Slope Of Response Research Articles

1348Childhood adversities and diurnal patterns of salivary cortisol in adulthood: two UK-based prospective cohort studies

Abstract Background Dysregulation of diurnal cortisol patterns may mediate between chronic stress and health problems. Findings on the association of childhood adversities with adult cortisol, however, are equivocal, mainly due to low statistical power, sample selection, and unstandardised indices of cortisol. Methods Participants were from Whitehall II study (n = 3434), and National Child Development Study (NCDS) (n = 2072). In Whitehall II, multilevel models were used to examine associations of retrospectively measured childhood adversities with two indices of diurnal cortisol patterns (awakening response and diurnal slope) at a median age of 65. In NCDS, regression was used to investigate associations of prospectively measured adversities with two measures of morning cortisol at the age of 44/45. We then regressed predicted values of cortisol from these models against count of adversities to examine dose-response effects. Results The prevalence of reporting at least one adversity was 67.8% in Whitehall II, and 47.8% in NCDS. None of the individual adversities were associated with overall cortisol levels in either study. However, for each additional adversity, there was a 1% elevated awakening response (95%CI: 0.8% to 1.19%), and, among men only, a 1.2% lower cortisol level at awakening (-1.98 to -0.40) with flatter diurnal slope (0.1 to 0.1) in Whitehall II; and a 1.3% lower cortisol level (-1.78 to -0.70) at 3.75 hrs after awakening in NCDS. Conclusions Experience of multiple childhood adversities may be associated with dysregulated salivary cortisol patterns later in life. Key messages Accumulation of childhood adversities might be associated with dysregulated diurnal cortisol patterns in adulthood.

Radiation therapy related cardiac disease risk in childhood cancer survivors: Updated dosimetry analysis from the Childhood Cancer Survivor Study

Background and purposeWe previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (HAtlas). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (HHybrid). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort. MethodsWe evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with HHybrid and mean heart dose (Dm), percent volume receiving ≥ 20 Gy (V20) and ≥ 5 Gy with V20 = 0 (V5,V20=0%) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3–5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with Dm, V20, and V5,V20=0% (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, Dm was also considered as a continuous variable. ResultsConsistent with previous findings with HAtlas, reevaluation using HHybrid dosimetry found that, Dm ≥ 10 Gy, V20 ≥ 0.1%, and V5,V20=0% ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P < 0.05) increases in risk with updated dosimetry for Dm in the category of 20 to 29.9 Gy and V20 in the category of 30% to 79.9%. When changes in the linear dose–response relationship for Dm were assessed, the slopes of the dose response were steeper (P < 0.001) with updated dosimetry. Changes were primarily observed among individuals with chest-directed RT with prescribed doses ≥ 20 Gy. ConclusionThese findings present a methodological advancement in heart RT dosimetry with improved estimates of RT-related late cardiac disease risk. While results are broadly consistent with our prior study, we report that, with updated cardiac dosimetry, risks of cardiac disease are significantly higher in two dose and volume categories and slopes of the Dm-specific RT-response relationships are steeper. These data support the use of contemporary RT to achieve lower heart doses for pediatric patients, particularly those requiring chest-directed RT.

Negative frequency-dependent prey selection by wolves and its implications on predator–prey dynamics

