Citations

Post‐mortem analyses have identified carotid body hypertrophy in conditions of chronic hypoxemia, including sleep apnea; however, post‐mortem assessment limits the clinical relevance of such findings. We tested the hypotheses that: 1) carotid body size can be detected in living individuals by computed tomographic angiography (CTA), and 2) patients with sleep disordered breathing [Apnea Hypopnea Index (AHI) ≥ 30 events/hour] exhibit larger carotid bodies than those without sleep disordered breathing (AHI < 5 events/hour). A chart review was conducted from patients seen at the Mayo Clinic between January 2000 and February 2015 who had undergone neck CTA and polysomnography. From an initial pool of 583, 109 patients met our strict inclusion criteria. Widest axial measurements of the right and left carotid bodies were performed independently by two radiologists blinded to condition and average carotid body size was calculated for each patient of interest. Carotid body identification was possible in 81% of patients. Intra‐class correlation coefficients ranged from 0.93 to 0.95 (right carotid body: 0.93; left: 0.94; average: 0.95). From subjects with identifiable carotid bodies, widest axial measurements were greater in patients with high AHI (n=32; right: 2.9±0.2mm, left: 3.1±0.2mm, average: 3.0±0.1mm) compared to patients with low AHI (n=46; right: 2.5±0.1mm, left: 2.7±0.1mm, average: 2.6±0.1mm; p=0.04, p=0.04, p=0.02, respectively). Because participants in the high AHI group were significantly older than those in the low AHI group (65±2 years vs. 50±2 years; p<0.01), an analysis of covariance was performed to control for the influence of age on carotid body size. After adjusting for age, no differences in carotid body size were observed between the patient groups (p=0.45, p=0.59, p=0.54 for right, left, and average carotid body, respectively). Main findings are two‐fold: 1) carotid body size can be identified by CTA in approximately 80% of patients with good inter‐observer agreement, and 2) adults that exhibit sleep disordered breathing do not have larger carotid bodies when compared to controls, after adjusting for age. Support or Funding Information This work was supported by the National Institutes of Health [grant numbers T32 GM008685 (ARE), R01 DK090541 (MJJ)].

The purpose of this study was to explore dose dependent vasodilation responses of the individual compounds of Shakuyakukanzoto (SKT), a 1:1 combination of extracts from Paeony and Licorice roots: glycyrrhetic acid (GA), paeoniflorin (PF), and isoliquiritigenin (ISO). 20 young, healthy participants (13M/7W) had four intradermal microdialysis fibers placed in the forearm skin for local delivery of: 1) control (diluent), 2) GA, 3) PF, or 4) ISO at doses of 1, 10, 50, or 100 μm. Cutaneous red cell flux, an index of skin blood flow, was measured by laser‐Doppler flowmetry. Blood pressure (BP) was monitored continuously during fixed measurement periods via finger photo‐plethsmography (Finapres). Cutaneous vascular conductance (CVC) was derived as red cell flux divided by BP and was normalized as a percentage of baseline (%CVCbl, saline at 4 μl/min) and the maximum CVC (%CVCmax, 28mM sodium nitroprusside at 4 μl/min, local temperature 43°C). Mean CVC did not statistically differ between baseline and individual compound plateau (average of last 5 minutes of infusion) at any dose. The peak flux was significantly higher from baseline at doses 50 and 100 μm for control (56.17±13.32 vs. 96.73±20.32 and 44.64±5.68 vs. 80.21±9.54), PF (62.70±10.09 vs. 115.72±16.16 and 62.37±16.2 vs. 150.21±34.26), GA (48.37±4.41 vs. 71.76±7.16 and 58.36±13.68 vs. 91.51±3.41), and ISO (96.50±23.20 vs. 128.57±27.90 and 44.95±8.78 vs. 91.18±20.37) (p<0.05). However, peak CVC was significantly higher only for GA at dose 50 μm, as well as for control and PF at dose 100 μm compared to their respected baselines (GA: 0.60±0.06 vs. 1.01±0.11, control: 0.61±0.09 vs.1.55±0.61, PF: 0.81±0.20 vs. 1.30±0.30, p<0.05). There were no other significant differences between the control and the compounds for change in CVC from baseline to peak (ΔCVC), %CVCbl, or %CVCmax. There were no significant differences between doses 1, 10, or 50 as compared to 100 μm for other variables. These results suggest that the doses may be lower or below the threshold to cause a vasodilatory effect. Future studies that investigate higher doses of these compounds may be needed. Support or Funding Information The University of Oxford Systems Biology Project sponsored by Tsumura.

