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Objective: This study aimed to assess how race, social vulnerability, and maternal age influence pediatric cochlear implant access and usage., Study Design: Retrospective cohort., Setting: Tertiary Pediatric University Hospital., Methods: This study included individuals aged 0 to 18 who received a cochlear implant at our center between the years 2000 and 2022. Social vulnerability data from 2020 was obtained from the Centers for Disease Control and Prevention., Results: Of the 302 patients included in our study, 43% were black and 50% were white. Patients from the highest to lowest social vulnerability quintiles comprised 31%, 25%, 18%, 10%, and 14% of our sample, respectively. Race was associated with social vulnerability index (SVI) (P < .001), with a mean score of 0.70 (±0.26) and 0.49 (±0.27) for black and white patients, respectively. Later age at hearing loss (HL) diagnosis and cochlear implantation (CI) were associated with more and most vulnerable SVI (P < .05). Delayed diagnosis was also associated with black and other racial groups (P = .041), and adolescent maternal age (P = .03). Greater SVI was associated with less daily cochlear implant usage (P = .004). The most vulnerable patients were more likely to be lost to follow-up (P = .03) despite no difference based on maternal age (P = .59) and insurance status (P = .47)., Conclusion: This study underscores the significance of mitigating disparities in timely diagnosis of HL, consistent CI usage, and appropriate follow-up care. This is a first step toward the formulation of novel strategies aimed at overcoming barriers and developing appropriate intervention programs., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

The Silva pattern-based classification of HPV-associated endocervical adenocarcinoma has become an integral part of the histologic assessment of these tumors. Unfortunately, the Silva system reproducibility has had mixed results in past studies, and clinical practice still favors the FIGO stage assessment in directing therapeutic interventions for patients. In our study, we aimed to assess our institution's concordance including not only gynecologic pathologists, but also pathology trainees through a series of 69 cases. The grouped total kappa concordance from all participants was 0.439 (Moderate), with an overall trainee kappa of 0.417 (moderate) and an overall pathologist kappa of 0.460 (moderate). Perfect concordance among all 10 study participants was seen in 8/69 cases (11.6 %), corresponding to 5/22 Pattern A cases (22.7 %), 0/16 Pattern B cases (0 %), and 3/31 Pattern C cases (9.7 %), with similar findings between trainees and pathologists when compared within their own cohorts. Recurrence was identified in 2 Pattern A cases, indicating a potential issue with limited excisional specimens which may not fully appreciate the true biologic aggressiveness of the lesions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21 + hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available single-nuclei RNAseq data, we identified a subpopulation of p21 + hepatocytes enriched in a unique secretome of factors, such as CXCL14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21 + hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, CXCL14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or CXCL14 with a neutralizing antibody. We found that targeting CXCL14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting senescent hepatocytes had no effect. These data support the conclusion that the sustained induction of p21 in hepatocytes with persistent CXCL14 secretion are critical mechanistic events leading to ALF in mice and human patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hartmut Jaeschke reports financial support was provided by National Institutes of Health. Anup Ramachandran reports financial support was provided by National Institutes of Health. David S. Umbaugh reports financial support was provided by National Institutes of Health. Hartmut Jaeschke reports a relationship with Johnson & Johnson Consumer Health that includes: consulting or advisory, funding grants, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Boric acid (BA) powder is commonly used to treat otologic conditions, such as mastoid bowl inflammation and chronic otitis externa. Exposure to 50 mg per day is thought to cause systemic toxicity in humans. Inflamed skin and mucosal surfaces readily absorb BA. The aim of this study was to measure the doses of BA commonly used in clinical otology and alert the otolaryngology community to BA's underappreciated potential source of systemic toxicity., Study Design: Prospective, controlled., Setting: Laboratory., Methods: BA dose administration was measured by weighing the BA generated by common insufflators: accordion bellows, House-Sheehy insufflator, DeVilbiss insufflator, and pneumatic powder blower. Manual insufflation was performed with 3 compressions of the bulb. The pneumatic blower was sprayed for 1 second. Measurements were repeated 10 times., Results: The DeVilbiss insufflator delivered the lowest mean BA dose, 6.1 mg (SD 3.4, range 2.1-13.7), followed by the House-Sheehy 8.9 mg (SD 8.4, range 1.6-27.8), the pneumatic blower 192.8 mg (SD 38.3, range 150.0-261.7), and the accordion, 284.1 mg (SD 215.0, range 37.8-730.8)., Conclusion: BA dose delivery is highly variable by insufflator type, and doses thought to cause systemic toxicity are commonly generated. Awareness of and further investigation into the potential toxicity of otic administration of BA seems warranted., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

The recent increase in available molecular and genomic data for diverse taxa helps to shed new light on long-standing theories. Research into sex chromosome evolution has particularly benefited from a growing number of studies of fish, motivated by their highly diverse mechanisms of sex determination. Sexual antagonism is regularly cited as an influential force in sex chromosome emergence; however, this so far proves difficult to demonstrate. In this review, we highlight recent developments in the investigation of sexual antagonism in sex chromosome research in fish. We find strong emphasis placed on study-organism specific genomic features and patterns of recombination, rather than evidence for a comprehensive role of sexual antagonism. In this light, we discuss the alternative models of sex chromosome evolution. We conclude that fish represents a key resource for further research, provided attention is given to species-specific effects while simultaneously integrating comparative studies across taxa for a vital and comprehensive understanding of sex chromosome evolution and investigation of proposed models., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Janus kinase (JAK)/signal transducer and activator of transcription signaling (STAT) has been implicated in the pathophysiology of hidradenitis suppurativa (HS). This study evaluated treatment-related transcriptomic and proteomic changes in patients with moderate-to-severe HS treated with the investigational oral JAK1-selective inhibitor povorcitinib (INCB054707) in two phase 2 trials. Lesional skin punch biopsies (baseline and Week 8) were taken from active HS lesions of patients receiving povorcitinib (15 or 30 mg) once daily (QD) or a placebo. RNA-seq and gene set enrichment analyses were used to evaluate the effects of povorcitinib on differential gene expression among previously reported gene signatures from HS and wounded skin. The number of differentially expressed genes was the greatest in the 30 mg povorcitinib QD dose group, consistent with the published efficacy results. Notably, the genes impacted reflected JAK/STAT signaling transcripts downstream of TNF-α signaling, or those regulated by TGF-β. Proteomic analyses were conducted on blood samples obtained at baseline and Weeks 4 and 8 from patients receiving povorcitinib (15, 30, 60, or 90 mg) QD or placebo. Povorcitinib was associated with transcriptomic downregulation of multiple HS and inflammatory signaling markers as well as the reversal of gene expression previously associated with HS lesional and wounded skin. Povorcitinib also demonstrated dose-dependent modulation of several proteins implicated in HS pathophysiology, with changes observed by Week 4. The reversal of HS lesional gene signatures and rapid, dose-dependent protein regulation highlight the potential of JAK1 inhibition to modulate underlying disease pathology in HS.

