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Background: Genetic mitochondrial diseases are a major challenge in modern medicine, impacting around 1:4,000 individuals. Leigh syndrome is the most common pediatric presentation of mitochondrial disease. There are currently no effective clinical treatments for mitochondrial disease. In humans, patients are often treated with antioxidants, vitamins, and strategies targeting energetics. The vitamin-E related compound vatiquinone (EPI-743, α-tocotrienol quinone) has been the subject of at least 19 clinical trials in the US since 2012, but the effects of vatiquinone on an animal model of mitochondrial disease have not yet been reported. Here, assessed the impact of vatiquinone on disease progression and in two animal models of mitochondrial disease., Methods: The efficacy of vatiquinone in vitro was assessed using human fibroblasts treated with the general mitochondrial oxidative stress inducer paraquat, the GPX4 inhibitor RSL3, or the glutathione synthase inhibitor BSO in combination with excess iron. The therapeutic potential of vatiquinone in vivo was assessed using tamoxifen-induced mouse model for GPX4 deficiency and the Ndufs4 knockout mouse model of Leigh syndrome. In both models, animals were treated daily with vatiquinone or vehicle and relevant disease endpoints were assessed., Results: Vatiquinone robustly prevented death in cultured cells induced by RSL3 or BSO/iron, but had no effect on paraquat induced cell death. Vatiquinone had no impact on disease onset, progression, or survival in either the tamoxifen-inducible GPX4 deficient model or the Ndufs4 (-/-) mouse model, though the drug may have reduced seizure risk., Conclusions: Vatiquinone provided no benefit to survival in two mouse models of disease, but may prevent seizures in the Ndufs4 (-/-) model. Our findings are consistent with recent press statements regarding clinical trial results and have implications for drug trial design and reporting in patients with rare diseases., Competing Interests: Competing interests None.

Aim: Leigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi-system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2 years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the Ndufs4(-/-) mouse model of LS: treatment of Ndufs4(-/-) mice with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon-gamma (IFNγ) and interferon gamma-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4(-/-) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFNγ and IP10 in LS., Methods: To establish the role of IFNγ and IP10 in LS, we generated IFNγ and IP10 deficient Ndufs4(-/-)/Ifng(-/-) and Ndufs4(-/-)/IP10(-/-) double knockout animals, as well as IFNγ and IP10 heterozygous, Ndufs4(-/-)/Ifng(+/-) and Ndufs4(-/-)/IP10(+/-), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFNγ and IP10 in LS., Results: Loss of IP10 does not significantly impact the onset or progression of disease in the Ndufs4(-/-) model. IFNγ loss significantly extends survival and delays disease progression in a gene dosage-dependent manner, though the benefits are modest compared to Csf1r inhibition., Conclusions: IFNγ contributes to disease onset and progression in LS. Our findings suggest that IFNγ targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFNγ alone would likely yield only modest benefits in LS., (© 2024 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Aims: The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis., Methods and Results: Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E-deficient (Apoe-/-) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade., Conclusion: Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production., Competing Interests: Conflict of interest: E.J.G., C.G., S.R., and D.L. are employed by and hold stocks or options in Cantargia AB. C.G., S.R., and D.L. are signed as co-inventors on a patent related to anti-IL1RAP monoclonal antibodies. D.E. received reagents related to the current study from Cantargia AB., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted interleukin-22 (IL-22) production by type 3 innate lymphoid cells (ILC3s) and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor (IL-22R) attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell-cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting., Competing Interests: HC, LS, LF, XH, YZ, WZ, ZZ, MM, WZ, YY No competing interests declared, (© 2023, Chen, Sun et al.)

Introduction: Mortality from preeclampsia (PE) and PE-associated morbidities are 3-to 5-fold higher in persons of African ancestry than in those of Asian and European ancestries., Methods: To elucidate placental contribution to worse PE outcomes in African ancestry pregnancies, we performed bulk RNA sequencing on 50 placentas from persons with severe PE (sPE) of African (n = 9), Asian (n = 18) and European (n = 23) ancestries and 73 normotensive controls of African (n = 10), Asian (n = 15) and European (n = 48) ancestries., Results: Previously described canonical preeclampsia genes, involved in metabolism and hypoxia/angiogenesis including: LEP, HK2, FSTL3, FLT1, ENG, TMEM45A, ARHGEF4 and HTRA1 were upregulated sPE versus normotensive placentas across ancestries. LTF, NPR3 and PHYHIP were higher in African vs. Asian ancestry sPE placentas. Allograft rejection/adaptive immune response genes were upregulated in placentas from African but not in Asian or European ancestry sPE patients; IL3RA was of particular interest because the patient with the highest placental IL3RA expression, a person of African ancestry with sPE, developed postpartum cardiomyopathy, and was the only patient out of 123, that developed this condition. Interestingly, the sPE patients with the highest IL3RA expression among persons of Asian and European ancestries developed unexplained tachycardia peripartum, necessitating echocardiography in the European ancestry patient. The association between elevated placental IL3RA levels and unexplained tachycardia or peripartum cardiomyopathy was found to be significant in the 50 sPE patients (p = .0005)., Discussion: High placental upregulation of both canonical preeclampsia and allograft rejection/adaptive immune response genes may contribute to worse PE outcomes in African ancestry sPE patients., Competing Interests: Declaration of competing interest All authors have no conflict of interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(-/-) mouse model of LS. While the dose-response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony-stimulating Factor 1 receptor (CSF1R) macrophage super-enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(-/-) animals, but onset of CNS lesions and sequalae in the Ndufs4(-/-), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(-/-) model., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background: Volatile anaesthetics are widely used in human medicine. Although generally safe, hypersensitivity and toxicity can occur in rare cases, such as in certain genetic disorders. Anaesthesia hypersensitivity is well-documented in a subset of mitochondrial diseases, but whether volatile anaesthetics are toxic in this setting has not been explored., Methods: We exposed Ndufs4(-/-) mice, a model of Leigh syndrome, to isoflurane (0.2-0.6%), oxygen 100%, or air. Cardiorespiratory function, weight, blood metabolites, and survival were assessed. We exposed post-symptom onset and pre-symptom onset animals and animals treated with the macrophage depleting drug PLX3397/pexidartinib to define the role of overt neuroinflammation in volatile anaesthetic toxicities., Results: Isoflurane induced hyperlactataemia, weight loss, and mortality in a concentration- and duration-dependent manner from 0.2% to 0.6% compared with carrier gas (O 2 100%) or mock (air) exposures (lifespan after 30-min exposures ∗P<0.05 for isoflurane 0.4% vs air or vs O 2 , ∗∗P<0.005 for isoflurane 0.6% vs air or O 2 ; 60-min exposures ∗∗P<0.005 for isoflurane 0.2% vs air, ∗P<0.05 for isoflurane 0.2% vs O 2 ). Isoflurane toxicity was significantly reduced in Ndufs4(-/-) exposed before CNS disease onset, and the macrophage depleting drug pexidartinib attenuated sequelae of isoflurane toxicity (survival ∗∗∗P=0.0008 isoflurane 0.4% vs pexidartinib plus isoflurane 0.4%). Finally, the laboratory animal standard of care of 100% O 2 as a carrier gas contributed significantly to weight loss and reduced survival, but not to metabolic changes, and increased acute mortality., Conclusions: Isoflurane is toxic in the Ndufs4(-/-) model of Leigh syndrome. Toxic effects are dependent on the status of underlying neurologic disease, largely prevented by the CSF1R inhibitor pexidartinib, and influenced by oxygen concentration in the carrier gas., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Autism spectrum disorder (ASD) is a developmental disorder characterized by stereotypies or repetitive behaviors and impairments in social behavior and socio-communicative skills. One hallmark phenotype of ASD is poor joint attention skills compared to neurotypical controls. In addition, individuals with ASD have lower scores on several of the Big 5 personality dimensions, including Extraversion. Here, we examine these traits in a nonhuman primate model (chimpanzees; Pan troglodytes ) to further understand the relationship between personality and joint attention skills, as well as the genetic and neural systems that contribute to these phenotypes. We used archival data including receptive joint attention (RJA) performance, personality based on caretaker ratings, and magnetic resonance images from 189 chimpanzees. We found that, like humans, chimpanzees who performed worse on the RJA task had lower Extraversion scores. We also found that joint attention skills and several personality dimensions, including Extraversion, were significantly heritable. There was also a borderline significant genetic correlation between RJA and Extraversion. A conjunction analysis examining gray matter volume showed that there were five main brain regions associated with both higher levels of Extraversion and social cognition. These regions included the right posterior middle and superior temporal gyrus, bilateral inferior frontal gyrus, left inferior frontal sulcus, and left superior frontal sulcus, all regions within the social brain network. Altogether, these findings provide further evidence that chimpanzees serve as an excellent model for understanding the mechanisms underlying social impairment related to ASD. Future research should further examine the relationship between social cognition, personality, genetics, and neuroanatomy and function in nonhuman primate models., Competing Interests: None of the authors declare any conflicts of interest., (© The Author(s) 2023.)