OBJECTIVE Men and women differ in cardiac output. We hypothesize a sex by genotype interaction may exist during a low‐dose adrenaline infusion affecting the β2 adrenergic receptor. METHODS Subjects: Ten males (mean ± SD: age=27.8±6.6, height=178.5±8.0cm, weight=83.9 ±12.4kg, BMI=26.3±2.9kg/m^2, BSA=2.0±0.2) and fourteen females (mean ± SD: age=26.3±5.9, height=164.3±7.0cm, weight=60.8±6.2kg, BMI=22.5±2.1kg/m^2, BSA=1.7±0.1) were studied. Three males were homozygous for Arginine (Arg/Arg) and 7 males were homozygous for Glycine (Gly/Gly) at position 16. In the female cohort, eight females were Arg/Arg and six females were Gly/Gly, at position 16. Procedure: A 1‐hour epinephrine infusion dosed at 5ng/kg/min was administered. BP was measured via an arterial catheter and HR via EKG. Stroke volume and Cardiac output were estimated via Modelflow and TPR was calculated. Plasma samples were collected at time: 0, 30, 45, 60, and 70 minutes and catecholamines measured using HPLC with electrochemical detection. Population Pharmacokinetic‐Pharmacodynamic Analysis: Plasma epinephrine concentrations and cardiac output responses were analyzed using the Nonlinear Mixed Effects (NLME) Stochastic Approximation Expectation‐Maximization (SAEM) algorithm in MATLAB® Simbiology TM (version 2015a, Mathworks, Natick, MA). The Visual Predictive Check was conducted using the R statistical software (version 3.2.2, The R Foundation for Statistical Computing, Vienna, Austria). RESULTS Epinephrine pharmacokinetics were well‐described using a one‐compartment model with an ‘effect compartment’ and elimination from the central compartment. The population mean estimates for the volume of distribution and elimination rate were 22.81 L (CV=27.52%) and 8.77 L/hour (13.00%), respectively. Cardiac Output was modeled using the Hill Stimulation Equation and resulted in mean population estimates of E0=4.94 L/min (13.56%) for baseline, Emax=34.86 L/min (38.61%), and EC50=2486.23 ng/L (CV=5.54%). Bodyweight (mean=70kg) and Sex:Genotypes were the main covariates for the model. A visual predictive check revealed adequate central tendency for the linked PK/PD model. Dosing (300ng/kg/hour for a 70kg individual) simulations resulted in a PK/PD profile stratified for the population mean and Sex:Genotype covariates. Plasma Concentration‐Response curves produced subpopulation (Male Arg/Arg, Male Gly/Gly, Female Arg/Arg, and Female Gly/Gly) differences. CONCLUSION Based on the plasma concentration‐response curves, the interaction of sex and genotype influences the ability to increase cardiac output during an infusion of low‐dose epinephrine. Support or Funding Information NIH T32 Clinical Pharmacology Fellowship Grant GM008685‐17.

