Sexual dimorphism during integrative endocrine and immune responses to ionizing radiation in mice.

Exposure to cosmic ionizing radiation is an innate risk of the spaceflight environment that can cause DNA damage and altered cellular function. In astronauts, longitudinal monitoring of physiological systems and interactions between these systems are important to consider for mitigation strategies. In addition, assessments of sex-specific biological responses in the unique environment of spaceflight are vital to support future exploration missions that include both females and males. Here we assessed sex-specific, multi-system immune and endocrine responses to simulated cosmic radiation. For this, 24-week-old, male and female C57Bl/6J mice were exposed to simplified five-ion, space-relevant galactic cosmic ray (GCRsim) radiation at 15 and 50 cGy, to simulate predicted radiation exposures that would be experienced during lunar and Martian missions, respectively. Blood and adrenal tissues were collected at 3- and 14-days post-irradiation for analysis of immune and endocrine biosignatures and pathways. Sexually dimorphic adrenal gland weights and morphology, differential total RNA expression with corresponding gene ontology, and unique immune phenotypes were altered by GCRsim. In brief, this study offers new insights into sexually dimorphic immune and endocrine kinetics following simulated cosmic radiation exposure and highlights the necessity for personalized translational approaches for astronauts during exploration missions.

In Vivo Longitudinal Monitoring of Cardiac Remodeling in Murine Ischemia Models With Adaptive Bayesian Regularized Cardiac Strain Imaging: Validation Against Histology.

Adaptive Bayesian regularized cardiac strain imaging (ABR-CSI) uses raw radiofrequency signals to estimate myocardial wall contractility as a surrogate measure of relative tissue elasticity incorporating regularization in the Bayesian sense. We determined the feasibility of using ABR-CSI -derived strain for in vivo longitudinal monitoring of cardiac remodeling in a murine ischemic injury model (myocardial infarction [MI] and ischemia-reperfusion [IR]) and validated the findings against ground truth histology. We randomly stratified 30 BALB/CJ mice (17 females, 13 males, median age = 10 wk) into three surgical groups (MI = 10, IR = 12, sham = 8) and imaged pre-surgery (baseline) and 1, 2, 7 and 14 d post-surgery using a pre-clinical high-frequency ultrasound system (VisualSonics Vevo 2100). We then used ABR-CSI to estimate end-systolic and peak radial (er) and longitudinal (el) strain estimates. ABR-CSI was found to have the ability to serially monitor non-uniform cardiac remodeling associated with murine MI and IR non-invasively through temporal variation of strain estimates post-surgery. Furthermore, radial end-systole (ES) strain images and segmental strain curves exhibited improved discrimination among infarct, border and remote regions around the myocardium compared with longitudinal strain results. For example, the MI group had significantly lower (Friedman's with Bonferroni-Dunn test, p = 0.002) ES er values in the anterior middle (infarcted) region at day 14 (n = 9, 9.23 ± 7.39%) compared with the BL group (n = 9, 44.32 ± 5.49). In contrast, anterior basal (remote region) mean ES er values did not differ significantly (non-significant Friedman's test, χ2 = 8.93, p = 0.06) at day 14 (n = 6, 33.05 ± 6.99%) compared with baseline (n = 6, 34.02 ± 6.75%). Histology slides stained with Masson's trichrome (MT) together with a machine learning model (random forest classifier) were used to derive the ground truth cardiac fibrosis parameter termed histology percentage of myocardial fibrosis (PMF). Both radial and longitudinal strain were found to have strong statistically significant correlations with the PMF parameter. However, radial strain had a higher Spearman's correlation value (εresρ = -0.67, n = 172, p < 0.001) compared with longitudinal strain (εlesρ = -0.60, n = 172, p < 0.001). Overall, the results of this study indicate that ABR-CSI can reliably perform non-invasive detection of infarcted and remote myocardium in small animal studies.

Persistent Asthma Is Associated With Carotid Plaque in MESA.

