OBJECTIVE To compare the doses of propofol required to induce general anesthesia in dogs premedicated with acepromazine maleate or trazodone hydrochloride and compare the effects of these premedicants on cardiovascular variables in dogs anesthetized for orthopedic surgery. DESIGN Prospective, randomized study. ANIMALS 30 systemically healthy client-owned dogs. PROCEDURES 15 dogs received acepromazine (0.01 to 0.03 mg/kg [0.005 to 0.014 mg/lb], IM) 30 minutes before anesthetic induction and 15 received trazodone (5 mg/kg [2.27 mg/lb] for patients > 10 kg or 7 mg/kg [3.18 mg/lb] for patients ≤ 10 kg, PO) 2 hours before induction. Both groups received morphine sulfate (1 mg/kg [0.45 mg/lb], IM) 30 minutes before induction. Anesthesia was induced with propofol (4 to 6 mg/kg [1.82 to 2.73 mg/lb], IV, to effect) and maintained with isoflurane or sevoflurane in oxygen. Bupivacaine (0.5 mg/kg [0.227 mg/lb]) and morphine (0.1 mg/kg [0.045 mg/lb]) were administered epidurally. Dogs underwent tibial plateau leveling osteotomy (n = 22) or tibial tuberosity advancement (8) and were monitored throughout anesthesia. Propofol induction doses and cardiovascular variables (heart rate and systemic, mean, and diastolic arterial blood pressures) were compared between groups. RESULTS The mean dose of propofol required for anesthetic induction and all cardiovascular variables evaluated did not differ between groups. Intraoperative hypotension developed in 6 and 5 dogs of the acepromazine and trazodone groups, respectively; bradycardia requiring intervention developed in 3 dogs/group. One dog that received trazodone had priapism 24 hours later and was treated successfully. No other adverse effects were reported. CONCLUSIONS AND CLINICAL RELEVANCE At the described dosages, cardiovascular effects of trazodone were similar to those of acepromazine in healthy dogs undergoing anesthesia for orthopedic surgery.
FKBP65 is an endoplasmic reticulum (ER)-localized chaperone and rotamase, with cargo proteins that include tropoelastin and collagen. In humans, mutations in FKBP65 have recently been shown to cause a form of osteogenesis imperfecta (OI), a brittle bone disease resulting from deficient secretion of mature type I collagen. In this work, we describe the rapid proteolysis of FKBP65 in response to ER stress signals that activate the release of ER Ca 2+ stores. A large-scale screen for stress-induced cellular changes revealed FKBP65 proteins to decrease within 6-12 h of stress activation. Inhibiting IP 3 R-mediated ER Ca 2+ release blocked this response. No other ER-localized chaperone and folding mediators assessed in the study displayed this phenomenon, indicating that this rapid proteolysis of folding mediator is distinctive. Imaging and cellular fractionation confirmed the localization of FKBP65 (72 kDa glycoprotein) to the ER of untreated cells, a rapid decrease in protein levels following ER stress, and the corresponding appearance of a 30-kDa fragment in the cytosol. Inhibition of the proteasome during ER stress revealed an accumulation of FKBP65 in the cytosol, consistent with retrotranslocation and a proteasome-based proteolysis. To assess the role of Ca 2+ -binding EF-hand domains in FKBP65 stability, a recombinant FKBP65-GFP construct was engineered to ablate Ca 2+ binding at each of two EF-hand domains. Cells transfected with the wild-type construct displayed ER localization of the FKBP65-GFP protein and a proteasome-dependent proteolysis in response to ER stress. Recombinant FKBP65-GFP carrying a defect in the EF1 Ca 2+ -binding domain displayed diminished protein in the ER when compared to wild-type FKBP65-GFP. Proteasome inhibition restored mutant protein to levels similar to that of the wild-type FKBP65-GFP. A similar mutation in EF2 did not confer FKBP65 proteolysis. This work supports a model in which stress-induced changes in ER Ca 2+ stores induce the rapid proteolysis of FKBP65, a chaperone and folding mediator of collagen and tropoelastin. The destruction of this protein may identify a cellular strategy for replacement of protein folding machinery following ER stress. The implications for stress-induced changes in the handling of aggregateprone proteins in the ER-Golgi secretory pathway are discussed.
Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children under the age of 18. While modern diagnostic technologies, risk-stratification, and therapy intensification have led to outstanding outcomes for many children with ALL, the side effects and consequences of therapy are not to be underestimated. Hypertension is a well-known acute and chronic side effect of treatment for childhood ALL, although limited data are available regarding the prevalence of hypertension in children undergoing treatment for ALL. In this review of hypertension in pediatric ALL patients, we examine the existing data on incidence and prevalence during treatment and in pediatric ALL survivors. We describe independent risk factors for development of hypertension along with treatment-related causes. Long-term consequences and the risk to survivors of pediatric ALL are further defined. While many ALL patients require antihypertensive medications during some portion of their treatment, there are no clear guidelines on treating inpatient hypertension given challenges that exist in recognizing and managing hypertension in this setting and in this population. Here, we propose an algorithmic approach to diagnose and treat pediatric ALL patients with HTN, along with monitoring and continuation versus cessation of antihypertensive therapy as an outpatient.
