Abstract Magnetic resonance imaging (MRI) is the principal method for studying structural age-related brain changes in vivo . However, previous research has yielded inconsistent results, precluding ...understanding of structural changes of the aging brain. This inconsistency is due to methodological differences and/or different aging patterns across samples. To overcome these problems, we tested age effects on 17 different neuroanatomical structures and total brain volume across five samples, of which one was split to further investigate consistency (883 participants). Widespread age-related volume differences were seen consistently across samples. In four of the five samples, all structures, except the brainstem, showed age-related volume differences. The strongest and most consistent effects were found for cerebral cortex, pallidum, putamen and accumbens volume. Total brain volume, cerebral white matter, caudate, hippocampus and the ventricles consistently showed non-linear age functions. Healthy aging appears associated with more widespread and consistent age-related neuroanatomical volume differences than previously believed.
Objectives An array of neuroprotective strategies has evolved to limit spinal cord injury during descending thoracic aneurysm and thoracoabdominal aortic aneurysm repair. This study prospectively ...assessed the neuroprotective impact of intrathecal papaverine added to other techniques in aortic aneurysm repairs. Methods From January 2002 to January 2010, 398 consecutive patients underwent descending thoracic aneurysm and thoracoabdominal aortic aneurysm repairs at Cleveland Clinic, 68 under hypothermic circulatory arrest. We focused on the remaining 330, in whom a combination of neuroprotective adjuncts was used intraoperatively to mitigate spinal cord ischemia. These included distal aortic perfusion with moderate hypothermia, cerebrospinal fluid drainage, and intrathecal papaverine. Two patient groups were discriminated according to whether intrathecal papaverine was (n = 250) or was not (n = 80) administered. Postoperative outcomes were analyzed from a prospectively maintained clinical database. Results Preoperative patient characteristics and comorbidities were similar between groups. Extent of aortic disease was also similar: descending thoracic aneurysm (34% with papaverine vs 28%) and Crawford types I (25% vs 34%), II (27% vs 24%), III (13% vs 13%), and IV (2% vs 2.5%). Groups had similar in-hospital mortality (6.4% vs 11%; P = .11) and permanent stroke (4.4% vs 7.5%; P = .3). Permanent paraplegia (3.6% vs 7.5%; P = .01) and paraparesis (1.6% vs 6.3%; P = .01) were significantly lower in the intrathecal papaverine group. Conclusions Adding intrathecal papaverine to the neuroprotective protocol for descending thoracic aneurysm and thoracoabdominal aortic aneurysm repairs may enhance spinal cord perfusion and provide additional spinal cord protection.
We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a role for the astroglial xCT in ventral dentate gyrus (vDG) in stress and ...antidepressant responses. We provide an RNA-seq roadmap for the stress-sensitive vDG. The transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27ac to regulate expression of xCT, which is also reduced in a genetic mouse model of inherent susceptibility to depressive-like behavior. Pharmacologically, modulating histone acetylation with acetyl-L-carnitine (LAC) or acetyl-N-cysteine (NAC) rapidly increases xCT and activates a network with mGlu2 receptors to prime an enhanced glutamate homeostasis that promotes both pro-resilient and antidepressant-like responses. Pharmacological xCT blockage counteracts NAC prophylactic effects. GFAP+-Cre-dependent overexpression of xCT in vDG mimics pharmacological actions in promoting resilience. This work establishes a mechanism by which vDG protection leads to stress resilience and antidepressant responses via epigenetic programming of an xCT-mGlu2 network.
•Stress differentially regulates glutamate homeostasis in dorsal and ventral hippocampus•The glutamate gene xCT in ventral dentate gyrus is a critical mediator of stress•Buffering histone acetylation can promote pro-resilient and antidepressant responses
Nasca et al. demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a mechanism by which buffering histone acetylation protects the stress-sensitive ventral dentate gyrus to promote resilience and antidepressant responses via epigenetic programming of an xCT-mGlu2 gene network.
