A 52-Year-Old Man with a Chronic Nasal Wound.

AbstractMorning Report is a time-honored tradition where physicians-in-training present cases to their colleagues and clinical experts to collaboratively examine an interesting patient presentation. The Morning Report section seeks to carry on this tradition by presenting a patient's chief concern and story, inviting the reader to develop a differential diagnosis and discover the diagnosis alongside the authors of the case. This report examines the story of a 52-year-old man who sought evaluation for a chronic nasal lesion that had eroded into his nasal septum. Using questions, physical examination, and testing, an illness script for the presentation emerges. As the clinical course progresses, the differential is refined until a diagnosis is made.

Direct and indirect activation of the adenosine triphosphate-sensitive potassium channel to induce spinal cord ischemic metabolic tolerance.

OBJECTIVES: The mitochondrial adenosine triphosphate-sensitive potassium channel is central to pharmacologically induced tolerance to spinal cord injury. We hypothesized that both direct and nitric oxide-dependent indirect activation of the adenosine triphosphate-sensitive potassium channel contribute to the induction of ischemic metabolic tolerance. METHODS: Spinal cord injury was induced in adult male C57BL/6 mice through 7 minutes of thoracic aortic crossclamping. Pretreatment consisted of intraperitoneal injection 3 consecutive days before injury. Experimental groups were sham (no pretreatment or ischemia, n = 10), spinal cord injury control (pretreatment with normal saline, n = 27), Nicorandil 1.0 mg/kg (direct and indirect adenosine triphosphate-sensitive potassium channel opener, n = 20), Nicorandil 1 mg/kg + carboxy-PTIO 1 mg/kg (nitric oxide scavenger, n = 21), carboxy-PTIO (n = 12), diazoxide 5 mg/kg (selective direct adenosine triphosphate-sensitive potassium channel opener, n = 25), and DZ 5 mg/kg+ carboxy-PTIO 1 mg/kg, carboxy-PTIO (n = 23). Limb motor function was assessed using the Basso Mouse Score (0-9) at 12-hour intervals for 48 hours after ischemia. RESULTS: Motor function was significantly preserved at all time points after ischemia in the Nicorandil pretreatment group compared with ischemic control. The addition of carboxy-PTIO partially attenuated Nicorandil's motor-preserving effect. Motor function in the Nicorandil + carboxy-PTIO group was significantly preserved compared with the spinal cord injury control group (P < .001), but worse than in the Nicorandil group (P = .078). Motor preservation in the diazoxide group was similar to the Nicorandil + carboxy-PTIO group. There was no significant difference between the diazoxide and diazoxide + carboxy-PTIO groups. CONCLUSIONS: Both direct and nitric oxide-dependent indirect activation of the mitochondrial adenosine triphosphate-sensitive potassium channel play an important role in pharmacologically induced motor function preservation.

The Impact of Suboptimal 25-Hydroxyvitamin D Levels and Cholecalciferol Replacement on the Pharmacokinetics of Oral Midazolam in Control Subjects and Patients With Chronic Kidney Disease.

