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Lysosomal acid sphingomyelinase (ASM; SMPD1) deficiency causes Niemann-Pick Disease (NPD) that, in Type B, manifests with interstitial lung disease and susceptibility to infections. Constitutional Smpd1 ( Smpd1 -/- mice) deletion causes lung inflammation with foamy dysfunctional macrophages, but is protective against acute lung injury. It is unknown whether these manifestations are from progressive accumulation of sphingomyelin, decreased ceramide, or compensatory alterations in sphingolipid metabolism. We developed a conditional knockout mouse, Smpd1 fl/fl xCAGG-CreERTM, induced by tamoxifen (5 weeks), with decreased Smpd1 expression (by 75%) and ASM activity (by up to 40%). We investigated how brief post-developmental ASM insufficiency affects lung sphingolipids and pathology including following lipopolysaccharide (LPS)-induced injury. Compared to controls, Smpd1 fl/fl mice exhibited modest sphingomyelin elevation with lower palmitoyl/lignoceroyl ceramide (C16/C24) ratios, increased de novo sphingolipid synthesis and sphingosine-1 phosphate levels. At 3 days following LPS instillation (20μg) control mice had increased lung (neutrophilic and monocytic) inflammation and apoptosis; Smpd1 fl/fl mice showed more exuberant inflammation with reduced apoptosis, particularly in endothelial cells. During repair (6-9 days), Smpd1 fl/fl lungs had increased cell proliferation with reduced autophagosome-tagging p62/SQSTM1. These results indicate that prior to significant lysosomal lipid storage, ASM insufficiency inhibits stress-induced lung apoptosis and promotes compensatory sphingolipid changes that favor exuberant inflammatory responses to LPS. Overall, ASM inhibition limits lung vascular injury and stimulates repair following inflammatory insults. These results provide novel insights into the function of ASM in the lung, which are relevant to understanding the pathogenesis and complications of NPD and the role of distinct sphingolipid metabolites in lung injury and repair.

Background: This study was conducted to investigate the cascade involving DNA damage, senescence, and senescence-associated secretory phenotype (SASP) in experimental diabetes and in a four-year follow-up study in patients with pre-diabetes and type 2 diabetes., Methods: Kidney, lung, and liver were studied in 4 months diabetic db/db mice and age-matched controls for the presence of DNA damage and fibrosis. DNA damage (comet-tail-length and ɤH2Ax-positivity in white blood cells), urinary p21-excretion, and plasma IL-6 and TGF-β1 were determined from 115 healthy participants, 34 patients with pre-diabetes and 221 with type 2 diabetes. Urinary albumin-creatinine-ratio, lung function, and transient elastography of the liver were performed in a prospective follow-up study over 4 years., Findings: db/db mice showed an increased nuclear ɤH2AX signal in all tissues as compared to the background control. Markers for DNA damage, senescence, and SASP were increased in patients with diabetes. The presence of nephropathy, restrictive lung disease (RLD), and increased liver stiffness was in a cross-sectional design associated with increased markers for DNA damage, senescence, and SASP. The progression of nephropathy over 4 years was predicted by increased DNA damage, senescence, and SASP, while the progression of RLD was associated with increased DNA damage and IL-6 only. The progression of liver stiffness was not associated with any of these parameters. HbA1c was not predictive for progression., Interpretation: In db/db mice, the cascade of DNA damage is associated with diabetes-related complications. In patients with diabetes, the progression of complications in the kidney and lung is predicted by markers reflecting DNA damage, and senescence-triggered organ fibrosis., Funding: This work was supported by the German Research Foundation (DFG) in the CRC 1118 and CRC 1158, by the GRK DIAMICOM, by the