Combining Near-Infrared Spectroscopy and Heart Rate Variability Derived Thresholds to Estimate the Critical Intensity of Exercise.

ABSTRACT: Fleitas-Paniagua, PR, de Almeida Azevedo, R, Trpcic, M, Murias, JM, and Rogers, B. Combining near-infrared spectroscopy and heart rate variability derived thresholds to estimate the critical intensity of exercise. J Strength Cond Res 38(1): e16-e24, 2024-Critical intensity determination often requires costly tools and several testing sessions. Alternative approaches display relatively large individual variation. Therefore, simpler estimations with improved precision are needed. This study evaluated whether averaging the heart rate (HR) and oxygen uptake (V̇O 2 ) responses associated with the muscle deoxyhemoglobin concentration breakpoint ([HHb] BP ) and the heart rate variability (HRV) given by the detrended fluctuation analysis second threshold (HRVT2) during ramp incremental (RI) test improved the accuracy of identifying the HR and V̇O 2 at the respiratory compensation point (RCP). Ten female and 11 male recreationally trained subjects performed a 15 W·minute -1 RI test. Gas exchange, near-infrared spectroscopy (NIRS), and RR interval were recorded to assess the RCP, [HHb] BP , and HRVT2. Heart rate (mean ± SD : 158 ± 14, 156 ± 13, 160 ± 14 and, 158 ± 12 bpm) and V̇O 2 (3.08 ± 0.69, 2.98 ± 0.58, 3.06 ± 0.65, and 3.02 ± 0.60 L·minute -1 ) at the RCP, [HHb] BP , HRVT2, and HRVT2&[HHb] BP average (H&H Av ), respectively, were not significantly different ( p > 0.05). The linear relationship between H&H Av and RCP was higher compared with the relationship between [HHb] BP vs RCP and HRVT2 vs RCP for both HR ( r = 0.85; r = 0.73; r = 0.79, p > 0.05) and V̇O 2 ( r = 0.94; r = 0.93; r = 0.91, p > 0.05). Intraclass correlation between RCP, [HHb] BP , HRVT2, and H&H AV was 0.93 for V̇O 2 and 0.79 for HR. The [HHb] BP and the HRVT2 independently provided V̇O 2 and HR responses that strongly agreed with those at the RCP. Combining [HHb] BP and the HRVT2 resulted in estimations of the V̇O 2 and HR at the RCP that displayed smaller variability compared with each modality alone.

Positive allosteric modulators of the α7 nicotinic acetylcholine receptor: SAR investigation around PNU-120596.

The α7 nicotinic acetylcholine receptor is a calcium permeable, ligand-gated ion channel that modulates synaptic transmission in the hippocampus, thalamus, and cerebral cortex. Previously disclosed work described PNU-120596 that acts as a powerful positive allosteric modulator of the α7 nicotinic acetylcholine receptor. The initial structure-activity relationships around PNU-120596 were gleaned from screening a large thiazole library. Independent systematic examination of the aryl and heteroaryl groups resulted in compounds with enhanced potency and improved physico-chemical properties culminating in the identification of 16 (PHA-758454). In the presence of acetylcholine, 16 enhanced evoked currents in rat hippocampal neurons. In a rat model of impaired sensory gating, treatment with 16 led to a reversal of the gating deficit in a dose-dependent manner. These results demonstrate that aryl heteroaryl ureas, like compound 16, may be useful tools for continued exploration of the unique biology of the α7 nicotinic acetylcholine receptor.

Validation of a non-linear index of heart rate variability to determine aerobic and anaerobic thresholds during incremental cycling exercise in women.