Background and Aims: The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD., Methods: The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9 -/- mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice., Results: In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9 -/- mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9 -/- mice, confirming target specificity., Conclusion: Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Age-related changes in cognition, brain morphology, and behavior are exhibited in several primate species. Baboons, like humans, naturally develop Alzheimer's disease-like pathology and cognitive declines with age and are an underutilized model for studies of aging. To determine age-related differences in gray matter covariation of 89 olive baboons (Papio anubis), we used source-based morphometry (SBM) to analyze data from magnetic resonance images. We hypothesized that we would find significant age effects in one or more SBM components, particularly those which include regions influenced by age in humans and other nonhuman primates (NHPs). A multivariate analysis of variance revealed that individual weighted gray matter covariation scores differed across the age classes. Elderly baboons contributed significantly less to gray matter covariation components including the brainstem, superior parietal cortex, thalamus, and pallidum compared to juveniles, and middle and superior frontal cortex compared to juveniles and young adults (p < 0.05). Future studies should examine the relationship between the changes in gray matter covariation reported here and age-related cognitive decline., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Prioritising teaching when clinical practice is hectic can be difficult. Often teaching is seen to be confined to formal structured events. This article aims to highlight the abundance of learning opportunities that arise outside of such formal teaching events in daily clinical practice. It first discusses the qualities and skills of a time-efficient, yet effective, teacher. Practical suggestions are then provided in order to maximise learning from important opportunities that occur daily from handovers, ward rounds, clinics to tea-trolley teaching aiming to give encouragement to all that valuable teaching is possible even when time is limited., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The immune checkpoint receptor lymphocyte-activation gene 3 (LAG3) is a new target for immune checkpoint blockade (ICB), but the effects of LAG3 on atherosclerosis are not known., Objectives: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis., Methods: To study the role of LAG3 in atherosclerosis, we investigated both bone marrow chimeras lacking LAG3 in hematopoietic cells as well as global Lag3 -/- knockout mice. Effects of anti-LAG3 monoclonal antibody monotherapy and combination therapy with anti-programmed cell death protein 1 (PD-1) were tested in hypercholesterolemic low-density lipoprotein receptor knockout ( Ldlr -/- ) mice and evaluated by histology and flow cytometry., Results: LAG3-deficiency or treatment with blocking anti-LAG3 monoclonal antibodies led to increased levels of both interferon gamma-producing T helper 1 cells and effector/memory T cells, balanced by increased levels of regulatory T cells. Plaque size was affected by neither LAG3 deficiency nor LAG3 blockade, although density of T cells in plaques was 2-fold increased by loss of LAG3. Combination therapy of anti-PD-1 and anti-LAG3 had an additive effect on T cell activation and cytokine production and promoted plaque infiltration of T cells., Conclusions: Loss of LAG3 function promoted T cell activation and accumulation in plaques while not affecting plaque burden. Our report supports further clinical studies investigating cardiovascular risk in patients treated with anti-LAG3 ICB., Competing Interests: Dr Engelbertsen was supported by the Swedish Heart-Lung Foundation (#20200522, #20190449), Dr Rodriguez was supported by National Institutes of Health HL131862 and the Linda and David Roth Chair for Cardiovascular Research; is an inventor of issued patents related to LAG3; and is the founder of Lipid Genomics. Dr Lichtman was supported by National Institutes of Health HL131862. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Humans and chimpanzees both exhibit a diverse set of tool use skills which suggests selection for tool manufacture and use occurred in the common ancestors of the two species. Our group has previously reported phenotypic and genetic associations between tool use skill and gray matter covariation, as quantified by source-based morphometry (SBM), in chimpanzees. As a follow up study, here we evaluated repeatability in heritability in SBM components and their phenotypic association with tool use skill in two genetically independent chimpanzee cohorts. Within the two independent cohorts of chimpanzees, we identified 8 and 16 SBM components, respectively. Significant heritability was evident for multiple SBM components within both cohorts. Further, phenotypic associations between tool use performance and the SBM components were largely consistent between the two cohorts; the most consistent finding being an association between tool use performance and an SBM component including the posterior superior temporal sulcus (STS) and superior temporal gyrus (STG), and the interior and superior parietal regions (p < 0.05). These findings indicate that the STS, STG, and parietal cortices are phenotypically and genetically implicated in chimpanzee tool use abilities., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease affecting children and young people today. However, it is not a single disease entity, but an umbrella term that gathers together a heterogeneous collection of complex, chronic inflammatory conditions with oligoarticular JIA the most common form in both Europe and North America. Due to its relative rarity in daily practice and potential to mimic other conditions, oligoarticular JIA can present a diagnostic and management challenge to healthcare professionals in both primary care and general paediatrics. The aim of this article is to provide a summary of the key aspects of diagnosis, investigation and management of this condition, with the hopes of building clinicians' confidence when facing a possible case of oligoarticular JIA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