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Genetically engineered chimeric antigen receptor (CAR) T cells have exhibited distinct effectiveness against chemotherapy refractory CD19 expressing B cell malignancies in both adults and children. This phase I clinical trial tests a novel anti-CD19 CAR T cell product in adults with relapsed/refractory (R/R) B-cell Non-Hodgkin’s Lymphoma (B-NHL). The CAR construct is comprised of the short chain variable regions of the anti-CD19 monoclonal antibody FMC63, the TNFRSF19-derived transmembrane domain, the 4-1BB costimulatory domain, and the CD3-zeta signaling domain. CD19 CAR T cells were manufactured utilizing the CliniMACS Prodigy® T Cell Transduction Process (CD3/CD28 TransAct™ reagent) allowing for highly automated production, with IL-7 and IL-15 used for T cell expansion for 8-12 days. To date, 7 patients have been treated with an average dose of 1.2 ± 0.2 x 108 CAR T cells. The histology includes marginal zone lymphoma (n=1), follicular lymphoma Grade IIIA (n=1), transformed lymphoma (n=3), follicular lymphoma low grade (n=2), and diffuse large B-cell lymphoma (n=1). One patient required a second apheresis due to poor cell expansion. Despite heterogeneity in disease subtype and leukapheresis product quality, CAR T production and expansion have been consistent with final transduction efficiencies between 14-45%, cell viability between 88-91%, and an overall average yield of 3.2 ± 0.3 x 109 cells before harvest, allowing for product banking. No safety-related out of specifications (OOS) events have occurred, however, 2 patients had OOS product infused due to low transduction efficiency (both at 14% rather than the ≥ 20% release criteria). Two patients experienced Grade 2 CRS, 1 patient experienced Grade 2 neurotoxicity; otherwise, no new safety signals were detected. Disease response was assessed on Days 90, 180, 270, and 360 post-infusion. The assessments were based on 2014 Lugano criteria. Even with 2 OOS products, Day 90 scans showed a complete metabolic remission (CMR) in 6 evaluable patients to date. Of the 6 patients with CMR, 1 patient progressed at Day 180 and the others remain in remission (median f/u = 12 months). Flow cytometry was utilized to measure CAR T cell peak expansion and persistence in 5 patients. Peak CAR T cell expansion (2.9-44.4% of CD3 cells) ranged from Day 5 to 15. Cell persistence was detected for the 5 patients through at least Day 180. ddPCR is currently in development to perform persistence testing in parallel. Additionally, cytokine concentrations including INFγ, IL-10, IL-12p70, IL-13, IL1β, IL-2, IL-4, IL-6, IL-8, and TNFα were evaluated over the first 30 days. Overall, 7 patients diagnosed with 5 different B-NHL subtypes have been treated with the CD19 CAR T cell product. Manufacturing was successful for all patients with no safety related OOS, and no new post-infusion safety signals detected. To date, 6 out of 7 patients are alive, 5 with CMR and with CD19 CAR T cell persistence through at least 180 days. Citation Format: Manali Kamdar, Cheri Adams, Steven Bair, Boro Dropulic, Jonathon Gutman, Bradley Haverkos, Kimberly Jordan, Rebecca Mallo, Russell Marians, Felicia Mast, Lindsey Murphy, Andrew Roth, Matthew Seefeldt, Andrew Worden, Mike Kadan, Ying Xiong, Dina Schneider, Rimas Orentas, Terry Fry, Michael Verneris. Feasibility and safety of a novel CD19 CAR T cell therapy in adults with R/R B-NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT522.
Given the fact that first responders are often the first point of contact with children in emergency events that could potentially be appraised as traumatic and have long lasting detrimental effects, the purpose of this study was to examine the lived experience of first responders within a Midwest Metropolitan Fire Department during emergency events involving children. Using descriptive phenomenology methods, 16 interviews were conducted with eight first responders. Results indicated four phenomena related to experienced child reactions during emergency events 1) lack of reactions, 2) emotion-based reactions, 3) information seeking reactions, and 4) observant reactions. First responders identified their role in supporting children on the scene in using distraction, providing calming and reassurance, and providing education. Current systems of emotional support identified by first responders included family members, neighbors, police officers, and hospital staff. Gaps in services identified by first responders included specialized and dedicated support for children and effective first responder training.
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