Arterial Plasma Research Articles

Comparison of Hemodynamic Effects of Dobutamine and Ephedrine Infusions in Isoflurane-Anesthetized Horses.

The objective of this study was to compare the hemodynamic effects of dobutamine and ephedrine during the management of anesthesia-related hypotension in healthy horses. Thirteen horses underwent general anesthesia with isoflurane and were randomly divided into two different groups, one of which received a dobutamine constant rate infusion (CRI) (1 µg/kg bwt/min) and the other received an ephedrine CRI (20 µg/kg bwt/min) when hypotension (<60 mmHg) was identified, following up to 15 min after the blood pressure reached 70 mmHg. All horses were equipped with a pulmonary artery catheter and a peripheral artery catheter, and multiparameter monitoring commenced as soon as they were under mechanical ventilation. Hemodynamic parameters were recorded, while tissue perfusion markers (peripheral oxygen saturation, arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial plasma bicarbonate concentration, arterial oxygen saturation, mixed venous oxygen saturation, mixed venous oxygen content, arterial oxygen content, arteriovenous oxygen difference, oxygen delivery index, oxygen consumption index, and oxygen extraction ratio), serum lactate concentration, and troponin I concentrations were analyzed before the start of infusions (T0), when the blood pressure reached 70 mmHg (T1), and 15 min after T1 (T2). The time to restore the arterial pressure was similar in both groups (p > 0.05); however, the heart rate was higher in the ephedrine group (p = 0.0098), and sinus bradyarrhythmia occurred in the dobutamine group. Furthermore, both experimental protocols increased cardiac output (p = 0.0012), cardiac index (p = 0.0013), systemic vascular resistance (p = 0.008), systemic vascular resistance index (p < 0.001), and ameliorated perfusion markers. In the dobutamine group, the pulmonary artery wedge pressure (p < 0.001) and systolic index (p = 0.003) were elevated, while the arteriovenous oxygen difference was reduced in the ephedrine group (p = 0.02). Troponin I was used as a myocardial injury indicator, and did not differ between moments or between groups (p > 0.05). We concluded that both drugs were effective and safe to treat anesthetic hypotension under the conditions of this study.

Brain exposure of osimertinib in patients with epidermal growth factor receptor mutation non-small cell lung cancer and brain metastases: A positron emission tomography and magnetic resonance imaging study.

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [11 C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90-min [11 C]osimertinib PET examinations were acquired together with metabolite-corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast-enhanced MRI was performed at screening and after 25-35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51-77 years) completed the study. At baseline, ~1.5% injected radioactivity reached the brain (IDmax[brain] ) 22 min (median, Tmax[brain] ) after injection. Total volume of distribution (VT ) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in VT in whole brain or BMs. After greater than or equal to 21 days' daily treatment, VT in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%-95% reduction in total BMs volume after 25-35 days of osimertinib 80 mg q.d. treatment. The [11 C]osimertinib crossed the blood-brain and brain-tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs.

High Casein-Lactalbumin Diet Accelerates Blood Coagulation in Rats

This study investigates the influence of a high protein intake on normal hemostasis, fluid balance and organ growth. Adult rats were fed semipurified diets that contained either 18 or 56 g/100 g casein-lactalbumin for 2 wk, and the following functions were measured: food and water intake, weight gain, blood pressure, bleeding and clotting time, ADP-stimulated platelet aggregation, thrombin time, prothrombin time and partial thromboplastin time. Although food intake was depressed by the high protein diet, weight gain was not affected by the regimen. Water consumption, 24-h urine excretion and kidney weight were significantly greater in rats fed the high protein diet than in controls. High protein intake resulted in shorter barbiturate-induced sleeping time. Bleeding time and clotting time were significantly lower in rats fed the high protein diet for 7 d. However, heart rate, mean arterial pressure, plasma protein and osmolarity, platelet aggregation, prothrombin time, partial thromboplastin time and thrombin time did not differ significantly. Because a high protein intake caused rapid coagulation of blood in rats without affecting the activity of clotting factors, we suggest that this diet sensitized rats to factors that initiate clotting in vivo.