German Center for Diabetes Research (DZD e.V.), and by the Ministry of Science, Research and the Arts, Baden-Württemberg (Kompetenznetzwerk Präventivmedizin)., Competing Interests: Declaration of interests There were no conflicts of interests reported from any author regarding the results which were presented here. Individual financial disclosures are reported in the COI form., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To describe the clinical and imaging findings of 33 dogs with Brucella canis discospondylitis (BDS)., Animals: 33 client owned dogs from four veterinary specialty hospitals within Colorado and Arizona with at least one positive B. canis test and spinal diagnostic imaging., Procedures: Retrospective review of signalment, physical and neurological examination findings, laboratory results, B. canis serology, and diagnostic imaging of 33 dogs with BDS. All imaging was reviewed by a board-certified veterinary neurologist. Radiographs were reviewed by a board-certified veterinary radiologist blinded to MRI and CT findings., Results: 31/33 (94%) dogs were <5 years old (median = 2.5 years, mean = 2.9 years, range 0.5-10 years). 21/29 (72%) dogs had signs of nonspecific pain, spinal pain, or lameness for >3 months (median = 6 months, mean = 8.2 months, range 5 days-4 years). Fever was seen in only 4/28 (14%) dogs. Multifocal lesions were evident on radiographs in 21/29 (72%) dogs and MRI in 12/18 (67%) dogs. Smooth, round, central end-plate lysis, defined as "hole punch" lesions, were identified radiographically in 25/29 (86%) dogs. Vertebral physitis or spondylitis without discitis was evident on MRI in 7/18 (39%) dogs., Clinical Relevance: Dogs with BDS typically present at a young age with a long duration of clinical signs. Identification of radiographic "hole punch" lesions and MRI evidence of vertebral physitis, spondylitis, and paravertebral inflammation without discitis should increase suspicion for BDS. BDS may be increasing in frequency in the southwestern United States, and dogs with signs of chronic spinal pain and/or lameness should be screened for B. canis ., 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 Long, Burgers, Copple, Stainback, Packer, Kopf, Schmidt, Emch and Windsor.)

The transmembrane receptor Frizzled 9 (FZD9) is important for fetal neurologic and bone development through both canonical and non-canonical WNT/FZD signaling. In the adult lung, however, Fzd9 helps to maintain a normal epithelium by signaling through peroxisome proliferator activated receptor γ (PPARγ). The effect of FZD9 loss on normal lung epithelial cells and regulators of its expression in the lung are unknown. We knocked down FZD9 in human bronchial epithelial cell (HBEC) lines and found that downstream EMT targets and PPARγ activity are altered. We used a FZD9 -/- mouse in the urethane lung adenocarcinoma model and found FZD9 -/- adenomas had more proliferation, increased EMT signaling, decreased activation of PPARγ, increased expression of lung cancer associated genes, increased transformed growth, and increased potential for invasive behavior. We identified PPARγ as a transcriptional regulator of FZD9. We also demonstrated that extended cigarette smoke exposure in HBEC leads to decreased FZD9 expression, decreased activation of PPARγ, and increased transformed growth, and found that higher exposure to cigarette smoke in human lungs leads to decreased FZD9 expression. These results provide evidence for the role of FZD9 in lung epithelial maintenance and in smoking related malignant transformation. We identified the first transcriptional regulator of FZD9 in the lung and found FZD9 negative lesions are more dangerous. Loss of FZD9 creates a permissive environment for development of premalignant lung lesions, making it a potential target for intervention., 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 Sompel, Dwyer-Nield, Smith, Elango, Vanderlinden, Kopf, Keith and Tennis.)

