Vascular Stiffening and the Brain: Direct Measures of Cerebrovascular Stiffness in Aging and Vasodilation

Dampening of pulsatile pressure waves within blood vessels is an essential feature of the arterial system. Vascular stiffening increases the speed and the pulsatile energy of the pressure wave, leaving low resistance organs like the brain vulnerable to microvascular mechanical damage. Due to access limitations, the effect of cerebrovascular stiffening on brain structure and neurological outcomes remains unknown. The purpose of this thesis was to assess the influence of vascular stiffening in peripheral arteries on white matter integrity (WMLv) (Chapter 2), obtain direct measures of cerebrovascular stiffness via phase contrast magnetic resonance imaging (PCMRI) (Chapter 3), and examine the impact of acute vasodilation on cerebrovascular stiffness (Chapter 4). We found that ischemic heart disease patients (IHD) had greater vascular stiffness compared with controls. However, IHD status did not influence WMLv. Regardless of vascular pathology, common carotid stiffness and ultrasound-based carotid-cerebral pulse wave transit times were associated with WMLv independently. Therefore, we applied PCMRI to the cerebral vessels to acquire direct measures of cerebrovascular stiffness in the internal carotid (ICA) and middle cerebral (MCA) arteries. Using cardiac-gated PCRMI, we collected blood flow velocity data at multiple segments of the ICA (icaPWV) and M1-M2 segment of the MCA (mcaPWV) to construct time–intensity curves and calculate PWV at temporal resolutions up to 25ms. We demonstrated that mcaPWV can detect vascular stiffening in a cross-section of young and older healthy individuals. Additionally, PWV increases from extracranial to intracranial segments, and this acceleration is amplified with age. We then measured peripheral and intracranial vascular stiffness in response to vasodilation using hypercapnia (HC; 6% CO2, 21% O2, balanced N2) and nitroglycerin (NTG; 0.4mg, sublingual) in healthy young adults. Vasodilation in the MCA increased PWV and characteristic impedance. Additionally, the preferential effect of HC on conduit and downstream vascular properties of cerebral vessels versus non-specific conduit vasodilation of NTG suggests that multiple mechanisms may contribute to cerebrovascular stiffening. This thesis provides a method to obtain direct measures of intracranial PWV and demonstrates the capacity for acute modification of cerebrovasculature stiffness. This work may advance future understanding of cerebrovascular changes, damage, and therapeutics in vulnerable populations

Cerebrovascular compliance within the rigid confines of the skull

© 2018 Zamir, Moir, Klassen, Balestrini and Shoemaker. Pulsatile blood flow is generally mediated by the compliance of blood vessels whereby they distend locally and momentarily to accommodate the passage of the pressure wave. This freedom of the blood vessels to exercise their compliance may be suppressed within the confines of the rigid skull. The effect of this on the mechanics of pulsatile blood flow within the cerebral circulation is not known, and the situation is compounded by experimental access difficulties. We present an approach which we have developed to overcome these difficulties in a study of the mechanics of pulsatile cerebral blood flow. The main finding is that while the innate compliance of cerebral vessels is indeed suppressed within the confines of the skull, this is compensated somewhat by compliance provided by other extravascular elements within the skull. The net result is what we have termed intracranial compliance, which we argue is more pertinent to the mechanics of pulsatile cerebral blood flow than is intracranial pressure