Impact of Upper Arm Prolonged Occlusion on Radial Artery Diameter Before Coronary Angiography in Patients With Coronary Artery Disease

BackgroundThe transradial approach (TRA) for percutaneous coronary angiography and intervention has been increasingly gaining popularity in clinical practice. However, there are cases in which it is difficult to insert a sheath or catheter due to spasm, pulsation loss, and occlusion. It has been reported that flow-mediated dilatation (FMD) contributed to the reduction of complications due to the TRA and the improvement of the number of puncture attempts. We hypothesized that FMD might increase the radial artery diameter and plasma nitric oxide (NO). Methods and resultsA prospective, single-blind, randomized, parallel-group, single-center study to investigate the effect of FMD on radial artery diameter. Fifty-four patients were enrolled and randomly assigned into the pressure group or non-pressure group. Radial artery diameter pre and post procedure and plasma NO after sheath canulation were analyzed in both groups. We measured the biological NO as its stable metabolic products, nitrite and nitrate, and express the results as total nitrogen oxides (NOx). The diameter of pre-procedural radial artery was similar between the 2 groups. However, in the pressure group, the increase of radial artery diameter between post- and pre-procedure was significantly greater than those in the non-pressure group (pressure group; 0.18 [0.07–0.29] mm vs. non-pressure group; −0.33 [−0.04 to −0.22] mm, p = 0.001). No significant differences were observed in terms of plasma NOx between the 2 groups. ConclusionsIt was possible to prove the increase in the radial artery diameter by performing FMD in the clinical practice, and to support the feasibility of FMD.

Safety and efficacy of intraosseous ropivacaine in lower extremity (SORE) study.

Day stay surgery for anterior cruciate ligament (ACL) reconstructions is an increasingly common practice and has driven clinicians to develop postoperative pain regimes that allow same day mobilization and a safe and timely discharge. There is a paucity of literature surrounding the use of intraosseous (IO) ropivacaine used as a Bier's block to provide both intraoperative and postoperative analgesia in lower limb surgery. This patient blinded, pilot study randomized 15 patients undergoing ACL reconstruction to receive either IO ropivacaine 1.5 or 2.0mg/kg; or 300 mg of ropivacaine as local infiltration. The primary outcome for this study was arterial plasma concentration of ropivacaine. Samples were taken via an arterial line at prespecified times after tourniquet deflation. Secondary outcomes included immediate postoperative pain scores using the visual analogue scale and perioperative opioid equivalent consumption. All patients in the intervention group receiving IO ropivacaine had plasma concentrations well below the threshold for central nervous system (CNS) toxicity (0.60 μg/mL). The highest plasma concentration was achieved in the intervention group receiving 1.5mg/kg dose of ropivacaine reaching 2.93 mg/mL. This would equate to 0.18 μg/mL of free plasma ropivacaine. There were no differences across the three groups regarding pain scores or perioperative opioid consumption. This study demonstrates that IO ropivacaine is both safe and effective in reducing perioperative pain in patients undergoing ACL reconstruction. There may be scope to increase the IO dose further or utilize other analgesics via the IO regional route to improve perioperative pain relief.

Aortic Distensibility Measured by Automated Analysis of Magnetic Resonance Imaging Predicts Adverse Cardiovascular Events in UK Biobank.

Background Automated analysis of cardiovascular magnetic resonance images provides the potential to assess aortic distensibility in large populations. The aim of this study was to compare the prediction of cardiovascular events by automated cardiovascular magnetic resonance with those of other simple measures of aortic stiffness suitable for population screening. Methods and Results Aortic distensibility was measured from automated segmentation of aortic cine cardiovascular magnetic resonance using artificial intelligence in 8435 participants. The associations of distensibility, brachial pulse pressure, and stiffness index (obtained by finger photoplethysmography) with conventional risk factors was examined by multivariable regression and incident cardiovascular events by Cox proportional-hazards regression. Mean (±SD) distensibility values for men and women were 1.77±1.15 and 2.10±1.45 (P<0.0001) 10-3 mm Hg-1, respectively. There was a good correlation between automatically and manually obtained systolic and diastolic aortic areas (r=0.980 and r=0.985, respectively). In regression analysis, distensibility associated with age, mean arterial pressure, heart rate, weight, and plasma glucose but not male sex, cholesterol or current smoking. During an average follow-up of 2.8±1.3 years, 86 participants experienced cardiovascular events 6 of whom died. Higher distensibility was associated with reduced risk of cardiovascular events (adjusted hazard ratio [HR], 0.61 per log unit of distensibility; P=0.016). There was no evidence of an association between pulse pressure (adjusted HR 1.00; P=0.715) or stiffness index (adjusted HR, 1.02; P=0.535) and risk of cardiovascular events. Conclusions Automated cardiovascular magnetic resonance-derived aortic distensibility may be incorporated into routine clinical imaging. It shows a similar association to cardiovascular risk factors as other measures of arterial stiffness and predicts new-onset cardiovascular events, making it a useful tool for the measurement of vascular aging and associated cardiovascular risk.

Simulation of a novel, non-invasive radiation detector to measure the arterial input function for dynamic positron emission tomography.