Many species exhibit selective foraging behaviour, where consumers use a nonrandom subset of available food types. Yet little is known about how selective foraging behaviour varies with environmental conditions and the community level consequences of such selection dynamics. We examined selective foraging by wolves preying primarily on elk in Yellowstone National Park (YNP) over a 12-year period and on moose in Isle Royale National Park (IRNP) over a 47-year period. Specifically, we assessed how selection for calves and senescent adults varied with their frequency in the environment, wolf abundance and winter severity. Selection for senescent adults decreased as the relative abundance of senescent prey increased (i.e. negative frequency-dependent selection) in both study sites. In IRNP, selection for calves was also negatively frequency dependent and declined with increasing wolf abundance. These results are inconsistent with the pattern of positive frequency-dependent selection expected under the prey-switching hypothesis. These results suggest that selection is primarily driven by intraspecific differences in prey vulnerability and wolves’ interest in minimizing their risk of injury, as opposed to maximizing intake rates. Lastly, we ran simulations to evaluate how predator–prey dynamics were influenced by dynamic patterns of selection, like those observed in YNP and IRNP. The simulations indicated that predators are more efficient (i.e. steeper slope of the numerical response) when selection for calves is negatively frequency dependent, which results in a lower mean abundance of prey. More importantly, predation is a stronger destabilizing force when selection for calves is negatively frequency dependent. That stronger destabilizing force is indicated by greater variability in the abundance of prey and predators, prey populations being less resilient and a steeper negative slope of the relationship between predation rate and prey population growth rate. As such, our simulation analyses suggest that some of the observed patterns of negative-frequency dependent selection may have important consequences for predator–prey dynamics. • Wolves showed negative frequency-dependent selection for calves and senescent prey. • Wolves did not exhibit prey-switching behaviour when preferred prey became rare. • Selection is likely driven by the predator's interest to reduce their risk of injury. • Selection for calves may result in more efficient predators and less resilient prey.

School commute time, chronotype, and altered HPA axis functioning during adolescence

Hypothalamic pituitary adrenal gland (HPA) axis functioning has been linked with daily demands during adolescence. A ubiquitous, yet understudied daily demand in the lives of youth is the commute to school, which may be associated with the diurnal rhythm of cortisol as demonstrated in prior research among adults. The current study hypothesized that longer school commute times would be associated with altered HPA axis functioning as demonstrated by a heightened cortisol awakening response (CAR) and flatter diurnal slope. Additionally, given that the HPA axis follows a diurnal rhythm and adolescence is marked by changes in the circadian rhythm, adolescents with a more evening chronotype were hypothesized to evince even more altered HPA axis functioning in the face of long school commute times. A total of 269 adolescents (M = 16.38 years, SD = 0.74) provided saliva samples at wake, 15-min. post-wake, and 30-min. post-wake for the calculation of CAR and at dinnertime and bedtime for the calculation of diurnal slope, completed up to 8 nights of sleep actigraphy, and self-reported school commute time. Results suggest that more evening chronotype youth with longer school commute times evince a higher CAR, but not an altered diurnal slope. The present findings may have implications for adolescent mental health as higher CAR has been associated poor mental health and heightened stress.

Behavioural and physiological response to frustration in autistic youth: associations with irritability

BackgroundIrritability is a common and impairing occurrence in autistic youth, yet the underlying mechanisms are not well-known. In typically developing populations, differences in frustration response have been suggested as important driver of the behavioural symptoms of irritability. Research exploring the role of frustration response as a risk factor for irritability in autistic populations is limited and often uses parent report or observer ratings; objective measures of frustration response appropriate for use in autistic populations are required to advance the field.MethodsIn the current study, fifty-two autistic adolescents aged 13–17 years from a population-based longitudinal study completed an experimental task designed to induce frustration through exposure to periods of unexpected delay. Behavioural (number of button presses) and physiological (heart rate; HR) metrics were collected during delay periods. Irritability was measured using the parent-rated Affective Reactivity Index (ARI). Analyses used mixed-level models to test whether irritability was associated with different slopes of behavioural and physiological response to experimentally induced frustration during the task. Age and baseline HR (for the physiological data only) were included as covariates.ResultsAnalyses showed a marginal association between irritability and the slope of behavioural response (incident rate ratio (IRR) =.98, p=.06), and a significant association with the slope of physiological response (b=−.10, p=.04); higher levels of irritability were associated with a dampened behavioural and physiological response, as indicated by flatter slopes of change over the course of the task. The pattern of results largely remained in sensitivity analyses, although the association with physiological response became non-significant when adjusting for IQ, autism symptom severity, and medication use (b=−.10, p=.10).ConclusionsResults suggest that the current experimental task may be a useful objective measure of frustration response for use with autistic populations, and that a non-adaptive response to frustration may be one biological mechanism underpinning irritability in autistic youth. This may represent an important target for future intervention studies.