microRNA-31 (miR-31) has been identified to be downregulated in pathologies associated with delayed wound repair. Thus, it was proposed that the delivery of a plasmid encoding miR-31 (pmiR-31) to the skin could hold potential in promoting wound healing. Effective delivery of pmiR-31 was potentiated by encapsulation with the CHAT peptide to form nanocomplexes, this improved cellular entry and elicited a potent increase in miR-31 expression in vitro in both skin human keratinocyte cell line (HaCaT) and human microvascular endothelial cell line (HMEC-1). Transfection efficiencies with CHAT/pEFGP-N1 were significant at 15.2 ± 8.1% in HMEC-1 cells and >40% in HaCaT cells. In this study, the CHAT/pmiR-31 nanocomplexes at a N:P ratio of 10 had an average particle size of 74.2 nm with a cationic zeta potential of 9.7 mV. Delivery of CHAT/pmiR-31 to HaCaT and HMEC-1 cells resulted in significant improvements in cell migration capacity and increased angiogenesis. In vivo studies were conducted in C57BL/6 J mice were CHAT/pmiR-31 was delivered via electrospun PVA nanofibres, demonstrating a significant increase in epidermal (increase of ∼38.2 µm) and stratum corneum (increase of 8.2 µm) layers compared to controls. Furthermore, treatment in vivo with CHAT/pmiR-31 increased angiogenesis in wounds compared to controls, with a significant increase in vessel diameter by ∼20.4 µm compared against a commercial dressing control (Durafiber™). Together, these data demonstrate that the delivery of CHAT/pmiR-31 nanocomplexes from electrospun PVA nanofibres represent an innovative therapy for wound repair, eliciting a positive therapeutic response across both stromal and epithelial tissue compartments of the skin. STATEMENT OF SIGNIFICANCE: This study advances research regarding the development of our unique electrospun nanofibre patch to deliver genetic nanoparticles into wounds in vivo to promote healing. The genetic nanoparticles are comprised of: (a) plasmid micro-RNA31 that has been shown to be downregulated in pathologies with delayed wound repair and (b) a 15 amino acid linear peptide termed CHAT. The CHAT facilitates complexation of miR-31 and cellular uptake. Herein, we report for the first time on the use of CHAT to deliver a therapeutic cargo pmiR-31 for wound healing applications from a nanofibre patch. Application of the nanofibre patch resulted in the controlled delivery of the CHAT/pmiR-31 nanoparticles with a significant increase in both epidermal and stratum corneum layers compared to untreated and commercial controls., Competing Interests: Declaration of Competing Interest The authors 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 © 2021. Published by Elsevier Ltd.)

We examined whether exercising indoors vs. outdoors reduced the cardio-respiratory effects of outdoor air pollution. Adults ≥55 were randomly assigned to exercise indoors when the Air Quality Health Index was ≥5 and outdoors on other days (intervention group, n = 37), or outdoors everyday (control group, n = 35). Both groups completed cardio-respiratory measurements before and after exercise for up to 10 weeks. Data were analyzed using linear mixed effect regression models. In the control group, an interquartile range increase in fine particulate matter (PM 2.5 ) was associated with increases of 1.4% in heart rate (standard error (SE) = 0.7%) and 5.6% (SE = 2.6%) in malondialdehyde, and decreases of 5.6% (SE = 2.5%) to 16.5% (SE = 7.5%) in heart rate variability measures. While the hypothesized benefit of indoor vs. outdoor exercise could not be demonstrated due to an insufficient number of intervention days (n = 2), the study provides evidence of short-term effects of air pollution in older adults. ISRCTN #26552763.

A 14-year-old girl with poorly controlled asthma attended the difficult-to-treat asthma clinic for review. Although she has eosinophilia and significantly raised immunoglobulin E levels, she is not currently a candidate for omalizumab (Xolair). She also suffers from chronic urticaria, eosinophilic eosophagitis and severe conjunctivitis. You wonder if omalizumab would be effective in treating her multiple atopic conditions, in particular her troublesome conjunctivitis. PubMed was searched using the following search terms: (Omalizumab) or (Xolair) and (conjunctivitis). Searches were conducted in November 2020. Abstracts were selected for full text review if the study population identified asthma as a comorbidity. Non-paediatric studies and those that were not written in English were excluded. The use of omalizumab has the potential to be effective in the treatment of conjunctivitis associated with asthma and other atopic conditions. However, research is needed to address the question, in the form of multicenter, double-blind randomized control trials., Competing Interests: Conflict-of-interest statement: No conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: The relationship between inflammation and lipid metabolism is complex and bidirectional. Lymphocyte-driven inflammation has been shown to modulate both atherosclerotic plaque development and cholesterol levels, but the mechanisms are incompletely understood., Methods: The cardiometabolic effects of IL-2Rβγ signalling in atherosclerotic Apoe -/- mice were investigated by treatment with an agonistic IL-2Rβγ-targeting IL-2/anti-IL-2 complex or a monoclonal anti-CD122 (IL-2Rβ) blocking antibody., Results: Administration of IL-2Rβγ agonistic IL-2/anti-IL-2 complexes to Apoe -/- mice augmented opposing arms of the adaptive immune system. Expansion of effector/memory T cells and increased levels of circulating pro-inflammatory cytokines were observed along with elevated levels of regulatory T cells and IL-10. Notably, IL-2/anti-IL-2 treatment did not affect plaque size but decreased levels of plasma cholesterol. The cholesterol lowering effect of IL-2Rβγ agonism was not affected by anti-CD8 or anti-NK1.1 depleting antibody treatment but was contingent on the presence of adaptive immunity. Expression of multiple liver X receptor (LXR)-related genes, including Pltp and Srebp1c in the liver, was decreased by IL-2/anti-IL-2 treatment. Although IL-2Rβγ agonism lowered cholesterol levels, blocking IL-2Rβγ signalling using an anti-CD122 monoclonal antibody did not impact cholesterol levels or plaque burden in Apoe -/- mice., Conclusions: Elevated IL-2Rβγ signalling results in activation of both inflammatory and regulatory lymphocytes with a net zero effect on atherosclerosis and decreased plasma cholesterol levels. Changes in cholesterol levels were associated with reductions in hepatic LXR-related gene expression. Further studies are needed to investigate the clinical significance of IL-2 mediated modulation of hepatic LXR signalling in inflammatory disorders., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The author explores the nexus of 'climate chaos' and how this intersects with and exacerbates the top issues of our time-from immigration to public health to mass incarceration. She challenges us to think about the implications of these intersections for social justice and why policy makers need to stop considering the climate emergency as a siloed issue. Climate policy needs to be framed and rethought in an intersectional manner that centers equity, justice, and the creation of jobs., (© Society for International Development 2020.)