Dynamic positron emission tomography (dPET) is a nuclear medicine imaging technique providing functional images for organs of interest with applications in oncology, cardiology, and drug discovery. This technique requires the acquisition of the time-course arterial plasma activity concentration, called the arterial input function (AIF), which is conventionally acquired via arterial bloodsampling. The aim of this study was to (A) optimize the geometry for a novel and cost efficient non-invasive detector called NID designed to measure the AIF for dPET scans through Monte Carlo simulations and (B) develop a clinical data analysis chain to successfully separate the arterial component of a simulated AIF signal from the venouscomponent. The NID was optimized by using an in-house Geant4-based software package. The sensitive volume of the NID consists of a band of 10 cm long and 1mm in diameter scintillating fibers placed over a wrist phantom. The phantom was simulated as a cylinder, 10 cm long and 6.413 cm in diameter comprised of polyethylene with two holes placed through it to simulate the patient's radial artery and vein. This phantom design was chosen to match the wrist phantom used in our previous proof of concept work. Two geometries were simulated with different arrangements of scintillating fibers. The first design used a single layer of 64 fibers. The second used two layers, an inner layer with 29 fibers and an outer layer with 30 fibers. Four positron emitting radioisotopes were simulated: 18 F, 11 C, 15 O, and 68 Ga with 100 million simulated decay events per run. The total and intrinsic efficiencies of both designs were calculated as well as the full width half maximum (FWHM) of the signal. In addition, contribution by the annihilation photons versus positrons to the signal was investigated. The results obtained from the two simulated detector models were compared. A clinical data analysis chain using an expectation maximization maximum likelihood algorithm was tested. This analysis chain will be used to separate arterial counts from the totalsignal. The second NID design with two layers of scintillating fibers had a higher efficiency for all simulations with a maximum increase of 17% total efficiency for 11 C simulation. All simulations had a significant annihilation photon contribution. The signal for 18 F and 11 C was almost entirely due to photons. The clinical data analysis chain was within 1% of the true value for 434 out of 440 trials. Further experimental studies to validate these simulations will berequired. The design of the NID was optimized and its efficiency increased through Monte Carlo simulations. A clinical data analysis chain was successfully developed to separate the arterial component of an AIF signal from the venous component. The simulations show that the NID can be used to accurately measure the AIF non-invasively for dPETscans.

Plasma Metabolome Alterations Discriminate between COVID-19 and Non-COVID-19 Pneumonia.

Pneumonia is a common cause of morbidity and mortality and is most often caused by bacterial pathogens. COVID-19 is characterized by lung infection with potential progressive organ failure. The systemic consequences of both disease on the systemic blood metabolome are not fully understood. The aim of this study was to compare the blood metabolome of both diseases and we hypothesize that plasma metabolomics may help to identify the systemic effects of these diseases. Therefore, we profiled the plasma metabolome of 43 cases of COVID-19 pneumonia, 23 cases of non-COVID-19 pneumonia, and 26 controls using a non-targeted approach. Metabolic alterations differentiating the three groups were detected, with specific metabolic changes distinguishing the two types of pneumonia groups. A comparison of venous and arterial blood plasma samples from the same subjects revealed the distinct metabolic effects of pulmonary pneumonia. In addition, a machine learning signature of four metabolites was predictive of the disease outcome of COVID-19 subjects with an area under the curve (AUC) of 86 ± 10 %. Overall, the results of this study uncover systemic metabolic changes that could be linked to the etiology of COVID-19 pneumonia and non-COVID-19 pneumonia.

RF12 | PSUN106 Quantifying Liver and Brain Levels of 11β-hydroxysteroid Dehydrogenase Type 1 in Obesity Using Positron Emission Tomography Imaging