Background Asthma and atherosclerotic cardiovascular disease share an underlying inflammatory pathophysiology. We hypothesized that persistent asthma is associated with carotid plaque burden, a strong predictor of atherosclerotic cardiovascular disease events. Methods and Results The MESA (Multi-Ethnic Study of Atherosclerosis) enrolled adults free of known atherosclerotic cardiovascular disease at baseline. Subtype of asthma was determined at examination 1. Persistent asthma was defined as asthma requiring use of controller medications, and intermittent asthma was defined as asthma without controller medications. B-mode carotid ultrasound was performed to detect carotid plaques (total plaque score [TPS], range 0-12). Multivariable regression modeling with robust variances evaluated the association of asthma subtype and carotid plaque burden. The 5029 participants were a mean (SD) age of 61.6 (10.0) years (53% were women, 26% were Black individuals, 23% were Hispanic individuals, and 12% were Chinese individuals). Carotid plaque was present in 50.5% of participants without asthma (TPS, 1.29 [1.80]), 49.5% of participants with intermittent asthma (TPS, 1.25 [1.76]), and 67% of participants with persistent asthma (TPS, 2.08 [2.35]) (P≤0.003). Participants with persistent asthma had higher interleukin-6 (1.89 [1.61] pg/mL) than participants without asthma (1.52 [1.21] pg/mL; P=0.02). In fully adjusted models, persistent asthma was associated with carotid plaque presence (odds ratio, 1.83 [95% confidence interval, 1.21-2.76]; P<0.001) and TPS (ß=0.66; P<0.01), without attenuation after adjustment for baseline interleukin-6 (P=0.02) or CRP (C-reactive protein) (P=0.01). Conclusions Participants with persistent asthma had higher carotid plaque burden and higher levels of inflammatory biomarkers, compared with participants without asthma. Adjustment for baseline inflammatory biomarkers did not attenuate the association between carotid plaque and asthma subtype, highlighting the increased atherosclerotic cardiovascular disease risk among those with persistent asthma may be multifactorial.

Murine cardiac fibrosis localization using adaptive Bayesian cardiac strain imaging in vivo.

An adaptive Bayesian regularized cardiac strain imaging (ABR-CSI) algorithm for in vivo murine myocardial function assessment is presented. We report on 31 BALB/CJ mice (n = 17 females, n = 14 males), randomly stratified into three surgical groups: myocardial infarction (MI, n = 10), ischemia-reperfusion (IR, n = 13) and control (sham, n = 8) imaged pre-surgery (baseline- BL), and 1, 2, 7 and 14 days post-surgery using a high frequency ultrasound imaging system (Vevo 2100). End-systole (ES) radial and longitudinal strain images were used to generate cardiac fibrosis maps using binary thresholding. Percentage fibrotic myocardium (PFM) computed from regional fibrosis maps demonstrated statistically significant differences post-surgery in scar regions. For example, the MI group had significantly higher PFMRadial (%) values in the anterior mid region (p = 0.006) at Day 14 (n = 8, 42.30 ± 14.57) compared to BL (n = 12, 1.32 ± 0.85). A random forest classifier automatically detected fibrotic regions from ground truth Masson's trichrome stained histopathology whole slide images. Both PFMRadial (r = 0.70) and PFMLongitudinal (r = 0.60) results demonstrated strong, positive correlation with PFMHistopathology (p < 0.001).

Bayesian Regularized Strain Imaging for Assessment of Murine Cardiac Function In vivo.