A mechanistic understanding of cell-autonomous skeletal muscle changes after injury can lead to novel interventions to improve functional recovery in an aged population. However, major knowledge gaps persist owing to limitations of traditional biological aging models. 2D cell culture represents an artificial environment, while aging mammalian models are contaminated by influences from non-muscle cells and other organs. Here, a 3D muscle aging system is created to overcome the limitations of these traditional platforms. It is shown that old muscle constructs (OMC) manifest a sarcopenic phenotype, as evidenced by hypotrophic myotubes, reduced contractile function, and decreased regenerative capacity compared to young muscle constructs. OMC also phenocopy the regenerative responses of aged muscle to two interventions, pharmacological and biological. Interrogation of muscle cell-specific mechanisms that contribute to impaired regeneration over time further reveals that an aging-induced increase of complement component 4b (C4b) delays muscle progenitor cell amplification and impairs functional recovery. However, administration of complement factor I, a C4b inactivator, improves muscle regeneration in vitro and in vivo, indicating that C4b inhibition may be a novel approach to enhance aged muscle repair. Collectively, the model herein exhibits capabilities to study cell-autonomous changes in skeletal muscle during aging, regeneration, and intervention., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Intestinal infection of many host species with Lawsonia intracellularis are widely reported. Analyses of infections among carnivorous falcons have not previously been reported. Fifty juvenile captive falcons (Falco spp.) with or without Lawsonia infection were investigated in the United Arab Emirates, including clinical laboratory methods. Fresh intestinal biopsy samples were analysed by microbiological techniques for Lawsonia and other bacteria and by standard parasitological and pathological methods. Lawsonia intracellularis infection was diagnosed by microbiological examination and qPCR in 10 of 50 juvenile falcons at case examination. Seven of these 10 falcons were of normal clinical appearance, and the other three had other contributing factors to ill-thrift. A range of other conditions were noted in 40 case control falcons. This first report of Lawsonia infection in falcons suggests that the agent may have a limited contribution to clinical disease in these birds, including ill-thrift syndromes. This lack of clinical disease association mimics that noted among Lawsonia infections recorded in other avian families., (© 2023 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

PRAME and NY-ESO-1 are cancer-testis antigens (CTAs) reported to be highly enriched in triple-negative breast cancers (TNBCs), against which vaccines and immunotherapies are currently being developed. This study aims to analyze PRAME and NY-ESO-1 expression in TNBCs and their correlation with clinical outcomes. This is a retrospective cohort study of TNBC patients who have undergone neoadjuvant chemotherapy. PRAME and NY-ESO-1 expression were assessed on pre-therapy biopsies as H-scores (percentage x intensity) with final H scores of 2-3 considered as positive. Association between expression and pathologic complete response (pCR), metastasis, and residual cancer burden (RCB) were assessed via logistic regression. Cox proportional hazards models were used to assess the association with progression-free survival. P-values < 0.05 were considered statistically significant. Sixty-three percent of 76 patients were positive for PRAME. In contrast, only 5 % were positive for NY-ESO-1. PRAME positivity was significantly associated with a lower likelihood of early metastatic disease (OR = 0.24, 95 % CI 0.08-0.62; P = 0.005). However, it was not significantly associated with pCR, RCB category, or progression-free survival. NY-ESO1 score was not significantly associated with early metastatic disease, pCR, RCB category, or progression-free survival. Our results suggest that PRAME positivity may be associated with a lower risk of early metastasis in TNBCs, but not with response to neoadjuvant chemotherapy or progression-free survival. The high expression of PRAME in TNBCs makes it a potential therapeutic target, while NY-ESO1 appears to be a less useful marker. However, further larger studies are needed to ascertain the utility of these markers., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Introduction: Patients who require mechanical ventilation after self-poisoning with ingested organophosphorus (OP) insecticides often die. Aspiration of stomach contents may contribute to lung injury and lethality. This study was designed to assess the severity of direct and indirect pulmonary injury created by pulmonary instillation of mixtures of OP insecticide, solvent (Solv) and porcine gastric juice (GJ) compared to controls., Methods: Terminally anaesthetised minipigs (groups n  = 5) were exposed to sham bronchoscopy or given mixtures (0.5 mL/kg) of: saline, GJ, OP insecticide and GJ (OP + GJ), or Solv and GJ (Solv + GJ), placed into the right lung, and monitored for 48 h. Lung injury was assessed through analysis of bronchoalveolar lavage fluid (BALF), computed tomography and histopathology., Results: OP + GJ created a direct lung injury consisting of neutrophil infiltration, oedema and haemorrhage, as well as indirect injury to the other lung. OP + GJ directly-injured lung parenchyma had increased concentrations of BALF protein, albumin, IL-6, IL-8 and C-reactive protein (CRP) at 24 h ( p  < 0.05), and BALF protein, albumin and CRP at 48 h ( p  < 0.05), when compared with controls. Aspiration of GJ produced similar direct effects to OP + GJ but less indirect lung injury. Lung injury was less severe after Solv + GJ, for combined lung histopathology scores (vs. OP + GJ, p  < 0.05) and for the proportion of directly-injured lung that was poorly/non-aerated at 48 h., Conclusion: Pulmonary instillation of OP + GJ created more lung damage than controls or Solv + GJ. In patients with severe OP insecticide poisoning and reduced consciousness, early airway protection is likely to reduce pulmonary damage.