Salivary cortisol patterns in psychopathic and non-psychopathic offenders

Previous research has described diverse biological correlates of the psychopathic personality. Efforts to understand the underpinnings of low fear responses in psychopathic individuals have drawn attention to the possible role of abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function, but studies to date have been largely limited to youth or to adult community samples. The current study therefore examined morning basal cortisol levels and responses to a psychosocial stress task in a forensic clinical sample of psychopathic offenders (n = 14), non-psychopathic offenders (n = 22), and non-offender controls (n = 14). Morning cortisol levels were similar in all three groups. Throughout the stress task, psychopathic offenders showed significantly lower cortisol than controls; non-psychopathic offenders showed a similar but non-significant trend towards lower cortisol. The three groups did not differ, however, in cortisol response slopes. Implications of these findings are discussed in the framework of current theories about biological mechanisms underlying psychopathic personality.

Numerical investigation of the structural response of a conduit buried within a soil slope

Buried conduits are commonly used for utility transportation around the world. Accordingly, to ensure the safe design and installation of conduits, it is important to understand soil-conduit interaction. This research paper presents a numerical investigation of the structural response of a conduit buried within a soil slope in response to applied surface pressure. Numerically simulated and analytically calculated soil-conduit interaction results have been employed in the study to analyze the effect of crest distance and burial depth of a conduit on: its deflection, shape deformation, developed sectional normal stress and bending moment. The structural response of the conduit buried within the soil slope was also compared to that of conduit buried under level ground. The results show that conduit buried within a soil slope experiences more structural deflection and sectional forces than conduit buried under level ground, unless crest distance and burial depth of the conduit exceed approximately 5Bc and 3Bc, respectively; where Bc represents the outer diameter of the conduit. By using the graphical illustrations, explained mechanisms and developed correlations presented in this paper, practicing engineers can ensure the efficient design and installation of conduits buried within soil slopes.

Carbon Isotope Fractionation in Noelaerhabdaceae Algae in Culture and a Critical Evaluation of the Alkenone Paleobarometer

AbstractThe carbon isotope fractionation in algal organic matter (εp), including the long‐chain alkenones produced by the coccolithophorid family Noelaerhabdaceae, is used to reconstruct past atmospheric CO2 levels. The conventional proxy linearly relates εp to changes in cellular carbon demand relative to diffusive CO2 supply, with larger εp values occurring at lower carbon demand relative to supply (i.e., abundant CO2). However, the response of Gephyrocapsa oceanica, one of the dominant alkenone producers of the last few million years, has not been studied closely. Here, we subject G. oceanica to various CO2 levels by increasing pCO2 in the culture headspace, as opposed to increasing dissolved inorganic carbon (DIC) and alkalinity concentrations at constant pH. We note no substantial change in physiology, but observe an increase in εp as carbon demand relative to supply decreases, consistent with DIC manipulations. We compile existing Noelaerhabdaceae εp data and show that the diffusive model poorly describes the data. A meta‐analysis of individual treatments (unique combinations of lab, strain, and light conditions) shows that the slope of the εp response depends on the light conditions and range of carbon demand relative to CO2 supply in the treatment, which is incompatible with the diffusive model. We model εp as a multilinear function of key physiological and environmental variables and find that both photoperiod duration and light intensity are critical parameters, in addition to CO2 and cell size. While alkenone carbon isotope ratios indeed record CO2 information, irradiance and other factors are also necessary to properly describe alkenone εp.

Obesity Blunts the Ventilatory Response to Exercise in Men and Women.