Studies highlight the usage of non-linear time series analysis of heart rate variability (HRV) using the short-term scaling exponent alpha1 of Detrended Fluctuation Analysis (DFA-alpha1) during exercise to determine aerobic and anaerobic thresholds. The present study aims to further verify this approach in women. Gas exchange and HRV data were collected from 26 female participants with different activity levels. Oxygen uptake (VO2) and heart rate (HR) at first (VT1) and second ventilatory thresholds (VT2) were compared with DFA-alpha1-based thresholds 0.75 (HRVT1) and 0.50 (HRVT2). Results: VO2 at VT1 and VT2 were 25.2 ml/kg/min (± 2.8) and 31.5 ml/kg/min (± 3.6) compared with 26.5 ml/kg/min (± 4.0) and 31.9 ml/kg/min (± 4.5) for HRVT1 and HRVT2, respectively (ICC3,1 = 0.77, 0.84; r = 0.81, 0.86, p < 0.001). The mean HR at VT1 was 147 bpm (± 15.6) and 167 bpm (± 12.7) for VT2, compared with 152 bpm (± 15.5) and 166 bpm (± 13.2) for HRVT1 and HRVT2, respectively (ICC3,1 = 0.87, 0.90; r = 0.87, 0.90, p < 0.001). Bland-Altman analysis for VT1 vs. HRVT1 showed a mean difference of - 1.3 ml/kg/min (± 2.4; LoA: 3.3, - 6.0 ml/kg/min) for VO2 and of - 4.7 bpm (± 7.8; LoA: 10.6, - 20.0 bpm) for HR. VT2 vs. HRVT2 showed a mean difference of - 0.4 ml/kg/min (± 2.3; LoA: 4.1, - 4.9 ml/kg/min) for VO2 and 0.5 bpm (± 5.7; LoA: 11.8, - 10.8 bpm) for HR. DFA-alpha1-based thresholds showed good agreement with traditionally used thresholds and could be used as an alternative approach for marking organismic transition zones for intensity distribution in women.

Correlation properties of heart rate variability to assess the first ventilatory threshold and fatigue in runners.

PURPOSE: The short-term scaling exponent alpha1 of detrended fluctuation analysis (DFA-a1) of heart rate variability (HRV) has shown potential to delineate the first ventilatory threshold (VT1). The aims of this study were to investigate the accuracy of this method for VT1 determination in runners using a consumer grade chest belt and to explore the effects of acute fatigue. METHODS: We compared oxygen uptake (V̇O2) and heart rate (HR) at gas exchange VT1 to V̇O2 and HR at a DFA-a1 value of 0.75. Gas exchange and HRV data were obtained from 14 individuals during a treadmill run involving two incremental ramps. Agreement was assessed using Bland-Altman analysis and linear regression. RESULTS: Bland-Altman analysis between gas exchange and HRV V̇O2 and HR at VT1 during the first ramp showed a mean (95% limits of agreement) bias of -0.5 (-6.8 to 5.8) ml∙kg-1∙min-1, and -0.9 (-12.2 to 10.5) beats∙min-1, with R2 of 0.83 and 0.56, respectively. During the second ramp, the differences were -7.3 (-18.1 to 3.5) ml∙kg-1∙min-1 and -12.3 (-30.4 to 5.9) beats∙min-1, with R2 of 0.62 and 0.43, respectively. CONCLUSION: A chest-belt derived DFA-a1 of 0.75 is closely related to gas exchange VT1, with the variability in accuracy at an individual level being similar to gas exchange methods. This suggests this to be a useful method for exercise intensity demarcation. The altered relationship during the second ramp indicates that DFA-a1 is only able to accurately demarcate exercise intensity thresholds in a non-fatigued state, but also opens opportunities for fatigue-based training prescription.

The first ventilatory threshold determined with a nonlinear method (DFA-a1) to analyse heart rate variability derived from a chest-belt shows close agreement to the gas exchange first ventilatory threshold, with the variability in accuracy at an individual level being similar to gas exchange methods. This suggests this to be a useful method for exercise intensity demarcation.The altered relationship during fatigue indicates that DFA-a1 is only able to accurately demarcate exercise intensity thresholds in a non-fatigued state, but this also opens opportunities for fatigue-based training prescription.

Improved Estimation of Exercise Intensity Thresholds by Combining Dual Non-Invasive Biomarker Concepts: Correlation Properties of Heart Rate Variability and Respiratory Frequency.