Understanding how organisms adapt to their local environment is central to evolution. With new whole-genome sequencing technologies and the explosion of data, deciphering the genomic basis of complex traits that are ecologically relevant is becoming increasingly feasible. Here, we studied the genomic basis of wing shape in two Neotropical butterflies that inhabit large geographical ranges. Heliconius butterflies at high elevations have been shown to generally have rounder wings than those in the lowlands. We reared over 1,100 butterflies from 71 broods of H. erato and H. melpomene in common-garden conditions and showed that wing aspect ratio, that is, elongatedness, is highly heritable in both species and that elevation-associated wing aspect ratio differences are maintained. Genome-wide associations with a published data set of 666 whole genomes from across a hybrid zone, uncovered a highly polygenic basis to wing aspect ratio variation in the wild. We identified several genes that have roles in wing morphogenesis or wing aspect ratio variation in Drosophila flies, making them promising candidates for future studies. There was little evidence for molecular parallelism in the two species, with only one shared candidate gene, nor for a role of the four known colour pattern loci, except for optix in H. erato. Thus, we present the first insights into the heritability and genomic basis of within-species wing aspect ratio in two Heliconius species, adding to a growing body of evidence that polygenic adaptation may underlie many ecologically relevant traits., (© 2021 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Background: Child with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of SARS-CoV-2-related illnesses that the viruses causes in children., Methods: We conducted a prospective cohort study of children and adolescents (aged <21 years) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time polymerase chain reaction assay., Results: Of 382 children, 293 (77%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (P < .0001), less likely to have asthma (P = .005), and more likely to have an infected sibling contact (P = .001) than uninfected children. Children aged 6-13 years were frequently asymptomatic (39%) and had respiratory symptoms less often than younger children (29% vs 48%; P = .01) or adolescents (29% vs 60%; P < .001). Compared with children aged 6-13 years, adolescents more frequently reported influenza-like (61% vs 39%; P < .001) , and gastrointestinal (27% vs 9%; P = .002), and sensory symptoms (42% vs 9%; P < .0001) and had more prolonged illnesses (median [interquartile range] duration: 7 [4-12] vs 4 [3-8] days; P = 0.01). Despite the age-related variability in symptoms, wWe found no difference in nasopharyngeal viral load by age or between symptomatic and asymptomatic children., Conclusions: Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while asthma is associated with decreased risk. Age-related differences in clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for coronavirus disease 2019 and in developing screening strategies for schools and childcare settings., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Lawsonia intracellularis is an obligate intracellular bacterium associated with enteric disease in pigs. Clinical signs include weight loss, diarrhea, and, in some cases, sudden death. The hallmark lesion is the thickening of the intestinal mucosa caused by increased epithelial cell replication, known as proliferative enteropathy. The immune response to L. intracellularis is not well defined, and detection of the infection, especially in the early stages, is still a significant challenge. We review here the main approaches used to identify this important but poorly understood pathogen. Detection of L. intracellularis infection as the cause of clinical disease is confounded by the high prevalence of the pathogen in many countries and that several other pathogens can produce similar clinical signs. A single L. intracellularis -specific ELISA and several amplification assays are available commercially to aid detection and surveillance, although histopathology remains the primary way to reach a conclusive diagnosis. There are major gaps in our understanding of L. intracellularis pathogenesis, especially how the host responds to infection and the factors that drive infection toward different clinical outcomes. Knowledge of pathogenesis will increase the predictive value of antemortem tests to guide appropriate interventions, including identification and treatment of subclinically affected pigs in the early stages of disease, given that this important manifestation reduces pig productivity and contributes to the economic burden of L. intracellularis worldwide.

Organophosphorus (OP) insecticide self-poisoning causes over 100,000 global deaths annually. Around a third of patients are intubated and up to half of these can die. Post-mortem analysis of OP poisoned patients' lungs reveals consolidation, edema and hemorrhage, suggesting that direct or indirect lung damage may contribute to mortality. The lung injury caused by these formulated agricultural preparations is poorly characterised in humans, and a valid histopathology scoring system is needed in a relevant animal model to further investigate the disease and potential treatments. We conducted two pilot studies in anesthetized minipigs, which are commonly used for toxicological studies. In the first, pigs were given 2.5 mL/kg of either OP (n = 4) or saline (n = 2) by gavage and compared with positive controls (iv oleic acid n = 2). The second study simulated ingestion followed by gastric content aspiration: mixtures of OP (n = 3) or saline (n = 2) (0.63-0.71mL/kg) were placed in the stomach, and then small volumes of the gastric content were placed in the lung. At post-mortem examination, lungs were removed and inflation-fixed with 10% neutral buffered formalin. Samples (n = 62) were taken from cranial and caudal regions of both lungs. Two experienced lung histopathologists separately scored these samples using 8 proposed features of damage and their scores related (Kendall rank order). Two elements had small and inconsistent scores. When these were removed, the correlation increased from 0.74 to 0.78. Eight months later, a subset of samples (n = 35) was re-scored using the modified system by one of the previous histopathologists, with a correlation of 0.88. We have developed a reproducible pulmonary histopathology scoring system for OP poisoning in pigs which will assist future toxicological research and improve understanding and treatment of human OP poisoning., Competing Interests: The authors have declared that no competing interests exist.

Echocardiographic measurement of cardiac output with automated software analyses of spectral curves in the left ventricular outflow tract has been introduced. This study aimed to assess the precision and accuracy of cardiac output measurements as well as the ability to track cardiac output changes over time comparing the automated echocardiographic method with the continuous pulmonary artery thermodilution cardiac output technique and the manual echocardiographic method in cardiac surgery patients. Cardiac output was measured simultaneously with all three methods in 50 patients on the morning after cardiac surgery. A second comparison was performed 90-180 min later. Precisions for each method were measured. Bias and limits of agreement (LoA) between methods were assessed and concordance- and polar plots were used for evaluating trending of cardiac output. When comparing the automated echocardiographic method with the thermodilution technique, the mean bias was 0.72 L/min with LoA - 1.89; 3.33 L/min corresponding to a percentage error of 46%. The concordance rate was 47%. The mean bias between the automated- and the manual echocardiographic methods was - 0.06 L/min (95% LoA - 2.33; 2.21 L/min, percentage error 42%). The concordance rate was 79%. The automated echocardiographic method did not meet the criteria for interchangeability with the thermodilution technique or the manual echocardiographic method. Trending ability was poor when compared to the continuous thermodilution technique, but moderate when compared to the manual echocardiographic method.Trial registry number: NCT03372863. Retrospectively registered December 14th 2017.

Transmission of SARS-CoV-2 leading to COVID-19 occurs through exhaled respiratory droplets from infected humans. Currently, however, there is much controversy over whether respiratory aerosol microdroplets play an important role as a route of transmission. By measuring and modeling the dynamics of exhaled respiratory droplets, we can assess the relative contribution of aerosols to the spreading of SARS-CoV-2. We measure size distribution, total numbers, and volumes of respiratory droplets, including aerosols, by speaking and coughing from healthy subjects. Dynamic modeling of exhaled respiratory droplets allows us to account for aerosol persistence times in confined public spaces. The probability of infection by inhalation of aerosols when breathing in the same space can then be estimated using current estimates of viral load and infectivity of SARS-CoV-2. The current known reproduction numbers show a lower infectivity of SARS-CoV-2 compared to, for instance, measles, which is known to be efficiently transmitted through the air. In line with this, our study of transmission of SARS-CoV-2 suggests that aerosol transmission is a possible but perhaps not a very efficient route, in particular from non-symptomatic or mildly symptomatic individuals that exhibit low viral loads., (© 2020 Author(s).)