Rationale: Obesity presents a mechanical load to the thorax, which could perturb the generation of minute ventilation (V̇e) during exercise. Because the respiratory effects of obesity are not homogenous among all individuals with obesity and obesity-related effects could vary depending on the magnitude of obesity, we hypothesized that the exercise ventilatory response (slope of the V̇e and carbon dioxide elimination [V̇co2] relationship) would manifest itself differently as the magnitude of obesity increases.Objectives: To investigate the V̇e/V̇co2 slope in an obese population that spanned across a wide body mass index (BMI) range.Methods: A total of 533 patients who presented to a surgical weight loss center for pre-bariatric surgery testing performed an incremental maximal cycling test and were studied retrospectively. The V̇e/V̇co2 slope was calculated up to the ventilatory threshold. Patients were examined in groups based on BMI (category 1: 30-39.9 kg/m2, category 2: 40-49.9 kg/m2, and category 3: ≥50 kg/m2). Because the respiratory effects of obesity could be sex and/or age specific, we further examined patients in groups by sex and age (younger: <50 yr and older: ≥50 yr). Differences in the V̇e/V̇co2 slope were then compared between BMI category, age, and sex using a three-way ANOVA.Results: No significant BMI category by sex by age interactions was detected (P = 0.75). The V̇e/V̇co2 slope decreased with increases in BMI (category 1, 29.1 ± 4.0; category 2, 28.4 ± 4.1; and category 3, 27.1 ± 3.3) and was elevated in women (28.9 ± 4.1) compared with men (26.7 ± 3.2) (BMI category by sex interaction, P < 0.05). No age-related differences were observed (BMI category by age interaction, P = 0.55). The partial pressure for end-tidal CO2 was elevated at the ventilatory threshold in BMI category 3 compared with BMI categories 1 and 2 (both P < 0.01).Conclusions: These findings suggest that obesity presents a unique challenge to augmenting ventilatory output relative to CO2 elimination, such that the increase in the exercise ventilatory response becomes blunted as the magnitude of obesity increases. Further studies are required to investigate the clinical consequences and the mechanisms that may explain the attenuation of exercise ventilatory response with increasing BMI in men and women with obesity.

Response Kinetics and Factors Predicting Survival Among Patients with Core Binding Factor (CBF) Acute Myeloid Leukemia (AML)