A cardiac strain imaging framework with adaptive Bayesian regularization (ABR) is proposed for in vivo assessment of murine cardiac function. The framework uses ultrasound (US) radio-frequency data collected with a high frequency (fc = 30MHz) imaging system and a multi-level block matching algorithm with ABR to derive inter-frame cardiac displacements. Lagrangian cardiac strain (radial, er and longitudinal, el) tensors were derived by segmenting the myocardial wall starting at the ECG R-wave and accumulating interframe deformations over a cardiac cycle. In vivo feasibility was investigated through a longitudinal study with two mice (one ischemia-perfusion (IR) injury and one sham) imaged at five sessions (pre-surgery (BL) and 1,2,7 and 14 days post-surgery). End-systole (ES) strain images and segmental strain curves were derived for quantitative evaluation. Both mice showed periodic variation of er and el strain at BL with segmental synchroneity. Infarcted regions of IR mouse at Day 14 were associated with reduced or sign reversed ES er and el values while the sham mouse had similar or higher strain than at BL. Infarcted regions identified in vivo were associated with increased collagen content confirmed with Masson's Trichrome stained ex vivo heart sections.Clinical Relevance-Higher quality cardiac strain images derived with RF data and Bayesian regularization can potentially improve the sensitivity and accuracy of non-invasive assessment of cardiovascular disease models.

Changes in carotid artery structure with smoking cessation.

Carotid artery grayscale ultrasound echogenicity and texture features predict cardiovascular disease events. We evaluated the longitudinal effects of smoking cessation on four grayscale ultrasound measures. This was a secondary analysis of data from 188 age, sex, and body mass index (BMI)-matched smokers (94 eventual abstainers [EA], 94 continued smokers [CS]) from a smoking cessation trial that had carotid ultrasound examinations at baseline and after 3 years. General linear models that included time, smoking group (EA or CS), and a time*smoking interaction term were used to examine the impact of smoking abstinence on carotid artery grayscale marker values at year 3. Participants were mean (SD) 50.3 (11.4) years old (57% female, 86% white). The baseline grayscale median value (GSM) was inversely correlated with age, BMI, insulin resistance, and smoking pack-years (r = -0.20 to -0.30, p < 0.007 for all). There was a significant time*smoking status interaction for predicting GSM at year 3: GSM decreased significantly in the EA group compared to the CS group (-3.63 [13.00] vs CS 0.39 [12.06] units; p = 0.029). BMI increased more in the EA than the CS group (2.42 [3.00] vs CS 0.35 [2.57] kg/m2; p < 0.001). After adjusting for changes in BMI, the time*smoking status interaction no longer was significant (p = 0.138). From baseline to year 3, contrast increased similarly in both groups. Entropy and angular second moment did not change significantly in either group. Changes in carotid ultrasound echogenicity and grayscale texture features during a smoking cessation attempt are modest and mostly related to weight gain. Clinicaltrials.gov Identifier: NCT01553084.

Carotid artery displacement and cardiovascular disease risk in the Multi-Ethnic Study of Atherosclerosis.

Novel technology permits quantification of common carotid artery (CCA) displacement, which is traditionally ignored. We evaluated associations with CCA displacement and cardiovascular disease (CVD) risk and events in a large, multi-ethnic cohort. Right CCA longitudinal displacement (LD), transverse displacement (TD), and grayscale median (GSM) were evaluated using ultrasound speckle-tracking and texture analysis software in 2050 participants. Regression analyses were used to define relationships between CCA LD, TD, GSM, and CVD risk factors. Cox proportional hazards models were used to assess relationships between LD, TD, and incident CVD events. Participants were mean (SD) 64 (10) years old. There were 791 cases with a CVD event over a 12-year median follow-up. The mean LD was 0.29 (0.20) mm. In multivariable models including age, sex, race/ethnicity, heart rate, and CVD risk factors, LD was associated positively with active smoking (ß = 0.08, p < 0.001) and inversely with black (ß = -0.08, p < 0.001), Chinese (ß = -0.05, p < 0.001), and Hispanic (ß = -0.04, p < 0.05) race/ethnicities relative to white individuals, heart rate (ß = -0.03/10 beats/min, p < 0.001), and diastolic blood pressure (ß = -0.01/5 mmHg, p < 0.05). In fully adjusted models, LD and TD were associated with GSM (p < 0.01), but neither predicted incident CVD events (LD: hazard ratio (HR) 0.77 [0.48 to 1.24], p = 0.3; TD: HR 1.12 [0.8 to 1.57], p = 0.5). CCA LD and TD are associated with race/ethnicity and CVD risk factors but not incident CVD events. LD and TD are not measures of arterial stiffness but their association with GSM suggests that lower LD and TD may be related to structural changes within the carotid arterial wall.