Autonomic Dysregulation in Adolescent Concussion Is Sex- and Posture-Dependent

Objective: To study autonomic responses to postural changes in concussed adolescents. The influence of sex was also studied. Design: Longitudinal cohort observational study. Participants: Concussed adolescents (CONC; n = 65; 26 male adolescents; age 15 ± 1 years, range = 12-18 years) and a control (CTRL) group of nonconcussed adolescents of similar age and sport (CTRL; n = 54; 29 male adolescents; age 14 ± 1 years, range = 12-18 years). Interventions: Concussed participants were monitored through 6 weekly visits throughout usual physician care. Control participants underwent 2 visits separated by at least 1 week to account for intrapersonal variation in testing measures. Main Outcome Measures: Heart rate variability as the root mean square of successive differences in R–R intervals (RMSSD), heart rate (HR), and blood pressure [mean arterial pressure (MAP) and diastolic blood pressure (DBP)] were measured in supine, sitting, and standing postures. Results: A mixed analysis of variance revealed a group 3 sex 3 posture interaction (P = 0.04) where seated values of RMSSD were less in concussed female participants versus control female participants (42 ± 4 vs 61 ± 7 ms; P = 0.01; Mann–Whitney rank test). Compared with CTRL, CONC exhibited increased pretesting seated DBP (69 ± 1 vs 74 ± 1 mm Hg; P\u3c 0.01), MAP (83 ± 1 vs 86 ± 1 mm Hg; P = 0.02), and baseline seated HR (72 ± 1 vs 77 ± 2 bpm; P = 0.03). Values of DBP (P = 0.03) and MAP (P, 0.01) improved at clinical discharge, whereas the RMSSD in female participants did not (P \u3e 0.5). Data are mean ± SEM. Conclusions: A modest reduction in female cardiac autonomic regulation was observed during seated postures. Alterations in seated concussed DBP and MAP, but not RMSSD, resolved at clinical discharge (median = 37 days). The results indicate that, in adolescents, concussion may impair cardiovagal function in a sex- and posture-dependent manner. The findings also suggest that BP metrics, but not RMSSD, are associated with clinical concussion recovery

Autonomic Dysregulation in Adolescent Concussion Is Sex- and Posture-Dependent

Objective: To study autonomic responses to postural changes in concussed adolescents. The influence of sex was also studied. Design: Longitudinal cohort observational study. Participants: Concussed adolescents (CONC; n = 65; 26 male adolescents; age 15 ± 1 years, range = 12-18 years) and a control (CTRL) group of nonconcussed adolescents of similar age and sport (CTRL; n = 54; 29 male adolescents; age 14 ± 1 years, range = 12-18 years). Interventions: Concussed participants were monitored through 6 weekly visits throughout usual physician care. Control participants underwent 2 visits separated by at least 1 week to account for intrapersonal variation in testing measures. Main Outcome Measures: Heart rate variability as the root mean square of successive differences in R–R intervals (RMSSD), heart rate (HR), and blood pressure [mean arterial pressure (MAP) and diastolic blood pressure (DBP)] were measured in supine, sitting, and standing postures. Results: A mixed analysis of variance revealed a group 3 sex 3 posture interaction (P = 0.04) where seated values of RMSSD were less in concussed female participants versus control female participants (42 ± 4 vs 61 ± 7 ms; P = 0.01; Mann–Whitney rank test). Compared with CTRL, CONC exhibited increased pretesting seated DBP (69 ± 1 vs 74 ± 1 mm Hg; P\u3c 0.01), MAP (83 ± 1 vs 86 ± 1 mm Hg; P = 0.02), and baseline seated HR (72 ± 1 vs 77 ± 2 bpm; P = 0.03). Values of DBP (P = 0.03) and MAP (P, 0.01) improved at clinical discharge, whereas the RMSSD in female participants did not (P \u3e 0.5). Data are mean ± SEM. Conclusions: A modest reduction in female cardiac autonomic regulation was observed during seated postures. Alterations in seated concussed DBP and MAP, but not RMSSD, resolved at clinical discharge (median = 37 days). The results indicate that, in adolescents, concussion may impair cardiovagal function in a sex- and posture-dependent manner. The findings also suggest that BP metrics, but not RMSSD, are associated with clinical concussion recovery

An essential function for the ATR-Activation-Domain (AAD) of TopBP1 in mouse development and cellular senescence

