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IntroductionThe purpose of this study was to provide an evidence base and conceptual framework to inform new guidelines for achieving a balance between sports and employment commitments (i.e., dual career, DC) of the employee-sportspersons. To shape a DC discourse in the workplace, the distinct and combined views of the employee-sportspersons (i.e., the Employee), the managers (i.e., the Employer) were considered.MethodsFollowing a concept mapping methodology, 257 international participants (25% employers and 75% employee-sportspersons) sorted and rated 50 potential statements associated with DC circumstances and supports in the workplace.ResultsSix distinct clusters emerged, with the combined employers-employee co-creation scenario assigning 6 statements to the micro dimension (Cluster 1 = Workplace Benefits), 4 statements to the meso dimension (Cluster 2 = Role of National Sports Governing Bodies), 19 statements to the macro dimension (Cluster 3 = Dual Career Policy Development), 4 and 5 statements to the organizational dimensions (Cluster 4 = Employee-Employer Collaboration and Responsibility; Cluster 5 = Sport Career Integration), and 12 statements to the policy (Cluster 6 = Workplace Strategies for Dual Career Support) dimension. With respect to the employers, the employee-sportspersons showed higher scores (p

Abstract Background Intraoperative testing of colonic anastomoses is routine in assuring anastamotic integrity. We sought to determine the efficacy of the methylene blue enema (MBE) as an intraoperative test for anastomotic leaks. Methods This study is a retrospective review of consecutive colonic operations performed from January 2001 to December 2004 in a community hospital setting by a general surgical group that uses the MBE exclusively. All operations featuring a colonic anastomosis and an intraoperative MBE were studied (n = 229). Intraoperative MBE via a rectal tube was used as the diagnostic test. Intraoperative leak (IOL) rate and clinically significant postoperative leak (POL) rate were the outcome measures. Results The IOL rate was 4.5% for proximal anastomoses, 8% for distal anastomoses, and 7% of total anastomoses. The POL rate was 3% of anastomosis. There were no other testing methods employed. There were no POLs in cases where an IOL led to concomitant intraoperative repair. POL rate for proximal anastomosis was 0.8% and for distal 3%, for stapled 1% and hand sewn 5%. Conclusion MBE IOL rate is comparable to published IOL rates for other methods of intraoperative testing. The MBE can be applied to proximal and distal anastomosis. Patients who were found to have an IOL, and underwent immediate repair, did not develop a clinical POL.

Understanding how the environment mediates an organism's ability to meet basic survival requirements is a fundamental goal of ecology. Vessel noise is a global threat to marine ecosystems and is increasing in intensity and spatiotemporal extent due to growth in shipping coupled with physical changes to ocean soundscapes from ocean warming and acidification. Odontocetes rely on biosonar to forage, yet determining the consequences of vessel noise on foraging has been limited by the challenges of observing underwater foraging outcomes and measuring noise levels received by individuals. To address these challenges, we leveraged a unique acoustic and movement dataset from 25 animal-borne biologging tags temporarily attached to individuals from two populations of fish-eating killer whales (Orcinus orca) in highly transited coastal waters to (1) test for the effects of vessel noise on foraging behaviors-searching (slow-click echolocation), pursuit (buzzes), and capture and (2) investigate the mechanism of interference. For every 1 dB increase in maximum noise level, there was a 4% increase in the odds of searching for prey by both sexes, a 58% decrease in the odds of pursuit by females and a 12.5% decrease in the odds of prey capture by both sexes. Moreover, all but one deep (≥75 m) foraging attempt with noise ≥110 dB re 1 μPa (15-45 kHz band; n = 6 dives by n = 4 whales) resulted in failed prey capture. These responses are consistent with an auditory masking mechanism. Our findings demonstrate the effects of vessel noise across multiple phases of odontocete foraging, underscoring the importance of managing anthropogenic inputs into soundscapes to achieve conservation objectives for acoustically sensitive species. While the timescales for recovering depleted prey species may span decades, these findings suggest that complementary actions to reduce ocean noise in the short term offer a critical pathway for recovering odontocete foraging opportunities., (© 2024 His Majesty the King in Right of Canada and The Author(s). Global Change Biology published by John Wiley & Sons Ltd. Reproduced with the permission of the Minister of Fisheries and Oceans Canada. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from patients with UC and controls. Here we identified colonic CD4 + and CD8 + T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in several mouse models of autoimmune disease. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to proinflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model in mice, we demonstrated that CD4 + T cells deficient in either BCL-6 or TCF1, transcription factors that promote T cell stemness, had decreased colon T cells and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Posttraumatic intradural hematomas of the cervical spine are rare findings that may yield significant neurological deficits if they compress the spinal cord. These compressive hematomas require prompt surgical evacuation. In certain instances, intradural hematomas may form from avulsion of cervical nerve roots., Observations: The authors present the case of a 29-year-old male who presented with right upper-extremity weakness in the setting of polytrauma after a motor vehicle accident. He had no cervical fractures but subsequently developed right lower-extremity weakness. Magnetic resonance imaging (MRI) demonstrated a compressive hematoma of the cervical spine that was initially read as an epidural hematoma. However, intraoperatively, it was found to be a subdural hematoma, eccentric to the right, stemming from an avulsion of the right C6 nerve root., Lessons: Posttraumatic cervical subdural hematomas require rapid surgical evacuation if neurological deficits are present. The source of the hematoma may be an avulsed nerve root, and the associated deficits may be unilateral if the hematoma is eccentric to one side. Surgeons should be prepared for the possibility of an intradural hematoma even in instances in which MRI appears consistent with an epidural hematoma.

In cooperative species, human-induced rapid environmental change may threaten cost-benefit tradeoffs of group behavioral strategies that evolved in past environments. Capacity for behavioral flexibility can increase population viability in novel environments. Whether the partitioning of individual responsibilities within social groups is fixed or flexible across populations is poorly understood, despite its relevance for predicting responses to global change at the population and species levels and designing successful conservation programs. We leveraged bio-logging data from two populations of fish-eating killer whales ( Orcinus orca ) to quantify patterns of fine-scale foraging movements and their relationships with demography. We reveal striking interpopulation differences in patterns of individual foraging behavior. Females from the endangered Southern Resident (SRKW) population captured less prey and spent less time pursuing prey than SRKW males or Northern Resident (NRKW) females, whereas NRKW females captured more prey than NRKW males. The presence of a calf (≤3 years) reduced the number of prey captured by adult females from both populations, but disproportionately so for SRKW. SRKW adult males with a living mother captured more prey than those whose mother had died, whereas the opposite was true for NRKW adult males. Across populations, males foraged in deeper areas than females, and SRKW captured prey deeper than NRKW. These population-level differences in patterns of individual foraging behavior challenge the existing paradigm that females are the disproportionate foragers in gregarious resident killer whales, and demonstrate considerable variation in the foraging strategies across populations of an apex marine predator experiencing different environmental stressors., Competing Interests: We have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Society for Behavioral Ecology.)

