To quantify the relationship between quadriceps strength and aerobic fitness following ACLR.
42 individuals with ACLR (29F/13M, 20.2 ± 3.3years, 71.8 ± 17.4 kg, 171.1 ± 9.4 cm, 21.9 ± 21.5months ...post-surgery) and 38 healthy controls (24F/14M, 20.1 ± 1.4years, 69.8 ± 10.2 kg, 172.9 ± 8.7 cm) completed quadriceps strength testing using an instrumented dynamometer then completed an incremental treadmill test to determine aerobic fitness (VO2max). Bivariate Pearson's correlations were calculated between strength and VO2max. Significant correlations were retained for a regression analysis.
Healthy controls demonstrated significantly greater VO2max compared to the ACLR group (d = 0.56). Unilateral strength variables were significantly correlated with VO2max (P ≤ 0.006) for both groups. Normalized peak isokinetic knee extensor torque was retained in the model, which explained 20.5% of the variance in healthy VO2max and 37.2% of the variance in ACLR VO2max.
Aerobic fitness was reduced in the ACLR group in comparison to the healthy controls, despite unrestricted return to activity and similar activity levels between groups. Unilateral quadriceps strength was significantly correlated with aerobic fitness, which may be an indicator that greater unilateral strength may be a proxy for assessing aerobic fitness. Furthermore, sports medicine professionals may consider incorporating techniques and exercises during rehabilitation to improve cardiovascular fitness following ACLR.
•ACLR had reduced aerobic fitness despite unrestricted return to activity.•Unilateral quadriceps strength was significantly correlated with aerobic fitness.•Isokinetic quadriceps torque explained 37.2% of variance in ACLR aerobic fitness.
Patent foramen ovale (PFO) is prevalent in patients with migraine with aura. Observational studies show that PFO closure resulted in migraine cessation or improvement in approximately 80% of such ...patients. We investigated the effects of PFO closure for migraine in a randomized, double-blind, sham-controlled trial.
Patients who suffered from migraine with aura, experienced frequent migraine attacks, had previously failed > or = 2 classes of prophylactic treatments, and had moderate or large right-to-left shunts consistent with the presence of a PFO were randomized to transcatheter PFO closure with the STARFlex implant or to a sham procedure. Patients were followed up for 6 months. The primary efficacy end point was cessation of migraine headache 91 to 180 days after the procedure. In total, 163 of 432 patients (38%) had right-to-left shunts consistent with a moderate or large PFO. One hundred forty-seven patients were randomized. No significant difference was observed in the primary end point of migraine headache cessation between implant and sham groups (3 of 74 versus 3 of 73, respectively; P=0.51). Secondary end points also were not achieved. On exploratory analysis, excluding 2 outliers, the implant group demonstrated a greater reduction in total migraine headache days (P=0.027). As expected, the implant arm experienced more procedural serious adverse events. All events were transient.
This trial confirmed the high prevalence of right-to-left shunts in patients with migraine with aura. Although no significant effect was found for primary or secondary end points, the exploratory analysis supports further investigation. The robust design of this study has served as the model for larger trials that are currently underway in the United States and Europe.
To inform the interpretation of dietary data in the context of sex differences in diet–disease relations, it is important to understand whether there are any sex differences in accuracy of dietary ...reporting.
To quantify sex differences in self-reported total energy intake (TEI) compared with a reference measure of total energy expenditure (TEE).
Six electronic databases were systematically searched for published original research articles between 1980 and April 2020. Studies were included if they were conducted in adult populations with measures for both females and males of self-reported TEI and TEE from doubly labeled water (DLW). Studies were screened and quality assessed independently by 2 authors. Random-effects meta-analyses were conducted to pool the mean differences between TEI and TEE for, and between, females and males, by method of dietary assessment.
From 1313 identified studies, 31 met the inclusion criteria. The studies collectively included information on 4518 individuals (54% females). Dietary assessment methods included 24-h recalls (n = 12, 2 with supplemental photos of food items consumed), estimated food records (EFRs; n = 11), FFQs (n = 10), weighed food records (WFRs, n = 5), and diet histories (n = 2). Meta-analyses identified underestimation of TEI by females and males, ranging from −1318 kJ/d (95% CI: −1967, −669) for FFQ to −2650 kJ/d (95% CI: −3492, −1807) for 24-h recalls for females, and from −1764 kJ/d (95% CI: −2285, −1242) for FFQ to −3438 kJ/d (95% CI: −5382, −1494) for WFR for males. There was no difference in the level of underestimation by sex, except when using EFR, for which males underestimated energy intake more than females (by 590 kJ/d, 95% CI: 35, 1,146).
Substantial underestimation of TEI across a range of dietary assessment methods was identified, similar by sex. These underestimations should be considered when assessing TEI and interpreting diet–disease relations.
Electron-based fragmentation methods have revolutionized biomolecular mass spectrometry, in particular native and top-down protein analysis. Here, we report the use of a new electromagnetostatic cell ...to perform electron capture dissociation (ECD) within a quadrupole/ion mobility/time-of-flight mass spectrometer. This cell was installed between the ion mobility and time-of-flight regions of the instrument, and fragmentation was fast enough to be compatible with mobility separation. The instrument was already fitted with electron transfer dissociation (ETD) between the quadrupole and mobility regions prior to modification. We show excellent fragmentation efficiency for denatured peptides and proteins without the need to trap ions in the gas phase. Additionally, we demonstrate native top-down backbone fragmentation of noncovalent protein complexes, leading to comparable sequence coverage to what was achieved using the instrument’s existing ETD capabilities. Limited collisional ion activation of the hemoglobin tetramer before ECD was reflected in the observed fragmentation pattern, and complementary ion mobility measurements prior to ECD provided orthogonal evidence of monomer unfolding within this complex. The approach demonstrated here provides a powerful platform for both top-down proteomics and mass spectrometry-based structural biology studies.