Identifying exercise intensity boundaries has been shown to be important during endurance training for performance enhancement and rehabilitation. Unfortunately, even though surrogate markers show promise when assessed on a group level, substantial deviation from gold standards can be present in each individual. The aim of this study was to evaluate whether combining two surrogate intensity markers improved this agreement. Electrocardiogram (ECG) and gas exchange data were obtained from 21 participants who performed an incremental cycling ramp to exhaustion and evaluated for first (VT1) and second (VT2) ventilatory thresholds, heart rate (HR) variability (HRV), and ECG derived respiratory frequency (EDR). HRV thresholds (HRVT) were based on the non-linear index a1 of a Detrended Fluctuation Analysis (DFA a1) and EDR thresholds (EDRT) upon the second derivative of the sixth-order polynomial of EDR over time. The average of HRVT and EDRT HR was set as the combined threshold (Combo). Mean VT1 was reached at a HR of 141 ± 15, HRVT1 at 152 ± 14 (p < 0.001), EDRT1 at 133 ± 12 (p < 0.001), and Combo1 at 140 ± 13 (p = 0.36) bpm with Pearson's r of 0.83, 0.78, and 0.84, respectively, for comparisons to VT1. A Bland-Altman analysis showed mean biases of 8.3 ± 7.9, -8.3 ± 9.5, and -1.7 ± 8.3 bpm, respectively. A mean VT2 was reached at a HR of 165 ± 13, HRVT2 at 167 ± 10 (p = 0.89), EDRT2 at 164 ± 14 (p = 0.36), and Combo2 at 164 ± 13 (p = 0.59) bpm with Pearson's r of 0.58, 0.95, and 0.94, respectively, for comparisons to VT2. A Bland-Altman analysis showed mean biases of -0.3 ± 8.9, -1.0 ± 4.6, and -0.6 ± 4.6 bpm, respectively. Both the DFA a1 and EDR intensity thresholds based on HR taken individually had moderate agreement to targets derived through gas exchange measurements. By combining both non-invasive approaches, there was improved correlation, reduced bias, and limits of agreement to the respective corresponding HRs at VT1 and VT2.

The Between-Day Reliability of Correlation Properties of Heart Rate Variability During Running.

The short-term scaling exponent of detrended fluctuation analysis (DFA-a1) of heart rate variability may be a helpful tool to assess autonomic balance as a prelude to daily, individualized training. For this concept to be useful, between-session reliability should be acceptable. The aim of this study was to explore the reliability of DFA-a1 during a low-intensity exercise session in both a non-fatigued and a fatigued condition in healthy males and females. Ten participants completed two sessions with each containing an exhaustive treadmill ramp protocol. Before and after the fatiguing ramp, a standardized submaximal low-intensity exercise bout was performed during which DFA-a1, heart rate, and oxygen consumption (VO2) were measured. We compared between-session reliability of all metrics prior to the ramps (i.e., non-fatigued status) and after the first ramp (i.e., fatigued status). Intraclass correlation coefficients (ICC) with 95% confidence intervals (CI), the standard error of measurement, and the smallest worthwhile change (SWC) were determined. The ICC and SWC pre fatiguing ramp were 0.85 (95% CI 0.39-0.96) and 5.5% for DFA-a1, 0.85 (0.38-0.96) and 2.2% for heart rate, and 0.84 (0.31-0.96) and 3.1% for VO2. Post fatiguing ramp, the ICC and SWC were 0.55 (0.00-0.89) and 7.9% for DFA-a1, 0.91 (0.62-0.98) and 1.6% for heart rate, and 0.80 (0.17-0.95) and 3.0% for VO2. DFA-a1 shows generally acceptable to good between-session reliability with a SWC of 0.06 and 0.07 (5.5-7.9%) during non-fatigued and fatigued conditions. This suggests that this metric may be useful to inform on training readiness.

Effects of Troponoids on Mitochondrial Function and Cytotoxicity.