Introduction: Inflammation is a common unifying factor in experimental models of non-alcoholic fatty liver disease (NAFLD) progression. Recent evidence suggests that housing temperature-driven alterations in hepatic inflammation correlate with exacerbated hepatic steatosis, development of hepatic fibrosis, and hepatocellular damage in a model of high fat diet-driven NAFLD. However, the congruency of these findings across other, frequently employed, experimental mouse models of NAFLD has not been studied., Methods: Here, we examine the impact of housing temperature on steatosis, hepatocellular damage, hepatic inflammation, and fibrosis in NASH diet, methionine and choline deficient diet, and western diet + carbon tetrachloride experimental models of NAFLD in C57BL/6 mice., Results: We show that differences relevant to NAFLD pathology uncovered by thermoneutral housing include: (i) augmented NASH diet-driven hepatic immune cell accrual, exacerbated serum alanine transaminase levels and increased liver tissue damage as determined by NAFLD activity score; (ii) augmented methionine choline deficient diet-driven hepatic immune cell accrual and increased liver tissue damage as indicated by amplified hepatocellular ballooning, lobular inflammation, fibrosis and overall NAFLD activity score; and (iii) dampened western diet + carbon tetrachloride driven hepatic immune cell accrual and serum alanine aminotransferase levels but similar NAFLD activity score., Discussion: Collectively, our findings demonstrate that thermoneutral housing has broad but divergent effects on hepatic immune cell inflammation and hepatocellular damage across existing experimental NAFLD models in mice. These insights may serve as a foundation for future mechanistic interrogations focused on immune cell function in shaping NAFLD progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oates, Sawada, Giles, Alarcon, Damen, Szabo, Stankiewicz, Moreno-Fernandez and Divanovic.)

Colitis is characterized by an exacerbated intestinal immune response, but the genetic and other mechanisms regulating immune activation remain incompletely understood. In order to identify new pathways leading to colitis, we sought to identify genes with increased expression in the colons of patients that also are near loci identified by genome wide association studies (GWAS) associated with IBD risk. One such SNP, rs9557195 was of particular interest because it is within an intron of G-protein-coupled receptor (GPR) 183 , known to be important for lymphocyte migration. Furthermore, this SNP is in close proximity to the gene encoding another G-protein coupled receptor, GPR18 . Analyzing publicly available datasets, we found transcripts of GPR183 and GPR18 to be increased in colon biopsies from ulcerative colitis and Crohn's disease patients, and GPR183 was even more increased in patients resistant to TNF treatment. Expression of both genes also was increased in mouse models of colitis. Therefore, our aim was to understand if increased expression of these GPRs in the intestine is related to disease severity in colitis models. Here we investigated the role of these receptors in the T cell transfer model and the dextran sulfate sodium model. In the T cell transfer model, GPR183 expression on donor T cells, as well as on other cell types in the Rag -/- recipients, was not essential for severe colitis induction. Furthermore, deficiency in Rag -/- mice for the enzyme that synthesizes a cholesterol metabolite that is a major ligand for GPR183 also did not affect disease. Similarly, lack of GPR18 expression in T cells or other cell types did not affect colitis pathogenesis in the T cell transfer or in the dextran sulfate sodium model. Therefore, despite increased expression of transcripts for these genes in the intestine during inflammation in humans and mice, they are not required for disease severity in mouse models of colitis induced by chemical injury or T cell cytokines, perhaps due to redundancy in mechanisms important for homing and survival of lymphocytes to the inflamed intestine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dicker, Li, Giles, Verstichel, Castelan, Ascui-Gac, Chou, Perez-Jeldres, Cheroutre and Kronenberg.)

Vessel traffic is prevalent throughout marine environments. However, we often have a limited understanding of vessel impacts on marine wildlife, particularly cetaceans, due to challenges of studying fully-aquatic species. To investigate vessel and acoustic effects on cetacean foraging behavior, we attached suction-cup sound and movement tags to endangered Southern Resident killer whales in their summer habitat while collecting geo-referenced proximate vessel data. We identified prey capture dives using whale kinematic signatures and found that the probability of capturing prey increased as salmon abundance increased, but decreased as vessel speed increased. When vessels emitted navigational sonar, whales made longer dives to capture prey and descended more slowly when they initiated these dives. Finally, whales descended more quickly when noise levels were higher and vessel approaches were closer. These findings advance a growing understanding of vessel and sound impacts on marine wildlife and inform efforts to manage vessel impacts on endangered populations., (Published by Elsevier Ltd.)

Social structure is a fundamental aspect of animal populations. In order to understand the function and evolution of animal societies, it is important to quantify how individual attributes, such as age and sex, shape social relationships. Detecting these influences in wild populations under natural conditions can be challenging, especially when social interactions are difficult to observe and broad-scale measures of association are used as a proxy. In this study, we use unoccupied aerial systems to observe association, synchronous surfacing, and physical contact within a pod of southern resident killer whales ( Orcinus orca ) . We show that interactions do not occur randomly between associated individuals, and that interaction types are not interchangeable. While age and sex did not detectably influence association network structure, both interaction networks showed significant social homophily by age and sex, and centrality within the contact network was higher among females and young individuals. These results suggest killer whales exhibit interesting parallels in social bond formation and social life histories with primates and other terrestrial social mammals, and demonstrate how important patterns can be missed when using associations as a proxy for interactions in animal social network studies.

Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3 + Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD., Competing Interests: Declaration of interests S.D. is a consultant for Janssen Research & Development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Inflammatory bowel disease is characterized by an exacerbated intestinal immune response, but the critical mechanisms regulating immune activation remain incompletely understood. We previously reported that the TNF-superfamily molecule TNFSF14 (LIGHT) is required for preventing severe disease in mouse models of colitis. In addition, deletion of lymphotoxin beta receptor (LTβR), which binds LIGHT, also led to aggravated colitis pathogenesis. Here, we aimed to determine the cell type(s) requiring LTβR and the mechanism critical for exacerbation of colitis. Specific deletion of LTβR in neutrophils (LTβR ΔN ), but not in several other cell types, was sufficient to induce aggravated colitis and colonic neutrophil accumulation. Mechanistically, RNA-Seq analysis revealed LIGHT-induced suppression of cellular metabolism, and mitochondrial function, that was dependent on LTβR. Functional studies confirmed increased mitochondrial mass and activity, associated with excessive mitochondrial ROS production and elevated glycolysis at steady-state and during colitis. Targeting these metabolic changes rescued exacerbated disease severity. Our results demonstrate that LIGHT signals to LTβR on neutrophils to suppress metabolic activation and thereby prevents exacerbated immune pathogenesis during colitis.

Innate lymphoid cells (ILCs) are a lymphocyte population that is mostly resident at mucosal surfaces. They help to induce an appropriate immune response to the microbiome at homeostasis. In healthy people, the mucosal immune system works symbiotically with organisms that make up the microbiota. ILCs play a critical role in orchestrating this balance, as they can both influence and in turn be influenced by the microbiome. ILCs also are important regulators of the early response to infections by diverse types of pathogenic microbes at mucosal barriers. Their rapid responses initiate inflammatory programs, production of antimicrobial products and repair processes. This review will focus on the role of ILCs in response to the microbiota and to microbial infections of the lung and intestine.

Innate lymphoid cells (ILCs) are important regulators of the early responses to infection at mucosal barriers, including the intestine. Recently, we have shown that specific ILC3 subsets protect against enteric bacterial pathogens. Here, we describe a mouse model of oral infection by Yersinia enterocolitica (Y. enterocolitica) and several different methodologies to assess the severity of the infection. We also detail how ILC3 subsets can be isolated from the mouse small intestine and transferred into recipient immune deficient mice to study the function of these ILCs in the small intestine.

Foraging behavior in odontocetes is fundamentally tied to the use of sound. Resident-type killer whales use echolocation to locate and capture elusive salmonid prey. In this investigation, acoustic recording tags were suction cup-attached to endangered Southern Resident killer whales to describe their acoustic behavior during different phases of foraging that, along with detections of prey handling sounds (e.g., crunches) and observed predation events, allow confirmation of prey capture. Echolocation click trains were categorized based on the inter-click interval (ICI) according to hypothesized foraging function. Whales produced slow click trains (ICI >100 ms) at shallowest depths but over the largest change of depth, fast click trains (10 ms < ICI ≤100 ms) at intermediate depths, and buzz trains (ICI ≤10 ms) at deepest depths over the smallest depth change. These results align with hypotheses regarding biosonar use to search, pursue and capture prey. Males exhibited a higher probability of producing slow click trains, buzzes and prey handling sounds, indicating higher levels of prey searching and capture to support the energy requirement of their larger body size. These findings identify relevant acoustic indicators of subsurface foraging behaviors of killer whales, enabling investigations of human impacts on sound use and foraging.

Current therapeutic options for autoimmune diseases, such as multiple sclerosis (MS), often require lifelong treatment with immunosuppressive drugs, yet strategies for antigen-specific immunomodulation are emerging. Biodegradable particles loaded with disease-specific antigen, either alone or with immunomodulators, have been reported to ameliorate disease. Herein, we hypothesized that the carrier could impact polarization of the immune cells that associate with particles and the subsequent disease progression. Single injection of three polymeric carriers, 50:50 poly (DL-lactide-co-glycolide) (PLG) with two molecular weights (Low, High) and poly (DL-lactide) (PLA), loaded with the disease-specific antigen, proteolipid protein (PLP 139-151 ), were investigated for the ability to attenuate clinical scores in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. At a low particle dose, mice treated with PLA-based particles had significantly lower clinical scores at the chronic stage of the disease over 200 days post immunization, while neither PLG-based particles nor OVA control particles reduced the clinical scores. Compared to PLG-based particles, PLA-based particles were largely associated with Kupffer cells and liver sinusoidal endothelial cells, which had a reduced co-stimulatory molecule expression that correlated with a reduction of CD4 + T-cell populations in the central nervous system. Delivery of PLA-based particles encapsulated with higher levels of PLP 139-151  at a reduced dose were able to completely ameliorate EAE over 200 days along with inhibition of Th1 and Th17 polarization. Collectively, our study demonstrates that the carrier properties and antigen loading determine phenotypes of immune cells in the peripheral organs, influencing the amelioration of both acute and chronic stages of autoimmunity., (Copyright © 2019. Published by Elsevier Ltd.)

Behavioral data can be important for effective management of endangered marine predators, but can be challenging to obtain. We utilized suction cup-attached biologging tags equipped with stereo hydrophones, triaxial accelerometers, triaxial magnetometers, pressure and temperature sensors, to characterize the subsurface behavior of an endangered population of killer whales (Orcinus orca). Tags recorded depth, acoustic and movement behavior on fish-eating killer whales in the Salish Sea between 2010-2014. We tested the hypotheses that (a) distinct behavioral states can be characterized by integrating movement and acoustic variables, (b) subsurface foraging occurs in bouts, with distinct periods of searching and capture temporally separated from travel, and (c) the probabilities of transitioning between behavioral states differ by sex. Using Hidden Markov modeling of two acoustic and four movement variables, we identified five temporally distinct behavioral states. Persistence in the same state on a subsequent dive had the greatest likelihood, with the exception of deep prey pursuit, indicating that behavior was clustered in time. Additionally, females spent more time at the surface than males, and engaged in less foraging behavior. These results reveal significant complexity and sex differences in subsurface foraging behavior, and underscore the importance of incorporating behavior into the design of conservation strategies.

