclear infiltrates were highest in groups 3 and 5, while Langerhans cells were observed in all groups. These results underpin the clinical benefits of the kINPen Med plasma system, particularly when combined with collagen during early inflammatory phases, and support the conduct of future human clinical trials.

peer-reviewed Background The regulation of endometrial inflammation has important consequences for the resumption of bovine fertility postpartum. All cows experience bacterial influx into the uterus after calving; however a significant proportion fail to clear infection leading to the development of cytological endometritis (CE) and compromised fertility. We hypothesised that early immunological changes could not only act as potential prognostic biomarkers for the subsequent development of disease but also shed light on the pathogenesis of endometritis in the postpartum dairy cow. Methods Endometrial biopsy RNA was extracted from 15 cows at 7 and 21 days postpartum (DPP), using the Qiagen RNeasy® Plus Mini kit and quality determined using an Agilent 2100 bioanalyser. Disease status was determined by histpathology based on inflammatory cell infiltrate. RNA-seq of both mRNA and miRNA libraries were performed on an Illumina® HiSeq™ 2000. Paired reads were aligned to the bovine genome with Bowtie2 and differentially expressed genes were identified using EdgeR. Significantly over-represented Gene Ontology terms were identified using GO-seq, and pathway analysis was performed using KEGG. Quanititative real-time PCR was also performed for validation (ABI 7500 fast). Haematology was assessed using an automated ADVIA 2120 analyser. Serum proteins were evaluated by ELISA and metabolite analysis was performed using a Beckman Coulter AU 400 clinical analyser. Terminal-restriction fragment length polymorphism (T-RFLP) was used to obtain fingerprints of the microbial communities present. Results Next-generation sequencing from endometrial biopsies taken at 7 DPP identified significant induction of inflammatory gene expression in all cows. Despite the common inflammatory profile and enrichment of the Toll-like receptor and NFκB pathways, 73 genes and 31 miRNAs were significantly differentially expressed between healthy cows (HC, n = 9) and cows which subsequently developed CE at 7 DPP (n = 6, FDR

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) toxicity may cause region-specific changes in serotonergic mRNA expression due to acute serotonin (5-hydroxytryptamine; 5-HT) syndrome. This hypothesis can be tested using in situ hybridization to detect the serotonin 5-HT2A receptor gene htr2a. In the past, such procedures, utilizing radioactive riboprobe, were difficult because of the complicated workflow that needs several days to perform and the added difficulty that the technique required the use of fresh frozen tissues maintained in an RNase-free environment. Recently, the development of short oligonucleotide probes has simplified in situ hybridization procedures and allowed the use of paraformaldehyde-prefixed brain sections, which are more widely available in laboratories. Here, we describe a detailed protocol using non-radioactive oligonucleotide probes on the prefixed brain tissues. Hybridization probes used for this study include dapB (a bacterial gene coding for dihydrodipicolinate reductase), ppiB (a housekeeping gene coding for peptidylprolyl isomerase B), and htr2a (a serotonin gene coding for 5-HT2A receptors). This method is relatively simply, cheap, reproducible and requires less than two days to complete.

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) toxicity may cause region-specific changes in serotonergic mRNA expression due to acute serotonin (5-hydroxytryptamine; 5-HT) syndrome. This hypothesis can be tested using in situ hybridization to detect the serotonin 5-HT2A receptor gene htr2a. In the past, such procedures, utilizing radioactive riboprobe, were difficult because of the complicated workflow that needs several days to perform and the added difficulty that the technique required the use of fresh frozen tissues maintained in an RNase-free environment. Recently, the development of short oligonucleotide probes has simplified in situ hybridization procedures and allowed the use of paraformaldehyde-prefixed brain sections, which are more widely available in laboratories. Here, we describe a detailed protocol using non-radioactive oligonucleotide probes on the prefixed brain tissues. Hybridization probes used for this study include dapB (a bacterial gene coding for dihydrodipicolinate reductase), ppiB (a housekeeping gene coding for peptidylprolyl isomerase B), and htr2a (a serotonin gene coding for 5-HT2A receptors). This method is relatively simply, cheap, reproducible and requires less than two days to complete.