Brachial artery intima-media thickness and grayscale texture changes in patients with peripheral artery disease receiving supervised exercise training in the PROPEL randomized clinical trial.

We performed an exploratory analysis to evaluate the effects of a treadmill exercise program on brachial artery (BA) intima-media thickness (IMT) and three BA grayscale ultrasound measures that may indicate subclinical arterial injury. Data were from a clinical trial in individuals with peripheral artery disease who were randomly assigned to treadmill exercise training or attention control. B-mode ultrasonography was performed at baseline and after 26 weeks. BA IMT, grayscale median (GSM), entropy, and gray-level difference statistic-contrast (GLDS-CON) were measured by a single reader. The 184 participants were (mean (SD)) 66.7 (8.2) years old and had an ankle-brachial index of 0.70 (0.18). Exercise training was associated with a 0.01 (0.06) mm ( p = 0.025) reduction in BA IMT compared to 0.00 (0.05) mm ( p = 0.807) in the control group (between-group p = 0.061). BA GSM, entropy, and GLDS-CON did not change significantly with exercise. Improvements in the 6-minute walk distance correlated with increases in resting BA blood flow ( r = 0.23, p = 0.032), flow-mediated dilation ( r = 0.24, p = 0.022), diameter ( r = 0.29, p = 0.005), entropy ( r = 0.21, p = 0.047), and GLDS-CON ( r = 0.22, p = 0.041). In a post hoc analysis, BA IMT improved significantly with treadmill exercise training but did not change with attention control; however, the between-group difference did not reach statistical significance. With exercise, improvements in the 6-minute walk distance were associated with improved endothelial function, increased resting blood flow, and BA dilation, as well as higher grayscale entropy and GLDS-CON, indicating that lower extremity exercise is associated with salutary changes in upper-extremity arterial wall structure and function. ClinicalTrials.gov Identifier: NCT01408901.

Echogenicity of the carotid arterial wall in active smokers.

This pilot study evaluated associations between carotid wall echogenicity, cardiovascular disease (CVD) risk factors, and three markers of smoking heaviness in a cohort of active smokers. Common carotid artery (CCA) grayscale median (GSM) values were measured from sonographic images. Univariable correlations and exploratory multivariable models were used to determine associations between CCA GSM, CVD risk factors, and measures of smoking heaviness. CCA GSM was measured in 162 smokers and was correlated inversely with cigarettes smoked/day (r=-0.16, p=0.048), pack-years (r=-0.204, p=0.009), CVD risk factors such as age, male sex, waist circumference, and low-density lipoprotein cholesterol (all p≤0.03) and positively with high-density lipoprotein cholesterol (p<0.001). Associations between CCA GSM and smoking heaviness markers were not statistically significant after adjustment for traditional risk factors. The results from this pilot study demonstrate the feasibility of measuring the GSM value of the CCA far wall and its association with measures of smoking heaviness and traditional CVD risk factors among current smokers.

The Safety of Multiple Flexible Sigmoidoscopies with Mucosal Biopsies in Healthy Clinical Trial Participants.

During Phase 1 pharmacokinetic/pharmacodynamics studies, participants may undergo multiple sigmoidoscopies, with a collection of 10-20 biopsies during each procedure. This article characterizes the safety of flexible sigmoidoscopies in clinical trial participants. We determined the number of flexible sigmoidoscopies and rectal biopsies that participants underwent and analyzed the frequency, duration, and severity of flexible sigmoidoscopy-related adverse events (AEs). During the study period, 278 participants underwent 1,004 flexible sigmoidoscopies with the collection of 15,930 rectal biopsies. The average number of procedures per participant was 3.6 (median 3; range 1-25), with an average time interval between procedures of 61.8 days (median 28 days; range 1-1,159). There were no serious AEs. Sixteen AEs were related to flexible sigmoidoscopy and occurred in 16 participants, leading to an overall 1.6% (16/1,004) AE rate per procedure and 0.1% (16/15,930) AE rate per biopsy. Of the 16 AEs, 8 (50%) involved abdominal pain, diarrhea, bleeding, flatulence, and bloating, with an average duration of 4.7 days (median 1 day; range 1-28). Most (14/16) AEs were categorized as Grade 1 (mild), whereas two of the AEs were Grade 2 (moderate). No participant withdrew due to procedure-related AEs. Overall, the number of AEs caused by flexible sigmoidoscopy with multiple biopsies was low and the severity was mild, suggesting that this procedure can be safely integrated into protocols requiring repeated intestinal mucosal sampling.