Abstract Objectives Cortisol is known to promote adipocyte differentiation and maturation, and prolonged exposure to excess cortisol contributes to the development of obesity and metabolic dysregulation. The intracellular 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme catalyzes the conversion of inactive cortisone to active cortisol. Recently, we demonstrated reduced brain 11β-HSD1 levels in vivo with increasing body mass index (BMI), using positron emission tomography (PET) radioligands [11C]- and [18F]AS2471907(1). PET imaging can simultaneously quantify uptake in multiple organs (e.g., liver/brain). [18F]AS2471907 has high uptake and specific binding in the brain and liver(2). Liver and brain 11β-HSD1 measured by PET imaging may help elucidate the roles of cortisol activation in the setting of metabolic dysregulation. Thus, we performed PET imaging studies to examine 11β-HSD1 levels in the liver and brain. Methods Nine individuals (5F/4M) with a range of BMIs (22.6-34.4 kg/m2) underwent a 90 min PET/CT acquisition with arterial plasma sampling after injection of [18F]AS2471907. Regions-of-interest (ROI) for the liver were manually drawn on a summed PET image (60-90 min). Seventeen brain ROIs were selected from the anatomical automatic labeling (AAL) template and applied to the dynamic PET images to generate time-activity-curves (TACs). Brain volume of distribution (VT, mL/cm3), the target tissue to plasma ratio of radioligand at equilibrium, was estimated for each ROI using the multilinear analysis-1 method with plasma input function. Mean whole-brain VT values were calculated by averaging all ROIs. Given the appearance of irreversible kinetics in the liver, Ki (min-1), the rate of irreversible tracer uptake, was calculated using the Patlak method. Results Qualitative brain and liver uptake was assessed by examining a summed PET image (SUV 60-90min). The parent fraction in plasma was 88±1% at 90 min, indicating negligible plasma radiolabeled-metabolites contributing the measured signal in the liver. Kinetic modeling estimates demonstrated decreasing whole brain VT with increasing BMI (R2=0.53), similar to our previously published study examining only brain in a larger cohort(1). Patlak methods provided good estimates of Ki. In an opposite manner from the brain, correlations seen in the liver using Ki were positively correlated with BMI (R2=0.57). Conclusions These preliminary studies suggest obesity is associated with increased 11β-HSD1 levels in the liver but decreased 11β-HSD1 levels in the brain. Clinically, liver specific 11β-HSD1 inhibitors may prove beneficial in treating metabolic sequalae of obesity such non-alcoholic fatty liver disease (NAFLD) by inhibiting activity of higher 11β-HSD1 levels. Further studies in NAFLD and obesity are necessary to determine appropriate populations that would benefit from 11β-HSD1 inhibitors and longitudinal in vivo PET imaging to help inform development of future therapeutics.

Dual pathway inhibition as compared to acetylsalicylic acid monotherapy in relation to endothelial function in peripheral artery disease, a phase IV clinical trial.

ObjectiveDual pathway inhibition (DPI) by combining acetylsalicylic acid (ASA) with low-dose rivaroxaban has been shown to reduce cardiovascular events in patients with peripheral arterial disease (PAD) when compared to ASA monotherapy. A potential explanation is that inhibition of factor Xa improves endothelial function through crosstalk between coagulation and inflammatory pathways, subsequently attenuating the occurrence of cardiovascular events. We hypothesize that the addition of rivaroxaban to ASA in PAD patients leads to improved endothelial function.DesignAn investigator-initiated, multicentre trial investigating the effect of DPI on endothelial function.MethodsPatients, diagnosed with PAD, were enrolled in two cohorts: cohort A (Rutherford I-III) and cohort B (Rutherford IV-VI). Participants received ASA monotherapy for a 4-weeks run-in period, followed by 12 weeks of DPI. Macro- and microvascular endothelial dysfunction were studied by measuring carotid artery reactivity upon sympathetic stimulus and by measuring plasma endothelin-1 concentrations, respectively. All measurements were performed during the use of ASA (baseline) and after 12 weeks of DPI.Results159 PAD patients (111 cohort A, 48 cohort B) were enrolled. Twenty patients discontinued study drugs early. Carotid artery constriction upon sympathetic stimulation at baseline (ASA) and after 12 weeks of DPI was similar in the total group, 22.0 vs. 22.7% (p = 1.000), and in the subgroups (Cohort A 22.6 vs. 23.7%, p = 1.000; cohort B 20.5 vs. 20.5%, p = 1.000), respectively. The mean concentration of plasma endothelin-1 at baseline and after 12 weeks of DPI did not differ, 1.70 ± 0.5 vs. 1.66 ± 0.64 pmol/L (p = 0.440) in the total group, 1.69 ± 0.59 vs. 1.62 ± 0.55 pmol/L in cohort A (p = 0.202), and 1.73 ± 0.53 vs. 1.77 ± 0.82 pmol/L in cohort B (p = 0.682), respectively.ConclusionMacro- and microvascular endothelial dysfunction, as reflected by carotid artery reactivity and plasma endothelin-1 concentrations, are not influenced in PAD patients by addition of low-dose rivaroxaban to ASA monotherapy for 12 weeks.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04218656.