Background: Although a growing body of literature has focused on the impacts leadership development programs have had on the individual surgeon, little effort has been focused on understanding the impacts these programs have had on surgical culture. The purpose of this study was to explore the impacts of implementing a leadership development program on the culture of the Department of Surgery at University of Michigan, Ann Arbor., Methods: Qualitative interviews were conducted with 14 surgery faculty in the first cohort of a leadership development program at University of Michigan. Using NVivo (version 11.4.3; QSR International, Melbourne, Australia), thematic analysis was used to locate, analyze, and report patterns within the data., Results: Thematic analysis demonstrated that participation in a leadership development program influenced surgical culture in the following ways: (1) promoted a more participative leadership style, providing tools for surgeons to create a more collaborative environment; (2) increased the culture of diversity, with leaders in the department valuing a more inclusive and wide range of skill sets; and (3) strengthened the collegial environment as evidenced by improved morale and relationships within the department. In addition, several participants expressed difficulty in teasing out what was a direct benefit of a leadership development program versus what could be attributable to other factors, referred to here as the chicken or egg argument., Conclusion: Almost all participants expressed experiencing at least some change that they believed was related to the leadership development program. This research may provide insight into the broader implications that programs like these have on surgical culture., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background & Aims: Pathogenic germline variants in CDH1 are associated with risk for diffuse gastric cancer (DGC) and lobular breast cancer. The reported high incidence of DGC and limited sensitivity of endoscopy in detection have prompted recommendation for total prophylactic gastrectomy for carriers of pathogenic or likely pathogenic (PLP) germline variants of CDH1. Multigene panel tests have identified increasing numbers of carriers of PLP variants in CDH1 who lack a family history of DGC. We evaluated outcomes of endoscopic surveillance for carriers of PLP variants of CDH1 with and without family history of DGC., Methods: Individuals from 13 families with germline PLP variants of CDH1 were evaluated at the Michigan Medicine Cancer Genetics Clinic from January 1998 through May 2018. Outcomes of esophagogastroduodenoscopy examinations, histopathology analyses, and surgery were compared between individuals with and without a family history of DGC., Results: We identified 20 carriers of germline CDH1 PLP variants; they underwent endoscopic examinations and/or gastrectomy. None had abnormal findings visible during endoscopy. Signet ring cell carcinoma (SRCC) was detected in 12 of 20 subjects. All but 1 of the carcinomas were tiny and confined to the lamina propria, and 1 was transmural. Seven of 12 subjects who had SRCC reported no diagnoses of DGC in first-degree relatives and did not meet established criteria for CDH1 analysis based on a 3-generation family pedigree., Conclusions: More than half of individuals with germlines variants of CDH1 that are PLP had histopathologic evidence for DGC on endoscopy and/or gastrectomy. Family history of DGC and endoscopic findings therefore do not appear to be reliable determinants of risk of SRCC in individuals with genetic predisposition to DGC., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Gastric mechanistic target of rapamycin (mTOR) signaling is inversely associated with the expression and secretion of ghrelin, a 28-aa peptide hormone produced by gastric X/A-like cells. Ghrelin contributes to obesity and hepatic steatosis. We sought to control global lipid metabolism via the manipulation of gastric mTOR signaling in X/A-like cells. We established a ghrl-cre transgene in which the Cre enzyme is expressed in X/A-like cells under the control of the ghrelin-promoter. mTOR flox/flox and tuberous sclerosis 1 (TSC1) flox/flox mice were separately bred with ghrl-cre mice to generate mTOR-ghrl-cre or TSC1-ghrl-cre mice, within which mTOR signaling was suppressed or activated, respectively. Lipid metabolism in liver and adipose depots was analyzed. Under the control of the ghrelin-promoter, the Cre enzyme was exclusively expressed in stomach X/A-like cells in adult animals. Knockout of mTOR in X/A-like cells increased circulating acyl-ghrelin and promoted hepatic lipogenesis with effects on adipose depots. Activation of mTOR signaling by deletion of its upstream inhibitor, TSC1, decreased ghrelin expression and secretion, altering lipid metabolism as evidenced by resistance to high-fat diet-induced obesity and hepatic steatosis. Both ghrelin administration and injection of rapamycin, an inhibitor of mTOR, altered the phenotypes of TSC1-ghrl-cre mice. Conclusion: Gastric mTOR signaling in X/A-like cells contributes to organism lipid homeostasis by regulating hepatic and adipose lipid metabolism. Gastric mTOR signaling may provide an alternative strategy for intervention in lipid disorders., (© 2018 by the American Association for the Study of Liver Diseases.)