The relationship between carotid artery plaque stability and white matter ischemic injury.

Higher local carotid artery strain has previously been shown to be a characteristic of unstable carotid plaques. These plaques may be characterized by microvascular changes that predispose to intraplaque hemorrhage, increasing the likelihood of embolization. Little is known however, about how these strain indices correspond with imaging markers of brain health and metrics of brain structure. White matter hyperintensities (WMHs), which are bright regions seen on T2-weighted brain MRI imaging, are postulated to result from cumulative ischemic vascular injury. Consequently, we hypothesized that plaques that are more prone to microvascular changes and embolization, represented by higher strain indices on ultrasound, would be associated with an increased amount of WMH lesion volume. This relationship would suggest not only emboli as a cause for the brain degenerative changes, but more importantly, a common microvascular etiology for large and small vessel contributions to this process. Subjects scheduled to undergo a carotid endarterectomy were recruited from a neurosurgery clinic. Prior to surgery, participating subjects underwent both ultrasound strain imaging and brain MRI scans as part of a larger clinical study on vascular health and cognition. A linear regression found that maximum absolute strain and peak to peak strain in the surgical side carotid artery were predictive of WMH burden. Furthermore, the occurrence of microembolic signals monitored using transcranial Doppler (TCD) ultrasound examinations also correlated with increasing lesion burden. It is becoming increasingly recognized that cognitive decline is often multifactorial in nature. One contributing extra-brain factor may be changes in the microvasculature that produce unstable carotid artery plaques. In this study, we have shown that higher strain indices in carotid artery plaques are significantly associated with an increased WMH burden, a marker of vascular mediated brain damage.

Dietary water and sodium intake of children and adolescents with sickle cell anemia.

Dietary fluid and sodium intake may influence the risk for vasoocclusive events in persons with sickle cell anemia (SCA). The objective of this study was to examine the dietary intake of water and sodium in children and adolescents with SCA and identify possible factors influencing intake. We compared water (mL) and sodium (mg) intake in 21 patients with SCA, aged 5 to 18 years, to reported adequate intake for water, daily fluid requirement, upper limit for sodium, and National Health and Nutrition Examination Survey 2005 to 2006 data for sodium, and sociodemographic factors. Dietary intake from 3-day food records was evaluated retrospectively. Median water intake was significantly lower than adequate intake, and median sodium intake was significantly higher than sodium upper limit. Sociodemographic factors were not associated with dietary water or sodium intake. Our results suggest that children and adolescents with SCA would benefit from education regarding increasing fluid intake and limiting high sodium foods.

Perceptions of knowledge, beliefs, and barriers to colorectal cancer screening.

BACKGROUND: Colorectal cancer (CRC) screening is an effective tool that aggressively identifies and treats preventable colorectal disease. Yet incidence and mortality disparities still exist. METHODS: A cross-sectional sample of persons at risk of CRC residing in a Midwestern metropolitan area (n = 43) reported their knowledge, beliefs, and perceived barriers of CRC screening. RESULTS: Minorities were significantly more likely to have inaccurate knowledge/beliefs and increased perceived internal/external barriers of CRC screening than Whites. CONCLUSIONS: Health education programs designed to increase CRC screening efficacy have to address the predisposed knowledge, beliefs, and perceived barriers of diverse persons at risk.