The α-hydroxytropolones (αHTs) are troponoid inhibitors of hepatitis B virus (HBV) replication that can target HBV RNase H with submicromolar efficacies. αHTs and related troponoids (tropones and tropolones) can be cytotoxic in cell lines as measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays that assess mitochondrial function. Previous studies suggest that tropolones induce cytotoxicity through inhibition of mitochondrial respiration. Therefore, we screened 35 diverse troponoids for effects on mitochondrial function, mitochondrial/nuclear genome ratios, cytotoxicity, and reactive oxygen species (ROS) production. Troponoids as a class did not inhibit respiration or glycolysis, although the α-ketotropolone subclass interfered with these processes. The troponoids had no impact on the mitochondrial DNA/nuclear DNA ratio after 3 days of compound exposure. The patterns of troponoid-induced cytotoxicity among three hepatic cell lines were similar for all compounds, but three potent HBV RNase H inhibitors were not cytotoxic in primary human hepatocytes. Tropolones and αHTs increased ROS production in cells at cytotoxic concentrations but had no effect at lower concentrations that efficiently inhibit HBV replication. Troponoid-mediated cytotoxicity was significantly decreased upon the addition of the ROS scavenger N-acetylcysteine. These studies show that troponoids can increase ROS production at high concentrations within cell lines, leading to cytotoxicity, but are not cytotoxic in primary hepatocytes. Future development of αHTs as potential therapeutics against HBV may need to mitigate ROS production by altering compound design and/or by coadministering ROS antagonists to ameliorate increased ROS levels.

Estimation of Respiratory Frequency in Women and Men by Kubios HRV Software Using the Polar H10 or Movesense Medical ECG Sensor during an Exercise Ramp.

Monitoring of the physiologic metric, respiratory frequency (RF), has been shown to be of value in health, disease, and exercise science. Both heart rate (HR) and variability (HRV), as represented by variation in RR interval timing, as well as analysis of ECG waveform variability, have shown potential in its measurement. Validation of RF accuracy using newer consumer hardware and software applications have been sparse. The intent of this report is to assess the precision of the RF derived using Kubios HRV Premium software version 3.5 with the Movesense Medical sensor single-channel ECG (MS ECG) and the Polar H10 (H10) HR monitor. Gas exchange data (GE), RR intervals (H10), and continuous ECG (MS ECG) were recorded from 21 participants performing an incremental cycling ramp to failure. Results showed high correlations between the reference GE and both the H10 (r = 0.85, SEE = 4.2) and MS ECG (r = 0.95, SEE = 2.6). Although median values were statistically different via Wilcoxon testing, adjusted median differences were clinically small for the H10 (RF about 1 breaths/min) and trivial for the MS ECG (RF about 0.1 breaths/min). ECG based measurement with the MS ECG showed reduced bias, limits of agreement (maximal bias, -2.0 breaths/min, maximal LoA, 6.1 to -10.0 breaths/min) compared to the H10 (maximal bias, -3.9 breaths/min, maximal LoA, 8.2 to -16.0 breaths/min). In conclusion, RF derived from the combination of the MS ECG sensor with Kubios HRV Premium software, tracked closely to the reference device through an exercise ramp, illustrates the potential for this system to be of practical usage during endurance exercise.

Validity of the Polar H10 Sensor for Heart Rate Variability Analysis during Resting State and Incremental Exercise in Recreational Men and Women.