Background: Core Binding Factor (CBF) leukemia, characterized by inversion (16) or t(8;21) cytogenetic abnormalities, is associated with a relatively favorable prognosis and highly responsive to treatment with fludarabine, cytarabine, and granulocyte colony stimulating factor combination (FLAG) along with either gemtuzumab ozogamicin (FLAG-GO) (Borthakur, Am J Hematol, 2014) or idarubicin (FLAG-IDA) (Borthakur ASH 2013). Response monitoring is facilitated by the use of real time polymerase chain reaction (qPCR) assessment for fusion gene transcripts. In this study, we assess factors underlying disease response kinetics and their predictive utility (including the role of quantitative fusion gene transcript ratio)in determining survival outcomes in CBF AML.Methods: One hundred and four patients (pts) with CBF AML were treated with frontline sequential regimens of FLAG-GO or FLAG-IDA at MDACC from 2007 to 2014. Baseline and periodic qPCR values were collected for analysis; logarithmic transformations were applied on qPCR data and depth (quality) of response expressed as quantitative changes in log reductions/increases (log (qPCR)). In order to determine the rate of response, random regression was applied on repeated measures of the log (qPCR) for all 104 pts. Regression coefficient for the each individual's PCR response over time was extracted from the model and measured as the slope [rate of log-reduction over time] (or rate of response). Stepwise cox regression models were applied to evaluate factors predicting for survival in the multivariate analysis. Maximally selected log rank statistics (MSLRS) methods were used to determine optimum cut-offs for continuous covariates, wherever applicable.Results: Baseline pt and disease characteristics are outlined in table 1. Median log (qPCR) reduction (∆qPCRind) over first FLAG induction cycle was 2.8 (0.0-7.0). Median number of FLAG consolidation cycles received were 6 (range, 1-6). Median log alteration from post-induction to post-consolidation phase (log (qPCR)end-induction - log (qPCR)end-consolidation = ∆qPCRcons) was 1.4 (-2.9-7.0). Rates of response (slopes) for the duration of treatment course for all cases are plotted in figure 1A. ∆qPCRind correlated strongly with the overall regression slope (p = 0.0012) indicating that depth of initial response predicts for an overall steep slope (i.e., faster rate of response). Also, there was a trend toward significance by regimen type (p = 0.07) and cytogenetics (p = 0.05), with FLAG-IDA and t(8;21) associated with slower rates of response. At a median follow up of 22 (1-76) months among survivors, 92 (88%) pts are alive; 18 (17%) have relapsed (5 pts during consolidation). Depth of initial response did not, however correlate with rate of log (qPCR) response during the consolidation phase of treatment. Among patients in continued remission at the end of consolidation phase, and not treated with further maintenance, RFS did not differ by the presence or absence of a detectable qPCR transcript-at-end-consolidation (p = 0.87). Among analyzed factors, ∆qPCRind, ∆qPCRcons predicted for a statistically significant improved relapse free survival (RFS); ∆qPCRind, ∆qPCRcons, age, and antecedent hematological disorder were significantly associated with overall survival (OS) (table 2). Importantly, rate of response did not predict either for RFS or OS. Patients with a ∆qPCRind of > 2.8 (by MSLRS on RFS) (n = 47, 45%) and a positive ∆qPCRcons (i.e., ∆qPCRcons > 0) (n = 84, 81%) had a significantly improved RFS compared to those without (Figures 1B & 1C, respectively). When accounting for both variables, pts who failed to achieve either of the two qPCR depth-of-response measures had the lowest RFS compared to those achieved at least one; pts who achieved both had the best RFS (Figure 1D).Conclusions: ∆qPCRind, ∆qPCRcons (both, measures of depth of response) are important predictors of RFS and OS, and quantitative cut-offs derived from our study serve as clinically useful estimates to identify pts at an increased risk of relapse. Patients with inv(16) and those treated with FLAG-GO have a faster rate of response (as measured by qPCR) to treatment. However, neither regimen, cytogenetics, nor rate of response to treatment impact RFS or OS. [Display omitted] DisclosuresCortes:Sun Pharma: Research Funding; Teva: Research Funding; ARIAD: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding.

Transplantation of adipose-derived stromal cells protects functional and morphological auditory nerve integrity in a model of cochlear implantation.

Cochlear implants are considered the gold standard therapy for subjects with severe hearing loss and deafness. Cochlear implants bypass the damaged hair cells and directly stimulate spiral ganglion neurons (SGNs) of the auditory nerve. Hence, the presence of functional SGNs is crucial for speech perception in electric hearing with a cochlear implant. In deaf individuals, SGNs progressively degenerate due to the lack of neurotrophic support, normally provided by sensory cells of the inner ear. Adipose-derived stromal cells (ASCs) are known to produce neurotrophic factors. In a guinea pig model of sensory hearing loss and cochlear implantation, ASCs were autologously transplanted into the scala tympani prior to insertion of a cochlear implant on one side. Electrically evoked auditory brain stem responses (eABR) were recorded 8 weeks after cochlear implantation. At conclusion of the experiment, the cochleae were histologically evaluated. Compared to untreated control animals, transplantation of ASCs resulted in an increased number of SGNs and their peripheral neurites. In ASC-transplanted animals, mean eABR thresholds were lower and suprathreshold amplitudes larger, suggesting a larger population of intact auditory nerve fibers. Moreover, when compared to controls, amplitude-level functions of eABRs in ASC transplanted animals demonstrated steeper slopes in response to increasing interphase gaps (IPGs), indicative of better functionality of the auditory nerve. In summary, results suggest that transplantation of autologous ASCs into the deaf inner ear may have protective effects on the survival of SGNs and their peripheral processes and may thus contribute to long-term benefits in speech discrimination performance in cochlear implant subjects.

Rho-associated kinases contribute to the regulation of tau phosphorylation and amyloid metabolism during neuronal plasticity.