The effects of Aronia berry (poly)phenol supplementation on arterial function and the gut microbiome in middle aged men and women: Results from a randomized controlled trial

Berry (poly)phenol consumption has been associated with cardioprotective benefits, however little is known on the role the gut microbiome may play on such health benefits. Our objective was to investigate the effects of aronia berry (poly)phenol consumption on cardiometabolic health and gut microbiome richness and composition in prehypertensive middle-aged men and women. A total of 102 prehypertensive participants were included in a parallel 12-week randomized double-blind placebo-controlled trial. Volunteers were randomly allocated to daily consume an encapsulated (poly)phenol-rich aronia berry extract (Aronia, n=51) or a matched maltodextrin placebo (Control, n=51). Blood pressure (BP) and arterial function (office and 24h), endothelial function (measured as flow-mediated dilation), serum biochemistry (including blood lipids), plasma and urine (poly)phenol metabolites as well as gut microbiome composition through shotgun metagenomic sequencing were monitored over the study period. Relationships between vascular outcomes, (poly)phenol metabolites and gut microbiome were investigated using an integrated multi-levels approach. A significant improvement in arterial indices measured as augmentation index (AIx) and pulse wave velocity (PWV) was found in the Aronia compared to Control group (awake Δ PWV=-0.24m/s; 95% CI:-0.79,-0.01m/s, P<0.05; 24h peripheral Δ AIx=-6.8;-11.2,-2.3, %, P=0.003; 24h central Δ AIx=-3.3;-5.5,-1.0, %, P=0.006). No changes in BP, endothelial function or blood lipids were found following the intervention. Consumption of aronia (poly)phenols led to a significant increase in gut microbiome gene richness and in the abundance of butyrate-producing species such as Lawsonibacter asaccharolyticus and Intestinimonas butyriciproducens species, compared to Control group. Results from an approach including metabolomic, metagenomic and clinical outcomes highlighted associations between aronia-derived phenolic metabolites, arterial stiffness, and gut microbiome. Aronia berry (poly)phenol consumption improved arterial function in prehypertensive middle-aged individuals, possibly via modulation of gut microbiome richness and composition based on the associations observed between these parameters. The National Institutes of Health (NIH)-randomized trial records held on the NIH ClinicalTrials.gov website (NCT03434574). Aronia Berry Consumption on Blood Pressure.

Effects of intravenous clonidine on hemodynamics and plasma cortisol level during laparoscopic urological surgeries in a tertiary care hospital

Background: Laparoscopic urologic surgeries causes rise in Blood pressure and heart rate. Maintenance of hemodynamics is an essential part of anaesthetic management. Aims and Objectives: The aim of the study was to observe the effects of intravenous clonidine on heart rate (HR) and mean arterial pressure (MAP) and plasma cortisol level during laparoscopic surgeries. Materials and Methods: In this ethical committee approved double-blind prospective interventional study, 50 adult patients of both sexes with ASA I and II were randomly allocated to two groups: Group C (3 mcg/kg Clonidine in 20 ml of Normal saline) and Group P (20 ml Normal saline). HR and MAP were recorded at different time intervals and blood samples were drawn before induction and after reversal from general anesthesia. Results: In Group P there was a significant increase in variables during intubation, pneumoperitoneum and release of gas from the abdomen (P&lt;0.001). In Group C mean plasma cortisol level increased from 19.36±1.49 (before induction) to 28.60±1.21 (after reversal) and in Group P from 19.33±1.30 to 32.28±1.66. Conclusion: Clonidine may be a suitable and safe medication to attenuate hemodynamic stress response during laparoscopic surgeries.

Time-dependent relationships between exercise training-induced changes in nitric oxide production and hormone regulation.

Aerobic exercise training (AT) reduces aging-induced deterioration of arterial stiffness and is associated with arterial nitric oxide (NO) production via changes in apelin and adropin as NO-upregulating hormones, and asymmetric dimethylarginine (ADMA) as a NO-downregulating hormone. However, the time-dependent effects of AT on NO production via NO-regulating hormones remain unclear. This study aimed to determine whether AT-induced changes in the time course of NO production via NO-regulating hormones, participate in the AT-induced improvement in central arterial stiffening with advancing age. Methods: Thirty-three healthy Japanese middle-aged and older subjects (67±1years) were randomly divided into two groups: AT intervention and sedentary controls. Subjects in the training group completed 8-week of AT. Carotid-femoral pulse wave velocity as an index of central arterial stiffness and plasma nitrate/nitrite levels significantly changed from baseline at weeks 6 (P<0.05) and 8 (P<0.01). Interestingly, circulating apelin and adropin levels gradually increased during AT intervention and significantly increased from baseline at weeks 4, 6, and 8 (P<0.01). Additionally, plasma ADMA levels significantly decreased at 8-week AT intervention (P<0.01). These results suggest that AT-induced changes in the time course of NO production via NO-regulating hormones may participate in AT-induced improvements of central arterial stiffening with advancing age.