Leucine-rich repeat G protein-coupled receptors (LGRs) and their endogenous ligands R-spondin1-4 (Rspo) are critical in embryonic development and in maintenance of stem cells. The functions of the Rspo-LGR system in differentiated cells remain uncharacterized. In this study, the expression profiles of LGRs and Rspos were characterized in mature hepatocytes. A liver-specific knockout of LGR4 in mouse was generated and used to study hepatic ischemia/reperfusion-induced injury (HIRI) as well as lipopolysaccharide/ D- galactosamine (LPS/D-Gal)-induced liver injury. We have demonstrated that, in adult liver, LGR4 is expressed in hepatocytes and responds to Rspo1 with internalization. Rspo1 is responsive to various nutritional states and to mTOR signaling. Activation of LGR4 by Rspo1 significantly reduced tumor necrosis factor-α (TNFα)-induced cell death, and levels of NF-κB-p65 and caspase-3 in cultured hepatocytes. Knockdown of hepatic LGR4 rendered hepatocytes more vulnerable to TNFα-induced damage in cultured primary cells and in the setting of HIRI and LPS/D-Gal-induced liver injury. Rspo1 potentiated both basal and Wnt3a-induced stabilization of β-catenin. Disruption of β-catenin signaling reversed the protective effects of Rspo1 on TNFα-induced hepatocyte toxicity. LGR4 knockdown increased nuclear translocation of NF-κB-p65 in response to acute injury. Overexpression of IKKβ attenuated the protective effects of Rspo1 on TNFα-induced cell death. In conclusion, the Rspo1-LGR4 system represents a novel pathway for cytoprotection and modulation of stress-induced tissue damage. NEW & NOTEWORTHY Functional LGR4 is present in mature hepatocytes. R-spodin1 protects hepatocytes from tumor necrosis factor-α-induced cell death. Liver-specific knockdown of LGR4 renders liver more susceptible to acute injury. LGR4 protects hepatocytes from injury by inhibition of NF-κB signaling.

Objective: The aim of this study was to assess cardiorespiratory effects of air pollution in older adults exercising outdoors in winter., Methods: Adults 55 years of age and older completed daily measurements of blood pressure, peak expiratory flow and oximetry, and weekly measurements of heart rate variability, endothelial function, spirometry, fraction of exhaled nitric oxide and urinary oxidative stress markers, before and after outdoor exercise, for 10 weeks. Data were analyzed using linear mixed effect models., Results: Pooled estimates combining 2014 (n = 36 participants) and 2015 (n = 34) indicated that an interquartile increase in the Air Quality Health Index was associated with a significant (P < 0.05) increase in heart rate (0.33%) and significant decreases in forced expiratory volume (0.30%), and systolic (0.28%) and diastolic blood pressure (0.39%)., Conclusion: Acute subclinical effects of air pollution were observed in older adults exercising outdoors in winter.

Objectives: The purpose of this article is to determine how many of the current peer-reviewed studies of ankle foot or-thoses (AFOs) on children with cerebral palsy (CP) have included adequate details of the design and material of the AFO, to enable the study to be reproduced and outcomes clearly understood., Methods: A thorough search of studies published in English was conducted in March 2015, with no restriction on dates, within all major databases using relevant phrases. These searches were then supplemented by tracking all key references from the appropriate articles identified., Study Selection: The inclusion criteria were as follows: (1) population - children with CP; (2) intervention - AFOs; and (3) outcome measure. One reviewer extracted data regarding the characteristics of the included studies, with the extracted data checked for accuracy and completeness by a second reviewer. None of the studies reviewed gave adequate details of the AFOs. Only 3.6% (n = 2) of papers tested the stiffness. Many studies (54.5%) did not describe the material used nor the material thickness (72.7 %). None of them gave any clinical justification for the chosen design of AFO., Conclusions: There is a clear paucity of detail regarding the design and material used in AFOs on studies involving children with CP. Such a lack of detail has the potential to affect the validity of the reported outcomes, the ability to reproduce the studies and may misinform clinical practice.

Hepatic steatosis renders liver more vulnerable to ischemia/reperfusion injury (IRI), which commonly occurs in transplantation, trauma, and liver resection. The underlying mechanism is not fully characterized. We aimed to clarify the role of mechanistic target of rapamycin (mTOR) signaling in hepatic ischemia/reperfusion injury (HIRI) in normal and steatotic liver using Alb - TSC1 -/- (Am) transgenic mice. Steatotic liver induced by high-fat diet was more vulnerable to IRI. Activation of hepatic mTOR in AT mice decreased lipid accumulation attenuated HIRI as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, circulating levels of alanine aminotransferase and lactate dehydrogenase, and inflammatory mediators such as monocyte chemoattractant protein 1 (MCP-1), TNF-α, and IL-6 and hepatic cleaved caspase 3 in mice fed either a normal chow diet or a high-fat diet. The effects of mTOR activation on hepatic cleaved caspase 3 were reversed by rapamycin, an inhibitor of mTOR signaling. Inhibition of hepatic mTOR in Am mice increased hepatic lipid deposition and HIRI. The increment in hepatic susceptibility to IRI was significantly attenuated by pretreatment with IKKβ inhibitor. Further, suppression of mTOR facilitated nuclear translocation of NF-κB p65. In conclusion, our study suggests that mTOR activity in hepatocytes decreases hepatic vulnerability to injury through a mechanism dependent on NF-κB proinflammatory cytokine signaling pathway in both normal and steatotic liver.-Li, Z., Zhang, J., Mulholland, M., Zhang, W. mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-κB pathway.Alb-mTOR -/- (Am) transgenic mice. Steatotic liver induced by high-fat diet was more vulnerable to IRI. Activation of hepatic mTOR in AT mice decreased lipid accumulation attenuated HIRI as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, circulating levels of alanine aminotransferase and lactate dehydrogenase, and inflammatory mediators such as monocyte chemoattractant protein 1 (MCP-1), TNF-α, and IL-6 and hepatic cleaved caspase 3 in mice fed either a normal chow diet or a high-fat diet. The effects of mTOR activation on hepatic cleaved caspase 3 were reversed by rapamycin, an inhibitor of mTOR signaling. Inhibition of hepatic mTOR in Am mice increased hepatic lipid deposition and HIRI. The increment in hepatic susceptibility to IRI was significantly attenuated by pretreatment with IKKβ inhibitor. Further, suppression of mTOR facilitated nuclear translocation of NF-κB p65. In conclusion, our study suggests that mTOR activity in hepatocytes decreases hepatic vulnerability to injury through a mechanism dependent on NF-κB proinflammatory cytokine signaling pathway in both normal and steatotic liver.-Li, Z., Zhang, J., Mulholland, M., Zhang, W. mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-κB pathway., (© FASEB.)