Background: Liver disease is a common cause of morbidity and mortality in dogs. Currently, it is challenging to prognosticate in these cases. The aim of this study was to evaluate the utility of the haematological variables in dogs with chronic hepatitis., Methods: Dogs with chronic hepatitis confirmed on histopathology had presenting haematological values retrospectively obtained and evaluated against survival time. Eighty-two dogs met the inclusion criteria and their data analysed., Results: Neutrophilic patients, with a count greater than 12×10 9 /l, controlled for sex and age, had a shorter survival time (P≤0.01). In dogs, neutrophilia at presentation predicted a poor outcome, whereas the other haematological parameters were not prognostically informative. When the dogs were split into even quarters on the basis of their neutrophil count, those within the higher quartiles had poorer survival times. Neutrophilia was associated with a poorer survival time in comparison to those patients with a lower count., Conclusion: The relationship between neutrophils, inflammation and clinical outcome is deserving of future study in dogs with chronic hepatitis., Competing Interests: Competing interests: None declared., (© British Veterinary Association 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Cascade genetic testing (CGT) of hereditary breast and ovarian cancer (HBOC) or Lynch Syndrome (LS) patients' relatives offers opportunities to prevent cancer, but CGT rates are not well described. We aimed to measure reported disclosure of genetic testing results and CGT rates in these families and evaluate patients' views of educational media., Methods: Patients with HBOC or LS identified from germline genetic testing at an academic institution between 2011 and 2016 were surveyed regarding disclosure, testing among relatives, and perceptions of educational materials. Medical records and pedigrees provided numbers of total and first-degree relatives., Results: Of 103 mutation carriers consented, 64 (63%) completed the survey an average of 38 months after receiving genetic testing results. Participants' mean age was 53 years, and thirty-one (48%) had a cancer diagnosis. The majority (86%) felt extremely or very comfortable sharing health information. Participants disclosed results to 87% of first-degree relatives, but reported that only 40% of first-degree relatives underwent testing. First-degree female relatives had significantly higher CGT rates than first-degree male relatives (59% versus 21%, P < 0.001). Participants with HBOC reported higher CGT rates than those with LS (49% versus 33%, P = 0.02). Participants did not identify any one educational medium as more helpful than the others for disclosing results., Conclusion: Disclosure rates are high among HBOC and LS mutation carriers, but reported CGT rates are low. Gender- and mutation-specific barriers prevent patients' family members from undergoing CGT. Future studies should implement materials to address these barriers and improve CGT rates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To investigate national and regional variations in pediatric tracheostomy rates, epidemiology, and outcomes from 2000 to 2012., Study Design: Retrospective cohort analysis., Setting: Previous research with the 1997 edition of the Kids' Inpatient Database (KID), a national database of pediatric hospital discharge data, demonstrated that rates and outcomes of pediatric tracheostomy vary among US geographic regions. The KID has since been released an additional 5 times, increasing in size with successive editions., Subjects and Methods: Patients ≤18 years old with procedure codes for permanent or temporary tracheostomy from 2000 to 2012 were included. Primary outcome was a weighted population-based rate of tracheostomy stratified by year. Secondary analysis included epidemiologic characteristics and outcomes stratified by year and geographic region., Results: A weighted total of 24,354 cases was analyzed. Population-based tracheostomy rates decreased from 6.8 ± 0.2 (mean ± SD) tracheostomies per 100,000 child-years in 2000 to 6.0 ± 0.2 in 2012. Minorities increased from 53.3% in 2000 to 56.4% in 2012. Patients experienced increased procedures, diagnoses, length of stay, and hospital charges with time. From 2000 to 2012, rates and outcomes varied by US geographic region. Mortality during hospitalization (8%) did not vary by year, patient age, region, or sex., Conclusions: Pediatric tracheostomy is associated with variation in incidence, epidemiology, and hospitalization outcomes in the United States from 2000 to 2012. While rates of pediatric tracheostomy decreased, patients became increasingly medically complicated and ethnically diverse with outcomes varying according to geographic region.

Campylobacter is the most common cause of bacterial food-borne diarrhoeal disease worldwide. Chicken meat is considered the main source of human infection; however, C. jejuni and C. coli have also been reported in a range of livestock and wildlife species, including pheasants. Wild pheasant meat reaches the consumer's table because of hunting but there is a lack of information concerning the risk of Campylobacter infection in humans. This study aimed to determine the prevalence of Campylobacter in wild game pheasants in Scotland, to identify the main sequence types (STs) present and to evaluate their impact on public health. A total of 287 caecal samples from five Scottish regions were collected during the hunting season 2013/2014. Campylobacter was detected and enumerated using standard culture methods. PCR and High Throughput Multi Locus Sequence Typing (HiMLST) were used for species identification and sequence typing. In total, 36.6% of 287 caecal samples (n = 105; 95% CI: 14-59.2) were Campylobacter positive. Using PCR, 62.6% of samples (n = 99) were identified as C. coli and 37.4% as C. jejuni. HiMLST (n = 80) identified 19 different STs. ST-828 (n = 19) was the most common, followed by ST-827 (n = 12) and ST19 (n = 7). Sixteen of the 19 STs isolated are present in humans and eight are C. coli STs that account for 6.96% of human infections, although the overall risk to public health from pheasant meat is still considered to be low., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It is generally recognized that only relatively small molecular weight (typically < ∼ 500 Da) drugs can effectively permeate through intact stratum corneum. Here, we challenge this orthodoxy using a 62-nucleotide (molecular weight = 20,395 Da) RNA-based aptamer, highly specific to the human IL-23 cytokine, with picomolar activity. Results demonstrate penetration of the aptamer into freshly excised human skin using two different fluorescent labels. A dual hybridization assay quantified aptamer from the epidermis and dermis, giving levels far exceeding the cellular half maximal inhibitory concentration values (>100,000-fold), and aptamer integrity was confirmed using an oligonucleotide precipitation assay. A T helper 17 response was stimulated in freshly excised human skin resulting in significantly upregulated IL-17f, and IL-22; topical application of the IL-23 aptamer decreased both IL-17f and IL-22 by approximately 45% but did not result in significant changes to IL-23 mRNA levels, confirming that the aptamer did not globally suppress mRNA levels. This study demonstrates that very-large-molecular-weight RNA aptamers can permeate across the intact human skin barrier to therapeutically relevant levels into both the epidermis and dermis and that the skin-penetrating aptamer retains its biologically active conformational structure capable of binding to endogenous IL-23., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and atopic dermatitis, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti-inflammatory properties of tapinarof are mediated through activation of the aryl hydrocarbon receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue-human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist and confirm that its efficacy is dependent on AhR., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Unchecked inflammation, impaired keratinocyte differentiation, and heightened host defense responses typify psoriasis. Lambert et al. make clever use of psoriasis patient genetics and whole transcriptome RNA-Seq analysis to implicate Act1 in these seemingly variegated processes by keeping IL-17 receptor signaling in check while supporting differentiation and limiting innate immune responses in human keratinocytes., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Four red squirrels (Sciurus vulgaris) were subjected to necropsy examination over a 3-year period as part of a broader surveillance study. The squirrels presented with cutaneous, subcutaneous and/or internal swellings and nodules that consisted microscopically of sheets of atypical round cells and multinucleated giant cells. There was moderate anisokaryosis with rare mitoses. Nuclei ranged from oval to indented or C-shaped and some were bizarre, twisted or multilobulated. Many giant cells also had a bizarre morphology, with anisokaryosis within individual cells. Giant cell nuclei were often multilobulated, ring-shaped or segmented. Affected internal organs varied depending on the squirrel, but included lymph node, kidney, intestinal tract and lungs. Representative lesions from each of the four squirrels were negative for acid-fast organisms. Formalin-fixed tissues from all four squirrels and ethanol-fixed tissue from one animal were negative for Mycobacterium by polymerase chain reaction. Immunohistochemically, the majority of mononuclear and multinucleated giant cells in all four squirrels strongly expressed vimentin and class II molecules of the major histocompatibility complex. Otherwise, the atypical mononuclear and multinucleated cells were negative for CD3, Pax-5, Mac387, CD18 and E-cadherin. Based on the combination of cellular morphology, arrangement and immunophenotype, a novel form of atypical histiocytosis is considered most likely in these squirrels, although the exact origin and triggering factors remain uncertain., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Lawsonia intracellularis is an obligate intracellular bacterial pathogen that causes proliferative enteropathy (PE) in pigs. L. intracellularis infection causes extensive intestinal crypt cell proliferation and inhibits secretory and absorptive cell differentiation. However, the affected host upstream cellular pathways leading to PE are still unknown. β-catenin/Wnt signalling is essential in maintaining intestinal stem cell (ISC) proliferation and self-renewal capacity, while Notch signalling governs differentiation of secretory and absorptive lineage specification. Therefore, in this report we used immunofluorescence (IF) and quantitative reverse transcriptase PCR (RTqPCR) to examine β-catenin/Wnt and Notch-1 signalling levels in uninfected and L. intracellularis infected pig ileums at 3, 7, 14, 21 and 28 days post challenge (dpc). We found that while the significant increase in Ki67+ nuclei in crypts at the peak of L. intracellularis infection suggested enhanced cell proliferation, the expression of c-MYC and ASCL2, promoters of cell growth and ISC proliferation respectively, was down-regulated. Peak infection also coincided with enhanced cytosolic and membrane-associated β-catenin staining and induction of AXIN2 and SOX9 transcripts, both encoding negative regulators of β-catenin/Wnt signalling and suggesting a potential alteration to β-catenin/Wnt signalling levels, with differential regulation of the expression of its target genes. We found that induction of HES1 and OLFM4 and the down-regulation of ATOH1 transcript levels was consistent with the increased Notch-1 signalling in crypts at the peak of infection. Interestingly, the significant down-regulation of ATOH1 transcript levels coincided with the depletion of MUC2 expression at 14 dpc, consistent with the role of ATOH1 in promoting goblet cell maturation. The lack of significant change to LGR5 transcript levels at the peak of infection suggested that the crypt hyperplasia was not due to the expansion of ISC population. Overall, simultaneous induction of Notch-1 signalling and the attenuation of β-catenin/Wnt pathway appear to be associated with the inhibition of goblet cell maturation and enhanced crypt cell proliferation at the peak of L. intracellularis infection. Moreover, the apparent differential regulation of apoptosis between crypt and lumen cells together with the strong induction of Notch-1 signalling and the enhanced SOX9 expression along crypts 14 dpc suggest an expansion of actively dividing transit amplifying and/or absorptive progenitor cells and provide a potential basis for understanding the development and maintenance of PE.