Heart rate variability (HRV) is frequently applied in sport-specific settings. The rising use of freely accessible applications for its recording requires validation processes to ensure accurate data. It is the aim of this study to compare the HRV data obtained by the Polar H10 sensor chest strap device and an electrocardiogram (ECG) with the focus on RR intervals and short-term scaling exponent alpha 1 of Detrended Fluctuation Analysis (DFA a1) as non-linear metric of HRV analysis. A group of 25 participants performed an exhaustive cycling ramp with measurements of HRV with both recording systems. Average time between heartbeats (RR), heart rate (HR) and DFA a1 were recorded before (PRE), during, and after (POST) the exercise test. High correlations were found for the resting conditions (PRE: r = 0.95, rc = 0.95, ICC3,1 = 0.95, POST: r = 0.86, rc = 0.84, ICC3,1 = 0.85) and for the incremental exercise (r > 0.93, rc > 0.93, ICC3,1 > 0.93). While PRE and POST comparisons revealed no differences, significant bias could be found during the exercise test for all variables (p < 0.001). For RR and HR, bias and limits of agreement (LoA) in the Bland−Altman analysis were minimal (RR: bias of 0.7 to 0.4 ms with LoA of 4.3 to −2.8 ms during low intensity and 1.3 to −0.5 ms during high intensity, HR: bias of −0.1 to −0.2 ms with LoA of 0.3 to −0.5 ms during low intensity and 0.4 to −0.7 ms during high intensity). DFA a1 showed wider bias and LoAs (bias of 0.9 to 8.6% with LoA of 11.6 to −9.9% during low intensity and 58.1 to −40.9% during high intensity). Linear HRV measurements derived from the Polar H10 chest strap device show strong agreement and small bias compared with ECG recordings and can be recommended for practitioners. However, with respect to DFA a1, values in the uncorrelated range and during higher exercise intensities tend to elicit higher bias and wider LoA.

The Movesense Medical Sensor Chest Belt Device as Single Channel ECG for RR Interval Detection and HRV Analysis during Resting State and Incremental Exercise: A Cross-Sectional Validation Study.

The value of heart rate variability (HRV) in the fields of health, disease, and exercise science has been established through numerous investigations. The typical mobile-based HRV device simply records interbeat intervals, without differentiation between noise or arrythmia as can be done with an electrocardiogram (ECG). The intent of this report is to validate a new single channel ECG device, the Movesense Medical sensor, against a conventional 12 channel ECG. A heterogeneous group of 21 participants performed an incremental cycling ramp to failure with measurements of HRV, before (PRE), during (EX), and after (POST). Results showed excellent correlations between devices for linear indexes with Pearson's r between 0.98 to 1.0 for meanRR, SDNN, RMSSD, and 0.95 to 0.97 for the non-linear index DFA a1 during PRE, EX, and POST. There was no significant difference in device specific meanRR during PRE and POST. Bland-Altman analysis showed high agreement between devices (PRE and POST: meanRR bias of 0.0 and 0.4 ms, LOA of 1.9 to -1.8 ms and 2.3 to -1.5; EX: meanRR bias of 11.2 to 6.0 ms; LOA of 29.8 to -7.4 ms during low intensity exercise and 8.5 to 3.5 ms during high intensity exercise). The Movesense Medical device can be used in lieu of a reference ECG for the calculation of HRV with the potential to differentiate noise from atrial fibrillation and represents a significant advance in both a HR and HRV recording device in a chest belt form factor for lab-based or remote field-application.

High integrin αVß6 affinity reached by hybrid domain deletion slows ligand-binding on-rate.

The role of the hybrid domain in integrin affinity regulation is unknown, as is whether the kinetics of ligand binding is modulated by integrin affinity state. Here, we compare cell surface and soluble integrin αVß6 truncation mutants for ligand-binding affinity, kinetics, and thermodynamics. Removal of the integrin transmembrane/cytoplasmic domains or lower legs has little effect on αVß6 affinity, in contrast to ß1 integrins. In integrin opening, rearrangement at the interface between the ßI and hybrid domains is linked to remodeling at the ligand-binding site at the opposite end of the ßI domain, which greatly increases in affinity in the open conformation. The larger size of the ßI-hybrid interface in the closed state suggests that the hybrid domain stabilizes closing. In agreement, deletion of the hybrid domain raised affinity by 50-fold. Surface plasmon resonance and isothermal titration calorimetry gave similar results and the latter revealed tradeoffs between enthalpy and entropy not apparent from affinity. At extremely high affinity reached in Mn2+ with hybrid domain truncation, αVß6 on-rate for both pro-TGF-ß1 and fibronectin declined. The results suggest that the open conformation of αVß6 has lower on-rate than the closed conformation, correlate with constriction of the ligand-binding pocket in open αVß6 structures, and suggest that the extended-closed conformation is kinetically selected for ligand binding. Subsequent transition to the extended-open conformation is stabilized by its much higher affinity for ligand and would also be stabilized by force exerted across ligand-bound integrins by the actin cytoskeleton.