The Effect of Glucagon on Protein Catabolism During Insulin Deficiency: Exchange of Amino Acids Across Skeletal Muscle and the Splanchnic Bed.

Transient insulin deprivation with concurrent hyperglucagonemia is a catabolic state that can occur in type 1 diabetes. To evaluate glucagon's catabolic effect in the setting of its glucogenic effect, we measured the regional exchanges of amino acid metabolites (amino-metabolites) across muscle and splanchnic beds in 16 healthy humans during either somatostatin followed by glucagon or saline infusion alone. Despite a twofold or greater increase in the regional exchange of amino-metabolites by glucagon, whole-body kinetics and concentrations of amino acids (AA) remained stable. Glucagon increased the splanchnic uptake of not only gluconeogenic but also essential (EAA) AA while increasing their release from the muscle bed. Regional tracer-based kinetics and 3-methylhistidine release indicate that EAA release from muscle is likely caused by reduced protein synthesis rather than increased protein degradation. Furthermore, many metabolites known to affect insulin action and metabolism were altered by hyperglucagonemia including increase in branched-chain AA and keto acids of leucine and isoleucine in arterial plasma. Further, an increase in arterial concentrations of α-aminoadipic acid arising from increased conversion from lysine in the splanchnic bed was noted. These results demonstrate that hyperglucagonemia during hypoinsulinemia increases net muscle protein catabolism and substantially increases the exchange of amino metabolites across splanchnic and muscle beds.

Oral digoxin effects on exercise performance, K+ regulation and skeletal muscle Na+ ,K+ -ATPase in healthy humans.

We investigated whether digoxin lowered muscle Na+,K+‐ATPase (NKA), impaired muscle performance and exacerbated exercise K+ disturbances. Ten healthy adults ingested digoxin (0.25 mg; DIG) or placebo (CON) for 14 days and performed quadriceps strength and fatiguability, finger flexion (FF, 105%peak‐workrate, 3 × 1 min, fourth bout to fatigue) and leg cycling (LC, 10 min at 33% VO2peak and 67% VO2peak, 90% VO2peak to fatigue) trials using a double‐blind, crossover, randomised, counter‐balanced design. Arterial (a) and antecubital venous (v) blood was sampled (FF, LC) and muscle biopsied (LC, rest, 67% VO2peak, fatigue, 3 h after exercise). In DIG, in resting muscle, [3H]‐ouabain binding site content (OB‐Fab) was unchanged; however, bound‐digoxin removal with Digibind revealed total ouabain binding (OB+Fab) increased (8.2%, P = 0.047), indicating 7.6% NKA–digoxin occupancy. Quadriceps muscle strength declined in DIG (−4.3%, P = 0.010) but fatiguability was unchanged. During LC, in DIG (main effects), time to fatigue and [K+]a were unchanged, whilst [K+]v was lower (P = 0.042) and [K+]a‐v greater (P = 0.004) than in CON; with exercise (main effects), muscle OB‐Fab was increased at 67% VO2peak (per wet‐weight, P = 0.005; per protein P = 0.001) and at fatigue (per protein, P = 0.003), whilst [K+]a, [K+]v and [K+]a‐v were each increased at fatigue (P = 0.001). During FF, in DIG (main effects), time to fatigue, [K+]a, [K+]v and [K+]a‐v were unchanged; with exercise (main effects), plasma [K+]a, [K+]v, [K+]a‐v and muscle K+ efflux were all increased at fatigue (P = 0.001). Thus, muscle strength declined, but functional muscle NKA content was preserved during DIG, despite elevated plasma digoxin and muscle NKA–digoxin occupancy, with K+ disturbances and fatiguability unchanged. Key points The Na+,K+‐ATPase (NKA) is vital in regulating skeletal muscle extracellular potassium concentration ([K+]), excitability and plasma [K+] and thereby also in modulating fatigue during intense contractions. NKA is inhibited by digoxin, which in cardiac patients lowers muscle functional NKA content ([3H]‐ouabain binding) and exacerbates K+ disturbances during exercise.In healthy adults, we found that digoxin at clinical levels surprisingly did not reduce functional muscle NKA content, whilst digoxin removal by Digibind antibody revealed an ∼8% increased muscle total NKA content.Accordingly, digoxin did not exacerbate arterial plasma [K+] disturbances or worsen fatigue during intense exercise, although quadriceps muscle strength was reduced.Thus, digoxin treatment in healthy participants elevated serum digoxin, but muscle functional NKA content was preserved, whilst K+ disturbances and fatigue with intense exercise were unchanged. This resilience to digoxin NKA inhibition is consistent with the importance of NKA in preserving K+ regulation and muscle function.

