Development of a multi-scanner facility for data acquisition for digital pathology artificial intelligence.

Whole slide imaging (WSI) of pathology glass slides using high-resolution scanners has enabled the large-scale application of artificial intelligence (AI) in pathology, to support the detection and diagnosis of disease, potentially increasing efficiency and accuracy in tissue diagnosis. Despite the promise of AI, it has limitations. 'Brittleness' or sensitivity to variation in inputs necessitates that large amounts of data are used for training. AI is often trained on data from different scanners but not usually by replicating the same slide across scanners. The utilisation of multiple WSI instruments to produce digital replicas of the same slides will make more comprehensive datasets and may improve the robustness and generalisability of AI algorithms as well as reduce the overall data requirements of AI training. To this end, the National Pathology Imaging Cooperative (NPIC) has built the AI FORGE (Facilitating Opportunities for Robust Generalisable data Emulation), a unique multi-scanner facility embedded in a clinical site in the NHS to (1) compare scanner performance, (2) replicate digital pathology image datasets across WSI systems, and (3) support the evaluation of clinical AI algorithms. The NPIC AI FORGE currently comprises 15 scanners from nine manufacturers. It can generate approximately 4,000 WSI images per day (approximately 7 TB of image data). This paper describes the process followed to plan and build such a facility. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Chemoselective Methionine Labelling of Recombinant Trastuzumab Shows High In Vitro and In Vivo Tumour Targeting.

A highly effective 2-step system for site-specific antibody modification and conjugation of the monoclonal antibody Herceptin (commercially available under Trastuzumab) in a cysteine-independent manner was used to generate labelled antibodies for in vivo imaging. The first step contains redox-activated chemical tagging (ReACT) of thioethers via engineered methionine residues to introduce specific alkyne moieties, thereby offering a novel easy way to fundamentally change the process of antibody bioconjugation. The second step involves modification of the introduced alkyne via azide-alkyne cycloaddition 'click' conjugation. The versatility of this 2-step approach is demonstrated here by the selective incorporation of a fluorescent dye but can also be applied to a wide variety of different conjugation partners depending on the desired application in a facile manner. Methionine-modified antibodies were characterised in vitro, and the diagnostic potential of the most promising variant was further analysed in an in vivo xenograft animal model using a fluorescence imaging modality. This study demonstrates how methionine-mediated antibody conjugation offers an orthogonal and versatile route to the generation of tailored antibody conjugates with in vivo applicability.

Aortic stiffness increases during prolonged sitting independent of intermittent standing or prior exercise.

INTRODUCTION: Adverse vascular responses can occur during prolonged sitting, including stiffening of the aortic artery which may contribute to cardiovascular disease. Few studies have investigated the impact of intermittent standing and/or prior exercise as strategies to attenuate these potentially deleterious vascular changes. PURPOSE: To investigate central vascular health responses during prolonged sitting, with and without intermittent standing and/or prior exercise. METHODS: Fifteen males aged 18 to 31 years were recruited. Subjects completed a control condition [Sitting Only (SO)], and three randomized strategy conditions [Sitting Plus Standing (SSt), Exercise Plus Sitting (ES), Exercise Plus Sitting Plus Standing (ESSt)]. For all conditions, measurements of carotid-femoral pulse wave velocity (cfPWV) were taken at pre- and post-intervention, and brachial and central blood pressure (BP) at pre-, 1-h, 2-h, and 3-h intervention. RESULTS: cfPWV significantly increased from pre- to post-intervention for all conditions (all p ≤ 0.043), as did brachial mean arterial pressure (MAP) and diastolic BP, and central MAP and diastolic BP for the control condition (all p ≤ 0.022). Brachial and central systolic BP were significantly higher during SO compared to ESSt at 1 h, and compared to ES for central systolic BP (all p ≤ 0.036). CONCLUSIONS: Strategies of intermittent standing and/or prior exercise may not prevent aortic stiffening during sitting but may attenuate BP elevations in the brachial and aortic arteries. Future research should investigate causal mechanistic links between sitting and aortic stiffening, and other attenuation strategies.