Influence of Artefact Correction and Recording Device Type on the Practical Application of a Non-Linear Heart Rate Variability Biomarker for Aerobic Threshold Determination.

Recent study points to the value of a non-linear heart rate variability (HRV) biomarker using detrended fluctuation analysis (DFA a1) for aerobic threshold determination (HRVT). Significance of recording artefact, correction methods and device bias on DFA a1 during exercise and HRVT is unclear. Gas exchange and HRV data were obtained from 17 participants during an incremental treadmill run using both ECG and Polar H7 as recording devices. First, artefacts were randomly placed in the ECG time series to equal 1, 3 and 6% missed beats with correction by Kubios software's automatic and medium threshold method. Based on linear regression, Bland Altman analysis and Wilcoxon paired testing, there was bias present with increasing artefact quantity. Regardless of artefact correction method, 1 to 3% missed beat artefact introduced small but discernible bias in raw DFA a1 measurements. At 6% artefact using medium correction, proportional bias was found (maximum 19%). Despite this bias, the mean HRVT determination was within 1 bpm across all artefact levels and correction modalities. Second, the HRVT ascertained from synchronous ECG vs. Polar H7 recordings did show an average bias of minus 4 bpm. Polar H7 results suggest that device related bias is possible but in the reverse direction as artefact related bias.

Correlation Properties of Heart Rate Variability during a Marathon Race in Recreational Runners: Potential Biomarker of Complex Regulation during Endurance Exercise.

There is only very limited data examining cardiovascular responses in real-world endurance training/competition. The present study examines the influence of a marathon race on non-linear dynamics of heart rate (HR) variability (HRV). Eleven male recreational runners performed a self-paced marathon road race on an almost flat profile. During the race, heart rate and beat-to-beat (RR) intervals were recorded continuously. Besides HRV time-domain measurements, fractal correlation properties using short-term scaling exponent alpha1 of Detrended Fluctuation Analysis (DFA-alpha1) were calculated. The mean finishing time was 3:10:22 ± 0:17:56 h:min:s with a blood lactate concentration of 4.04 ± 1.12 mmol/L at the end of the race. Comparing the beginning to the end segment of the marathon race (Begin vs. End) significant increases could be found for km split time (p < .001, d = .934) and for HR (p = .010, d = .804). Significant decreases could be found for meanRR (p = .013, d = .798) and DFA-alpha1 (p = .003, d = 1.132). DFA-alpha1 showed an appropriate dynamic range throughout the race consisting of both uncorrelated and anti-correlated values. Lactate was consistent with sustained high intensity exercise when measured at the end of the event. Despite the runners slowing after halfway, DFA-alpha1 continued to fall to values seen in the highest intensity domain during incremental exercise testing in agreement with lactate assessment. Therefore, the discrepancy between the reduced running pace with that of the decline of DFA-alpha1, demonstrate the benefit of using this dimensionless HRV index as a biomarker of internal load during exercise over the course of a marathon race.

Nonstructural carbohydrate dynamics of lodgepole pine dying from mountain pine beetle attack.

Bark beetle outbreaks are an important cause of tree death, but the process by which trees die remains poorly understood. The effect of beetle attack on whole-tree nonstructural carbohydrate (NSC) dynamics is particularly unclear, despite the potential role of carbohydrates in plant defense and survival. We monitored NSC dynamics of all organs in attacked and protected lodgepole pines (Pinus contorta) during a mountain pine beetle (Dendroctonus ponderosae) outbreak in British Columbia, starting before beetle flight in June 2011 through October 2012, when most attacked trees had died. Following attack, NSC concentrations were first reduced in the attacked region of the bole. The first NSC reduction in a distant organ appeared in the needles at the end of 2011, while branch and root NSC did not decline until much later in 2012. Attacked trees that were still alive in October 2012 had less beetle damage, which was negatively correlated with initial bark sugar concentrations in the attack region. The NSC dynamics of dying trees indicate that trees were killed by a loss of water conduction and not girdling. Further, our results identify locally reduced carbohydrate availability as an important mechanism by which stressors like drought may increase tree susceptibility to biotic attack.