Size-selective and passive paracellular diffusion of amyloid-β across tight junctions of the blood-brain barrier in Alzheimer’s disease., The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain.

Receptor families of the innate immune response engage in 'cross-talk' to tailor optimal immune responses against invading pathogens. However, these responses are subject to multiple levels of regulation to keep in check aberrant inflammatory signals. Here, we describe a role for the orphan receptor interleukin-17 receptor D (IL-17RD) in negatively regulating Toll-like receptor (TLR)-induced responses. Deficiency of IL-17RD expression in cells leads to enhanced pro-inflammatory signalling and gene expression in response to TLR stimulation, and Il17rd(-/-) mice are more susceptible to TLR-induced septic shock. We demonstrate that the intracellular Sef/IL-17R (SEFIR) domain of IL-17RD targets TIR adaptor proteins to inhibit TLR downstream signalling thus revealing a paradigm involving cross-regulation of members of the IL-17R and TLR families.

Mandeville’s first publication – the thesis Disputatio Philosophica de Brutorum Operationibus (1689) – advocated the Cartesian position that both denied feeling and sensation, let alone thought, to non-human animals and stressed the inherent distinctiveness of the conscious sensory and inferential capacities of human agents. Yet his later writings subscribed to a directly opposed Enlightenment position. His translation of La Fontaine’s Fables drew comparisons between humans and animals throughout, and by the time of the Fable of the Bees, Mandeville was clearly in the camp stressing the continuity of human and non-human animal nature, a tradition following Hobbes, Montaigne and La Rochefoucauld, and later to include Helvetius, de la Mettrie and Hume. The function of pride in Mandeville’s ethics is examined in terms of this debate, framed by Bayle’s famous ‘Rorarius’ entry in his Dictionary. With this background in place, Mandeville’s claim regarding the psychological role of pride as the ‘other Recompense…[of] the vain Satisfaction of making our Species appear more exalted and remote from that of other Animals’ is then discussed. It is presented as a critique of Shaftesbury’s discussion in the Characteristics relating to the norm of fulfilling one’s human nature.

A three-year-old female Irish setter dog presented with a history of shallow breathing, pyrexia and regurgitation. CT imaging revealed a 13×7×5 cm caudal mediastinal mass extending from the level of the right atrium to the diaphragm and surrounding the oesophagus. Total excision was achieved by a left sixth intercostal thoracotomy approach. Histological examination was consistent with a sterile abscess. The dog recovered uneventfully and was discharged on the third day after surgery. One year following surgery, the dog was in excellent physical condition with no evidence of recurrence of clinical signs. Total excision using a left sixth intercostal thoracotomy was a feasible and effective surgical option in this case. Benefit of total excision versus partial excision for caudal mediastinal paraoesophageal abscesses in dogs remains to be determined.

Purpose: Pathogenic leptospires colonize the renal tubules of reservoir hosts of infection and are excreted via urine into the environment. Asymptomatic reservoir hosts include a wide range of domestic and wild animal species and include cattle, dogs, and rats that can persistently excrete large numbers of pathogenic leptospires over many months. A similar presentation has been observed in humans categorized as "long-term asymptomatic individuals" as they excreted leptospires in the absence of any clinical symptoms or positive serology. Experimental design: In the current study, the urine of experimentally infected rats, which showed no clinical signs or positive serology, was analyzed by CE-MS to identify urinary biomarkers of chronic infection. Results: A discriminating peptide pattern of 43 polypeptides provided a sensitivity of 93%, a specificity of 83%, and an accuracy of 90% for the identification of urine from chronically infected rats (p < 0.05, AUC > 90%). The majority of discriminating peptides were decreased in abundance in urine of chronically infected rats, including a peptide derived from neprilysin, a membrane metalloendopeptidase, the expression of which has previously been shown to be diminished in infected urine. Conclusion and clinical relevance: Results highlight the diagnostic capabilities of urinary biomarkers to identify reservoir hosts of leptospirosis using CE coupled to MS.