Child Abuse and Neglect and Subclinical Cardiovascular Disease Among Midlife Women.

OBJECTIVE: A childhood history of abuse or neglect may be associated with elevated adult cardiovascular disease (CVD) risk. No studies have examined associations between child abuse/neglect and subclinical CVD using a validated measure of abuse and neglect. We hypothesized that midlife women with a history of childhood abuse or neglect would have increased subclinical CVD beyond standard CVD risk factors. We tested moderation of associations by sleep, hot flashes, and race/ethnicity. METHODS: Two hundred ninety-five midlife women completed the Child Trauma Questionnaire, physiologic hot flash and actigraphic sleep monitoring, blood draw, and carotid ultrasound (intima media thickness [IMT]; plaque). Relations between abuse/neglect and outcomes were tested in linear regression models adjusting for demographic, psychosocial, and CVD risk factors. Interactions with sleep, hot flashes, and race/ethnicity were tested. RESULTS: Forty-five percent of women reported a history of child abuse or neglect. Women with any child abuse or neglect had higher IMT [b(SE) = .039 (.011), p = .001] and carotid plaque [odds ratio (95% [CI] = 1.95 [1.15-3.33]); p = .014] than nonabused/neglected women. Furthermore, physical abuse, emotional abuse, and emotional neglect were associated with higher subclinical CVD. Sexual abuse was associated with higher IMT among nonwhite women. Interactions with sleep time and sleep hot flashes (p values < .05) indicated that higher subclinical CVD with an abuse/neglect history was observed primarily among women sleeping less than 6 hours/night or with sleep hot flashes. CONCLUSIONS: A history of child abuse or neglect is associated with higher subclinical CVD in women, particularly when paired with short sleep or hot flashes. Findings underscore the importance of childhood adversity in midlife women's CVD risk.

Menopausal Hot Flashes and Carotid Intima Media Thickness Among Midlife Women.

BACKGROUND AND PURPOSE: There has been a longstanding interest in the role of menopause and its correlates in the development of cardiovascular disease (CVD) in women. Menopausal hot flashes are experienced by most midlife women; emerging data link hot flashes to CVD risk indicators. We tested whether hot flashes, measured via state-of-the-art physiologic methods, were associated with greater subclinical atherosclerosis as assessed by carotid ultrasound. We considered the role of CVD risk factors and estradiol concentrations in these associations. METHODS: A total of 295 nonsmoking women free of clinical CVD underwent ambulatory physiologic hot flash assessments; a blood draw; and carotid ultrasound measurement of intima media thickness and plaque. Associations between hot flashes and subclinical atherosclerosis were tested in regression models controlling for CVD risk factors and estradiol. RESULTS: More frequent physiologic hot flashes were associated with higher carotid intima media thickness (for each additional hot flash: ß [SE]=0.004 [0.001]; P=0.0001; reported hot flash: ß [SE]=0.008 [0.002]; P=0.002, multivariable) and plaque (eg, for each additional hot flash, odds ratio [95% confidence interval] plaque index ≥2=1.07 [1.003-1.14]; P=0.04, relative to no plaque, multivariable] among women reporting daily hot flashes; associations were not accounted for by CVD risk factors or by estradiol. Among women reporting hot flashes, hot flashes accounted for more variance in intima media thickness than most CVD risk factors. CONCLUSIONS: Among women reporting daily hot flashes, frequent hot flashes may provide information about a woman's vascular status beyond standard CVD risk factors and estradiol. Frequent hot flashes may mark a vulnerable vascular phenotype among midlife women.

Novel methodology to evaluate renal cysts in polycystic kidney disease.

AIM: To develop and assess a semiautomated method for segmenting and counting individual renal cysts from mid-slice MR images in patients with autosomal dominant polycystic kidney disease (ADPKD). METHODS: A semiautomated method was developed to segment and count individual renal cysts from mid-slice MR images in 241 subjects with ADPKD from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease. For each subject, a mid-slice MR image was selected from each set of coronal T2-weighted MR images covering the entire kidney. The selected mid-slice image was processed with the semiautomated method to segment and count individual renal cysts. The number of cysts from the mid-slice image of each kidney was also measured by manual counting. The level of agreement between the semiautomated and manual cyst counts was compared using intraclass correlation (ICC) and a Bland-Altman plot. RESULTS: Individual renal cysts were successfully segmented using the semiautomated method in all 241 cases. The number of cysts in each kidney measured with the semiautomated and manual counting methods correlated well (ICC = 0.96 for the right or left kidney), with a small average difference (-0.52, with higher semiautomated counts, for the right kidney, and 0.13, with higher manual counts, for the left kidney) in the semiautomated method. However, there was substantial variation in a small number of subjects; 6 of 241 participants (2.5%) had a difference in the total cyst count of more than 15. CONCLUSION: We have developed a semiautomated method to segment individual renal cysts from mid-slice MR images in ADPKD kidneys as a quantitative indicator of characterization and disease progression of ADPKD.