Warming temperatures cause temporal changes in growing seasons and prey abundance that drive earlier breeding by birds, especially dietary specialists within homogeneous habitat. Less is known about how generalists respond to climate-associated shifts in growing seasons or prey phenology, which may occur at different rates across land cover types. We studied whether breeding phenology of a generalist predator, the American kestrel (Falco sparverius), was associated with shifts in growing seasons and, presumably, prey abundance, in a mosaic of non-irrigated shrub/grasslands and irrigated crops/pastures. We examined the relationship between remotely-sensed normalized difference vegetation index (NDVI) and abundance of small mammals that, with insects, constitute approximately 93% of kestrel diet biomass. We used NDVI to estimate the start of the growing season (SoGS) in irrigated and non-irrigated lands from 1992 to 2015 and tested whether either estimate of annual SoGS predicted the timing of kestrel nesting. Finally, we examined relationships among irrigated SoGS, weather and crop planting. NDVI was a useful proxy for kestrel prey because it predicted small mammal abundance and past studies showed that NDVI predicts insect abundance. NDVI-estimated SoGS advanced significantly in irrigated lands (β = -1·09 ± 0·30 SE) but not in non-irrigated lands (β = -0·57 ± 0·53). Average date of kestrel nesting advanced 15 days in the past 24 years and was positively associated with the SoGS in irrigated lands, but not the SoGS in non-irrigated lands. Advanced SoGS in irrigated lands was related to earlier planting of crops after relatively warm winters, which were more common in recent years. Despite different patterns of SoGS change between land cover types, kestrel nesting phenology shifted with earlier prey availability in irrigated lands. Kestrels may preferentially track prey in irrigated lands over non-irrigated lands because of higher quality prey on irrigated lands, or earlier prey abundance may release former constraints on other selective pressures to breed early, such as seasonal declines in fecundity or competition for high-quality mates. This is one of the first examples of an association between human adaptation to climate change and shifts in breeding phenology of wildlife., (© 2016 The Authors. Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)

Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM) have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2R141W/+) recapitulated the human phenotype, developing left ventricular dilation and reduced contractility. There was a gene dosage effect, so that the phenotype in Tnnt2R141W/+mice was attenuated by transgenic overexpression of wildtype Tnnt2 mRNA transcript. Male mice exhibited poorer survival than females. Biomechanical studies on skinned fibers from Tnnt2R141W/+ hearts showed a significant decrease in pCa50 (-log[Ca2+] required for generation of 50% of maximal force) relative to wildtype hearts, indicating Ca2+ desensitization. Optical mapping studies of Langendorff-perfused Tnnt2R141W/+ hearts showed marked increases in diastolic and peak systolic intracellular Ca2+ ([Ca2+]i), and prolonged systolic rise and diastolic fall of [Ca2+]i. Perfused Tnnt2R141W/+ hearts had slower intrinsic rates in sinus rhythm and reduced peak heart rates in response to isoproterenol. Tnnt2R141W/+ hearts exhibited a reduction in phosphorylated phospholamban relative to wildtype mice. However, crossing Tnnt2R141W/+ mice with phospholamban knockout (Pln-/-) mice, which exhibit increased Ca2+ transients and contractility, had no effect on the DCM phenotype. We conclude that the Tnnt2 R141W mutation causes a Ca2+ desensitization and mice adapt by increasing Ca2+-transient amplitudes, which impairs Ca2+ handling dynamics, metabolism and responses to β-adrenergic activation., Competing Interests: The authors have declared that no competing interests exist.