Bone cancer pain can be difficult to control, as it appears to be driven simultaneously by inflammatory, neuropathic and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to ...modulate inflammatory and neuropathic pain states, we focused on a novel NGF sequestering antibody and demonstrated that two administrations of this therapy in a mouse model of bone cancer pain produces a profound reduction in both ongoing and movement-evoked bone cancer pain-related behaviors that was greater than that achieved with acute administration of 10 or 30 mg/kg of morphine. This therapy also reduced several neurochemical changes associated with peripheral and central sensitization in the dorsal root ganglion and spinal cord, whereas the therapy did not influence disease progression or markers of sensory or sympathetic innervation in the skin or bone. Mechanistically, the great majority of sensory fibers that innervate the bone are CGRP/TrkA expressing fibers, and if the sensitization and activation of these fibers is blocked by anti-NGF therapy there would not be another population of nociceptors, such as the non-peptidergic IB4/RET-IR nerve fibers, to take their place in signaling nociceptive events.
Abstract
DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express ...elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.
•The Approach Avoid Task (AAT) has garnered interest as an addiction treatment.•Cannabis AAT (CAAT) reduced cannabis use and approach bias in a prior study.•CAAT-training is not associated with ...altered whole-brain cannabis cue-reactivity.•CAAT-training is associated with moderate reductions in activation in several ROIs.•No significant ROI activation differences were found in the CAAT vs control group.
Cognitive Bias Modification (CBM) has garnered interest as a potential addiction treatment. CBM interventions such as Approach Avoidance Training (AAT) are designed to alter automatic tendencies to approach drugs or drug-related cues. In our previous work, the cannabis AAT (CAAT) reduced cannabis approach bias, which was related to reduced cannabis use, among 80 non-treatment-seeking cannabis-using youth (Jacobus et al., 2018). In this preliminary examination, a subsample of these youth underwent neuroimaging to explore CAAT’s effect on cannabis cue-related neural activation.
Sub-study participants were 41 cannabis-using youth ages 17–21 (mean age = 18.83; 47.5% female). Participants completed a cannabis cue-reactivity task during a functional MRI scan pre- and post CAAT-training or CAAT-sham to examine CAAT-related neural changes.
Thirty-seven youth completed all six CAAT (n = 19) or CAAT-sham (n = 18) training sessions and had usable neuroimaging data. The group*time interaction on cannabis approach bias reached trend-level significance (p = .055). Change in approach bias slopes from pre-to post-treatment was positive for CAAT-sham (increased approach bias) and negative for CAAT-training (change to avoidance bias), consistent with the larger study. No significant changes emerged for cannabis cue-induced activation following CAAT-training or CAAT-sham in whole brain or region of interest analyses. However, active CAAT-training was associated with small-to-medium decreases in amygdala (Cohen’s dz = 0.36) and medial prefrontal cortex (Cohen’s dz = 0.48) activation to cannabis cues.
Despite reducing cannabis use in the larger sample, CAAT-training did not alter neural cannabis cue-reactivity in the sub-study compared to CAAT-sham. More research is needed to understand neural mechanisms underlying AAT-related changes in substance use.
Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world's working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related ...transcription factor 1 (RUNX1) as a gene upregulated in CD31
vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVMs and angiogenic tufts in the retina of mice with oxygen-induced retinopathy, suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis. Inhibition of RUNX1 activity with the Ro5-3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.
Little is known about how frailty has shaped experiences of living through the COVID-19 pandemic. In this cross-sectional mixed methods study, we analyzed data from the nationwide COVID-19 Coping ...Study from December 2020 through January 2021 (N = 2094 US adults aged ≥55) to investigate quantitative associations between frailty and the prevalence of physical isolation, worry about COVID-19, and loneliness. Reflexive thematic analysis explored aging adults’ lived experiences of frailty during the pandemic. In multivariable-adjusted population-weighted modified Poisson regression models, we found that frailty was associated with increased prevalence of physical isolation, worry about COVID-19, and loneliness. Qualitative experiences of aging with frailty during the pandemic were diverse, and encompassed isolation, worry, and loneliness, as well as coping strategies and resilience. The findings may inform individualized multi-factorial strategies (e.g., physical activity, nutrition, and social interaction) to support well-being among adults aging with frailty during the pandemic.
We have employed immunohistochemistry for multiple markers to investigate the structure and possible function of the different compartments of human cerebral wall from the formation of cortical plate ...at 8 postconceptional weeks (PCW) to the arrival of thalamocortical afferents at 17 PCW. New observations include the subplate emerging as a discrete differentiated layer by 10 PCW, characterized by synaptophysin and vesicular gamma-aminobutyric acid transporter expression also seen in the marginal zone, suggesting that these compartments may maintain a spontaneously active synaptic network even before the arrival of thalamocortical afferents. The subplate expanded from 13 to 17 PCW, becoming the largest compartment and differentiated further, with NPY neurons located in the outer subplate and KCC2 neurons in the inner subplate. Glutamate decarboxylase and calretinin-positive inhibitory neurons migrated tangentially and radially from 11.5 PCW, appearing in larger numbers toward the rostral pole. The proliferative zones, marked by Ki67 expression, developed a complicated structure by 12.5 PCW reflected in transcription factor expression patterns, including TBR2 confined to the inner subventricular and outer ventricular zones and TBR1 weakly expressed in the subventricular zone (SVZ). PAX6 was extensively expressed in the proliferative zones such that the human outer SVZ contained a large reservoir of PAX6-positive potential progenitor cells.
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