ATR activation is dependent on temporal and spatial interactions with partner proteins. In the budding yeast model, three proteins – Dpb11TopBP1, Ddc1Rad9 and Dna2 - all interact with and activate Mec1ATR. Each contains an ATR activation domain (ADD) that interacts directly with the Mec1ATR:Ddc2ATRIP complex. Any of the Dpb11TopBP1, Ddc1Rad9 or Dna2 ADDs is sufficient to activate Mec1ATR in vitro. All three can also independently activate Mec1ATR in vivo: the checkpoint is lost only when all three AADs are absent. In metazoans, only TopBP1 has been identified as a direct ATR activator. Depletion-replacement approaches suggest the TopBP1-AAD is both sufficient and necessary for ATR activation. The physiological function of the TopBP1 AAD is, however, unknown. We created a knock-in point mutation (W1147R) that ablates mouse TopBP1-AAD function. TopBP1-W1147R is early embryonic lethal. To analyse TopBP1-W1147R cellular function in vivo, we silenced the wild type TopBP1 allele in heterozygous MEFs. AAD inactivation impaired cell proliferation, promoted premature senescence and compromised Chk1 signalling following UV irradiation. We also show enforced TopBP1 dimerization promotes ATR-dependent Chk1 phosphorylation. Our data suggest that, unlike the yeast models, the TopBP1-AAD is the major activator of ATR, sustaining cell proliferation and embryonic development

A multi-decade record of high quality fCO2 data in version 3 of the Surface Ocean CO2 Atlas (SOCAT)

The Surface Ocean CO2 Atlas (SOCAT) is a synthesis of quality-controlled fCO2 (fugacity of carbon dioxide) values for the global surface oceans and coastal seas with regular updates. Version 3 of SOCAT has 14.7 million fCO2 values from 3646 data sets covering the years 1957 to 2014. This latest version has an additional 4.6 million fCO2 values relative to version 2 and extends the record from 2011 to 2014. Version 3 also significantly increases the data availability for 2005 to 2013. SOCAT has an average of approximately 1.2 million surface water fCO2 values per year for the years 2006 to 2012. Quality and documentation of the data has improved. A new feature is the data set quality control (QC) flag of E for data from alternative sensors and platforms. The accuracy of surface water fCO2 has been defined for all data set QC flags. Automated range checking has been carried out for all data sets during their upload into SOCAT. The upgrade of the interactive Data Set Viewer (previously known as the Cruise Data Viewer) allows better interrogation of the SOCAT data collection and rapid creation of high-quality figures for scientific presentations. Automated data upload has been launched for version 4 and will enable more frequent SOCAT releases in the future. High-profile scientific applications of SOCAT include quantification of the ocean sink for atmospheric carbon dioxide and its long-term variation, detection of ocean acidification, as well as evaluation of coupled-climate and ocean-only biogeochemical models. Users of SOCAT data products are urged to acknowledge the contribution of data providers, as stated in the SOCAT Fair Data Use Statement. This ESSD (Earth System Science Data) “living data” publication documents the methods and data sets used for the assembly of this new version of the SOCAT data collection and compares these with those used for earlier versions of the data collection (Pfeil et al., 2013; Sabine et al., 2013; Bakker et al., 2014). Individual data set files, included in the synthesis product, can be downloaded here: doi:10.1594/PANGAEA.849770. The gridded products are available here: doi:10.3334/CDIAC/OTG.SOCAT_V3_GRID

Commentaries on viewpoint : physiology and fast marathons

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Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition

Dravet syndrome is an archetypal rare severe epilepsy, considered “monogenic”, typically caused by loss-of-function SCN1A variants. Despite a recognisable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. Polygenic risk scores for intelligence are lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Physician-Scientist trainees: A “call to action” to confront future career challenges

Throughout their careers, physician-scientists must adapt to the dynamic landscape of the medical research environment. As such, current physicianscientist trainees must overcome unique obstacles on the path to productive research careers. In the paper by Levit et al. in this month’s Clinical and Investigative Medicine issue, Canadian research leaders describe the challenges and opportunities for the next generation of physician-scientists [1]. They paint a cautiously optimistic picture. The current article is an outlook and concurrent “call to action” for how ongoing physician-scientist concerns can be conquered from the perspective of a current Canadian MD-PhD student