Objective: To examine cardio-respiratory effects of air pollution in rural older adults exercising outdoors., Methods: Adults 55 and over completed measurements of blood pressure, peak expiratory flow and oximetry daily, and of heart rate variability, endothelial function, spirometry, fraction of exhaled nitric oxide and urinary oxidative stress markers weekly, before and after outdoor exercise, for 10 weeks. Data were analyzed using linear mixed effect models., Results: Pooled estimates combining 2013 (n = 36 participants) and 2014 (n = 41) indicated that an interquartile increase in the air quality health index (AQHI) was associated with a significant (P < 0.05) increase in heart rate (2.1%) and significant decreases in high frequency power (-19.1%), root mean square of successive differences (-9.5%), and reactive hyperemia index (-6.5%)., Conclusions: We observed acute subclinical adverse effects of air pollution in rural older adults exercising outdoors.

Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-CoA-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-CoA-Tat increases glucose- induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders.

The mechanisms underlying alterations in brain functions in response to physical exercise are not fully understood. The present study examined the central effect of irisin, a 112 amino acid polypeptide hormone secreted from the skeletal muscle after exercise, on the locomotion in rats. Central administration of irisin significantly increased the locomotion. Relative to control animals treated with IgG Fc peptide, rats receiving irisin demonstrated a marked increase in total travel distance, ambulatory counts and time, and vertical counts and time. These changes were associated with a significant decrease in resting time. Central treatment of irisin also induced significant increases in oxygen consumption, carbon dioxide production and heat production, indicating an increase in metabolic activity. Our study suggests that physical activity may signal to the central nervous system to coordinate locomotion with metabolic activity via irisin., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Irisin is a newly identified 112 amino acid hormone, derived as a product of fibronectin type III domain containing 5 (FNDC5), which is highly related to metabolic activity in skeletal muscle and brown fat. The effects of irisin on cardiovascular functions are unknown., Purpose: To explore the effects of central and peripheral irisin on cardiovascular functions., Methods: Irisin was either administrated into 3rd ventricle of rats or intravenously, and its effects on blood pressure and cardiac contractibility measured., Results: Administration of recombinant human irisin into the 3rd brain ventricle of rats activated neurons in the paraventricular nuclei of the hypothalamus. Central administration of irisin increased blood pressure and cardiac contractibility. Exogenous irisin reversed atenolol-induced inhibition of cardiac contractibility. In contrast, peripheral administration of irisin reduced blood pressure in both control and spontaneously hypertensive rats. Irisin dilated mesenteric artery rings through ATP-sensitive potassium channels., Conclusion: Our studies indicate that central and peripheral irisin may differentially regulate cardiovascular activities.

Background: Acute increases in ambient air pollution have been associated with increased hospitalization for cardiac diseases and stroke. Triggering of cardiac arrhythmia by changes in air quality could theoretically predispose individuals to cardiac arrest or heart failure, or stroke through precipitation of atrial fibrillation. We investigated the association between air quality and cardiac rate and rhythm characteristics measured by ambulatory cardiac monitoring., Methods and Results: Daily ambient 3-h maximum concentrations of ozone, nitrogen dioxide and fine particulate matter, and an index summarizing these pollutants called the Air Quality Health Index (AQHI) were compared to the results of 24-h ambulatory cardiac monitoring performed for clinical purposes in 8662 patients and analyzed at the University of Ottawa Heart Institute, Canada, between 2004 and 2009. An interquartile increase in the daily 3 h- maximum AQHI was associated with a 0.9% (95% CI 0.3%, 1.5%) increase in the daily maximum heart rate and a 1.17% (95% CI 1.07%, 1.29%) increase in heart block frequency. An interquartile increase in NO2 was associated with an increase in the percentage of time in atrial fibrillation of 4.39% (-0.15, 9.15) among those ≤50 years old, and 7.1% (0.24, 14.5) among males., Conclusions: We found evidence that air pollution may affect cardiac rate and rhythm. This may be one mechanism partially explaining the increase in strokes and cardiac events observed on days of higher air pollution., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Macrocyclic olefin metathesis has seen advances in the areas of stereochemistry, chemoselectivity, and catalyst stability, but strategies aimed at controlling dilution effects in macrocyclizations are rare. Herein, a protocol to promote macrocyclic olefin metathesis, one of the most common synthetic tools used to prepare macrocycles, at relatively high concentrations (up to 60 mM) is described by exploitation of a phase-separation strategy. A variety of macrocyclic skeletons could be prepared having either different alkyl, aryl, or amino acids spacers., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although ghrelin has been demonstrated to stimulate energy intake and storage through a central mechanism, its effect on hepatic lipid metabolism remains largely uncharacterized. Ghrelin receptor antagonism or gene deletion significantly decreased obesity-associated hepatic steatosis by suppression of de novo lipogenesis, whereas exogenous ghrelin stimulated lipogenesis, leading to hepatic lipid accumulation in mice. The effects of ghrelin were mediated by direct activation of its receptor on hepatocytes. Cultured hepatocytes responded to ghrelin with increased lipid content and expression of lipogenesis-related genes. Ghrelin increased phosphorylation of S6, the downstream target of mammalian target of rapamycin (mTOR) signaling in cultured hepatocytes, whereas ghrelin receptor antagonism reduced hepatic phosphorylation of S6 in db/db mice. Inhibition of mTOR signaling by rapamycin markedly attenuated ghrelin-induced up-regulation of lipogenesis in hepatocytes, whereas activation of hepatic mTOR signaling by deletion of TSC1 increased hepatic lipogenesis. By interacting with peroxisome proliferator-activated receptor-γ (PPARγ), mTOR mediates the ghrelin-induced up-regulation of lipogenesis in hepatocytes. The stimulatory effect of ghrelin on hepatic lipogenesis was significantly attenuated by PPARγ antagonism in cultured hepatocytes and in PPARγ gene-deficient mice. Our study indicates that ghrelin activates its receptor on hepatocytes to promote lipogenesis via a mechanism involving the mTOR-PPARγ signaling pathway.