The aim of this study was to investigate the impact of suboptimal 25-hydroxyvitamin D (25-VitD) and cholecalciferol (VitD3 ) supplementation on the pharmacokinetics of oral midazolam (MDZ) in control subjects and subjects with chronic kidney disease (CKD). Subjects with CKD (n = 14) and controls (n = 5) with suboptimal 25-VitD levels (<30 ng/mL) were enrolled in a 2-phase study. In phase 1 (suboptimal), subjects were administered a single oral dose of VitD3 (5000 IU) and MDZ (2 mg). In phase 2 (replete) subjects who achieved 25-VitD repletion after receiving up to 16 weeks of daily cholecalciferol were given the identical single oral doses of VitD3 and MDZ as in phase 1. Concentrations of MDZ and metabolites, 1'-hydroxymidazolam (1'-OHMDZ), and 1'-OHMDZ glucuronide (1'-OHMDZ-G) were measured by liquid chromatography-tandem mass spectrometry and pharmacokinetic analysis was performed. Under suboptimal 25-VitD, reductions in MDZ clearance and renal clearance of 47% and 87%, respectively, and a 72% reduction in renal clearance of 1'-OHMDZ-G were observed in CKD vs controls. In phase 1 versus phase 2, MDZ clearance increased in all control subjects, with a median (interquartile range) increase of 10.5 (0.62-16.7) L/h. No changes in MDZ pharmacokinetics were observed in subjects with CKD between phases 1 and 2. The effects of 25-VitD repletion on MDZ disposition was largely observed in subjects without kidney disease. Impaired MDZ metabolism and/or excretion alterations due to CKD in a suboptimal 25-VitD state may not be reversed by cholecalciferol therapy. Suboptimal 25-VitD may augment the reductions in MDZ and 1'-OHMDZ-G clearance values observed in patients with CKD.

Optimizing Nicorandil for Spinal Cord Protection in a Murine Model of Complex Aortic Intervention.

There are currently no clinically utilized pharmacological agents for the induction of metabolic tolerance to spinal cord ischemia-reperfusion injury in the setting of complex aortic intervention. Nicorandil, a nitric oxide donor and ATP-sensitive potassium (KATP) channel opener, has shown promise in neuroprotection. However, the optimized clinical application of the drug and its mechanism of neuroprotection remains unclear. We hypothesized that 3-days pretreatment would confer the most effective neuroprotection, mediated by mitochondrial KATP channel activation. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Time course: mice received 0.1 mg/kg nicorandil for 10 min, 4 hours, and 3 consecutive days prior to ischemia compared with control. Dose challenge: mice received 3-days nicorandil pretreatment comparing 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, and saline administration. Mitochondrial KATP channel blocker 5-hydroxy-decanoate (5HD) was co-administered to elucidate mechanism. Limb motor function was evaluated, and viable anterior horn neurons quantified. Nicorandil pretreatment at 4 hours and 3 days before ischemia demonstrated significant motor function preservation; administration 10 minutes before ischemia showed no neuroprotection. All nicorandil doses showed significant motor function preservation. Three days administration of Nicorandil 1.0 mg/kg was most potent. Neuroprotection was completely abolished by 5HD co-administration. Histological analysis showed significant neuron preservation with nicorandil pretreatment, which was attenuated by 5HD co-administration. Three days administration of Nicorandil 1.0 mg/kg showed near-total motor function preservation in a murine spinal cord ischemia-reperfusion model, mediated by the mitochondrial KATP channel.

An evaluation of a novel nanoformulation of imatinib mesylate in a mouse model of lupus nephritis.

Studies have suggested imatinib mesylate (ImM) as a potential treatment for systemic lupus erythematosus nephritis (SLEN). However, ImM has limited renal excretion. The goal of the current research was to develop an ImM containing nanoformulation, conduct studies to evaluate pharmacokinetics, and determine whether kidney deposition can be enhanced in a mouse model of SLEN. A fish oil-based ImM oil-in-water nanoemulsion was developed and characterized for particle size, zeta potential, pH, and stability. MRL/MpJ-Faslrp (model of SLEN) and MRL/MpJ (control) mice (12-13 weeks) received one dose of ImM as either a nanoemulsion or naked drug. Pharmacokinetics and kidney deposition studies were performed. Statistics were conducted with a student's T-test. The nanoemulsion characteristics included particle size range of 60-80 nm, zeta potential of -6.6 to -7.8 mV, polydispersity index < 0.3, 3-day stability at 4 °C, and limited ImM leakage from the nanoemulsion in serum. Pharmacokinetics of the nanoformulation showed changes to pharmacokinetic parameters suggesting reduced systemic exposures (with reduced potential for toxicities) to ImM. Kidney deposition of ImM was threefold higher after 4 h in the MRL/MpJ-Faslrp mice that received the nanoformulation vs. naked drug. The current study showed encouraging results for development of a stable and well-characterized nanoemulsion for optimizing kidney deposition of ImM. Future strategies will define dose-efficacy and dose-toxicity relationships and evaluate approaches to further enhance kidney delivery and optimize deposition to the mesangial location of the kidney.