Systematic N-methylation of oxytocin: Impact on pharmacology and intramolecular hydrogen bonding network.

Oxytocin (OT) is a peptide hormone agonist of the OT receptor (OTR) that plays an important role in social behaviors such as pair bonding, maternal bonding and trust. The pharmaceutical development of OT as an oral peptide therapeutic has been hindered historically by its unfavorable physicochemical properties, including molecular weight, polarity and number of hydrogen bond donors, which determines poor cell permeability. Here we describe the first systematic study of single and multiple N-methylations of OT and their effect on physicochemical properties as well as potency at the OT receptor. The agonist EC50 and percent effect for OTR are reported and show that most N-methylations are tolerated but with some loss in potency compared to OT. The effect of N-methylation on exposed polarity is assessed through the EPSA chromatographic method and the results validated against NMR temperature coefficient experiments and the determination of NMR solution structures. We found that backbone methylation of residues not involved in IMHB and removal of the N-terminal amine can significantly reduce the exposed polarity of peptides, and yet retain a significant OTR agonist activity. The results of this study also expose the potential challenge of using the N-methylation strategy for the OT system; while exposed polarity is reduced, in some cases backbone methylation produces a significant conformational change that compromises agonist activity. The data presented provides useful insights on the SAR of OT and suggests future design strategies that can be used to develop more permeable OTR agonists based on the OT framework.

Discovery of a novel Kv7 channel opener as a treatment for epilepsy.

Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.

Heart Rate Variability Thresholds: Agreement with Established Approaches and Reproducibility in Trained Females and Males.

PURPOSE: To determine in trained females and males i) the agreement between the gas exchange threshold (GET), lactate threshold 1 (LT1), and heart rate variability threshold 1 (HRVT1), as well as between the respiratory compensation point (RCP), lactate threshold 2 (LT2), and heart rate variability threshold 2 (HRVT2), and ii) the reproducibility of HRVT1 and HRVT2 during 2-min incremental step protocols. METHODS: Fifty-seven trained participants (24 females) completed a 2-min step incremental test to task failure. Nineteen participants (eight females) completed a second test to evaluate reproducibility. Gas exchange and ventilatory responses, blood lactate concentration, and RR time series were recorded to assess the oxygen consumption (V̇O 2 ) and heart rate (HR) associated with the GET, RCP, LT1, LT2, HRVT1, and HRVT2. RESULTS: V̇O 2 -GET versus V̇O 2 -HRVT1 and HR-GET versus HR-HRVT1 were statistically different for females (29.5 ± 4.0 vs 34.6 ± 6.1 mL·kg -1 ·min -1 ; 154 ± 11 vs 166 ± 12 bpm) and for males (33.9 ± 4.2 vs 42.7 ± 4.6 mL·kg -1 ·min -1 ; 145 ± 11 vs 165 ± 9 bpm; P < 0.001). V̇O 2 and HR at HRVT1 were greater than at LT1 ( P < 0.05). V̇O 2 -RCP versus V̇O 2 -HRVT2 and HR-RCP versus HR-HRVT2 were not statistically different for females (40.1 ± 4.7 vs 39.5 ± 6.7 mL·kg -1 ·min -1 ; 177 ± 9 vs 176 ± 9 bpm) and males (48.4 ± 5.4 vs 47.8 ± 4.8 mL·kg -1 ·min -1 ; 176 ± 8 vs 175 ± 9 bpm; P > 0.05). V̇O 2 and HR responses at LT2 were similar to HRVT2 ( P > 0.05). Intraclass correlation coefficient for V̇O 2 -HRVT1, HR-HRVT1, V̇O 2 -HRVT2, and HR-HRVT2 indicated good reproducibility when comparing the two different time points to standard methods. CONCLUSIONS: Whereas HRVT2 is a valid and reproducible estimate of the RCP/LT2, current approaches for HRVT1 estimation did not show good agreement with outcomes at GET and LT1.