Neural plasticity under physiological condition develops together with normal tau phosphorylation and amyloid precursor protein (APP) processing. Since restoration of PI3-kinase signaling has therapeutic potential in Alzheimer's disease, we investigated plasticity-related changes in tau and APP metabolism by the selective Rho-kinase inhibitor fasudil. Field potentials composed of a field excitatory post-synaptic potential (fEPSP) and a population spike (PS) were recorded from a granule cell layer of the dentate gyrus. Plasticity of synaptic strength and neuronal function was induced by strong tetanic stimulation (HFS) and low-frequency stimulation (LFS) patterns. Infusions of saline or fasudil were given for 1h starting from the application of the induction protocols. Total and phosphorylated tau levels and soluble APPα levels were measured in the hippocampus, which was removed after at least 1h post-induction period. Fasudil infusion resulted in attenuation of fEPSP slope and PS amplitude in response to both HFS and LFS. Fasudil reduced total tau and phosphorylated tau at residue Thr181 in the HFS-stimulated hippocampus, while Thr231 phosphorylation was reduced by fasudil treatment in the LFS-stimulated hippocampus. Ser416 phosphorylation was increased by fasudil treatment in both HFS- and LFS-stimulated hippocampus. Fasudil significantly increased soluble APPα in LFS-stimulated hippocampus, but not in HFS-stimulated hippocampus. In light of our findings, we suggest that increased activity of Rho kinase could trigger a mechanism that goes awry during synaptic plasticity which is reversed by a Rho-kinase inhibitor. Thus, Rho-kinase inhibition might be a therapeutic target in cognitive disorders.

Pubertal transition with current life stress and support alters longitudinal diurnal cortisol patterns in adolescents exposed to early life adversity.

Current and early life stress (ELS) are associated with diurnal cortisol patterns, which themselves are associated with mental and physical health. The pubertal recalibration hypothesis suggests that the social environment can impact dysregulated cortisol patterns for previously ELS-exposed youth as they transition through puberty. This study examined longitudinal change in cortisol awakening response (CAR) and diurnal slope (DS) across puberty as a function of ELS in infancy, current stress, and social support (N = 290, 7-17 years). The CAR and DS were examined thrice annually with an accelerated longitudinal design with nurse-assessed puberty to assess associations between diurnal cortisol and pubertal recalibration with ELS and the current social environment. Exposure to ELS was associated with less steep DS but not changes in CAR, and no evidence of pubertal calibration was found. The DS became less steep for youth in later pubertal stages and as youth progressed through puberty. The CAR was steeper for youth in later pubertal stages. Across the cohort, current life stress and support were associated with changes in the DS and the CAR through the pubertal transition. The pubertal stage and the peripubertal and pubertal social environment may have important implications for adrenocortical functioning with or without exposure to ELS.

Polymeric membrane-modified voltammetric sensors for lipophilic analytes with nanomolar detection limit: Key parameters influencing the response characteristics

Thin plasticized PVC membrane-coated glassy carbon working electrodes have been used for the voltammetric measurement of highly lipophilic, electroactive drugs. Compared to conventional working electrodes, these membrane-coated electrodes exhibit remarkable detection limit and selectivity and are less prone to electrode fouling. The unique performance characteristics of these sensors are related to the large partition coefficient of the analyte in the membrane coating where it is oxidized in a non-aqueous membrane phase. To analyze the influence of the key parameters of the response of membrane-coated sensors, we derived theoretical expressions on the voltammetric response of the sensors. In our analysis we considered 1) the partition coefficient (Pmw) of the analyte between the aqueous sample and the organic membrane, 2) the membrane volume to sample volume ratio (Vm/Vw), and 3) the binding constant of constituents in the sample that bind the analyte (K). The results of our theoretical analysis have been tested through voltammetric measurement of highly lipophilic analytes with logPow values (logarithm of the partition coefficient between octanol and water) ranging between 0.3 and 7.5. By understanding of the influence of the sensor design parameters on the overall sensor response, these parameters can be tuned for optimized response slope, detection limit, etc., for solving specific analytical tasks.