The inflammatory Bowel diseases (IBDs) are a chronic, relapsing inflammatory diseases of the gastrointestinal tract with heterogeneous behavior and prognosis. The introduction of biological therapies including anti-TNF, anti-IL-12/23, and anti-integrins, has revolutionized the treatment of IBD, but these drugs are not universally effective. Due to the complex molecular structures of biologics, they are uniformly immunogenic. New discoveries concerning the underlying mechanisms involved in the pathogenesis of IBD have allowed for progress in the development of new treatment options. The advantage of small molecules (SMs) over biological therapies includes their lack of immunogenicity, short half-life, oral administration, and low manufacturing cost. Among these, the Janus Kinases (JAKs) inhibition has emerged as a novel strategy to modulate downstream cytokine signaling during immune-mediated diseases. These drugs target various cytokine signaling pathways that participate in the pathogenesis of IBD. Tofacitinib, a JAK inhibitor targeting predominantly JAK1 and JAK3, has been approved for the treatment of ulcerative colitis (UC), and there are other specific JAK inhibitors under development that may be effective in Crohn's. Similarly, the traffic of lymphocytes can now be targeted by another SM. Sphingosine-1-phosphate receptor (S1PR) agonism is a novel strategy that acts, in part, by interfering with lymphocyte recirculation, through blockade of lymphocyte egress from lymph nodes. S1PR agonists are being studied in IBD and other immune-mediated disorders. This review will focus on SM drugs approved and under development, including JAK inhibitors (tofacitinib, filgotinib, upadacitinib, peficitinib) and S1PR agonists (KRP-203, fingolimod, ozanimod, etrasimod, amiselimod), and their mechanism of action.

Studies of odontocete foraging ecology have been limited by the challenges of observing prey capture events and outcomes underwater. We sought to determine whether subsurface movement behavior recorded from archival tags could accurately identify foraging events by fish-eating killer whales. We used multisensor bio-logging tags attached by suction cups to Southern Resident killer whales ( Orcinus orca ) to: (1) identify a stereotyped movement signature that co-occurred with visually confirmed prey capture dives; (2) construct a prey capture dive detector and validate it against acoustically confirmed prey capture dives; and (3) demonstrate the utility of the detector by testing hypotheses about foraging ecology. Predation events were significantly predicted by peaks in the rate of change of acceleration ('jerk peak'), roll angle and heading variance. Detection of prey capture dives by movement signatures enabled substantially more dives to be included in subsequent analyses compared with previous surface or acoustic detection methods. Males made significantly more prey capture dives than females and more dives to the depth of their preferred prey, Chinook salmon. Additionally, only half of the tag deployments on females (5 out of 10) included a prey capture dive, whereas all tag deployments on males exhibited at least one prey capture dive (12 out of 12). This dual approach of kinematic detection of prey capture coupled with hypothesis testing can be applied across odontocetes and other marine predators to investigate the impacts of social, environmental and anthropogenic factors on foraging ecology., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS), induced by the adoptive transfer of myelin-reactive CD4+ T cells into naive syngeneic mice. It is widely used as a rodent model of multiple sclerosis (MS). The development of EAE lesions is initiated when transferred CD4+ T cells access the CNS and are reactivated by local antigen-presenting cells (APCs) bearing endogenous myelin peptide/MHC class II complexes. The identity of the CNS-resident, lesion-initiating APCs is widely debated. Here we demonstrate that classical dendritic cells (cDCs) normally reside in the meninges, brain, and spinal cord in the steady state. These cells are unique among candidate CNS APCs in their ability to stimulate naive, as well as effector, myelin-specific T cells to proliferate and produce proinflammatory cytokines directly ex vivo. cDCs expanded in the meninges and CNS parenchyma in association with disease progression. Selective depletion of cDCs led to a decrease in the number of myelin-primed donor T cells in the CNS and reduced the incidence of clinical EAE by half. Based on our findings, we propose that cDCs, and the factors that regulate them, be further investigated as potential therapeutic targets in MS.

Over 1.5 million individuals in the United States are afflicted with inflammatory bowel disease (IBD). While the progression of IBD is multifactorial, chronic, unresolved inflammation certainly plays a key role. Additionally, while multiple immune mediators have been shown to affect pathogenesis, a comprehensive understanding of disease progression is lacking. Previous work has demonstrated that a member of the TNF superfamily, TNFSF14 (LIGHT), which is pro-inflammatory in several contexts, surprisingly plays an important role in protection from inflammation in mouse models of colitis, with LIGHT deficient mice having more severe disease pathogenesis. However, LIGHT is a single member of a complex signaling network. It signals through multiple receptors, including herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTβR); these two receptors in turn can bind to other ligands. It remains unknown which receptors and competing ligands can mediate or counteract the outcome of LIGHT-signaling during colitis. Here we demonstrate that LIGHT signaling through LTβR, rather than HVEM, plays a critical role in the progression of DSS-induced colitis, as LTβR deficient mice exhibit a more severe disease phenotype. Further, mice deficient in LTαβ do not exhibit differential colitis progression compared to WT mice. However, deletion of both LIGHT and LTαβ, but not deletion of both LTαβ and LTβR, resulted in a reversal of the adverse effects associated with the loss of LIGHT. In sum, the LIGHT/LTαβ/LTβR signaling network contributes to DSS colitis, but there may be additional receptors or indirect effects, and therefore, the relationships between these receptors and ligands remains enigmatic.

The Southern Resident killer whale population (Orcinus orca) was listed as endangered in 2005 and shows little sign of recovery. Exposure to contaminants and risk of an oil spill are identified threats. Previous studies on contaminants have largely focused on legacy pollutants. Here we measure polycyclic aromatic hydrocarbons (PAHs) in whale fecal (scat) samples. PAHs are a diverse group of hazardous compounds (e.g., carcinogenic, mutagenic), and are a component of crude and refined oil as well as motor exhaust. The central finding from this study indicates low concentrations of the measured PAHs (<10 ppb, wet weight), as expected; however, PAHs were as high as 104 ppb prior to implementation of guidelines mandating increased distance between vessels and whales. While causality is unclear, the potential PAH exposure from vessels warrants continued monitoring. Historical precedent similarly emphasizes the importance of having pre-oil spill exposure data available as baseline to guide remediation goals., (Copyright © 2018. Published by Elsevier Ltd.)