Reactive Oxygen Species Mediate Nicorandil-induced Metabolic Tolerance to Spinal Cord Injury.

BACKGROUND: Spinal cord injury remains a devastating complication of thoracoabdominal aortic surgery. We previously demonstrated that pretreatment with nicorandil preserved motor function in a murine spinal cord injury model through mitochondrial adenosine triphosphate-sensitive potassium channel activation. We hypothesized that the neuroprotective effect of nicorandil is mediated by downstream generation of reactive oxygen species. METHODS: Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Five groups were evaluated: ischemic control (n = 19); nicorandil 1.0 mg/kg (n = 17); nicorandil 1.0 mg/kg plus N acetyl L-cysteine (NAC [reactive oxygen species scavenger, n = 18)]) 150 mg/kg; NAC 150 mg/kg (n = 13); and sham (n = 10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. RESULTS: Mice in the sham group showed no functional deficits after surgery. Compared with ischemic control, motor function was significantly preserved in the nicorandil pretreatment group at every timepoint after ischemia. In the nicorandil plus NAC group, the motor-preserving effect of nicorandil was completely abolished (P < .001). Viable neuron quantification showed significant neuron preservation in the nicorandil group (29.± 2.6) compared with the ischemic control group (18.5 ± 2.1, P = .024) and nicorandil plus NAC group (14 ± 8.3, P = .001); no significant difference was observed between the ischemic control group and nicorandil plus NAC group (P = 0.768). CONCLUSIONS: Reactive oxygen species generation plays a key role in the nicorandil-induced metabolic tolerance to spinal cord injury. Manipulation of mitochondrial adenosine triphosphate-sensitive potassium channels may lead to improvement in preventing spinal cord injury after thoracoabdominal aortic interventions.

Utility of neuromonitoring in hypothermic circulatory arrest cases for early detection of stroke: Listening through the noise.

OBJECTIVE: Stroke remains a potentially devastating complication of aortic arch intervention. The value of neurophysiologic intraoperative monitoring (NIOM) in the early identification of stroke is unclear. We evaluated the utility of NIOM for early stroke detection in aortic arch surgery. METHODS: Across 8 years at our institution, 365 patients underwent aortic arch surgery with hypothermic circulatory arrest, and 224 cases utilized NIOM. One patient was excluded for intraoperative death. In the remaining cohort, we reviewed the incidence, timing, and location of strokes, and the incidence and nature of NIOM alerts. RESULTS: Hemiarch was performed in 154 patients and total arch replacement in 69 patients. Stroke occurred in 6.3% of all cases (14 out of 223), 15.9% of total arches (11 out of 69), and 2.0% of hemiarches (3 out of 154). There were 33 NIOM alerts (14.8%), and 9 patients had both alerts and stroke. Of these, NIOM deficits plausibly correlated with imaging findings in 7 cases (78%). Of the 5 stroke patients without NIOM alerts, 2 developed neurologic symptoms 3 days or more postoperatively, and infarcts in 3 patients did not result in sensory or motor deficits. Excluding 2 patients with late stroke, the sensitivity of NIOM for stroke detection was 75%, specificity was 88.5%, positive predictive value was 27.3%, and negative predictive value was 97.4%. CONCLUSIONS: Despite a low positive predictive value requiring a high level of discrimination when interpreting abnormal findings, NIOM has high sensitivity and specificity for the early stroke detection. Furthermore, its high negative predictive valve is reassuring for low risk of stroke in the absence of alerts.

Predictors of Acute Kidney Injury Following Aortic Arch Surgery.