Tail docking of neonatal pigs is widely used as a measure to reduce the incidence of tail biting, a complex management problem in the pig industry. Concerns exist over the long-term consequences of tail docking for possible tail stump pain sensitivity due to the development of traumatic neuromas in injured peripheral nerves. Tail stumps were obtained post mortem from four female pigs at each of 1, 4, 8 and 16 weeks following tail amputation (approximately two-thirds removed) by a gas-heated docking iron on post natal day 3. Tissues were processed routinely for histopathological examination. Non-neural inflammatory and reparative epidermal and dermal changes associated with tissue thickening and healing were observed 1 to 4 months after docking. Mild neutrophilic inflammation was present in some cases, although this and other degenerative and non-neural reparative changes are not likely to have caused pain. Traumatic neuroma and neuromatous tissue development was not observed 1 week after tail docking, but was evident 1 month after tail docking. Over time there was marked nerve sheath and axonal proliferation leading to the formation of neuromata, which were either localized and circumscribed or comprised of multiple axons dispersed within granulation tissue. Four months after tail resection, neuroma formation was still incomplete, with possible implications for sensitivity of the tail stump., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Psoriasis is a chronic inflammatory skin disorder involving marked immunological changes. IL-17-targeting biologics have been successful in reducing the disease burden of psoriasis patients with moderate-to-severe disease. Unfortunately, the stratum corneum prevents penetration of large molecule weight proteins, including monoclonal antibodies. Thus, for the majority of psoriasis patients ineligible for systemic treatments, a small molecule targeting RORγt, the master regulator of IL-17 family cytokines, may represent an alternative topical medicine with biologic-like efficacy., Methods and Findings: The preclinical studies described in this manuscript bridge the gap from bench to bedside to provide the scientific foundation for a compound entering clinical trials for patients with mild to moderate psoriasis. In addition to several ex vivo reporter assays, primary T cell cultures, and the imiquimod mouse model, we demonstrate efficacy in a newly developed human ex vivo skin assay, where Th17-skewed cytokine expression is induced from skin-resident immune cells. Importantly, the skin barrier remains intact allowing for the demonstration of topical drug delivery. With the development of this novel assay, we demonstrate potent compound activity in the target tissue: human skin. Finally, target engagement by this small molecule was confirmed in ex vivo lesional psoriatic skin., Conclusions: Our work describes a progressive series of assays to demonstrate the potential clinical value of a novel RORγ inverse agonist small molecule with high potency and selectivity, which will enter clinical trials in late 2015 for psoriasis patients.

Fourteen surveys were conducted at Farallon De Medinilla (a U.S. Department of Defense bombing range in the Mariana Archipelago) between 1997 and 2012; annual surveys were conducted from 1999 through 2012. There was no evidence that the condition of the biological resources assessed had changed, or been adversely impacted to a significant degree by the training activities being conducted there. Restricted access has resulted in a de-facto preserve effect and outweighs minor negative impacts from training. The health, abundance and biomass of fishes, corals and other marine resources are comparable to or superior to those in similar habitats at other locations within the Mariana Archipelago. Our research suggests that the greatest threat to FDM's marine resources is from fishermen, not military training activities., (Published by Elsevier Ltd.)

The morphology of the dorsal conchal bulla (DCB) and ventral conchal bulla (VCB) are poorly described. The recent recognition that these bullae can become infected, causing chronic unilateral nasal discharge, has stimulated interest in these structures. Fourteen cadaveric horse heads were transected sagittally midline and dissected to expose the nasal conchal bullae. The dimensions of each bulla, the number and orientation of drainage apertures, and cellulae septae were recorded. Randomly selected samples were examined histologically. The mean DCB and VCB lengths were 78  and 57 mm, respectively; equivalent to 13.9 per cent and 10.2 per cent of skull length, respectively. The mean DCB and VCB heights were 29  and 28 mm, respectively; equivalent to 5.2 per cent and 5 per cent of skull length, respectively. The DCB was larger than the VCB, containing more septae, cellulae and drainage apertures. No communications were identified between the bullae and the immediately adjacent paranasal sinuses. Histology revealed that the bullae consist of ciliated, pseudostratified, columnar epithelium over glandular submucosa often overlying turbinate bone and, variably, hyaline cartilage. This more detailed description of equine DCB and VCB anatomy will hopefully facilitate successful treatment of their disorders., (British Veterinary Association.)

The expression patterns of secreted (MUC2 and MUC5AC) and membrane-tethered (MUC1, MUC4, MUC12 and MUC13) mucins were monitored in healthy pigs and pigs challenged orally with Lawsonia intracellularis. These results showed that the regulation of mucin gene expression is distinctive along the GI tract of the healthy pig, and may reflect an association between the function of the mucin subtypes and different physiological demands at various sites. We identified a specific depletion of secreted MUC2 from goblet cells in infected pigs that correlated with the increased level of intracellular bacteria in crypt cells. We concluded that L. intracellularis may influence MUC2 production, thereby altering the mucus barrier and enabling cellular invasion., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Reasons for Performing Study: The morphology of the dorsal (DCB) and ventral (VCB) nasal conchal bullae, including their cellulae, drainage and histology, are poorly described. The recent recognition that these bullae can become infected, causing chronic unilateral nasal discharge has stimulated interest in these structures. A more complete understanding of their anatomy would be useful in the diagnosis and treatment of their disorders., Objectives: To document the structure, drainage and histology of the equine DCB and VCB., Study Design: Descriptive., Methods: Fourteen fresh cadaveric horse heads, were transected sagittally midline and dissected to expose the nasal conchal bullae. The dimensions of each bulla, the number of drainage apertures, the number of cellulae and orientation of the septae were recorded. Representative samples were collected for histopathology., Results: The mean lengths of the DCB and VCB were 77.7 mm (range 48-105 mm) and 57.1 mm (range 34-86 mm) respectively; equivalent to 13.8% and 10.2% of skull length, respectively. The mean widths of the DCB and VCB were 28.5 mm (range 21-35 mm) and 28.2 mm (range 13-41 mm) respectively; equivalent to 5.1% and 5% of skull length respectively. The median number of drainage apertures from the DCB and VCB were 2 and 1 respectively. The median number of cellulae within the DCB and VCB were 3 and 2, respectively. No communications were identified between the DCB and VCB and the adjacent paranasal sinuses. Histology revealed that the bullae consisted of ciliated, pseudostratified, columnar epithelium supported by a glandular submucosa often overlying turbinate bone and, variably, hyaline cartilage., Conclusions: The morphology of the equine nasal conchal bullae is quite variable. The DCB is generally a more complex structure than the VCB, containing more septae, cellulae and drainage apertures. This more detailed description of DCB and VCB anatomy will hopefully facilitate successful treatment of their disorders. Ethical animal research: Research ethics committee oversight not currently required by this conference: the study was performed on material obtained from an abattoir., Source of Funding: None. Competing interests: None declared., (© 2015 The Author(s). Equine Veterinary Journal © 2015 EVJ Ltd.)