Secondary Degeneration of Oligodendrocyte Precursor Cells Occurs as Early as 24 h after Optic Nerve Injury in Rats.

Optic nerve injury causes secondary degeneration, a sequela that spreads damage from the primary injury to adjacent tissue, through mechanisms such as oxidative stress, apoptosis, and blood-brain barrier (BBB) dysfunction. Oligodendrocyte precursor cells (OPCs), a key component of the BBB and oligodendrogenesis, are vulnerable to oxidative deoxyribonucleic acid (DNA) damage by 3 days post-injury. However, it is unclear whether oxidative damage in OPCs occurs earlier at 1 day post-injury, or whether a critical 'window-of-opportunity' exists for therapeutic intervention. Here, a partial optic nerve transection rat model of secondary degeneration was used with immunohistochemistry to assess BBB dysfunction, oxidative stress, and proliferation in OPCs vulnerable to secondary degeneration. At 1 day post-injury, BBB breach and oxidative DNA damage were observed, alongside increased density of DNA-damaged proliferating cells. DNA-damaged cells underwent apoptosis (cleaved caspase3+), and apoptosis was associated with BBB breach. OPCs experienced DNA damage and apoptosis and were the major proliferating cell type with DNA damage. However, the majority of caspase3+ cells were not OPCs. These results provide novel insights into acute secondary degeneration mechanisms in the optic nerve, highlighting the need to consider early oxidative damage to OPCs in therapeutic efforts to limit degeneration following optic nerve injury.

Shutting the studio: the impact of the Covid-19 pandemic on architectural education in the United Kingdom.

The Covid-19 pandemic instigated a rapid shift to remote learning in schools of architecture in the United Kingdom. Through the largest survey of its kind of architectural students and tutors in the UK, this research compares experiences in the physical design studio and its remote equivalent. The context of the pandemic provided a unique opportunity to survey a range of cohorts, at different stages in their architectural education to compare these two modes of studio delivery. The findings show a fall in student satisfaction after the move to remote learning in every metric assessed. Peer interaction and support were particularly effected. More formal teaching interactions, such as reviews, crits and tutorials, also suffered but to a lesser extent. For teaching staff, some small improvements in the working environment were observed as well as organisational factors. However, these small gains were outweighed by the negative changes. The research suggests that despite the replication of teaching activities digitally, the situated learning of design education and the facilitation of informal learning scenarios are critical components of design education. This research contributes to the ongoing characterisation of architectural education's signature pedagogy and suggests that for effective remote learning, design studio education must be reconceptualised, and alternative pedagogies embraced. This can direct educators looking to develop remote design studio learning as well as highlighting areas in which the traditional model of architectural education may be enhanced.

A comparison of monitoring designs to assess wildlife community parameters across spatial scales.

Dedicated long-term monitoring at appropriate spatial and temporal scales is necessary to understand biodiversity losses and develop effective conservation plans. Wildlife monitoring is often achieved by obtaining data at a combination of spatial scales, ranging from local to broad, to understand the status, trends, and drivers of individual species or whole communities and their dynamics. However, limited resources for monitoring necessitates tradeoffs in the scope and scale of data collection. Careful consideration of the spatial and temporal allocation of finite sampling effort is crucial for monitoring programs that span multiple spatial scales. Here we evaluate the ability of five monitoring designs-stratified random, weighted effort, indicator unit, rotating panel, and split panel-to recover parameter values that describe the status (occupancy), trends (change in occupancy), and drivers (spatially varying covariate and an autologistic term) of wildlife communities at two spatial scales. Using an amphibian monitoring program that spans a network of US national parks as a motivating example, we conducted a simulation study for a regional community occupancy sampling program to compare the monitoring designs across varying levels of sampling effort (ranging from 10% to 50%). We found that the stratified random design outperformed the other designs for most parameters of interest at both scales and was thus generally preferable in balancing the estimation of status, trends, and drivers across scales. However, we found that other designs had improved performance in specific situations. For example, the rotating panel design performed best at estimating spatial drivers at a regional level. Thus, our results highlight the nuanced scenarios in which various design strategies may be preferred and offer guidance as to how managers can balance common tradeoffs in large-scale and long-term monitoring programs in terms of the specific knowledge gained. Monitoring designs that improve accuracy in parameter estimates are needed to guide conservation policy and management decisions in the face of broad-scale environmental challenges, but the preferred design is sensitive to the specific objectives of a monitoring program.

Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling.

Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/ß-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.

An acute bout of controlled subconcussive impacts can alter dynamic cerebral autoregulation indices: a preliminary investigation.

OBJECTIVES: There is growing concern repetitive head contacts sustained by soccer players may lead to long-term health ramifications. Therefore, this preliminary investigation examined the impact an acute soccer heading bout has on dynamic cerebral autoregulation (dCA) metrics. METHODS: In this preliminary investigation, 40 successful soccer headers were performed in 20 min by 7 male elite soccer players (24.1 ± 1.5 years). Soccer balls were launched at 77.5 ± 3.7 km/h from JUGS soccer machine, located 35 m away from participants. Linear and rotational head accelerations impacts were measured using an accelerometer (xPatch). The SCAT3 indexed concussion symptom score and severity before and after: soccer headers, sham (body contact only), and control conditions. Squat-stand maneuvers were performed at 0.05 Hz and 0.10 Hz to quantity dCA through measures of coherence, phase, and gain. RESULTS: Cumulative linear and rotational accelerations during soccer headers were 1574 ± 97.9 g and 313,761 ± 23,966 rads/s2, respectively. SCAT3 symptom severity was elevated after the soccer heading bout (pre 3.7 ± 3.6, post 9.4 ± 7.6: p = 0.030) and five of the seven participants reported an increase in concussion-like symptoms (pre: 2.6 ± 3.0, post: 6.7 ± 6.2; p = 0.078). Phase at 0.10 Hz was elevated following soccer heading (p = 0.008). No other dCA metric differed following the three conditions. CONCLUSION: These preliminary results indicate an acute bout of soccer heading resulted in alterations to dCA metrics. Therefore, future research with larger sample sizes is warranted to fully comprehend short- and long-term physiological changes related to soccer heading.

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5-lipoxygenase expression in aggressive subtypes of endometrial cancer.

Eicosanoids comprise a diverse group of bioactive lipids which orchestrate inflammation, immunity, and tissue homeostasis, and whose dysregulation has been implicated in carcinogenesis. Among the various eicosanoid metabolic pathways, studies of their role in endometrial cancer (EC) have very much been confined to the COX-2 pathway. This study aimed to determine changes in epithelial eicosanoid metabolic gene expression in endometrial carcinogenesis; to integrate these with eicosanoid profiles in matched clinical specimens; and, finally, to investigate the prognostic value of candidate eicosanoid metabolic enzymes. Eicosanoids and related mediators were profiled using liquid chromatography-tandem mass spectrometry in fresh frozen normal, hyperplastic, and cancerous (types I and II) endometrial specimens (n = 192). Sample-matched epithelia were isolated by laser capture microdissection and whole genome expression analysis was performed using microarrays. Integration of eicosanoid and gene expression data showed that the accepted paradigm of increased COX-2-mediated prostaglandin production does not apply in EC carcinogenesis. Instead, there was evidence for decreased PGE2 /PGF2α inactivation via 15-hydroxyprostaglandin dehydrogenase (HPGD) in type II ECs. Increased expression of 5-lipoxygenase (ALOX5) mRNA was also identified in type II ECs, together with proportional increases in its product, 5-hydroxyeicosatetraenoic acid (5-HETE). Decreased HPGD and elevated ALOX5 mRNA expression were associated with adverse outcome, which was confirmed by immunohistochemical tissue microarray analysis of an independent series of EC specimens (n = 419). While neither COX-1 nor COX-2 protein expression had prognostic value, low HPGD combined with high ALOX5 expression was associated with the worst overall and progression-free survival. These findings highlight HPGD and ALOX5 as potential therapeutic targets in aggressive EC subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A Prospective Transcranial Doppler Ultrasound-Based Evaluation of the Effects of Repetitive Subconcussive Head Trauma on Neurovascular Coupling Dynamics.