Innate lymphoid cells (ILCs) are important regulators of early infection at mucosal barriers. ILCs are divided into three groups based on expression profiles, and are activated by cytokines and neuropeptides. Yet, it remains unknown if ILCs integrate other signals in providing protection. We show that signaling through herpes virus entry mediator (HVEM), a member of the tumor necrosis factor (TNF) receptor superfamily, in ILC3 is important for host defense against oral infection with the bacterial pathogen Yersinia enterocolitica. HVEM stimulates protective interferon-γ (IFN-γ) secretion from ILCs, and mice with HVEM-deficient ILC3 exhibit reduced IFN-γ production, higher bacterial burdens and increased mortality. In addition, IFN-γ production is critical as adoptive transfer of wild-type but not IFN-γ-deficient ILC3 can restore protection to mice lacking ILCs. We identify the TNF superfamily member, LIGHT, as the ligand inducing HVEM signals in ILCs. Thus HVEM signaling mediated by LIGHT plays a critical role in regulating ILC3-derived IFN-γ production for protection following infection. VIDEO ABSTRACT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Myelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th)1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocyte-predominant spinal cord infiltrates, in C57BL/6 wildtype (WT) hosts. The same T cells induce an atypical form of EAE (aEAE), characterized by ataxia and neutrophil-predominant brainstem infiltrates, in syngeneic IFNγ receptor (IFNγR)-deficient hosts. Production of ELR+ CXC chemokines within the CNS is required for the development of aEAE, but not cEAE. The cellular source(s) and localization of ELR+ CXC chemokines in the CNS and the IFNγ-dependent pathways that regulate their production remain to be elucidated., Methods: The spatial distribution of inflammatory lesions and CNS expression of the ELR+ CXC chemokines, CXCL1 and CXCL2, were determined via immunohistochemistry and/or in situ hybridization. Levels of CXCL1 and CXCL2, and their cognate receptor CXCR2, were measured in/on leukocyte subsets by flow cytometric and quantitative PCR (qPCR) analysis. Bone marrow neutrophils and macrophages were cultured with inflammatory stimuli in vitro prior to measurement of CXCL2 and CXCR2 by qPCR or flow cytometry., Results: CNS-infiltrating neutrophils and monocytes, and resident microglia, are a prominent source of CXCL2 in the brainstem of IFNγRKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFNγ directly suppresses CXCL2 transcription in microglia and myeloid cells, and CXCR2 transcription in CNS-infiltrating neutrophils. Consequently, infiltration of the brainstem parenchyma from the adjacent meninges is blocked during cEAE. CXCL2 directly stimulates its own expression in cultured neutrophils, which is enhanced by IL-1 and suppressed by IFNγ., Conclusions: We provide evidence for an IFNγ-regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFNγ signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFNγ, produced within the CNS of WT recipients, suppresses myeloid cell CXCR2 and CXCL2 production, thereby skewing the location of neuroinflammatory infiltrates to the spinal cord and the clinical phenotype to an ascending paralysis. These data reveal a novel mechanism by which IFNγ and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations.

Eotaxins are C-C motif chemokines first identified as potent eosinophil chemoattractants. They facilitate eosinophil recruitment to sites of inflammation in response to parasitic infections as well as allergic and autoimmune diseases such as asthma, atopic dermatitis, and inflammatory bowel disease. The eotaxin family currently includes three members: eotaxin-1 (CCL11), eotaxin-2 (CCL24), and eotaxin-3 (CCL26). Despite having only ~30% sequence homology to one another, each was identified based on its ability to bind the chemokine receptor, CCR3. Beyond their role in innate immunity, recent studies have shown that CCL11 and related molecules may directly contribute to degenerative processes in the central nervous system (CNS). CCL11 levels increase in the plasma and cerebrospinal fluid of both mice and humans as part of normal aging. In mice, these increases are associated with declining neurogenesis and impaired cognition and memory. In humans, elevated plasma levels of CCL11 have been observed in Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and secondary progressive multiple sclerosis when compared to age-matched, healthy controls. Since CCL11 is capable of crossing the blood-brain barrier of normal mice, it is plausible that eotaxins generated in the periphery may exert physiological and pathological actions in the CNS. Here, we briefly review known functions of eotaxin family members during innate immunity, and then focus on whether and how these molecules might participate in the progression of neurodegenerative diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) represents a disease spectrum ranging from benign steatosis to life-threatening cirrhosis and hepatocellular carcinoma. Elevated levels of reactive oxygen species (ROS) and exacerbated inflammatory responses have been implicated in NAFLD progression. Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 (NOX2; also known as gp91 Phox ), the main catalytic subunit of the nicotinamide adenine dinucleotide phosphate (reduced) oxidase complex, modulates ROS production, immune responsiveness, and pathogenesis of obesity-associated metabolic derangements. However, the role of NOX2 in the regulation of immune cell function and inflammatory vigor in NAFLD remains underdefined. Here, we demonstrate that obesogenic diet feeding promoted ROS production by bone marrow, white adipose tissue, and liver immune cells. Genetic ablation of NOX2 impeded immune cell ROS synthesis and was sufficient to uncouple obesity from glucose dysmetabolism and NAFLD pathogenesis. Protection from hepatocellular damage in NOX2-deficient mice correlated with reduced hepatic neutrophil, macrophage, and T-cell infiltration, diminished production of key NAFLD-driving proinflammatory cytokines, and an inherent reduction in T-cell polarization toward Th17 phenotype. Conclusion : Current findings demonstrate a crucial role of the NOX2-ROS axis in immune cell effector function and polarization and consequent NAFLD progression in obesity. Pharmacologic targeting of NOX2 function in immune cells may represent a viable approach for reducing morbidity of obesity-associated NAFLD pathogenesis. ( Hepatology Communications 2018;2:546-560).

Nonalcoholic fatty liver disease (NAFLD), a metabolic predisposition for development of hepatocellular carcinoma (HCC), represents a disease spectrum ranging from steatosis to steatohepatitis to cirrhosis. Acox1, a rate-limiting enzyme in peroxisomal fatty acid β-oxidation, regulates metabolism, spontaneous hepatic steatosis, and hepatocellular damage over time. However, it is unknown whether Acox1 modulates inflammation relevant to NAFLD pathogenesis or if Acox1-associated metabolic and inflammatory derangements uncover and accelerate potential for NAFLD progression. Here, we show that mice with a point mutation in Acox1 (Acox1Lampe1) exhibited altered cellular metabolism, modified T cell polarization, and exacerbated immune cell inflammatory potential. Further, in context of a brief obesogenic diet stress, NAFLD progression associated with Acox1 mutation resulted in significantly accelerated and exacerbated hepatocellular damage via induction of profound histological changes in hepatocytes, hepatic inflammation, and robust upregulation of gene expression associated with HCC development. Collectively, these data demonstrate that β-oxidation links metabolism and immune responsiveness and that a better understanding of peroxisomal β-oxidation may allow for discovery of mechanisms central for NAFLD progression.