Non-resolving inflammation is a major contributor to chronic disease pathogenesis, including that of cancer, chronic obstructive pulmonary disease, asthma, arthritis, inflammatory bowel disease, multiple sclerosis and obesity. Some cytokines, such as IL-1α and IL-33, may act as endogenous alarmins that contribute to non-resolving inflammation. These cytokines are constitutively expressed in the nucleus and are thought to promote inflammation only upon release during tissue damage or cell necrosis. However, the importance of their nuclear localization in immune homeostasis is not fully understood. We describe herein a novel mouse model in which the nuclear localization signal of IL-33 is abolished and demonstrate for the first time that, alone, altered subcellular localization of IL-33 dramatically affects immune homeostasis. Heterozygous IL33(tm1/+) mice display elevated serum IL-33 levels, indicating that IL-33 is constitutively released when not actively targeted to the nucleus. IL33(tm1/+) mice succumb to lethal inflammation characterized by eosinophil-dominated immune cell infiltration of multiple organs. The profound inflammatory phenotype is dependent on mediators downstream of ST2 as ST2-null mice are protected in spite of high serum IL-33 levels. Importantly, IL-33 transcript levels in this knock-in mouse model remain under endogenous control. We adopt the term "nuclear alarmin" to describe a danger signal that is primarily regulated by nuclear compartmentalization in this fashion., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Neospora caninum is recognized as a major cause of reproductive losses worldwide but its pathogenesis is not completely understood. Immune mediated placental pathology has been reported as being responsible for compromising pregnancy probably due to the adverse effects of exacerbated Th1 type response at the maternal-foetal interface. Different clinical outcomes are known to occur following experimental infections of cattle at different stages of gestation, with foetal death being the most common finding during early gestation, and the birth of live congenitally infected calves following infection later in gestation. The aim of the current study was to characterize the cytokine expression in the placenta of cattle experimentally challenged with tachyzoites of the Nc-1 strain during early, mid and late gestation. Moderate to severe infiltration of IL-12, IFN-γ and TNF-α expressing cells was observed in the placentas collected at early gestation and this infiltration was more pronounced in the samples collected from challenged dams carrying non-viable foetuses, compared with the mothers carrying viable foetuses. In contrast, the infiltration of Th1 cytokine expressing-cells was mild following N. caninum infection in mid gestation and scarce during infection in late gestation. Scarce expression of IL-4 was observed in the placentas from N. caninum-challenged and negative control animals throughout gestation. The milder Th1 immune response observed during later stages of gestation following Nc-1 infection could partially explain the less severe clinical outcome when compared to early pregnancy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Donkey pulmonary fibrosis (DPF) is a spontaneous syndrome of aged donkeys with a high prevalence (35%). No previous detailed characterization of DPF has been performed. We sought to determine the similarities between DPF and recognized patterns of human pulmonary fibrosis., Methods: Whole lungs were collected from 32 aged donkeys at routine necropsy. Gross examination revealed pulmonary fibrosis in 19 donkeys (DPF cases), whereas 13 (control cases) had grossly normal lungs. Eighteen whole inflated ex vivo lungs (11 DPF cases, seven control cases) were imaged with high-resolution CT (HRCT) scan, whereas the remainder were sectioned and photographed. Tissue samples were collected from all lungs for histopathologic evaluation using a standardized protocol. HRCT images and histology sections underwent independent blinded review. Lung tissue was analyzed for herpes virus, fungal hyphae, mycobacteria, and dust content., Results: Ten of 19 DPF lungs were categorized as being consistent with pleuroparenchymal fibroelastosis (PPFE) according to previously defined histologic and imaging criteria. All 10 PPFE-like lungs had marked pleural and subpleural fibrosis, predominantly within the upper lung zone, with accompanying intraalveolar fibrosis and elastosis. Asinine herpesvirus was ubiquitously expressed within control and DPF lung tissue. No other etiologic agents were identified., Conclusions: Many cases of DPF share key pathologic and imaging features with human PPFE, a rare interstitial pneumonia. Consequently, further study of DPF may help to elucidate the etiopathogenesis of human PPFE.

Lawsonia intracellularis is an obligate intracellular bacterium, responsible for the disease complex known as proliferative enteropathy (PE). L. intracellularis is associated with intestinal crypt epithelial cell proliferation but the mechanisms responsible are yet to be defined. Microarray analysis was used to investigate the host-pathogen interaction in experimentally infected pigs to identify pathways that may be involved. Ileal samples originating from twenty-eight weaner pigs experimentally challenged with a pure culture of L. intracellularis (strain LR189/5/83) were subjected to microarray analysis. Microarray transcriptional signatures were validated using immunohistochemistry and quantitative real time PCR of selected genes at various time points post challenge. At peak of infection (14 days post challenge) 86% of altered transcripts were down regulated, particularly those involved in maintenance of mucosal integrity and regulation of cell transport. Among the up-regulated transcripts, CD163 and CDK1 were novel findings and considered to be important, due to their respective roles in innate immunity and cellular proliferation. Overall, targeted cellular mechanisms included those that are important in epithelial restitution, migration and protection; maintenance of stable inter-epithelial cell relationships; cell transport of nutrients and electrolytes; innate immunity; and cell cycle.

Infection with Neospora caninum stimulates host cell-mediated immune responses, which may be responsible for placental damage leading to bovine abortion. The aim of this study was to compare immune responses in the bovine placenta, following experimental infection in different stages of pregnancy. Placentomes were examined by immunohistochemistry and inflammation in early gestation was generally moderate to severe, particularly in the placentas carrying non-viable foetuses, whereas it was milder in later stages, mainly characterised by the presence of CD3+, CD4+ and γδ T-cells. This distinctive cellular immune response may explain the milder clinical outcome observed when animals are infected in later gestation.

Rationale: Glia, including astrocytes and microglia, can profoundly modulate neuronal function and behavior; however, very little is known about the signaling molecules that govern neuronal-glial communication and in turn affect behavior. Morphine treatment activates microglia and astrocytes in the nucleus accumbens (NAcc) to induce the synthesis of cytokines and chemokines, and this has important implications for addictive behavior. Blocking morphine-induced glial activation using the nonspecific glial inhibitor, ibudilast, has no effect on the initial rewarding properties of morphine, but completely prevents the relapse of drug-seeking behavior months later., Objectives: We sought to determine the cellular source of these cytokines and chemokines in the NAcc in response to morphine, and the cell-type-specific expression pattern of their receptors to determine whether neurons have the capacity to respond to these immune signals directly., Methods: We used fluorescence-activated cell sorting of neurons (Thy1+), astrocytes (GLT1+), and microglia (CD11b+) from the NAcc for the analysis of cell type specific gene expression following morphine or saline treatment., Results: The results indicate that microglia and neurons each produce a subset of chemokines in response to morphine and that neurons have the capacity to respond directly to a select group of these chemokines via their receptors. In addition, we provide evidence that microglia are capable of responding directly to dopamine release in the NAcc., Conclusions: Future studies will examine the mechanism(s) by which neurons respond to these immune signals produced by microglia in an effort to understand their effect on addictive behaviors.

The spleen regulatory B cell subset with the functional capacity to express IL-10 (B10 cells) modulates both immune responses and autoimmune disease severity. However, the peritoneal cavity also contains relatively high frequencies of functionally defined IL-10-competent B10 cells. In this study, peritoneal cavity B10 cells shared similar cell surface phenotypes with their spleen counterparts. However, peritoneal cavity B10 cells were 10-fold more frequent among B cells than occurred within the spleen, intestinal tract, or mesenteric lymph nodes and were present at higher proportions among the phenotypically defined peritoneal B1a > B1b > B2 cell subpopulations. The development or localization of B10 cells within the peritoneal cavity was not dependent on the presence of commensal microbiota, T cells, IL-10 or B10 cell IL-10 production, or differences between their fetal liver or adult bone marrow progenitor cell origins. The BCR repertoire of peritoneal cavity B10 cells was diverse, as occurs in the spleen, and predominantly included germline-encoded VH and VL regions commonly found in either the conventional or B1 B cell compartments. Thereby, the capacity to produce IL-10 appears to be an intrinsic functional property acquired by clonally diverse B cells. Importantly, IL-10 production by peritoneal cavity B cells significantly reduced disease severity in spontaneous and induced models of colitis by regulating neutrophil infiltration, colitogenic CD4(+) T cell activation, and proinflammatory cytokine production during colitis onset. Thus, the numerically small B10 cell subset within the peritoneal cavity has regulatory function and is important for maintaining homeostasis within gastrointestinal tissues and the immune system.