OBJECTIVE: To determine the effects of repetitive subconcussive head trauma on neurovascular coupling (NVC) responses. DESIGN: Prospective cohort study collected between September 2013 and December 2016. SETTING: University laboratory. PARTICIPANTS: One hundred seventy-nine elite, junior-level (age, 19.6 ± 1.5 years) contact sport (ice hockey, American football) athletes recruited for preseason testing. Fifty-two nonconcussed athletes returned for postseason testing. Fifteen noncontact sport athletes (age, 20.4 ± 2.2 years) also completed preseason and postseason testing. EXPOSURE(S): Subconcussive sport-related head trauma. MAIN OUTCOME MEASURES: Dynamics of NVC were estimated during cycles of 20 seconds eyes closed and 40 seconds eyes open to a visual stimulus (reading) by measuring cerebral blood flow (CBF) velocity in the posterior (PCA) and middle (MCA) cerebral arteries via transcranial Doppler ultrasound. RESULTS: Both athlete groups demonstrated no significant differences in PCA or MCA NVC dynamics between preseason and postseason, despite exposure to a median of 353.5 (range, 295.0-587.3) head impacts (>2g) over the course of the season for contact sport athletes. CONCLUSIONS: Within the context of growing concern over detrimental effects of repetitive subconcussive trauma, the current results encouragingly suggest that the dynamics of NVC responses are not affected by 1 season of participation in junior-level ice hockey or American football. This is an important finding because it indicates an appropriate postseason CBF response to elevated metabolic demand with increases in neural activity.

Human Disc Nucleotomy Alters Annulus Fibrosus Mechanics at Both Reference and Compressed Loads.

Nucleotomy is a common surgical procedure and is also performed in ex vivo mechanical testing to model decreased nucleus pulposus (NP) pressurization that occurs with degeneration. Here, we implement novel and noninvasive methods using magnetic resonance imaging (MRI) to study internal 3D annulus fibrosus (AF) deformations after partial nucleotomy and during axial compression by evaluating changes in internal AF deformation at reference loads (50 N) and physiological compressive loads (∼10% strain). One particular advantage of this methodology is that the full 3D disc deformation state, inclusive of both in-plane and out-of-plane deformations, can be quantified through the use of a high-resolution volumetric MR scan sequence and advanced image registration. Intact grade II L3-L4 cadaveric human discs before and after nucleotomy were subjected to identical mechanical testing and imaging protocols. Internal disc deformation fields were calculated by registering MR images captured in each loading state (reference and compressed) and each condition (intact and nucleotomy). Comparisons were drawn between the resulting three deformation states (intact at compressed load, nucleotomy at reference load, nucleotomy at compressed load) with regard to the magnitude of internal strain and direction of internal displacements. Under compressed load, internal AF axial strains averaged -18.5% when intact and -22.5% after nucleotomy. Deformation orientations were significantly altered by nucleotomy and load magnitude. For example, deformations of intact discs oriented in-plane, whereas deformations after nucleotomy oriented axially. For intact discs, in-plane components of displacements under compressive loads oriented radially outward and circumferentially. After nucleotomy, in-plane displacements were oriented radially inward under reference load and were not significantly different from the intact state at compressed loads. Re-establishment of outward displacements after nucleotomy indicates increased axial loading restores the characteristics of internal pressurization. Results may have implications for the recurrence of pain, design of novel therapeutics, or progression of disc degeneration.

Cross-sectional comparison of spiral versus block integrated curriculums in preparing medical students to diagnose and manage concussions.