Giles, DA and Draper, N. Heart rate variability during exercise: a comparison of artefact correction methods. J Strength Cond Res 32(3): 726-735, 2018-There is a need for standard practice in the collection and processing of RR interval data recorded using heart rate monitors (HRMs) in research. This article assessed the validity of RR intervals and heart rate variability (HRV) data obtained using an HRM during incremental exercise and artefact correction methods. Eighteen participants completed an active orthostatic test and incremental running V[Combining Dot Above]O2max test, while simultaneous recordings using a Polar V800 HRM and an electrocardiogram were made. Artefacts were corrected by deletion; degree zero, linear, cubic, and spline interpolation; and Kubios HRV software. Agreement was assessed using percentage bias, effect size (ES), intraclass correlation coefficients (ICC), and Bland-Altman limits of agreement (LoA). Artefacts increased relative to exercise intensity, to a peak of 4.46% during 80-100% V[Combining Dot Above]O2max. Correction of RR intervals was necessary with unacceptably increased bias, LoA, and ES and reduced ICC in all but resting recordings. All correction methods resulted in data with reduced percentage bias and ES for resting and <60% V[Combining Dot Above]O2max recordings. However, at >60% V[Combining Dot Above]O2max, even with correction, large amounts of variation were present in HRV measures of root mean square of the successive difference of intervals, low-to-high frequency ratio, Poincaré dispersion perpendicular to the axis (SD1), and sample entropy. Linear interpolation produced RR intervals with the lowest bias and ES. However, caution should be given to HRV parameters at high exercise intensities, as large amounts of variation were still present. Recommendations for minimizing artefacts are discussed, along with guidelines for their identification, correction, and reporting.

Objective: Myeloid cells, including macrophages and dendritic cells, are a prominent component of central nervous system (CNS) infiltrates during multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE). Although myeloid cells are generally thought to be proinflammatory, alternatively polarized subsets can serve noninflammatory and/or reparative functions. Here we investigate the heterogeneity and biological properties of myeloid cells during central nervous system autoimmunity., Methods: Myeloid cell phenotypes in chronic active MS lesions were analyzed by immunohistochemistry. In addition, immune cells were isolated from the CNS during exacerbations and remissions of EAE and characterized by flow cytometric, genetic, and functional assays., Results: Myeloid cells expressing inducible nitric oxide synthase (iNOS), indicative of a proinflammatory phenotype, were detected in the actively demyelinating rim of chronic active MS lesions, whereas macrophages expressing mannose receptor (CD206), a marker of alternatively polarized human myeloid cells, were enriched in the quiescent lesion core. During EAE, CNS-infiltrating myeloid cells, as well as microglia, shifted from expression of proinflammatory markers to expression of noninflammatory markers immediately prior to clinical remissions. Murine CNS myeloid cells expressing the alternative lineage marker arginase-1 (Arg1) were partially derived from iNOS + precursors and were deficient in activating encephalitogenic T cells compared with their Arg1 - counterparts., Interpretation: These observations demonstrate the heterogeneity of CNS myeloid cells, their evolution during the course of autoimmune demyelinating disease, and their plasticity on the single cell level. Future therapeutic strategies for disease modification in individuals with MS may be focused on accelerating the transition of CNS myeloid cells from a proinflammatory to a noninflammatory phenotype. Ann Neurol 2018;83:131-141., (© 2018 American Neurological Association.)

Understanding cumulative effects of multiple threats is key to guiding effective management to conserve endangered species. The critically endangered, Southern Resident killer whale population of the northeastern Pacific Ocean provides a data-rich case to explore anthropogenic threats on population viability. Primary threats include: limitation of preferred prey, Chinook salmon; anthropogenic noise and disturbance, which reduce foraging efficiency; and high levels of stored contaminants, including PCBs. We constructed a population viability analysis to explore possible demographic trajectories and the relative importance of anthropogenic stressors. The population is fragile, with no growth projected under current conditions, and decline expected if new or increased threats are imposed. Improvements in fecundity and calf survival are needed to reach a conservation objective of 2.3% annual population growth. Prey limitation is the most important factor affecting population growth. However, to meet recovery targets through prey management alone, Chinook abundance would have to be sustained near the highest levels since the 1970s. The most optimistic mitigation of noise and contaminants would make the difference between a declining and increasing population, but would be insufficient to reach recovery targets. Reducing acoustic disturbance by 50% combined with increasing Chinook by 15% would allow the population to reach 2.3% growth.

This corrects the article DOI: 10.1038/nm.4346.

Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.

Preterm birth (PTB) is a leading worldwide cause of morbidity and mortality in infants. Maternal inflammation induced by microbial infection is a critical predisposing factor for PTB. However, biological processes associated with competency of pathogens, including viruses, to induce PTB or sensitize for secondary bacterial infection-driven PTB are unknown. We show that pathogen/pathogen-associated molecular pattern-driven activation of type I IFN/IFN receptor (IFNAR) was sufficient to prime for systemic and uterine proinflammatory chemokine and cytokine production and induction of PTB. Similarly, treatment with recombinant type I IFNs recapitulated such effects by exacerbating proinflammatory cytokine production and reducing the dose of secondary inflammatory challenge required for induction of PTB. Inflammatory challenge-driven induction of PTB was eliminated by defects in type I IFN, TLR, or IL-6 responsiveness, whereas the sequence of type I IFN sensing by IFNAR on hematopoietic cells was essential for regulation of proinflammatory cytokine production. Importantly, we also show that type I IFN priming effects are conserved from mice to nonhuman primates and humans, and expression of both type I IFNs and proinflammatory cytokines is upregulated in human PTB. Thus, activation of the type I IFN/IFNAR axis in pregnancy primes for inflammation-driven PTB and provides an actionable biomarker and therapeutic target for mitigating PTB risk., Competing Interests: Conflict of interest: The authors have declared that no conflict of interest exists.

Objectives: Obesity and obesity-associated inflammation is central to a variety of end-organ sequelae including atherosclerosis, a leading cause of death worldwide. Although mouse models have provided important insights into the immunopathogenesis of various diseases, modeling atherosclerosis in mice has proven difficult. Specifically, wild-type (WT) mice are resistant to developing atherosclerosis, while commonly used genetically modified mouse models of atherosclerosis are poor mimics of human disease. The lack of a physiologically relevant experimental model of atherosclerosis has hindered the understanding of mechanisms regulating disease development and progression as well as the development of translational therapies. Recent evidence suggests that housing mice within their thermoneutral zone profoundly alters murine physiology, including both metabolic and immune processes. We hypothesized that thermoneutral housing would allow for augmentation of atherosclerosis induction and progression in mice., Methods: ApoE -/- and WT mice were housed at either standard (T S ) or thermoneutral (T N ) temperatures and fed either a chow or obesogenic "Western" diet. Analysis included quantification of (i) obesity and obesity-associated downstream sequelae, (ii) the development and progression of atherosclerosis, and (iii) inflammatory gene expression pathways related to atherosclerosis., Results: Housing mice at T N , in combination with an obesogenic "Western" diet, profoundly augmented obesity development, exacerbated atherosclerosis in ApoE -/- mice, and initiated atherosclerosis development in WT mice. This increased disease burden was associated with altered lipid profiles, including cholesterol levels and fractions, and increased aortic plaque size. In addition to the mild induction of atherosclerosis, we similarly observed increased levels of aortic and white adipose tissue inflammation and increased circulating immune cell expression of pathways related to adverse cardiovascular outcome., Conclusions: In sum, our novel data in WT C57Bl/6 mice suggest that modulation of a single environmental variable, temperature, dramatically alters mouse physiology, metabolism, and inflammation, allowing for an improved mouse model of atherosclerosis. Thus, thermoneutral housing of mice shows promise in yielding a better understanding of the cellular and molecular pathways underlying the pathogenesis of diverse diseases.