Background: Low socioeconomic status is consistently associated with reduced physical and mental health, but the mechanisms remain unclear. Increased levels of urban air pollutants interacting with parental stress have been proposed to explain health disparities in respiratory disease, but the impact of such interactions on mental health is unknown., Objectives: We aimed to determine whether prenatal air pollution exposure and stress during pregnancy act synergistically on offspring to induce a neuroinflammatory response and subsequent neurocognitive disorders in adulthood., Methods: Mouse dams were intermittently exposed via oropharyngeal aspiration to diesel exhaust particles (DEP; 50 μg × 6 doses) or vehicle throughout gestation. This exposure was combined with standard housing or nest material restriction (NR; a novel model of maternal stress) during the last third of gestation., Results: Adult (postnatal day 60) offspring of dams that experienced both stressors (DEP and NR) displayed increased anxiety, but only male offspring of this group had impaired cognition. Furthermore, maternal DEP exposure increased proinflammatory interleukin (IL)-1β levels within the brains of adult males but not females, and maternal DEP and NR both decreased anti-inflammatory IL-10 in male, but not female, brains. Similarly, only DEP/NR males showed increased expression of the innate immune recognition gene toll-like receptor 4 (Tlr4) and its downstream effector, caspase-1., Conclusions: These results show that maternal stress during late gestation increases the susceptibility of offspring-particularly males-to the deleterious effects of prenatal air pollutant exposure, which may be due to a synergism of these factors acting on innate immune recognition genes and downstream neuroinflammatory cascades within the developing brain.

Background: Osteoarthritis (OA) is a clinically important and common disease of older cats. The pathological changes and molecular mechanisms which underpin the disease have yet to be described. In this study we evaluated selected histological and transcriptomic measures in the articular cartilage and subchondral bone (SCB) of the humeral condyle of cats with or without OA., Results: The histomorphometric changes in humeral condyle were concentrated in the medial aspect of the condyle. Cats with OA had a reduction in articular chondrocyte density, an increase in the histopathological score of the articular cartilage and a decrease in the SCB porosity of the medial part of the humeral condyle. An increase in LUM gene expression was observed in OA cartilage from the medial part of the humeral condyle., Conclusions: Histopathological changes identified in OA of the feline humeral condyle appear to primarily affect the medial aspect of the joint. Histological changes suggest that SCB is involved in the OA process in cats. Differentiating which changes represent OA rather than the aging process, or the effects of obesity and or bodyweight requires further investigation.

A 9-year-old female neutered collie-cross dog was presented with a 2-month history of persistent diarrhoea, weight loss and intermittent vomiting. Abdominal ultrasonography revealed one loop of jejunum with a markedly thickened and multifocally hyperechoic wall, without loss of wall layering. Laparotomies were performed for biopsy and resection of affected intestine. Histopathological examination revealed small intestinal ganglioneuromatosis (GN). The dog recovered well from surgery and the diarrhoea resolved. Eleven months later the dog has gained weight and remains asymptomatic. This is the first report of small intestinal GN affecting a mature dog, in which pathology was localized to the mucosal lamina propria and surgical treatment resulted in a successful outcome., (Copyright © 2012. Published by Elsevier Ltd.)

A seven-year-old, ovariohysterectomised female dwarf lop rabbit (Oryctolagus cuniculus) was referred with severe swelling and erythema of the mucocutaneous junctions of the lips, nares and vulva. Bilateral, severe periocular dermatitis was also present. Heavy pure growths of a member of the Staphylococcus intermedius group were cultured from nasal and aural swabs and skin biopsies. Other possible differential diagnoses were eliminated by standard tests. The clinical features and histopathological characteristics of the biopsies were most consistent with mucocutaneous pyoderma, a dermatosis previously reported in dogs but not in rabbits. Treatment of the bacterial infection with oral marbofloxacin and topical ofloxacin eye drops together with supportive therapy resulted in resolution of the lesions. To the authors' knowledge, this is the first report of mucocutaneous bacterial pyoderma, similar to mucocutaneous pyoderma of dogs, in a rabbit., (© 2013 British Small Animal Veterinary Association.)

'Salivary abomasum disease' is a common syndrome in Greece affecting lambs and kids from three to 17 days of age. In this case series, we present clinical and laboratory findings from 37 affected lambs presented alive and subsequently euthanased for welfare reasons and necropsied, and also from 24 other lambs submitted dead that were also necropsied. The clinical signs in the 37 lambs presented alive included lethargy (100 per cent), absence of sucking (83.8 per cent), weakness (37.8 per cent), abdominal distension (40.5 per cent) and increased frequency of urination (24.3 per cent). Diarrhoea was not observed in any affected lambs. At necropsy of these 37 lambs, the abomasum was distended with gas (70.3 per cent), saliva (43.2 per cent) along with mixed milk clots and gastric secretions; while multiple small mucosal and serosal haemorrhages with blood clots ('coffee grains') were recorded (91.9 per cent). Eight of 37 lambs that were examined alive, had elevated blood urea nitrogen concentrations (21.6 per cent). The pH of the abomasal contents ranged from 1.0 to 2.8; Escherichia coli was cultured from six of 37 (16.2 per cent) abomasal fluid samples. A mild to moderate inflammatory cell infiltrate was present in the mucosal lamina propria of 13 of 15 abomasal samples (86.6 per cent). Kidneys were paler than normal in 13 of the total 61 lambs necropsied (21.3 per cent); while acute tubular necrosis was evident on histopathological examination of 11 of 12 examined pale kidneys (91.6 per cent). The low abomasal pH and reported successful treatment with oral sodium bicarbonate suggest that metabolic acidosis may develop during the disease; however, further studies, including blood gas analysis, and determination of D- and L-lactic acid concentrations, are necessary to confirm this hypothesis.

Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pregnant mice were exposed to filtered air (FA) or diesel exhaust (DE) on embryonic days (E) 9-17. Prenatal DE induced a significant fetal brain cytokine response at E18 (46-390% over FA). As adults, offspring were fed either a low-fat diet (LFD) or high-fat diet (HFD) for 6 wk. Adult DE male offspring weighed 12% more and were 35% less active than FA male offspring at baseline, whereas there were no differences in females. Following HFD, DE males gained weight at the same rate as FA males, whereas DE females gained 340% more weight than FA females. DE-HFD males had 450% higher endpoint insulin levels than FA-HFD males, and all males on HFD showed decreased activity and increased anxiety, whereas females showed no differences. Finally, both DE males and females fed HFD showed increased microglial activation (30-66%) within several brain regions. Thus, prenatal air pollution exposure can "program" offspring for increased susceptibility to diet-induced weight gain and neuroinflammation in adulthood in a sex-specific manner.