BACKGROUND: An integrated curriculum is designed to be repetitive yet progressive and the concept has rapidly established itself within medical education. National organizations have recommended a shift to a spiral curriculum design, which uses both vertical and horizontal integration. This study examined differences between the recently implemented integrated spiral (class of 2019) and conventional block (classes of 2016-2018) MD curricula at the University of British Columbia (UBC) with respect to knowledge of concussion. METHODS: Cross-sectional online survey (FluidSurveys: Fluidware, Ottawa, ON), distributed via email to UBC medical students during the 2015-2016 academic year. Questions focused on demographic data, knowledge of concussion definition, and management considerations. Differences in responses across the two groups were assessed using chi-square tests. Ordinal Likert-scale data were analyzed using Mann-Whitney U-Tests. Statistical significance was determined a priori at p < 0.05. RESULTS: One hundred forty eight medical students (57% female) responded with 78 students in the spiral curriculum and 70 students the block curriculum. Important differences between responses from spiral versus block curricula students included: formal exposure to concussion-related educational material (10.8 h spiral vs. 3.95 h block), understanding concussions can occur without direct head impacts (90% spiral vs. 70% block, X21,148 = 9.41, p = 0.002) and identifying long-term consequences (dementia: 90% spiral vs. 66% block, X21,148 = 12.57, p < 0.0001; second impact syndrome: 80% spiral vs. 57% block, X21,148 = 8.60, p = 0.003; Parkinsonism: 47% spiral vs. 17% block, X21,148 = 14.87, p < 0.001). Block students identified the need for a full neurological exam (X21,148 = 17.63, p < 0.001) and had greater clinical exposure to acute concussion (47% block vs. 14% spiral, X21,148 = 19.27, p < 0.001) and post-concussion syndrome (37% block vs. 19% spiral, X21,148 = 5.91, p = 0.015). CONCLUSIONS: The findings from this preliminary study suggest the spiral curriculum design, which emphasizes and revisits clinical competencies, promotes a strong understanding and retention of knowledge in highly prevalent clinical conditions such as concussion.

Intratumoral stromal morphometry predicts disease recurrence but not response to 5-fluorouracil-results from the QUASAR trial of colorectal cancer.

AIMS: The biological importance of tumour-associated stroma is becoming increasingly apparent, but its clinical utility remains ill-defined. For stage II/Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC. METHODS AND RESULTS: Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified on digitised haematoxylin and eosin (H&E) sections derived from 1800 patients enrolled in QUASAR, which randomised 3239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic and predictive values of PoT/PoS measurements were determined by the use of stratified log-rank analyses. A high proportion of tumour stroma (≥50%) was associated with an increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1343) for <50% [rate ratio (RR) 1.62; 95% confidence interval (CI) 1.30-2.02; P < 0.0001]. Of patients with stromal proportions of ≥65%, 40% (46/115) had recurrent disease within 10 years. The adverse prognostic effect of a high stromal proportion was independent of established prognostic variables, and was maintained in stage II/Dukes B patients (RR 1.62; 95% CI 1.26-2.08; P = 0.0002). KRAS mutation in the presence of a high stromal proportion augmented recurrence risk (RR 2.93; 95% CI 1.87-4.59; P = 0.0005). Stromal morphometry did not predict response to FUFA chemotherapy. CONCLUSIONS: Simple digital morphometry applied to a single representative H&E section identifies CRC patients with a >50% higher risk of disease recurrence. This technique can reliably partition patients into subpopulations with different risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted.

Microbubble-enhanced dielectric barrier discharge pretreatment of microcrystalline cellulose.

Cellulose recalcitrance is one of the major barriers in converting renewable biomass to biofuels or useful chemicals. A pretreatment reactor that forms a dielectric barrier discharge plasma at the gas-liquid interface of the microbubbles has been developed and tested to pretreat α-cellulose. Modulation of the plasma discharge provided control over the mixture of species generated, and the reactive oxygen species (mainly ozone) were found to be more effective in breaking-up the cellulose structure compared to that of the reactive nitrogen species. The effectiveness of pretreatment under different conditions was determined by measuring both the solubility of treated samples in sodium hydroxide and conversion of cellulose to glucose via enzymatic hydrolysis. Solutions pretreated under pH 3 buffer solutions achieved the best result raising the solubility from 17% to 70% and improving the glucose conversion from 24% to 51%. Under the best conditions, plasma-microbubble treatment caused pronounced crevices on the cellulose surface enhancing access to the reactive species for further breakdown of the structure and to enzymes for saccharification.

Challenges and opportunities in developing targeted molecular imaging to determine inner ear defects of sensorineural hearing loss.