Occupational burnout, manifested by emotional exhaustion, lack of a sense of personal achievement, and depersonalization, is not a new phenomenon, but thusfar, there is no clear definition or diagnostic guidelines. The aim of this article wasto summarize all empirical studies to date that have used medical neuroimaging techniques to provide evidence or links regarding changes in brain function in occupational burnout syndrome from a neuroscientific perspective, and then use these to propose a fuzzy-based computational model of burnout.A comprehensive literature search was conducted in two major databases (PubMed and Medline Complete). The search period was 2006–2021, and searches were limited to the English language. Each article was carefully reviewed and appropriately selected on the basis of raw data, validity of methods used, clarity of results, and scales for measuring burnout. The results showed that the brain structures of patients with job burnout that are associated with emotion, motivation, and empathy weresignificantly different from healthy controls. These altered brain regions included the thalamus, hippocampus, amygdala, caudate, striatum, dorso-lateral prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, anterior insula, inferior frontal cingulate cortex, middle frontal cingulate cortex, temporoparietal junction, and grey matter. Deepening our understanding of how these brain structures are related to burnout will pave the way for better approaches fordiagnosis and intervention. As an alternative to the neuroimaging approach, the paper presents a late proposal of the PLUS (personal living usual satisfaction) parameter. It is based on a fuzzy model, wherein the data source is psychological factors—the same or similar to the neuroimaging approach. As the novel approach to searching for neural burnout mechanisms, we have shown that computational models, including those based on fuzzy logic and artificial neural networks, can play an important role in inferring and predicting burnout. Effective computational models of burnout are possible but need further development to ensure accuracy across different populations. There is also a need to identify mechanisms and clinical indicators of chronic fatigue syndrome, stress, burnout, and natural cognitive changes associated with, for example, ageing, in order to introduce more effective differential diagnosis and screening.

We previously reported that testis‐specific Y‐encoded‐like protein (TSPYLs) are transcription regulators for CYP3A4, CYP2C9, and CYP2C19. Here, we observed dual roles for TSPYLs in mediating serotonin transport and the metabolism of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD). The widely prescribed SSRIs, citalopram, and escitalopram are metabolized mainly by CYP2C19. The TSPYL1 rs3828743 single nucleotide polymorphism (SNP), which decreases its suppression of CYP2C19 expression, was associated with rapid escitalopram metabolism and worse treatment response in the Mayo PGRN‐AMPS clinical trial. We also found that TSPYLs can regulate expression of the serotonin transporter protein, SLC6A4, and, in turn, serotonin transport into cells. The SNPs in tight linkage disequilibrium with the TSPYL1 rs10223646 SNP were significantly correlated with baseline severity of depression in patients with MDD in the Sequenced Treatment Alternatives to Relieve Depression and International SSRI Pharmacogenomics Consortium clinical trials. Our findings suggest that genetic variation in TSPYL genes may be novel indicators for baseline severity of depression and SSRI poor response.

The vasodilatory mechanism of Nntroglycerin (NTG) is similar to sodium nitroprusside (SNP) in regard to action on guanosine 3′5′-monophosphate (cyclic GMP) via nitric oxide. However, it is unknown whether NTG can achieve the same magnitude of vasodilation in the forearm as SNP. Therefore, the purpose of the study was to evaluate the differences in forearm blood flow (FBF) and forearm vascular conductance (FVC) during escalating infusions of NTG vs. SNP at similar concentration doses and rates. We measured FBF using venous occlusion plethysmography (VOP) and Doppler ultrasound in eight young, healthy participants (mean age = 28 ± 2 yr) during four forearm volume (FAV)-specific doses (0.25, 0.5, 1, and 2 µg·100 ml FAV−1·min−1) of SNP and NTG infused via a brachial artery catheter. There was a significant difference in FVC of SNP vs. NTG only at the higher doses, as measured by VOP (14.9 ± 1.4 and 18.3 ± 1.5 vs. 11.6 ± 1.2 and 12.5 ± 1.2 ml/dl FAV−1·min−1·100 mmHg−1). FVC as measured by Doppler ultrasound unadjusted for FAV was significantly different at the lowest and the higher two doses of SNP compared with NTG (202.1 ± 25.8, 329.4 ± 46.7, and 408 ± 63.5 vs. 142.9 ± 22.4, 217.2 ± 18.8, and 247.5 ± 18.2 ml·min−1·100 mmHg−1). SNP induces significantly higher vasodilatory actions compared with NTG. However, NTG is comparable in eliciting equivalent vasodilator effects to SNP during low concentration doses when measured by VOP. Importantly, for forearm pharmacology studies, NTG can elicit marked endothelium-independent forearm vasodilation. NEW & NOTEWORTHY We compared the vasodilatory capacities of NTG vs. SNP at similar concentration doses and rates into the forearm. Based on the results of the study, it may be feasible to use intra-arterial NTG as a measure of endothelial-independent vasodilator in research studies. However, NTG dosing may need to be higher if used as an endothelial-independent vasodilator due to significant differences in the vasodilatory effects during higher doses of SNP compared with NTG.

Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration–time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men.