The mechanical and microstructural properties of the pediatric skull

The pediatric skull differs drastically from the adult skull in terms of composition, rigidity, and structure. However, there is limited data which quantifies the mechanical properties of the pediatric skull. The lack of mechanical data may inhibit desired pediatric craniofacial surgical outcomes as current methodologies and materials employed for the pediatric population are adapted from those used for adults. In this study, normally discarded parietal bone tissue from eight pediatric craniosynostosis surgery patients (aged 4 to 10 months) was collected during reconstructive surgery and prepared for microstructural analysis and mechanical testing. Up to 12 individual coupon samples of fresh, never frozen tissue were harvested from each specimen and prepared for four-point bending testing to failure. The microstructure of each sample was analyzed using micro-computed tomography before and after each mechanical test. From this analysis, effective geometric and mechanical properties were determined for each sample (n = 68). Test results demonstrated that the pediatric parietal skull was 2.0 mm (±0.4) thick, with a porosity of 36% (±14). The effective modulus of the tissue samples, determined from the initial slope of the sample stress-strain response using Euler beam theory and a nonlinear Ramberg-Osgood stress-strain relationship, was 4.2 GPa (±2.1), which was approximately three times less stiff than adult skull tissue reported in the literature. Furthermore, the pediatric skull was able to bend up to flexural failure strains of 6.7% (±2.0), which was approximately five times larger than failure strains measured in adult skull. The disparity between the measured mechanical properties of pediatric skull tissue and adult skull tissue points towards the need to reevaluate current surgical technologies, such as pediatric cranial surgical hardware, so that they are more compatible with pediatric tissue.

Near Stall Unsteady Flow Responses to Morphing Flap Deflections

The unsteady flow characteristics and responses of an NACA 0012 airfoil fitted with a bio-inspired morphing trailing edge flap (TEF) at near-stall angles of attack (AoA) undergoing downward deflections are investigated at a Reynolds number of 0.62 × 106 near stall. An unsteady geometric parametrization and a dynamic meshing scheme are used to drive the morphing motion. The objective is to determine the susceptibility of near-stall flow to a morphing actuation and the viability of rapid downward flap deflection as a control mechanism, including its effect on transient forces and flow field unsteadiness. The dynamic flow responses to downward deflections are studied for a range of morphing frequencies (at a fixed large amplitude), using a high-fidelity, hybrid RANS-LES model. The time histories of the lift and drag coefficient responses exhibit a proportional relationship between the morphing frequency and the slope of response at which these quantities evolve. Interestingly, an overshoot in the drag coefficient is captured, even in quasi-static conditions, however this is not seen in the lift coefficient. Qualitative analysis confirms that an airfoil in near stall conditions is receptive to morphing TEF deflections, and that some similarities triggering the stall exist between downward morphing TEFs and rapid ramp-up type pitching motions.

In patients with heart failure, enhanced ventilatory response to exercise is associated with severe obstructive sleep apnea.

Patients with congestive heart failure (CHF) frequently exhibit an elevated ratio of minute ventilation over CO2 output (VE/VCO2 slope) while undergoing exercise tests. One of the factors contributing to this elevated slope is an increased chemosensitivity to CO2 in that this slope significantly correlates with the slope of the ventilatory response to CO2 rebreathing at rest. A previous study in patients with CHF and central sleep apnea showed that the highest VE/VCO2 slope during exercise was associated with the most severe central sleep apnea. In the current study, we tested the hypothesis that in patients with CHF and obstructive sleep apnea (OSA), the highest VE/VCO2 slope is also associated with the most severe OSA. If the hypothesis is correct, then it implies that in CHF, augmented instability in the negative feedback system controlling breathing predisposes to both OSA and central sleep apnea. This preliminary study involved 70 patients with stable CHF and a spectrum of OSA severity who underwent full-night polysomnography, echocardiography, and cardiopulmonary exercise testing. Peak oxygen consumption and the VE/VCO2 slope were calculated. There was significant positive correlation between the apnea-hypopnea index and the VE/VCO2 slope (r = .359; P = .002). In the regression model, involving the relevant variables of age, body mass index, sex, VE/VCO2 slope, peak oxygen consumption, and left ventricular ejection fraction, the apnea-hypopnea index retained significance with VE/VCO2. In patients with CHF, the VE/VCO2 slope obtained during exercise correlates significantly to the severity of OSA, suggesting that an elevated CO2 response should increase suspicion for the presence of severe OSA, a treatable disorder that is potentially associated with excess mortality. Registry: ClinicalTrials.gov; Name: Comparison Between Exercise Training and CPAP Treatment for Patients With Heart Failure and Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/record/NCT01538069; Identifier: NCT01538069. Bittencourt L, Javaheri S, Servantes DM, Pelissari Kravchychyn AC, Almeida DR, Tufik S. In patients with heart failure, enhanced ventilatory response to exercise is associated with severe obstructive sleep apnea. J Clin Sleep Med. 2021;17(X):1875-1880.

