Eosinophils preserve bone homeostasis by inhibiting excessive osteoclast formation and activity via eosinophil peroxidase.

Eosinophils are involved in tissue homeostasis. Herein, we unveiled eosinophils as important regulators of bone homeostasis. Eosinophils are localized in proximity to bone-resorbing osteoclasts in the bone marrow. The absence of eosinophils in ΔdblGATA mice results in lower bone mass under steady-state conditions and amplified bone loss upon sex hormone deprivation and inflammatory arthritis. Conversely, increased numbers of eosinophils in IL-5 transgenic mice enhance bone mass under steady-state conditions and protect from hormone- and inflammation- mediated bone loss. Eosinophils strongly inhibit the differentiation and demineralization activity of osteoclasts and lead to profound changes in the transcriptional profile of osteoclasts. This osteoclast-suppressive effect of eosinophils is based on the release of eosinophil peroxidase causing impaired reactive oxygen species and mitogen-activated protein kinase induction in osteoclast precursors. In humans, the number and the activity of eosinophils correlates with bone mass in healthy participants and rheumatoid arthritis patients. Taken together, experimental and human data indicate a regulatory function of eosinophils on bone.

Systemic PPARγ Antagonism Reduces Metastatic Tumor Progression in Adipocyte-Rich Bone in Excess Weight Male Rodents.

Primary tumors are widely associated with an excess in body fat. The role of adipose tissue on tumor cell homing to bone is yet poorly defined. In this study, we aimed to assess whether bone colonization by tumor cells is favored by an adipocyte-rich bone marrow. We delineated the accompanying alterations of the bone microenvironment and established a treatment approach that interferes with high fat diet (HFD)-induced bone metastasis formation. We were able to show that adipocytes affect skeletal tumor growth in a metastatic model of breast cancer in male rats and melanoma in male mice as well as in human breast cancer bone biopsies. Indeed, HFD-induced bone marrow adiposity was accompanied by accelerated tumor progression and increased osteolytic lesions. In human bone metastases, bone marrow adiposity correlated with tumor cell proliferation. By antagonization of the adipocyte differentiation and storage pathway linked to the peroxisome proliferator-activated receptor gamma (PPARγ) with bisphenol-A-diglycidylether (BADGE), we were able to decelerate tumor progression and subsequent osteolytic damage in the bones of two distinct metastatic animal models exposed to HFD. Overall these data show that adipose tissue is a critical factor in bone metastases and cancer-induced bone loss. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.

Feasibility Evaluation of Commercially Available Video Conferencing Devices to Technically Direct Untrained Nonmedical Personnel to Perform a Rapid Trauma Ultrasound Examination.

Introduction: Point-of-care ultrasound (POCUS) is a rapidly expanding discipline that has proven to be a valuable modality in the hospital setting. Recent evidence has demonstrated the utility of commercially available video conferencing technologies, namely, FaceTime (Apple Inc, Cupertino, CA, USA) and Google Glass (Google Inc, Mountain View, CA, USA), to allow an expert POCUS examiner to remotely guide a novice medical professional. However, few studies have evaluated the ability to use these teleultrasound technologies to guide a nonmedical novice to perform an acute care POCUS examination for cardiac, pulmonary, and abdominal assessments. Additionally, few studies have shown the ability of a POCUS-trained cardiac anesthesiologist to perform the role of an expert instructor. This study sought to evaluate the ability of a POCUS-trained anesthesiologist to remotely guide a nonmedically trained participant to perform an acute care POCUS examination. Methods: A total of 21 nonmedically trained undergraduate students who had no prior ultrasound experience were recruited to perform a three-part ultrasound examination on a standardized patient with the guidance of a remote expert who was a POCUS-trained cardiac anesthesiologist. The examination included the following acute care POCUS topics: (1) cardiac function via parasternal long/short axis views, (2) pneumothorax assessment via pleural sliding exam via anterior lung views, and (3) abdominal free fluid exam via right upper quadrant abdominal view. Each examiner was given a handout with static images of probe placement and actual ultrasound images for the three views. After a brief 8 min tutorial on the teleultrasound technologies, a connection was established with the expert, and they were guided through the acute care POCUS exam. Each view was deemed to be complete when the expert sonographer was satisfied with the obtained image or if the expert sonographer determined that the image could not be obtained after 5 min. Image quality was scored on a previously validated 0 to 4 grading scale. The entire session was recorded, and the image quality was scored during the exam by the remote expert instructor as well as by a separate POCUS-trained, blinded expert anesthesiologist. Results: A total of 21 subjects completed the study. The average total time for the exam was 8.5 min (standard deviation = 4.6). A comparison between the live expert examiner and the blinded postexam reviewer showed a 100% agreement between image interpretations. A review of the exams rated as three or higher demonstrated that 87% of abdominal, 90% of cardiac, and 95% of pulmonary exams achieved this level of image quality. A satisfaction survey of the novice users demonstrated higher ease of following commands for the cardiac and pulmonary exams compared to the abdominal exam. Conclusions: The results from this pilot study demonstrate that nonmedically trained individuals can be guided to complete a relevant ultrasound examination within a short period. Further evaluation of using telemedicine technologies to promote POCUS should be evaluated.

Comparison of Postoperative Opioid Consumption and Pain Scores in Primary Versus Repeat Cesarean Delivery in Opioid Naïve Patients.

BACKGROUND: Cesarean deliveries represent a large percentage of deliveries worldwide. Patients undergoing repeat cesarean deliveries are known to have increased risks for surgical complications. However, little is known regarding potential differences in pain. We sought to compare postoperative opioid consumption and pain scores in opioid naïve patients undergoing primary versus repeat non-emergent cesarean delivery. METHODS: This was a retrospective cohort study. Patient inclusion criteria included: having a non-emergent cesarean delivery, receiving a spinal procedure for surgical anesthesia without general anesthesia, and following the same postoperative pain management protocols. Exclusion criteria included: history of opioid tolerance, illicit drug use, or prior, non-obstetric, major abdominal surgery. The primary outcome marker was total morphine equivalents consumed 0-72 h post-procedure compared between the primary versus repeat cesarean delivery groups. Secondary outcome markers were opioid consumption and pain scores in 24-h period increments for the first 72 h postoperatively. RESULTS: 1617 patients were screened. 217 primary and 377 repeat cesarean deliveries met criteria for comparison. Reduced opioid consumption was demonstrated for the total opioid consumption 0-72 h for the repeat cesarean delivery group (median = 35) compared to the primary cesarean delivery group (median = 58), p = 0.0005. When divided into 24-h periods, differences were demonstrated for the 24-48 and 48-72 h periods but not the 0-24 h period. Pain scores did not differ statistically. CONCLUSION: Opioid naïve obstetric patients who undergo non-emergent repeat cesarean delivery demonstrate lower opioid consumption in the postoperative period. Providers should be aware of this potential difference in order to better educate patients and provide adequate pain management. HIGHLIGHTS: The study reviewed differences in opioid consumption between primary and repeat cesarean deliveries. All patients received the same protocol for spinal dosage and pain management. Repeat cesarean deliveries were associated with lower opioid consumption.