Persistent organic pollutants (POPs), specifically PCBs, PBDEs, and DDTs, in the marine environment are well documented, however accumulation and mobilization patterns at the top of the food-web are poorly understood. This study broadens the understanding of POPs in the endangered Southern Resident killer whale population by addressing modulation by prey availability and reproductive status, along with endocrine disrupting effects. A total of 140 killer whale scat samples collected from 54 unique whales across a 4 year sampling period (2010-2013) were analyzed for concentrations of POPs. Toxicant measures were linked to pod, age, and birth order in genotyped individuals, prey abundance using open-source test fishery data, and pregnancy status based on hormone indices from the same sample. Toxicant concentrations were highest and had the greatest potential for toxicity when prey abundance was the lowest. In addition, these toxicants were likely from endogenous lipid stores. Bioaccumulation of POPs increased with age, with the exception of presumed nulliparous females. The exceptional pattern may be explained by females experiencing unobserved neonatal loss. Transfer of POPs through mobilization of endogenous lipid stores during lactation was highest for first-borns with diminished transfer to subsequent calves. Contrary to expectation, POP concentrations did not demonstrate an associated disruption of thyroid hormone, although this association may have been masked by impacts of prey abundance on thyroid hormone concentrations. The noninvasive method for measuring POP concentrations in killer whales through scat employed in this study may improve toxicant monitoring in the marine environment and promote conservation efforts.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. While it is well-accepted that inflammation is central to NAFLD pathogenesis, the immune pathway(s) orchestrating disease progression are poorly defined. Notably, IL-17RA signaling, via IL-17A, plays an important role in obesity-driven NAFLD pathogenesis. However, the role of the IL-17F, another IL-17RA ligand, in NAFLD pathogenesis has not been examined. Further, the cell types expressing IL-17RA and producing IL-17RA ligands in the pathogenesis of NAFLD have not been defined. Here, IL-17RA-/-, IL-17A-/-, IL-17F-/- and wild-type (WT) mice were fed either standard chow diet or methionine and choline deficient diet (MCDD)--a diet known to induce steatosis and hepatic inflammation through beta-oxidation dysfunction--and hepatic inflammation and NAFLD progression were subsequently quantified. MCDD feeding augmented hepatic IL-17RA expression and significantly increased hepatic infiltration of macrophages and IL-17A and IL-17F producing CD4+ and CD8+ T cells in WT mice. In contrast, IL-17RA-/-, IL-17A-/-, and IL-17F-/- mice, despite increased steatosis, exhibited significant protection from hepatocellular damage compared to WT controls. Protection from hepatocellular damage correlated with decreased levels of hepatic T-cell and macrophage infiltration and decreased expression of inflammatory mediators associated with NAFLD. In sum, our results indicate that the IL-17 axis also plays a role in a MCDD-induced model of NAFLD pathogenesis. Further, we show for the first time that IL-17F, and not only IL-17A, plays an important role in NAFLD driven inflammation.

Objective: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH., Methods: To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mt(FVB/N) mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8)., Results: At baseline conditions, C57BL/6J-mt(FVB/N) mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mt(FVB/N) mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells., Conclusions: We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress, was required to cause hepatic steatosis and inflammation. This study suggests a causative role of hepatic mitochondrial dysfunction in the development of experimental NASH.

Whale watching has become increasingly popular as an ecotourism activity around the globe and is beneficial for environmental education and local economies. Southern Resident killer whales (Orcinus orca) comprise an endangered population that is frequently observed by a large whale watching fleet in the inland waters of Washington state and British Columbia. One of the factors identified as a risk to recovery for the population is the effect of vessels and associated noise. An examination of the effects of vessels and associated noise on whale behavior utilized novel equipment to address limitations of previous studies. Digital acoustic recording tags (DTAGs) measured the noise levels the tagged whales received while laser positioning systems allowed collection of geo-referenced data for tagged whales and all vessels within 1000 m of the tagged whale. The objective of the current study was to compare vessel data and DTAG recordings to relate vessel traffic to the ambient noise received by tagged whales. Two analyses were conducted, one including all recording intervals, and one that excluded intervals when only the research vessel was present. For all data, significant predictors of noise levels were length (inverse relationship), number of propellers, and vessel speed, but only 15% of the variation in noise was explained by this model. When research-vessel-only intervals were excluded, vessel speed was the only significant predictor of noise levels, and explained 42% of the variation. Simple linear regressions (ignoring covariates) found that average vessel speed and number of propellers were the only significant correlates with noise levels. We conclude that vessel speed is the most important predictor of noise levels received by whales in this study. Thus, measures that reduce vessel speed in the vicinity of killer whales would reduce noise exposure in this population.