BACKGROUND: Acute kidney injury (AKI) following open aortic arch surgery is a frequent complication associated with increased morbidity and mortality. The primary purpose of this study was to evaluate risk factors for postoperative AKI in patients who underwent open aortic arch surgery utilizing hypothermic circulatory arrest (HCA). MATERIALS AND METHODS: Included were 295 patients undergoing surgery between January 2011 and March 2018. AKI was defined according to Kidney Disease: Improving Global Outcomes guidelines. Preoperative and intraoperative variables were stratified by no AKI versus any AKI, and bivariate analysis was performed. Multivariable logistic regression analysis used statistically and clinically significant characteristics from the bivariate analysis. RESULTS: Of the 295 patients, 93 (32%) developed AKI. In the bivariate analysis, significant predictors of AKI included the following: history of hypertension (P < 0.001), diabetes (P = 0.03), operative urgency (P = 0.009), cardiopulmonary bypass (CPB) time (P < 0.0001), HCA time (0.02), total intraoperative transfusions (P = 0.002), and concomitant procedures (coronary artery bypass grafting, or mitral/tricuspid interventions, P = 0.0009). In the multivariable analysis, significant predictors of AKI were history of hypertension (P = 0.03) and CPB time (P = 0.02). Age, operative urgency, circulatory arrest time, and any intraoperative transfusion were not significant in the multivariable analysis. CONCLUSION: In conclusion, given that CPB time is the only modifiable risk factor identified in the analysis, approaches to reducing bypass time should continue to be the focus of decreasing risk for postoperative AKI in HCA cases.

Pretreatment With Diazoxide Attenuates Spinal Cord Ischemia-Reperfusion Injury Through Signaling Transducer and Activator of Transcription 3 Pathway.

BACKGROUND: Delayed paraplegia remains a feared complication of thoracoabdominal aortic intervention. Pharmacologic preconditioning with diazoxide (DZ), an adenosine 5'-triphosphate-sensitive potassium channel opener, results in neuroprotection against ischemic insult. However, the effects of DZ in spinal cord ischemia-reperfusion injury have not been fully elucidated. We hypothesized that DZ attenuates spinal cord ischemia-reperfusion injury through the signaling transducer and activator of transcription (STAT) 3 pathway. METHODS: Adult male C57/BL6 mice received DZ (20 mg/kg) by oral gavage. Spinal cords were harvested at 0, 12, 24, 36, 48, and 60 hours after administration of DZ. The expression of phosphorylated STAT3 was assessed by Western blot analysis. Five groups were studied: DZ (DZ pretreatment, n = 8), ischemic control (phosphate-buffered saline pretreatment, n = 11), DZ + STAT3 inhibitor LY5 (DZ pretreatment + LY5, n = 8), LY5 (phosphate-buffered saline pretreatment + LY5, n = 8), and sham (without cross-clamping, n = 5). Spinal cord ischemia was induced by 4 minutes of thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-hour intervals until 48 hours, and spinal cords were harvested for the evaluation of B-cell lymphoma 2 expression and histologic changes. RESULTS: The expression of phosphorylated STAT3 was significantly upregulated 36 hours after the administration of DZ. The motor function in the DZ group was significantly preserved compared with all other groups. The expression of B-cell lymphoma 2 in the DZ group was significantly higher than in the ischemic control, DZ + LY5, and LY5 groups 48 hours after reperfusion. CONCLUSIONS: DZ preserves motor function in spinal cord ischemia-reperfusion injury by the STAT3 pathway. DZ may be beneficial clinically for use in spinal protection in aortic intervention.

Effect of Disease Pathologies on Transporter Expression and Function.

Transporters are important determinants of drug absorption, distribution, and excretion. The clinical relevance of drug transporters in drug disposition and toxicology depends on their localization in liver, kidney, and brain. There has been growing evidence regarding the importance of disease status on alterations in metabolizing enzymes and transporter proteins. This review focuses on uptake and efflux transporter proteins in liver, kidney, and brain and discusses mechanisms of altered transporter expression and function secondary to disease.