Physicochemical Analysis of Mixed Venous and Arterial Blood Acid-Base State in Horses at Core Temperature during and after Moderate-Intensity Exercise.

Simple SummaryThe purposes of the present study were to determine the effect of core body temperature on acid-base variables and determine the origins of acid-base changes in the arterial and mixed venous blood of horses during exercise and recovery. Moderate intensity exercise resulted in an increase in body temperature that, in addition to exercise, affected acid-base status and gas partial pressures. Moderate intensity exercise resulted in a mild alkalosis that had markedly different origins in arterial blood than in mixed venous blood, and this was affected by the increase in core temperature during exercise and its resolution during recovery. In order to fully understand how acid-base status changes during exercise and recovery, it is importance to quantify the changes in both arterial and mixed venous blood, with adjustment to core temperature. Acid-base assessments using jugular vein blood samples are limited in comparison.The present study determined the independent contributions of temperature, strong ion difference ([SID]), total weak acid concentration ([Atot]) and PCO2 to changes in arterial and mixed venous [H+] and total carbon dioxide concentration ([TCO2]) during 37 min of moderate intensity exercise (~50% of heart rate max) and the first 60 min of recovery. Six horses were fitted with indwelling carotid and pulmonary artery (PA) catheters, had PA temperature measured, and had blood samples withdrawn for immediate analysis of plasma ion and gas concentrations. The increase in core temperature during exercise (+4.5 °C; p < 0.001) significantly (p < 0.05) increased PO2, PCO2, and [H+], but without a significant effect on [TCO2] (p > 0.01). The physicochemical acid-base approach was used to determine contributions of independent variables (except temperature) to the changes in [H+] and [TCO2]. In both arterial and venous blood, there was no acidosis during exercise and recovery despite significant (p < 0.05) increases in [lactate] and in venous PCO2. In arterial blood plasma, a mild alkalosis with exercise was due to primarily to a decrease in PCO2 (p < 0.05) and an increase in [SID] (p < 0.1). In venous blood plasma, a near absence of change in [H+] was due to the acidifying effects of increased PCO2 (p < 0.01) being offset by the alkalizing effects of increased [SID] (p < 0.05). The effect of temperature on PO2 (p < 0.001) resulted in an increased arterio-venous PO2 difference (p < 0.001) that would facilitate O2 transfer to contracting muscle. The simultaneous changes in the PCO2 and the concentrations of the other independent acid-base variables (contributions from individual strong and weak ions as manifest in [SID] and [Atot]) show complex, multilevel control of acid-base states in horses performing even moderate intensity exercise. Correction of acid-base variables to core body temperature presents a markedly different physiological response to exercise than that provided by variables measured and presented at an instrument temperature of 37 °C.

Higher and lower caffeine consumers: exercise performance and biological responses during a simulated soccer-game protocol following caffeine ingestion.

Research on whether caffeine habituation reduces its ergogenicity is scarce and conflicting. The purpose of the present study was to examine the influence of habitual caffeine consumption on exercise performance and biological responses during a simulated soccer-game protocol following acute caffeine ingestion. Twenty professional male soccer players were categorized as higher (n = 9) or lower caffeine consumers (n = 11) after answering a validated questionnaire. Participants performed a simulated treadmill soccer-game protocol on treadmill following either caffeine (6mg kg-1) or placebo ingestion, during which several variables were evaluated. Time to exhaustion, countermovement jump height, mean arterial pressure, heart rate, plasma glucose, and lactate were higher (P ≤ 0.001), while rating of perceived exertion (RPE) was lower (P = 0.002), following caffeine compared to placebo ingestion, with no differences between groups (P > 0.05). Plasma non-esterified fatty acids exhibited a higher response to caffeine in the higher vs lower caffeine consumers. Reaction time, plasma glycerol and epinephrine, carbohydrate and fat oxidation, and energy expenditure were not affected by caffeine (P > 0.05). Caffeine ingestion largely improved cardiovascular and neuromuscular performance, while reducing RPE, in both higher and lower caffeine consuming athletes during prolonged intermitted exercise to exhaustion.

Innate immune cells and myelin profile in multiple sclerosis: a multi-tracer PET/MR study.