Submillimetre (submm) galaxies are among the most rapidly star-forming and most massive high-redshift galaxies; thus, their properties provide important constraints on galaxy evolution models. ...However, there is still a debate about their stellar masses and their nature in the context of the general galaxy population. To test the reliability of their stellar mass determinations, we used a sample of simulated submm galaxies for which we created synthetic photometry. The photometry were used to derived their stellar masses via spectral energy distribution (SED) modelling, as is generally done with real observations. We used various SED codes (Grasil, Magphys, Hyperz, and LePhare) and various alternative assumed star formation histories (SFHs). We found that the assumption of SFHs with two independent components enables the SED modelling codes to most accurately recover the true stellar masses of the simulated submm galaxies. Exponentially declining SFHs (tau models) lead to lower masses (albeit still formally consistent with the true stellar masses), while the assumption of single-burst SFHs results in a significant underestimation of the stellar masses. Thus, we conclude that studies based on the higher masses inferred from fitting the SEDs of real submm galaxies with double SFHs are most likely to be correct, implying that submm galaxies lie on the high-mass end of the main sequence of star-forming galaxies. This conclusion appears robust to assumptions of whether submm galaxies are driven by major mergers, since the suite of simulated galaxies modelled here contains examples of both merging and isolated galaxies. We identified discrepancies between the true and inferred stellar ages (rather than the dust attenuation) as the primary determinant of the success or failure of the mass recovery. Regardless of the choice of SFH, the SED-derived stellar masses exhibit a factor of ~2 scatter around the true value, and this scatter is an inherent limitation of the SED modelling due to simplified assumptions (regarding, e.g., the SFH, detailed galaxy geometry and wavelength dependence of the dust attenuation). Finally, we found that the contribution of active galactic nuclei (<60% at the K-band in these simulations) does not have any significant impact on the derived stellar masses.
Bicuspid aortic valves (BAV) are associated with incompletely characterized aortopathy. Our objectives were to identify distinct patterns of aortopathy using machine-learning methods and characterize ...their association with valve morphology and patient characteristics.
We analyzed preoperative 3-dimensional computed tomography reconstructions for 656 patients with BAV undergoing ascending aorta surgery between January 2002 and January 2014. Unsupervised partitioning around medoids was used to cluster aortic dimensions. Group differences were identified using polytomous random forest analysis.
Three distinct aneurysm phenotypes were identified: root (n = 83; 13%), with predominant dilatation at sinuses of Valsalva; ascending (n = 364; 55%), with supracoronary enlargement rarely extending past the brachiocephalic artery; and arch (n = 209; 32%), with aortic arch dilatation. The arch phenotype had the greatest association with right–noncoronary cusp fusion: 29%, versus 13% for ascending and 15% for root phenotypes (P < .0001). Severe valve regurgitation was most prevalent in root phenotype (57%), followed by ascending (34%) and arch phenotypes (25%; P < .0001). Aortic stenosis was most prevalent in arch phenotype (62%), followed by ascending (50%) and root phenotypes (28%; P < .0001). Patient age increased as the extent of aneurysm became more distal (root, 49 years; ascending, 53 years; arch, 57 years; P < .0001), and root phenotype was associated with greater male predominance compared with ascending and arch phenotypes (94%, 76%, and 70%, respectively; P < .0001). Phenotypes were visually recognizable with 94% accuracy.
Three distinct phenotypes of bicuspid valve–associated aortopathy were identified using machine-learning methodology. Patient characteristics and valvular dysfunction vary by phenotype, suggesting that the location of aortic pathology may be related to the underlying pathophysiology of this disease.
Background:
Injury and illness surveillance, and epidemiological studies, are fundamental elements of concerted efforts to protect the health of the athlete. To encourage consistency in the ...definitions and methodology used, and to enable data across studies to be compared, research groups have published 11 sport- or setting-specific consensus statements on sports injury (and, eventually, illnesses) epidemiology to date.
Objective:
To further strengthen consistency in data collection, injury definitions, and research reporting through an updated set of recommendations for sports injury and illness studies, including a new Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist extension.
Study Design:
Consensus statement of the International Olympic Committee (IOC).
Methods:
The IOC invited a working group of international experts to review relevant literature and provide recommendations. The procedure included an open online survey, several stages of text drafting and consultation by working groups, and a 3-day consensus meeting in October 2019.
Results:
This statement includes recommendations for data collection and research reporting covering key components: defining and classifying health problems, severity of health problems, capturing and reporting athlete exposure, expressing risk, burden of health problems, study population characteristics, and data collection methods. Based on these, we also developed a new reporting guideline as a STROBE extension—the STROBE Sports Injury and Illness Surveillance (STROBE-SIIS).