Prevention of premalignant lesion progression is a promising approach to reducing lung cancer burden in high-risk populations. Substantial preclinical and clinical evidence has demonstrated efficacy of the prostacyclin analogue iloprost for lung cancer chemoprevention. Iloprost activates peroxisome proliferator-activated receptor gamma (PPARG) to initiate chemopreventive signaling and in vitro , which requires the transmembrane receptor Frizzled 9 (FZD 9 ). We hypothesized a Fzd 9 -/- mouse would not be protected by iloprost in a lung cancer model. Fzd 9 -/- mice were treated with inhaled iloprost in a urethane model of lung adenoma. We found that Fzd 9 -/- mice treated with iloprost were not protected from adenoma development compared to wild-type mice nor did they demonstrate increased activation of iloprost signaling pathways. Our results established that iloprost requires FZD 9 in vivo for lung cancer chemoprevention. This work represents a critical advancement in defining iloprost's chemopreventive mechanisms and identifies a potential response marker for future clinical trials., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Upon returning from deployment to Afghanistan, a substantial number of U.S. military personnel report deployment-related lung disease (DRLD) symptoms, including those consistent with an asthma-like airways disease. DRLD is thought to be caused by prolonged inhalation of toxic desert particulate matter, which can persist in the postdeployment setting such as exposure to common household allergens. The goal of this study was to define the transcriptomic responses of lung leukocytes of mice exposed to Afghanistan desert particulate matter (APM) and house dust mite (HDM). C57BL/6 mice (n = 15/group) were exposed to filtered air or aerosolized APM for 12 days, followed by intranasal PBS or HDM allergen challenges for 24 h. Bronchoalveolar lavage (BAL) cells were collected for single-cell RNA sequencing (scRNAseq), and assessment of inflammation and airway hyper-responsiveness. Unsupervised clustering of BAL cell scRNAseq data revealed a unique monocyte population induced only by both APM and allergen treatments. This population of monocytes is characterized by the expression of genes involved in allergic asthma, including Alox15. We validated Alox15 expression in monocytes via immunostaining of lung tissue. APM pre-exposure, followed by the HDM challenge, led to significantly increased total respiratory system resistance compared with filtered air controls. Using this mouse model to mimic DRLD, we demonstrated that inhalation of airborne PM during deployment may prime airways to be more responsive to allergen exposure after returning home, which may be linked to dysregulated immune responses such as induction of a unique lung monocyte population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The primary study objective was to determine whether clinical examination and magnetic resonance imaging (MRI) can underestimate canine gliomatosis cerebri (GC); we also investigated immunohistochemical features. Seven dogs with GC were studied; four recruited specifically because of minimal MRI changes. Neuroanatomic localization and the distribution of MRI, gross and sub-gross lesions were compared with the actual histological distribution of neoplastic cells. In six cases, clinical examination predicted focal disease and MRI demonstrated a single lesion or appeared normal. Neoplastic cells infiltrated many regions deemed normal by clinical examination and MRI, and were Olig2-positive and glial fibrillary acid protein-negative. Four dogs had concurrent gliomas. GC is a differential diagnosis for dogs with focal neurological deficits and a normal MRI or a focal MRI lesion. Canine GC is probably mainly oligodendrocytic. Type II GC, a solid glioma accompanying diffuse central nervous system neoplastic infiltration, occurs in dogs as in people., (© 2014 John Wiley & Sons Ltd.)

Problem: Fractures of the distal humerus are difficult to treat. In elderly patients, diminished bone mineral quality and increased trauma-associated joint destruction may make stable joint reconstruction even more problematic. Furthermore, comorbidities and poor tolerance of joint immobilization might be additional factors which influence elbow function negatively. Until now, disagreement has existed on how to treat these fractures in elderly patients. Recommendations range from conservative treatment to primary total elbow replacement. So far, reports in the literature on whether or not open reduction and internal fixation in these patients is justified are very rare., Aim of the Study: To analyze fracture patterns, surgical approach, complications, and functional results after open reduction and internal fixation in patients of age 60 years and older., Patients and Methods: Retrospective clinical study of two university level 1 trauma centers, including 45 patients (median age 73 years; range, 61-92 years) with surgically treated distal humerus fractures. Fracture patterns were recorded according to their AO classification. All patients were treated by open reduction and internal fixation. A clinical and radiological follow-up was obtained after a minimum of 24 months following surgery (median 87 months; range, 24-121 months). Functional results were evaluated according to the Mayo Elbow Score., Results: Fractures with complete joint involvement were seen most often. Taking the fracture type into consideration, functional results deteriorated with degree of joint involvement. Postoperative complication rate was high, predominantly seen as screw loosening and/or implant failure at the lateral column. Neverthless, functional results were preponderating good or excellent. Factors negatively influencing outcome were joint immobilization longer than 14 days and severe joint involvement., Discussion: In elderly patients, distal humerus fractures, which are often considered "osteoporotic fractures," still remain one of the most demanding challenges in trauma surgery. The present study demonstrates that despite diminished bone quality and a high complication rate, open reduction and internal fixation in elderly patients is justified., Conclusion: Open reduction and internal fixation of distal humerus fractures in elderly patients should be the main goal, since good elbow function can be achieved in the majority of patients. Elbow immobilization longer than 14 days should be avoided. Stable implant anchorage at the lateral column remains problematic, reflecting a general potential for further implant improvements.