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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: Glioblastoma (GBM), being a highly vascularised and locally invasive tumour, is an attractive target for anti-angiogenic and anti-invasive therapies. The GBM/endothelial cell response to gossypol/temozolomide (TMZ) treatment was investigated with a particular aim to assess treatment effects on cancer hallmarks. Methods: Cell viability, endothelial tube formation and GBM tumour cell invasion were variously assessed following combined treatment in vitro. The U87MG-luc2 subcutaneous xenograft model was used to investigate therapeutic response in vivo. Viable tumour response to treatment was interrogated using immunohistochemistry. Combined treatment protocols were also tested in primary GBM patient-derived cultures. Results: An endothelial/GBM cell viability inhibitory effect, as well as an anti-angiogenic and anti-invasive response, to combined treatment have been demonstrated in vitro. A significantly greater anti-proliferative (P=0.020, P=0.030), anti-angiogenic (P=0.040, P

Illicit use of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) may cause a mild or severe form of the serotonin syndrome. The syndrome intensity is not just influenced by drug doses but also by environmental factors. Warm environmental temperatures and physical activity are features of raves. The purpose of this study was to assess how these two factors can potentially intensify the syndrome. Rats were administered MDMA at doses of 0.3, 1, or 3 mg/kg and examined in the absence or presence of warm temperature and physical activity. The syndrome intensity was estimated by visual scoring for behavioral syndrome and also instrumentally measuring changes in symptoms of the syndrome. Our results showed that MDMA at 3 mg/kg, but not 0.3 or 1 mg/kg, caused a mild serotonin syndrome in rats. Each environmental factor alone moderately intensified the syndrome. When the two factors were combined, the intensification became more severe than each factor alone highlighting a synergistic effect. This intensification was blocked by the 5-HT2A receptor antagonist M100907, competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist CGS19755, autonomic ganglionic blocker hexamethonium, and the benzodiazepine-GABAA receptor agonist midazolam but not by the 5-HT1A receptor antagonist WAY100635 or nicotinic receptor antagonist methyllycaconitine. Our data suggest that, in the absence of environmental factors, the MDMA-induced syndrome is mainly mediated through the serotonergic transmission (5-hydroxytryptamine (5HT)-dependent mechanism) and therefore is relatively mild. Warm temperature and physical activity facilitate serotonergic and other neural systems such as glutamatergic and autonomic transmissions, resulting in intensification of the syndrome (non-5HT mechanisms).

The difference between the method of metaphysics and the method of mathematics was an issue of central concern for Kant in both the Pre-Critical and Critical periods. I will argue that when Kant speaks of the ‘philosophical method’ in the Doctrine of Method in the Critique of Pure Reason (CPR), he frequently has in mind not his own methodology but rather the method of conceptual analysis associated with rationalism. The particular target is Moses Mendelssohn’s picture of analysis contained in his submission for the 1763 Prize Essay competition. By the time of the first Critique, I argue, Kant wants to maintain his own longstanding commitment to the distinctness of the methods of metaphysics and mathematics. However, Kant wants to use this same analysis of the source of the distinction to diagnose the origins of the dogmatism that is engendered by the method of the rationalists.

Non-suppurative meningoencephalitis is a breed-restricted canine neuroinflammatory disorder affecting young greyhounds in Ireland. A genetic risk factor is suspected because of the development of disease in multiple siblings and an inability to identify a causative infectious agent. The aim of this study was to examine potential associations between dog leucocyte antigen (DLA) class II haplotype and the presence of the disease. DLA three locus haplotypes were determined in 31 dogs with non-suppurative meningoencephalitis and in 115 healthy control dogs using sequence-based typing (SBT) methods. All dogs were unrelated at the parental level. Two haplotypes (DRB1*01802/DQA1*00101/DQB1*00802 and DRB1*01501/DQA1*00601/DQB1*02201) were significantly (P = 0.0099 and 0.037) associated with the presence of meningoencephalitis, with odds ratios (95% confidence interval) of 5.531 (1.168-26.19) and 3.736 (1.446-9.652), respectively. These results confirm that there is an association between DLA class II haplotype and greyhound meningoencephalitis, suggesting an immunogenetic risk factor for the development of the disease. Greyhound meningoencephalitis may be a suitable model for human neuroinflammatory diseases with an immunogenetic component.