The development of inner ear gene carriers and delivery systems has enabled genetic defects to be repaired and hearing to be restored in mouse models. Today, promising advances in translational therapies provide confidence that targeted molecular therapy for inner ear diseases will be developed. Unfortunately, the currently available non-invasive modalities, such as Computerized Tomography scan or Magnetic Resonance Imaging provide insufficient resolution to identify most pathologies of the human inner ear, even when the current generation of contrast agents is utilized. The development of targeted contrast agents may play a critical role in determining the cause of, and treatment for, sensorineural hearing loss. Such agents should be able to pass through the cochlea barriers, possess minimal cytotoxicity, and easily conjugate to a targeting agent, without distorting the anatomic details. This review focuses on a series of contrast agents which may fit these criteria for potential clinical application.

Systolic and Diastolic Regulation of the Cerebral Pressure-Flow Relationship Differentially Affected by Acute Sport-Related Concussion.

OBJECTIVE: To determine whether acute sports-related concussion (SRC) exerts differential effects on cerebral autoregulatory properties during systole versus diastole. MATERIALS AND METHODS: One hundred and thirty-six contact-sport athletes tested preseason; 14 sustained a concussion and completed follow-up testing at 72 hours, 2 weeks, and 1 month post-injury. Five minutes of repetitive squat-stand maneuvers induced blood pressure (BP) oscillations at both 0.05 and 0.10 Hz. Beat-by-beat peak-systolic and end-diastolic BP (sysBP/ diasBP) and middle cerebral artery blood velocity (sysMCAv/diasMCAv) were recorded using finger photoplethysmography and transcranial Doppler ultrasound, respectively. Relationships between sysBP-sysMCAv and diasBP-diasMCAv were quantified using transfer function analysis to estimate coherence (correlation), gain (response magnitude), and phase (response latency). RESULTS: Significant main effects of the cardiac cycle were observed across all outcome metrics. A significant main effect of SRC was observed for 0.10 Hz phase: systolic and diastolic phases were reduced at 72 h (21.8 ± 5.2%) and 2 weeks (22.7 ± 7.1%) compared to preseason but recovered by 1 month. Concussion significantly impaired diastolic, but not systolic, gain: 0.10 Hz diastolic gain was increased (27.2 ± 7.7%) at 2 weeks, recovering by 1 month. CONCLUSIONS: Impairments in autoregulatory capacity, observed for a transient period following SRC that persist beyond symptom resolution and clinical recovery, appear to be differentially affected across the cardiac cycle. Similar patterns of impairment were observed for systolic and diastolic phases (response latency); however, normalized gain (response magnitude) impairments were identified only in diastole. These findings may explain the increased cerebral vulnerability as well as exercise-induced symptom exacerbation observed post-SRC.

Differential Systolic and Diastolic Regulation of the Cerebral Pressure-Flow Relationship During Squat-Stand Manoeuvres.

OBJECTIVE: Cerebral pressure-flow dynamics are typically reported between mean arterial pressure and mean cerebral blood velocity. However, by reporting only mean responses, potential differential regulatory properties associated with systole and diastole may have been overlooked. MATERIALS AND METHODS: Twenty young adults (16 male, age: 26.7 ± 6.6 years, BMI: 24.9 ± 3.0 kg/m2) were recruited for this study. Middle cerebral artery velocity was indexed via transcranial Doppler. Cerebral pressure-flow dynamics were assessed using transfer function analysis at both 0.05 and 0.10 Hz using squat-stand manoeuvres. This method provides robust and reliable measures for coherence (correlation index), phase (timing buffer) and gain (amplitude buffer) metrics. RESULTS: There were main effects for both cardiac cycle and frequency for phase and gain metrics (p < 0.001). The systolic phase (mean ± SD) was elevated at 0.05 (1.07 ± 0.51 radians) and 0.10 Hz (0.70 ± 0.46 radians) compared to the diastolic phase (0.05 Hz: 0.59 ± 0.14 radians; 0.10 Hz: 0.33 ± 0.11 radians). Conversely, the systolic normalized gain was reduced (0.05 Hz: 0.49 ± 0.12%/%; 0.10 Hz: 0.66 ± 0.20%/%) compared to the diastolic normalized gain (0.05 Hz: 1.46 ± 0.43%/%; 0.10 Hz: 1.97 ± 0.48%/%). CONCLUSIONS: These findings indicate there are differential systolic and diastolic aspects of the cerebral pressure-flow relationship. The oscillations associated with systole are extensively buffered within the cerebrovasculature, whereas diastolic oscillations are relatively unaltered. This indicates that the brain is adapted to protect itself against large increases in systolic blood pressure, likely as a mechanism to prevent cerebral haemorrhages.

Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development.

Myocardin is a muscle-restricted transcriptional coactivator that activates a serum response factor (SRF)-dependent gene program required for cardiogenesis and embryonic survival. To identify myocardin-dependent functions in smooth muscle cells (SMCs) during postnatal development, mice harboring a SMC-restricted conditional, inducible Myocd null mutation were generated and characterized. Tamoxifen-treated SMMHC-Cre(ERT2)/Myocd(F/F) conditional mutant mice die within 6 mo of Myocd gene deletion, exhibiting profound derangements in the structure of great arteries as well as the gastrointestinal and genitourinary tracts. Conditional mutant mice develop arterial aneurysms, dissection, and rupture, recapitulating pathology observed in heritable forms of thoracic aortic aneurysm and dissection (TAAD). SMCs populating arteries of Myocd conditional mutant mice modulate their phenotype by down-regulation of SMC contractile genes and up-regulation of extracellular matrix proteins. Surprisingly, this is accompanied by SMC autonomous activation of endoplasmic reticulum (ER) stress and autophagy, which over time progress to programmed cell death. Consistent with these observations, Myocd conditional mutant mice develop remarkable dilation of the stomach, small intestine, bladder, and ureters attributable to the loss of visceral SMCs disrupting the muscularis mucosa. Taken together, these data demonstrate that during postnatal development, myocardin plays a unique, and important, role required for maintenance and homeostasis of the vasculature, gastrointestinal, and genitourinary tracts. The loss of myocardin in SMCs triggers ER stress and autophagy, which transitions to apoptosis, revealing evolutionary conservation of myocardin function in SMCs and cardiomyocytes.

A History of Concussion Does Not Lead to an Increase in Ocular Near Point of Convergence.

Ocular near point of convergence (NPC) has been shown to be sensitive to the effects of concussion and subconcussive impacts. To determine if NPC is also sensitive to a previous history of concussion, male contact-sport athletes either with (n=26) or without (n=16) a history of at least one previous concussion had their NPC assessed. The results showed that participants with a history of concussion displayed NPC values (9.4±1.6 cm) indistinguishable from those with no history of concussion (8.4±2.1 cm, t-test, p=0.09). This was the case regardless of whether 1, 2, or 3 or more concussions had occurred and despite the fact participants with concussion (mean time since last concussion: 1136 days) suffered from an increased number and severity of symptoms as assessed with the SCAT 3 (3.6±2.2 vs. 2.13±1.89 symptoms, 6.1±4.1 vs. 3.19±2.99 severity, t-test, p<0.05). Taken together, these results imply that NPC may not be a suitable tool to assess the potential long-term effects of one or more concussions over a longer time frame.: Future research using larger sample sizes is warranted to evaluate the potential dose-response relationship between number of prior concussions and NPC.

Fish kairomones induce spine elongation and reduce predation in marine crab larvae.

Specialized defense strategies are induced in zooplankton upon detection of predator chemical cues or kairomones. These defenses are well-described for freshwater zooplankters, with morphological defenses being particularly striking, but few studies have reported kairomone-induced morphological defenses in marine zooplankton. Here, we compare morphological responses to kairomones in the larvae of two marine crab species, estuarine mud crabs (Rhithropanopeus harrisii) and Asian shore crabs (Hemigrapsus sanguineus). When reared in the presence of fish kairomones, spine length increased by 2-3% in larval R. harrisii, while no morphological changes were identified in H. sanguineus. In subsequent feeding assays with a co-occurring fish predator (Atlantic silversides, Menidia menidia), consumption of R. harrisii was lower on larvae that had been reared with kairomones. In addition, we found that broods with smaller larvae are more likely to exhibit increases in spine length after kairomone exposure. Hence, the observed morphological response is likely influenced by larval size.