Nonlinear progression across the occult transition establishes cancer lethality.

Cancer screening is based upon a linear model of growth and invasion. Yet, early dissemination during the lengthy pre-diagnostic phase suggests that nonlinearity in growth can also occur. Therefore, we quantitatively traced the invisible and visible phases of tumorigenesis in the mammary gland for more than two-thousand tumors. Dynamic mathematical models of the invisible phase revealed an occult checkpoint resulting in nonlinear progression of transformed field cells. We found that expansile fields have increased dwell time at the occult checkpoint resulting in a large reservoir of image detectable precursors prior to invasion. In contrast, slowly proliferating lesions disseminate early and then transition rapidly through an occult checkpoint in a process we term nascent lethality. Our data illustrate how nonlinear growth across an occult checkpoint can account for a paradoxical increase in early-stage cancer detection without a dramatic reduction in metastatic burden. Highlights: Growth during the invisible phase of tumorigenesis is a nonlinear processField size and field growth rate are uncoupled from metastatic potentialOccult transition rates vary by genotypeNascent lethal lesions are currently undetectable.

Effect of ramp slope on intensity thresholds based on correlation properties of heart rate variability during cycling.

An index of heart rate variability (HRV), detrended fluctuation analysis (DFA a1) has gathered interest as a surrogate marker of exercise intensity boundaries. The aim of this report was to examine heart rate variability threshold (HRVT) behavior across different ramp incremental (RI) slopes. Seventeen participants completed a series of three RI (15, 30, and 45 W · min-1 slopes) with monitoring of gas exchange parameters, heart rate (HR) and HRV. HRVT1 was defined as the V̇O2 or HR at which DFA a1 reached 0.75 and the HRVT2 at which these values reached 0.5. HRVTs were compared by Pearson's r, Bland-Altman analysis, ICC3,1 , ANOVA, and paired t-testing. An excellent degree of reliability was seen across all three ramps, with an ICC3,1 of 0.93 and 0.88 for the HRVT1 V̇O2 and HR, respectively, and 0.90 and 0.92 for the HRVT2 V̇O2 and HR, respectively. Correlations between HRVT1/2 of the individual ramps were high with r values 0.84-0.95 for both HR and V̇O2 . Bland-Altman differences ranged between -1.4 and 1.2 mL · kg-1 · min-1 and -2 and +2 bpm. Paired t-testing showed no mean differences between any HRVT1/2 ramp comparisons. Cycling ramp slope does not appear to affect either HRVT1 or HRVT2 in terms of HR or V̇O2 .

Understanding childhood obesity in America: linkages between household income, community resources, and children's behaviors.

BACKGROUND: Understanding childhood obesity's root causes is critical to the creation of strategies to improve our children's health. We sought to define the association between childhood obesity and household income and how household income and childhood behaviors promote childhood obesity. METHODS: We assessed body mass index in 109,634 Massachusetts children, identifying the percentage of children who were overweight/obese versus the percentage of children in each community residing in low-income homes. We compared activity patterns and diet in 999 sixth graders residing in 4 Michigan communities with varying annual household income. RESULTS: In Massachusetts, percentage of overweight/obese by community varied from 9.6% to 42.8%. As household income dropped, percentage of overweight/obese children rose. In Michigan sixth graders, as household income goes down, frequency of fried food consumption per day doubles from 0.23 to 0.54 (P < .002), and daily TV/video time triples from 0.55 to 2.00 hours (P < .001), whereas vegetable consumption and moderate/vigorous exercise go down. CONCLUSIONS: The prevalence of overweight/obese children rises in communities with lower household income. Children residing in lower income communities exhibit poorer dietary and physical activity behaviors, which affect obesity.