epinephrine (epinephrine, Dey / EpiPen / epinephrine, Mylan)

NOR-1 is an upstream regulator of Ca2+ homeostasis and calmodulin kinase II-dependent arrhythmogenesis.

Vázquez-Sufuentes Paula P, Jiménez-Sábado Verónica V, Ballester-Servera Carme C, Casabella-Ramón Sergi S et al.

Dysregulation of NOR-1 has been reported in cardiovascular diseases associated with altered calcium handling. We therefore investigated how NOR-1 affects calcium homeostasis and arrhythmogenesis to identify the underlying mechanisms. We assessed the expression of NOR-1 and calcium regulatory proteins in myocardial samples from humans and mice that overexpress human NOR-1 in the heart (TgNOR-1). Gene promoter activity was determined by transient co-transfection assays. Calcium imaging, patch-clamp recordings and immunofluorescent labeling was performed in mouse cardiomyocytes. Experimental data were used for mathematical modeling. Arrhythmias were induced in vivo by an epinephrine/caffeine challenge. In human cardiac samples, mRNA levels of genes coding for SERCA2a, CASQ2, TN-C1 and PLB correlated with those of NOR-1, while TgNOR-1 mice exhibited higher cardiac levels of these calcium regulatory proteins than wild-type animals (WT). NOR-1 increased luciferase activity driven by the proximal promoter of both human and mouse genes. Calcium transients were smaller in TgNOR-1 cardiomyocytes while L-type calcium current and SR calcium content were unchanged. Mathematical modeling revealed that more calcium binds to CASQ2 and is released from the SR in TgNOR-1 cardiomyocytes, but the resulting calcium transient is smaller because more calcium is buffered by TN-C1. Furthermore, NOR-1 transgenesis increased the level of reactive oxygen species and CAMKII oxidation, as well as RyR2 phosphorylation at Ser-2814, which led to a higher incidence of calcium waves and afterdepolarizations in resting TgNOR-1 cardiomyocytes. In electrically paced myocytes, NOR-1 transgenesis promoted extra-transients at low frequencies and calcium alternans at high frequencies. Importantly, these derangements in intracellular calcium handling concurred with a dramatic increase in epinephrine/caffeine-induced bidirectional ventricular tachycardia in TgNOR-1 mice. Moreover, the antioxidant N-acetylcysteine and the CAMKII inhibitor KN-93 attenuated arrythmia in TgNOR-1 mice and arrhythmogenic calcium release in isolated myocytes. Our findings highlight NOR-1 as an upstream regulator of CAMKII-oxidation underlying arrhythmia induced by defective calcium homeostasis, pointing to therapies targeting CAMKII as a means to attenuate arrhythmia triggered by pathological upregulation of NOR-1.

Risk Factors of Inferior Alveolar Nerve Block Failure: A Dental Student-Centred Study.

Gürses Gökhan G, Taşkin Emine E, Akti Ahmet A, Arun Funda F et al.

The inferior alveolar nerve block (IANB) is the most widely used mandibular anaesthesia technique; however, it remains prone to failure due to both anatomical and operator-related factors. Understanding these factors is essential to enhancing student training and patient comfort. This study aimed to identify risk factors associated with IANB failure among dental students. A prospective observational study was conducted at Selcuk University Faculty of Dentistry (February 2023-July 2024). Fourth- and fifth-year right-handed dental students administered IANBs to 340 patients using the Halstead technique with 4% articaine and epinephrine. Anaesthesia success was evaluated after 10 min through both clinical testing and patient feedback by a blinded assessor. Logistic regression analyses identified significant predictors of failure, while receiver operating characteristic (ROC) curves assessed discriminative performance. Out of 340 procedures, 301 were successful, yielding an overall success rate of 88.5%. Failures were associated with limited interincisal opening, higher body mass index (BMI) and lower student experience level. Multiple logistic regression confirmed these three as independent predictors (p < 0.05). Among these, BMI showed the strongest predictive performance (AUC = 0.72), followed by interincisal distance (AUC = 0.68) and student grade (AUC = 0.66). IANB success depends on both operator experience and patient morphology. Incorporating structured psychomotor and simulation-based anaesthesia training early in dental education may reduce failure rates and improve clinical proficiency.

Association of calculated weight-indexed first-bolus epinephrine with outcomes after out-of-hospital cardiac arrest: EPIKILO study.

Marouk Alexis A, Blandin Maël M, Lapostolle Frédéric F

Local Anesthetic Systemic Toxicity Following High-Volume Ropivacaine, Epinephrine, Clonidine, and Ketorolac (RECK) Infiltration During Total Knee Arthroplasty: A Case Report.

Mendelson Brian B, Perdomo Trejo Jose J, Bekele Soliana S

Local infiltration analgesia is widely used for post-operative pain control following joint arthroplasty and is generally considered to carry a low risk of local anesthetic systemic toxicity. We report a case of local anesthetic systemic toxicity in a 72-year-old woman following primary total knee arthroplasty performed under spinal anesthesia with adjunctive adductor canal block and high-volume periarticular infiltration with ropivacaine, epinephrine, clonidine, and ketorolac (RECK) solution. The cumulative perioperative ropivacaine dose was 286 mg (3.9 mg/kg). Soon after arrival in the post-anesthesia care unit, the patient developed acute confusion and focal myoclonic activity in the right arm without cardiovascular instability. Lipid emulsion was administered with rapid and complete neurological recovery. This case highlights the importance of considering cumulative dosing across regional and surgical infiltration techniques, the influence of patient-specific factors on susceptibility to toxicity, and the need for vigilance for delayed manifestations of local anesthetic systemic toxicity following high-volume infiltration.