Background: In inflammatory bowel disease, autonomic dysfunction contributes to symptoms, morbidity, and health care resource utilization. Efferent vagal neurons, which provide the primary parasympathetic input to the gastrointestinal tract, are housed in the dorsal motor nucleus of the vagus (DMV) in the brainstem. This study seeks to characterize the effects of IBD on DMV neuronal survival and function., Methods: TNBS (picrylsulfonic acid) was administered by enema to induce colitis in rats. Brain sections through the DMV were examined for neuronal apoptosis using TUNEL labeling, and for glial cell activation by immunofluorescence. Prothrombin production was evaluated via quantitative RT-PCR from DMV tissue, as well as by double immunofluorescence in DMV sections. To investigate the effects of thrombin in the DMV, thrombin or thrombin and an antagonist to its receptor were administered into the fourth ventricle via a stereotactically placed cannula. DMV sections were then examined for apoptosis by TUNEL assay. To evaluate the effect of thrombin on DMV neuronal function, we examined calcium signaling in primary DMV neuron cultures following exposure to thrombin and other neurotransmitters., Results: TNBS colitis is associated with significantly increased rates of DMV neuronal apoptosis, affecting 12.7 % of DMV neurons in animals with colitis, compared to 3.4 % in controls. There was a corresponding increase in DMV neuron activated caspase-3 immunoreactivity (14.8 vs. 2.6 % of DMV neurons). TNBS-treated animals also demonstrated significantly increased DMV astrocyte and microglial immunoreactivity, indicating glial cell activation. DMV prothrombin production was significantly increased in TNBS colitis, with a close anatomic relationship between prothrombin and microglia. Direct DMV exposure to thrombin replicated the apoptosis and activation of caspase-3 seen in TNBS colitis; these effects were prevented by coadministration of the PAR-1 inhibitor FR171113. Cultured DMV neurons exhibited impaired calcium signaling in response to neurotransmitters following exposure to thrombin. Glutamate-induced calcium transients decreased by 59 %, and those triggered by GABA were reduced by 61 %. PAR-1 antagonism prevented these thrombin-induced changes in calcium signaling., Conclusions: IBD is associated with DMV microglial activation and production of prothrombin. Thrombin in the DMV causes vagal neuron apoptosis and decreased sensitivity to neurotransmitters.

There has been an exponential increase in the use of home noninvasive ventilation (NIV). Despite growing use, there is a paucity of evidence-based guidelines and practice standards in the United States to assist clinicians in the initiation and ongoing management of home NIV. Consequently, home NIV practices are being influenced by complicated local reimbursement policies and coding. This article aims to provide a practice management perspective for clinicians providing home NIV, including Local Coverage Determination reimbursement criteria for respiratory assist devices, Durable Medical Equipment coding, and Current Procedural Terminology coding to optimize clinical care and minimize lost revenue. It highlights the need for further research and development of evidence-based clinical practice standards to ensure best practice policies are in place for this rapidly evolving patient population.

Background & Aims: Ghrelin, a gut hormone with pleiotropic effects, may act as a protective signal in parenchymal cells. We investigated the protective effects of ghrelin on hepatocytes after ischaemia/reperfusion (I/R)., Methods: Hepatic injury was assessed by measurement of plasma alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), histological analysis, and TUNEL assay. Effects of exogenous ghrelin and ghrelin receptor gene deletion on I/R induced injury of liver were evaluated., Results: Ischaemia/reperfusion induced a profound injury to hepatocytes. This was accompanied by elevations in plasma ALT and LDH. Pretreatment with ghrelin significantly reduced elevations in plasma ALT and LDH, and attenuated tissue damage induced by hepatic I/R in mice. Hepatic injury induced by I/R was more pronounced in ghrelin receptor gene null mice. Ghrelin administration blocked the up-regulation of AMP-activated protein kinase (AMPK) activity induced by hepatic I/R., Conclusions: This study demonstrates that ghrelin contributes to the cytoprotection during hepatic I/R., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims/hypothesis: The actions of peripherally administered nesfatin-1 on glucose homeostasis remain controversial. The aim of this study was to characterize the mechanisms by which peripheral nesfatin-1 regulates glucose metabolism., Methods: The effects of nesfatin-1 on glucose metabolism were examined in mice by continuous infusion of the peptide via osmotic pumps. Changes in AKT phosphorylation and Glut4 were investigated by Western blotting and immnuofluorescent staining. Primary myocytes, adipocytes and hepatocytes were isolated from male mice., Results: Continuous peripheral infusion of nesfatin-1 altered glucose tolerance and insulin sensitivity in mice fed either normal or high fat diet, while central administration of nesfatin-1 demonstrated no effect. Nesfatin-1 increases insulin secretion in vivo, and in vitro in cultured min6 cells. In addition, nesfatin-1 up-regulates the phosphorylation of AKT in pancreas and min6 islet cells. In mice fed normal diet, peripheral nesfatin-1 significantly increased insulin-stimulated phosphorylation of AKT in skeletal muscle, adipose tissue and liver; similar effects were observed in skeletal muscle and adipose tissue in mice fed high fat diet. At basal conditions and after insulin stimulation, peripheral nesfatin-1 markedly increased GLUT4 membrane translocation in skeletal muscle and adipose tissue in mice fed either diet. In vitro studies showed that nesfatin-1 increased both basal and insulin-stimulated levels of AKT phosphorylation in cells derived from skeletal muscle, adipose tissue and liver., Conclusions: Our studies demonstrate that nesfatin-1 alters glucose metabolism by mechanisms which increase insulin secretion and insulin sensitivity via altering AKT phosphorylation and GLUT 4 membrane translocation in the skeletal muscle, adipose tissue and liver.

The reactivity of a Cu catalyst for oxidative coupling is modulated by a small molecule additive, diethyl malonate, that slows over-oxidation of 2-naphthols. Efficient heterocoupling between electron-rich and electron-poor 2-naphthols/2-naphthylamines affords C(1)-symmetric BINOLs with yields ranging from 35-98%.

A transcript of unknown function, regulated by fasting and feeding, was identified by microarray analysis. The transcript is up-regulated in the fasting state. An 1168-bp cDNA was cloned from rat hypothalamus and sequenced. This sequence is consistent with adipogenesis down-regulating transcript 3 (AGD3) (also known as human OCC-1) mRNA. A protein sequence identical to AGD3 was determined by mass spectrometry. In the rat brain, AGD3 mRNA is distributed in the arcuate nucleus, ventromedial hypothalamus, amygdaloid nuclei, hippocampus, and somatic cortex. Double in situ hybridisation showed that AGD3 mRNA is co-localised with pro-opiomelanocortin and neuropeptide Y in arcuate nucleus neurones. AGD3 binds with insulin receptor substrate 4 and increases insulin-stimulated phospho-Akt and regulates AMP-activated protein kinase and mammalian target of rapamycin downstream target S6 kinase phosphorylation., (© 2012 British Society for Neuroendocrinology.)