Neuropathological studies have demonstrated distinct profiles of microglia activation and myelin injury among different multiple sclerosis (MS) phenotypes and disability stages. PET imaging using specific tracers may uncover the in vivo molecular pathology and broaden the understanding of the disease heterogeneity. We used the 18-kDa translocator protein (TSPO) tracer (R)-[11C]PK11195 and [11C]PIB PET images acquired in a hybrid PET/MR 3T system to characterize, respectively, the profile of innate immune cells and myelin content in 47 patients with MS compared to 18 healthy controls (HC). For the volume of interest (VOI)-based analysis of the dynamic data, (R)-[11C]PK11195 distribution volume (VT) was determined for each subject using a metabolite-corrected arterial plasma input function while [11C]PIB distribution volume ratio (DVR) was estimated using a reference region extracted by a supervised clustering algorithm. A voxel-based analysis was also performed using Statistical Parametric Mapping. Functional disability was evaluated by the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Symbol Digit Modality Test (SDMT). In the VOI-based analysis, [11C]PIB DVR differed between patients and HC in the corpus callosum (P = 0.019) while no differences in (R)-[11C]PK11195 VT were observed in patients relative to HC. Furthermore, no correlations or associations were observed between both tracers within the VOI analyzed. In the voxel-based analysis, high (R)-[11C]PK11195 uptake was observed diffusively in the white matter (WM) when comparing the progressive phenotype and HC, and lower [11C]PIB uptake was observed in certain WM regions when comparing the relapsing-remitting phenotype and HC. None of the tracers were able to differentiate phenotypes at voxel or VOI level in our cohort. Linear regression models adjusted for age, sex, and phenotype demonstrated that higher EDSS was associated with an increased (R)-[11C]PK11195 VT and lower [11C]PIB DVR in corpus callosum (P = 0.001; P = 0.023), caudate (P = 0.015; P = 0.008), and total T2 lesion (P = 0.007; P = 0.012), while better cognitive scores in SDMT were associated with higher [11C]PIB DVR in the corpus callosum (P = 0.001), and lower (R)-[11C]PK11195 VT (P = 0.013). Widespread innate immune cells profile and marked loss of myelin in T2 lesions and regions close to the ventricles may occur independently and are associated with disability, in both WM and GM structures.

Modeling venous plasma samples in [18F] FDG PET studies: a nonlinear mixed-effects approach.

The gold-standard approach to quantifying dynamic PET images relies on using invasive measures of the arterial plasma tracer concentration. An attractive alternative is to employ an image-derived input function (IDIF), corrected for spillover effects and rescaled with venous plasma samples. However, venous samples are not always available for every participant. In this work, we used the nonlinear mixed-effects modeling approach to develop a model which infers venous tracer kinetics by using venous samples obtained from a population of healthy individuals and integrating subject-specific covariates. Population parameters (fixed effects), their between-subject variability (random effects), and the effects of covariates were estimated. The selected model will allow to reliably infer venous tracer kinetics in subjects with missing measurements. Clinical relevance - The derived model will be relevant for fully noninvasive dynamic FDG PET quantification using image-derived input functions in both healthy and patient populations when hemodynamics is not impaired.

The Comparative Effect of Different Timings of Whole Body Cryotherapy Treatment With Cold Water Immersion for Post-Exercise Recovery.

Despite several established benefits of Whole Body Cryotherapy (WBC) for post-exercise recovery, there is a scarcity of research which has identified the optimum WBC protocol for this purpose. This study investigated the influence of WBC treatment timing on physiological and functional responses following a downhill running bout. An additional purpose was to compare such responses with those following cold water immersion (CWI), since there is no clear consensus as to which cold modality is more effective for supporting athletic recovery. Thirty-three male participants (mean ± SD age 37.0 ± 13.3 years, height 1.76 ± 0.07 m, body mass 79.5 ± 13.7 kg) completed a 30 min downhill run (15% gradient) at 60% VO2 max and were then allocated into one of four recovery groups: WBC1 (n = 9) and WBC4 (n = 8) underwent cryotherapy (3 min, −120°C) 1 and 4 h post-run, respectively; CWI (n = 8) participants were immersed in cold water (10 min, 15°C) up to the waist 1 h post-run and control (CON, n = 8) participants passively recovered in a controlled environment (20°C). Maximal isometric leg muscle torque was assessed pre and 24 h post-run. Blood creatine kinase (CK), muscle soreness, femoral artery blood flow, plasma IL-6 and sleep were also assessed pre and post-treatment. There were significant decreases in muscle torque for WBC4 (10.9%, p = 0.04) and CON (11.3% p = 0.00) and no significant decreases for WBC1 (5.6%, p = 0.06) and CWI (5.1%, p = 0.15). There were no significant differences between groups in muscle soreness, CK, IL-6 or sleep. Femoral artery blood flow significantly decreased in CWI (p = 0.02), but did not differ in other groups. WBC treatments within an hour may be preferable for muscle strength recovery compared to delayed treatments; however WBC appears to be no more effective than CWI. Neither cold intervention had an impact on inflammation or sleep.