Characterization of Potency of the P2Y13 Receptor Agonists: A Meta-Analysis.

P2Y13 is an ADP-stimulated G-protein coupled receptor implicated in many physiological processes, including neurotransmission, metabolism, pain, and bone homeostasis. Quantitative understanding of P2Y13 activation dynamics is important for translational studies. We systematically identified PubMed annotated studies that characterized concentration-dependence of P2Y13 responses to natural and synthetic agonists. Since the comparison of the efficacy (maximum response) is difficult for studies performed in different systems, we normalized the data and conducted a meta-analysis of EC50 (concentration at half-maximum response) and Hill coefficient (slope) of P2Y13-mediated responses to different agonists. For signaling events induced by heterologously expressed P2Y13, EC50 of ADP-like agonists was 17.2 nM (95% CI: 7.7–38.5), with Hills coefficient of 4.4 (95% CI: 3.3–5.4), while ATP-like agonists had EC50 of 0.45 μM (95% CI: 0.06–3.15). For functional responses of endogenously expressed P2Y13, EC50 of ADP-like agonists was 1.76 μM (95% CI: 0.3–10.06). The EC50 of ADP-like agonists was lower for the brain P2Y13 than the blood P2Y13. ADP-like agonists were also more potent for human P2Y13 compared to rodent P2Y13. Thus, P2Y13 appears to be the most ADP-sensitive receptor characterized to date. The detailed understanding of tissue- and species-related differences in the P2Y13 response to ADP will improve the selectivity and specificity of future pharmacological compounds.

Does the drought tolerance of guar [Cyamopsis tetragonoloba (L.) Taub.] extend belowground to root nodules?

AbstractIn cultivating guar [Cyamopsis tetragonoloba (L.) Taub], a drought‐tolerant legume, producers anticipate soil N credits through biological N fixation (BNF), but it has been speculated that root nodulation is poor under dry conditions and little is known about how nodules recover from drought stress. To provide better insight, two greenhouse studies were conducted to investigate static (25%, 50%, 75% and 100% ET replacement in two soils) and dynamic (50%, 75% and 100%, plus 50% and 75% relieved to 100% at 20 and 30 days after planting) water regimes on guar over 50 days. Water stress generally had the greatest negative impact on nodule weight, followed by aboveground biomass, reproductive nodes, height and then nodule number. Parameter responses were either linear or quadratic with ET replacement and response slopes differed between soils for nodule weight and biomass. The relatively minor effect on nodule number indicated the basic machinery for BNF (nodules) remained largely intact until water stress was extreme. This was likely a key factor that enabled strong and rapid recovery of nodule growth following relief of water stress. Biomass recovery was likewise robust, with production equal to the stress‐free control, regardless of the intensity and duration of the stress. These results show that nodule growth in guar is highly sensitive to water stress, but the plant is resilient in maintaining nodules under water stress and recovering nodule growth upon moisture restoration.

The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

RationaleCytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats.MethodsTo investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release.ResultsCYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization.ConclusionsCYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.