Originally identified in the hypothalamus as a satiety factor, recent studies provide evidence that nefatin-1/NUCB2 is a gutbrain peptide with a broader array of actions. Detection of abundant nesfatin-1/NUCB2 in gastric X/A like endocrine cells, which also produce the orexigenic hormone ghrelin, indicates that gastric mucosa may be one of the predominant sources of nesfatin-1/NUCB2. Functional studies have revealed significant effects of nefatin-1 on inhibition of feeding behavior and on glucose homeostasis. These metabolic functions make nesfatin-1/NUCB2 a novel candidate for treatment of obesity and diabetes. However, deficiencies in our understanding of nesfatin-1/NUCB2 receptor pose a significant hurdle for therapies that target its action. Defining novel pathways to alter the production of nesfatin-1/NUCB2 would shift therapeutic focus to gastric targets. A necessary precondition is improved understanding of the mechanisms by which nesfatin-1/NUCB2 is synthesized and secreted by gastric X/A like cells. Recent studies provide evidence that mTOR is a critical regulatory molecule in these endocrine cells and that its activity is linked to the production of ghrelin and nesfatin- 1/NUCB2. These findings suggest that gastric mTOR is involved in the regulation of food intake and overall energy metabolism through modulation of ghrelin and nesfatin-1/NUCB2. In this review, we first summarize current advances in the relationship between organism energy status and nesfatin-1/NUCB2 levels, and then discuss the novel finding on mTOR as the gastric fuel sensor and its role in the regulation of nesfatin-1/NUCB2 expression.

Aims/hypothesis: Rapamycin impairs glucose tolerance and insulin sensitivity. Our previous study demonstrated that rapamycin significantly increases the production of gastric ghrelin, which is critical in the regulation of glucose metabolism. Here, we investigated whether ghrelin contributes to derangements of glucose metabolism induced by rapamycin., Methods: The effects of rapamycin on glucose metabolism were examined in mice receiving ghrelin receptor antagonist or with Ghsr1a gene knockout. Changes in GLUT4, c-Jun N-terminal kinase (JNK) and phosphorylated ribosomal protein S6 (pS6) were investigated by immunofluorescent staining or western blotting. Related hormones were detected by radioimmunoassay kits., Results: Rapamycin impaired glucose metabolism and insulin sensitivity not only in normal C57BL/6J mice but also in both obese mice induced by a high fat diet and db/db mice. This was accompanied by elevation of plasma acylated ghrelin. Rapamycin significantly increased the levels of plasma acylated ghrelin in normal C57BL/6J mice, high-fat-diet-induced obese mice and db/db mice. Elevation in plasma acylated ghrelin and derangements of glucose metabolism upon administration of rapamycin were significantly correlated. The deterioration in glucose homeostasis induced by rapamycin was blocked by D: -Lys3-GHRP-6, a ghrelin receptor antagonist, or by deletion of the Ghsr1a gene. Ghrelin receptor antagonism and Ghsr1a knockout blocked the upregulation of JNK activity and downregulation of GLUT4 levels and translocation in the gastrocnemius muscle induced by rapamycin., Conclusions/interpretation: The current study demonstrates that ghrelin contributes to derangements of glucose metabolism induced by rapamycin via altering the content and translocation of GLUT4 in muscles.

Background: A previous study demonstrated the presence of protease-activated receptor (PAR) 1 and 2 in the dorsal motor nucleus of vagus (DMV). The aim of this study is to characterize the effect of thrombin on the apoptosis of DMV neurons., Methods: The dorsal motor nucleus of vagus neurons were isolated from neonatal rat brainstems using micro-dissection and enzymatic digestion and cultured. Apoptosis of DMV neurons were examined in cultured neurons. Apoptotic neuron was examined by TUNEL and ELISA. Data were analyzed using anova and Student's t-test., Key Results: Exposure of cultured DMV neurons to thrombin (0.1 to 10 U mL(-1)) for 24 h significantly increased apoptosis. Pretreatment of DMV neurons with hirudin attenuated the apoptotic effect of thrombin. Similar induction of apoptosis was observed for the PAR1 receptor agonist SFLLR, but not for the PAR3 agonist TFRGAP, nor for the PAR4 agonist YAPGKF. Protease-activated receptors 1 receptor antagonist Mpr(Cha) abolished the apoptotic effect of thrombin, while YPGKF, a specific antagonist for PAR4, demonstrated no effect. After administration of thrombin, phosphorylation of JNK and P38 occurred as early as 15 min, and remained elevated for up to 45 min. Pretreatment of DMV neurons with SP600125, a specific inhibitor for JNK, or SB203580, a specific inhibitor for P38, significantly inhibited apoptosis induced by thrombin., Conclusions & Inferences: Thrombin induces apoptosis in DMV neurons through a mechanism involving the JNK and P38 signaling pathways., (© 2010 Blackwell Publishing Ltd.)

Constructed wetlands (CWs) have been used to treat agricultural effluents with varying success especially with respect to their operational efficiency in winter and ability to retain phosphorus. Dirty water (DW) from dairy farms is a mixture of manure contaminated runoff and milk parlour washings with a highly polluting biochemical oxygen demand (BOD) < or =3000 mg/L. The initial performance a CW of a 1.2 ha horizontal flow CW consisting of five ponds in series designed to treat DW from a dairy unit was assessed over four years. Ponds were earth-lined and shallow (0.3 m) with a water residence time of 100 days and planted with five species of emergent macrophytes. In comparison to CW inflow, annual reductions were as follows: BOD 99%, P 95% and N 92.8%. Coliforms were reduced by a 10(-5) factor to natural levels. From May to October there was little CW discharge due to evaporative losses. Final effluent quality was poorest in February but remained within a regulatory effluent standard for BOD of 40 mg/L. If the CW had only four ponds (25% less surface area) effluent would have failed the BOD standard in three years.

The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine kinase, is an intracellular fuel sensor critical for cellular energy homeostasis. Gastrointestinal endocrine cells play a vital role in the regulation of energy balance by secreting hormones that inform the brain about energy supply. Here we showed the localization of mTOR signaling molecules in more than 90% of gastric ghrelin cells and 36±3% of gastrin cells, while no somatostatin-positive cell showed phospho-S6K1 immunoreactivity. Inhibition of mTOR significantly stimulated expression of gastric ghrelin mRNA and protein, and the concentration of plasma ghrelin (2.06±0.34 ng/ml vs. 12.53±3.9 ng/ml, p<0.05), inhibited gastrin synthesis and secretion (75.01±6.71 pg/ml vs. 54.04±3.65 pg/ml, p<0.05), but had no effect on somatostatin production (165.2±25.07 pg/ml vs. 178.9±29.14 pg/ml, p=0.73). Gastric mTOR is a gastric sensor whose activity is linked to the differential regulation of gastric hormone production and release., (Copyright © 2010 Elsevier Inc. All rights reserved.)