Preliminary in vivo atherosclerotic carotid plaque characterization using the accumulated axial strain and relative lateral shift strain indices.

In this paper, we explore two parameters or strain indices related to plaque deformation during the cardiac cycle, namely, the maximum accumulated axial strain in plaque and the relative lateral shifts between plaque and vessel wall under in vivo clinical ultrasound imaging conditions for possible identification of vulnerable plaque. These strain indices enable differentiation between calcified and lipidic plaque tissue utilizing a new perspective based on the stiffness and mobility of the plaque. In addition, they also provide the ability to distinguish between softer plaques that undergo large deformations during the cardiac cycle when compared to stiffer plaque tissue. Soft plaques that undergo large deformations over the cardiac cycle are more prone to rupture and to release micro-emboli into the cerebral bloodstream. The ability to identify vulnerable plaque, prone to rupture, would significantly enhance the clinical utility of this method for screening patients. We present preliminary in vivo results obtained from ultrasound radio frequency data collected over 16 atherosclerotic plaque patients before these patients undergo a carotid endarterectomy procedure. Our preliminary in vivo results indicate that the maximum accumulated axial strain over a cardiac cycle and the maximum relative lateral shift or displacement of the plaque are useful strain indices that provide differentiation between soft and calcified plaques.

Going provincial: preceptoring and mentoring revisited in the health sciences. Part II--The evaluation.

Part I of this two part series, which was published in the Spring 2003 issue of Healthcare Management FORUM, described the Preceptor & Mentor Initiative for Health Sciences in BC, a provincial strategy to facilitate preceptoring and mentoring. Activities included creation of an educational web site and a UBC Continuing Studies preceptor course, and provincial workshops on preceptoring and mentoring. The purpose of this second article is to outline the philosophy, framework, results and interpretation of the Preceptor & Mentor Initiative's evaluation component.

Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate.

Exposure to the human carcinogen inorganic arsenic (iAs) occurs daily. However, the disposition of arsenic after repeated exposure is not well known. This study examined the disposition of arsenic after repeated po administration of arsenate. Whole-body radioassay of adult female B6C3F1 mice was used to estimate the terminal elimination half-life of arsenic after a single po dose of [(73)As]arsenate (0.5 mg As/kg). From these data, it was estimated that steady-state levels of whole-body arsenic could be attained after nine repeated daily doses of [(73)As]arsenate (0.5 mg As/kg). The mice were whole-body radioassayed immediately before and after the repeated dosing. Excreta were collected daily and analyzed for arsenic-derived radioactivity and arsenicals. Whole-body radioactivity was determined 24 h after the last repeated dose, and five mice were then euthanized and tissues analyzed for radioactivity. The remaining mice were whole-body radioassayed for 8 more days, and then their tissues were analyzed for radioactivity. Other mice were administered either a single or nine repeated po doses of non-radioactive arsenate (0.5 mg As/kg). Twenty-four hours after the last dose, the mice were euthanized, and tissues were analyzed for arsenic by atomic absorption spectrometry (AAS). Whole-body radioactivity was rapidly eliminated from mice after repeated [(73)As]arsenate exposure, primarily by urinary excretion in the form of dimethylarsinic acid (DMA(V)). Accumulation of radioactivity was highest in bladder, kidney, and skin. Loss of radioactivity was most rapid in the lung and slowest in the skin. There was an organ-specific distribution of arsenic as determined by AAS. Monomethylarsonic acid was detected in all tissues except the bladder. Bladder and lung had the highest percentage of DMA(V) after a single exposure to arsenate, and it increased with repeated exposure. In kidney, iAs was predominant. There was a higher percentage of DMA(V) in the liver than the other arsenicals after a single exposure to arsenate. The percentage of hepatic DMA(V) decreased and that of iAs increased with repeated exposure. A trimethylated metabolite was also detected in the liver. Tissue accumulation of arsenic after repeated po exposure to arsenate in the mouse corresponds to the known human target organs for iAs-induced carcinogenicity.