The aim of the current study is to describe the complication rates and clinical outcomes in patients who either underwent repeat intervention or conservative management with radiographic surveillance when presenting with aneurysmal recurrence after endovascular treatment. Since publication of the international subarachnoid aneurysm trial (ISAT), an increasing number of patients are treated with endovascular therapy. However, recurrence after endovascular therapy continues to pose a challenge, and there is minimal evidence to guide its management. We performed a retrospective review of all patients who underwent endovascular treatment of an intracranial aneurysm from January 2005 to February 2013. The patients who had an aneurysmal recurrence following the initial endovascular treatment were identified and divided into two groups: those followed with conservative management (n=24), and those who underwent reintervention (n=65). The groups were compared for complications and clinical outcomes. When a reintervention was undertaken, microsurgical clip ligation was associated with a higher rate of occlusion than additional endovascular therapy (p<0.001). When comparing conservative treatment and reintervention, there was no statistically significant difference in complications or clinical outcomes. Reintervention was more common in patients who were younger, had presented with subarachnoid hemorrhage, or had a greater degree of recurrence. We conclude that clinical outcomes and repeat subarachnoid hemorrhage are similar in patients who underwent retreatment versus those who had conservative management for their recurrent cerebral aneurysms., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

CD4(+) T-helper (Th) cells reactive against myelin antigens mediate the mouse model experimental autoimmune encephalomyelitis (EAE) and have been implicated in the pathogenesis of multiple sclerosis (MS). It is currently debated whether encephalitogenic Th cells are heterogeneous or arise from a single lineage. In the current study, we challenge the dogma that stimulation with the monokine IL-23 is universally required for the acquisition of pathogenic properties by myelin-reactive T cells. We show that IL-12-modulated Th1 cells readily produce IFN-γ and GM-CSF in the CNS of mice and induce a severe form of EAE via an IL-23-independent pathway. Th1-mediated EAE is characterized by monocyte-rich CNS infiltrates, elicits a strong proinflammatory cytokine response in the CNS, and is partially CCR2 dependent. Conversely, IL-23-modulated, stable Th17 cells induce EAE with a relatively mild course via an IL-12-independent pathway. These data provide definitive evidence that autoimmune disease can be driven by distinct CD4(+) T-helper-cell subsets and polarizing factors., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: We hypothesized that the subset of patients with early hydrocephalus following aneurysmal subarachnoid hemorrhage may represent a subset of patients with a more vehement inflammatory reaction to blood products in the subarachnoid space. We thus examined risk factors for early hydrocephalus and examined the relationship between early hydrocephalus and symptomatic vasospasm as well as clinical outcome., Methods: We retrospectively analyzed all patients presenting to our institution with subarachnoid hemorrhage over a 7-year period. We examined for risk factors, including early hydrocephalus, for poor clinical outcome and symptomatic vasospasm., Results: We found intraventricular hemorrhage to be strongly associated with the development of early hydrocephalus. In univariate analysis, early hydrocephalus was strongly associated with both poor functional outcome and symptomatic vasospasm. In multivariate analysis, intraventricular hemorrhage and tobacco use were associated with symptomatic vasospasm; intraventricular hemorrhage, intraparenchymal hemorrhage, and symptomatic vasospasm were associated with poor functional outcome., Conclusions: We found that intraventricular hemorrhage was strongly associated with early hydrocephalus. Further exploration of the mechanistic explanation is needed, but we suggest this may be from a combination of obstruction of cerebrospinal fluid pathways by blood products and inflammation in the choroid plexus resulting in increased cerebrospinal fluid production. Further, we suggest that both early hydrocephalus and cerebral vasospasm may be parts of the overall inflammatory cascade that occurs with intraventricular hemorrhage and ultimately results in a poorer clinical outcome., (Georg Thieme Verlag KG Stuttgart · New York.)

A major function of T helper (Th) 17 cells is to induce the production of factors that activate and mobilize neutrophils. Although Th17 cells have been implicated in the pathogenesis of multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE), little attention has been focused on the role of granulocytes in those disorders. We show that neutrophils, as well as monocytes, expand in the bone marrow and accumulate in the circulation before the clinical onset of EAE, in response to systemic up-regulation of granulocyte colony-stimulating factor (G-CSF) and the ELR(+) CXC chemokine CXCL1. Neutrophils comprised a relatively high percentage of leukocytes infiltrating the central nervous system (CNS) early in disease development. G-CSF receptor deficiency and CXCL1 blockade suppressed myeloid cell accumulation in the blood and ameliorated the clinical course of mice that were injected with myelin-reactive Th17 cells. In relapsing MS patients, plasma levels of CXCL5, another ELR(+) CXC chemokine, were elevated during acute lesion formation. Systemic expression of CXCL1, CXCL5, and neutrophil elastase correlated with measures of MS lesion burden and clinical disability. Based on these results, we advocate that neutrophil-related molecules be further investigated as novel biomarkers and therapeutic targets in MS., (© 2015 Rumble et al.)

Obesity is a primary risk factor for the development of non-alcoholic fatty liver disease (NAFLD). NAFLD, the most common chronic liver disease in the world, represents a spectrum of disorders that range from steatosis (NAFL) to steatohepatitis (NASH) to cirrhosis. It is anticipated that NAFLD will soon surpass chronic hepatitis C infection as the leading cause for needing liver transplantation. Despite its clinical and public health significance no specific therapies are available. Although the etiology of NAFLD is multifactorial and remains largely enigmatic, it is well accepted that inflammation is a central component of NAFLD pathogenesis. Despite the significance, critical immune mediators, loci of immune activation, the immune signaling pathways and the mechanism(s) underlying disease progression remain incompletely understood. Recent findings have focused on the role of Interleukin 17 (IL-17) family of proinflammatory cytokines in obesity and pathogenesis of obesity-associated sequelae. Notably, obesity favors a Th17 bias and is associated with increased IL-17A expression in both humans and mice. Further, in mice, IL-17 axis has been implicated in regulation of both obesity and NAFLD pathogenesis. However, despite these recent advances several important questions require further evaluation including: the relevant cellular source of IL-17A production; the critical IL- 17RA-expressing cell type; the critical liver infiltrating immune cells; and the underlying cellular effector mechanisms. Addressing these questions may aid in the identification and development of novel therapeutic targets for prevention of inflammation- driven NAFLD progression.

Unlabelled: Inflammation plays a central pathogenic role in the pernicious metabolic and end-organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)-17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL-17RA signaling in the progression of NAFLD. We further examined whether microbe-driven IL-17A regulated NAFLD development and progression. We show here that IL-17RA(-/-) mice respond to high-fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild-type controls. However, obesity-driven lipid accumulation was uncoupled from its end-organ consequences in IL-17RA(-/-) mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme expression, and hepatocellular damage. Neutralization of IL-17A significantly reduced obesity-driven hepatocellular damage in wild-type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL-17A production, exacerbated obesity-induced hepatocellular damage. In contrast, SFB depletion protected from obesity-induced hepatocellular damage., Conclusion: These data indicate that obesity-driven activation of the IL-17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL-17 pathway as a novel therapeutic target in this condition., (Copyright © 2014 The Authors. HEPATOLOGY published by Wiley on behalf of the American Association for the Study of Liver Diseases.)