Obesity is characterized by chronic inflammation associated with neutrophil and M1 macrophage infiltration into white adipose tissue. However, the mechanisms underlying this process remain largely unknown. Based on the ability of oil-based adjuvants to induce immune responses, we hypothesized that endogenous oils derived from necrotic adipocytes may function as an immunological “danger signal.” Here we show that endogenous oils of human origin are potent adjuvants, enhancing antibody responses to a level comparable to Freund’s incomplete adjuvant. The endogenous oils were capable of promoting interleukin (IL)-1α–dependent recruitment of neutrophils and M1-like macrophages, while simultaneously diminishing M2-like macrophages. We found that endogenous oils from subcutaneous and omental adipocytes, and from healthy and unhealthy obese individuals, promoted comparable inflammatory responses. Furthermore, we also confirmed that white adipocytes in visceral fat of metabolically unhealthy obese (MUO) individuals are significantly larger than those in metabolically healthy obese individuals. Since adipocyte size is positively correlated with adipocyte death, we propose that endogenous oils have a higher propensity to be released from hypertrophied visceral fat in MUO individuals and that this is the key factor in driving inflammation. In summary, this study shows that adipocytes contain a potent oil adjuvant which drives IL-1α–dependent proinflammatory responses in vivo.

Squirrelpox virus (SQPV) is a significant factor in red squirrel (Sciurus vulgaris) population declines but has previously been unconfirmed in the Republic of Ireland. In 2011 a juvenile red squirrel from Wicklow presented with facial, perivulval, and nail bed SQPV skin lesions confirmed by histopathology, PCR, and electron microscopy.

Kant criticizes the so-called ‘preformation’ hypothesis – a nativist account of the origin of the categories – at the end of the B-Deduction on the ground that it entails scepticism. I examine the historical context of Kant's criticism, and identify the targets as both Crusius and Leibniz. There are two claims argued for in this paper: first, that attending to the context of the opposition to certain forms of nativism affords a way of understanding Kant's commitment to the so-called ‘discursivity thesis’, by contrasting the possession conditions for the categories with those for innate ideas; secondly, it provides an insight with regard to Kant's understanding of the dialectic with scepticism. Kant's claim is that a certain explanatory lacuna that attaches to Humean empiricism can be seen to apply equally to any nativist theory. The lacuna concerns the explanation of the modal purport ofa priorinecessity, i.e. how it is that our consciousness can even distinguish contents that are representedasnecessary features of objects.

Endometrial epithelial cells play a critical role in mediating inflammatory mechanisms key to bacterial clearance and tissue re-modelling postpartum. This study characterised innate immune gene expression by bovine endometrial epithelial cells from three animals in response to Escherichia coli, a common cause of bovine uterine disease. Expression of key innate immune genes, encoding Toll-like receptor 4 (TLR4), the transcription factor NFkB1, the chemokine interleukin 8 (IL8), inflammatory cytokines (interleukins IL1β, IL6; tumour necrosis factor, TNF), β-defensins (lingual antimicrobial peptides LAP, tracheal antimicrobial peptide TAP) and acute phase proteins (haptoglobin, HP; serum amyloid A, SAA3) was examined in endometrial epithelial cells stimulated with E. coli for 6 and 24h using qRT-PCR. Expression of all genes was increased significantly (P

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.

Greyhound nonsuppurative meningoencephalitis is an idiopathic breed-associated fatal meningoencephalitis with lesions usually occurring within the rostral cerebrum. This disorder can only be confirmed by postmortem examination, with a diagnosis based upon the unique topography of inflammatory lesions. Our purpose was to describe the magnetic resonance (MR) imaging features of this disease. Four Greyhounds with confirmed Greyhound nonsuppurative meningoencephalitis were evaluated by MR imaging. Lesions predominantly affected the olfactory lobes and bulbs, frontal, and frontotemporal cortical gray matter, and caudate nuclei bilaterally. Fluid attenuation inversion recovery (FLAIR) and T2 weighted spin-echo (T2W) sequences were most useful to assess the nature, severity, extension, and topographic pattern of lesions. Lesions were predominantly T2-hyperintense and T1-isointense with minimal or absent contrast enhancement.

Staphylococcal mastitis is one of the main reasons for culling adult does from commercial rabbitries. The aim of this study was describe the spectrum of gross and microscopic lesions in 178 cases of chronic staphylococcal mastitis in adult does and to determine whether there is a correlation between Staphylococcus aureus genotypes and pathology. On the basis of histopathology, chronic mastitis was differentiated into abscesses (66.3%), suppurative mastitis with a lobular pattern (7.9%), cellulitis (19.6%) and mixed lesions (6.2%). Pathological presentations were not related to S. aureus genotype.