Conclusion:
The IOC encourages ongoing in- and out-of-competition surveillance programs and studies to describe injury and illness trends and patterns, understand their causes, and develop measures to protect the health of the athlete. The implementation of the methods outlined in this statement will advance consistency in data collection and research reporting.
Management of coronary artery disease (CAD) in patients with severe aortic stenosis (AS) referred for transcatheter aortic valve replacement (TAVR) is posing challenges. Due to limited and ...heterogeneous data on the prevalence and clinical impact of CAD on the outcomes of TAVR and the management strategies for CAD in patients undergoing TAVR, we performed a comprehensive review of the literature. Significant CAD is present in 40% to 75% of patients undergoing TAVR. The impact of CAD on outcomes after TAVR remains understudied. Based on existing data, not all patients require revascularization before TAVR. Percutaneous coronary intervention (PCI) should be considered for severely stenotic lesions in proximal coronaries that subtend a large area of myocardium at risk. Ongoing studies randomizing patients to surgical or percutaneous management strategies for severe AS will help provide valuable data regarding the impact of CAD on TAVR outcomes, the role of PCI, and its timing in relation to TAVR.
Purpose: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib benefit some non–small
cell lung cancer (NSCLC) patients, but most do not respond ...(primary resistance) and those who initially respond eventually
progress (acquired resistance). EGFR TKI resistance is not completely understood and has been associated with certain EGFR
and K-RAS mutations and MET amplification.
Experimental Design: We hypothesized that dual inhibition of the vascular endothelial growth factor (VEGF) and EGFR pathways may overcome primary
and acquired resistance. We investigated the VEGF receptor/EGFR TKI vandetanib, and the combination of bevacizumab and erlotinib
in vivo using xenograft models of EGFR TKI sensitivity, primary resistance, and three models of acquired resistance, including models
with mutated K-RAS and secondary EGFR T790M mutation.
Results: Vandetanib, gefitinib, and erlotinib had similar profiles of in vitro activity and caused sustained tumor regressions in vivo in the sensitive HCC827 model. In all four resistant models, vandetanib and bevacizumab/erlotinib were significantly more
effective than erlotinib or gefitinib alone. Erlotinib resistance was associated with a rise in both host and tumor-derived
VEGF but not EGFR secondary mutations in the KRAS mutant-bearing A549 xenografts. Dual inhibition reduced tumor endothelial
proliferation compared with VEGF or EGFR blockade alone, suggesting that the enhanced activity of dual inhibition is due at
least in part to antiendothelial effects.
Conclusion: These studies suggest that erlotinib resistance may be associated with a rise in both tumor cell and host stromal VEGF and
that combined blockade of the VEGFR and EGFR pathways can abrogate primary or acquired resistance to EGFR TKIs. This approach
merits further evaluation in NSCLC patients.
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that ...strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124A), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (−0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10−88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio OR = 2.2, 95% confidence interval CI = 1.78–2.78, p = 1.26 × 10−12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19–1.64, p = 2.63 × 10−5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
Between 43,000 and 47,000 people die annually in the United States from diseases of the aorta and its branches and continues to increase. For the thoracic aorta, these diseases are increasingly ...treated by stent-grafting. No prospective randomized study exists comparing stent-grafting and open surgical treatment, including for disease subgroups. Currently, one stent-graft device is approved by the Food and Drug Administration for descending thoracic aortic aneurysms although two new devices are expected to obtain FDA approval in 2008. Stent-graft devices are used “off label” or under physician Investigational Device Exemption studies for other indications such as traumatic rupture of the aorta and aortic dissection. Early first-generation devices suffered from problems such as stroke with insertion, ascending aortic dissection or aortic penetration from struts, vascular injury, graft collapse, endovascular leaks, graft material failure, continued aneurysm expansion or rupture, and migration or kinking; however, the newer iterations coming to market have been considerably improved. Although the devices have been tested in pulse duplicators out to 10 years, long-term durability is not known, particularly in young patients. The long-term consequences of repeated computed tomography scans for checking device integrity and positioning on the risk of irradiation-induced cancer remains of concern in young patients. This document (1) reviews the natural history of aortic disease, indications for repair, outcomes after conventional open surgery, currently available devices, and insights from outcomes of randomized studies using stent-grafts for abdominal aortic aneurysm surgery, the latter having been treated for a longer time by stent-grafts; and (2) offers suggestions for treatment.
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