Novel approach to estimate kidney and cyst volumes using mid-slice magnetic resonance images in polycystic kidney disease.

OBJECTIVE: To evaluate whether kidney and cyst volumes can be accurately estimated based on limited area measurements from magnetic resonance (MR) images of patients with autosomal dominant polycystic kidney disease (ADPKD). MATERIALS AND METHODS: MR coronal images of 178 ADPKD participants from the Consortium for Radiologic Imaging Studies of ADPKD (CRISP) were analyzed. For each MR image slice, we measured kidney and renal cyst areas using stereology and region-based thresholding methods, respectively. The kidney and cyst 'observed' volumes were calculated by summing up the area measurements of all the slices covering the kidney. To estimate the volume, we selected a coronal mid-slice in each kidney and multiplied its area by the total number of slices ('PANK2' for kidney and 'PANC2' for cyst). We then compared the kidney and cyst volumes predicted from PANK2 and PANC2, respectively, to the corresponding observed volumes, using a linear regression analysis. RESULTS: The kidney volume predicted from PANK2 correlated extremely well with the observed kidney volume (R(2) = 0.994 for the right kidney and 0.991 for the left kidney). The linear regression coefficient multiplier to PANK2 that best fit the kidney volume was 0.637 (95% CI: 0.629-0.644) for the right kidney and 0.624 (95% CI: 0.616-0.633) for the left kidney. The correlation between the cyst volume predicted from PANC2 and the observed cyst volume was also very high (R(2) = 0.984 for the right kidney and 0.967 for the left kidney). The least squares linear regression coefficient for PANC2 was 0.637 (95% CI: 0.624-0.649) for the right kidney and 0.608 (95% CI: 0.591-0.625) for the left kidney. CONCLUSION: Kidney and cyst volumes can be closely approximated by multiplying the product of the mid-slice area measurement and the total number of slices in the coronal MR images of ADPKD kidneys by 0.61-0.64. This information will help save processing time needed to estimate total kidney and cyst volumes of ADPKD kidneys.

Physiologically assessed hot flashes and endothelial function among midlife women.

OBJECTIVE: Hot flashes are experienced by most midlife women. Emerging data indicate that they may be associated with endothelial dysfunction. No studies have tested whether hot flashes are associated with endothelial function using physiologic measures of hot flashes. We tested whether physiologically assessed hot flashes were associated with poorer endothelial function. We also considered whether age modified associations. METHODS: Two hundred seventy-two nonsmoking women reporting either daily hot flashes or no hot flashes, aged 40 to 60 years, and free of clinical cardiovascular disease, underwent ambulatory physiologic hot flash and diary hot flash monitoring; a blood draw; and ultrasound measurement of brachial artery flow-mediated dilation to assess endothelial function. Associations between hot flashes and flow-mediated dilation were tested in linear regression models controlling for lumen diameter, demographics, cardiovascular disease risk factors, and estradiol. RESULTS: In multivariable models incorporating cardiovascular disease risk factors, significant interactions by age (P < 0.05) indicated that among the younger tertile of women in the sample (age 40-53 years), the presence of hot flashes (beta [standard error] = -2.07 [0.79], P = 0.01), and more frequent physiologic hot flashes (for each hot flash: beta [standard error] = -0.10 [0.05], P = 0.03, multivariable) were associated with lower flow-mediated dilation. Associations were not accounted for by estradiol. Associations were not observed among the older women (age 54-60 years) or for self-reported hot flash frequency, severity, or bother. Among the younger women, hot flashes explained more variance in flow-mediated dilation than standard cardiovascular disease risk factors or estradiol. CONCLUSIONS: Among younger midlife women, frequent hot flashes were associated with poorer endothelial function and may provide information about women's vascular status beyond cardiovascular disease risk factors and estradiol.

Physiologically assessed hot flashes and endothelial function among midlife women.

OBJECTIVE: Hot flashes are experienced by most midlife women. Emerging data indicate that they may be associated with endothelial dysfunction. No studies have tested whether hot flashes are associated with endothelial function using physiologic measures of hot flashes. We tested whether physiologically assessed hot flashes were associated with poorer endothelial function. We also considered whether age modified associations. METHODS: Two hundred seventy-two nonsmoking women reporting either daily hot flashes or no hot flashes, aged 40 to 60 years, and free of clinical cardiovascular disease, underwent ambulatory physiologic hot flash and diary hot flash monitoring; a blood draw; and ultrasound measurement of brachial artery flow-mediated dilation to assess endothelial function. Associations between hot flashes and flow-mediated dilation were tested in linear regression models controlling for lumen diameter, demographics, cardiovascular disease risk factors, and estradiol. RESULTS: In multivariable models incorporating cardiovascular disease risk factors, significant interactions by age (P < 0.05) indicated that among the younger tertile of women in the sample (age 40-53 years), the presence of hot flashes (beta [standard error] = -2.07 [0.79], P = 0.01), and more frequent physiologic hot flashes (for each hot flash: beta [standard error] = -0.10 [0.05], P = 0.03, multivariable) were associated with lower flow-mediated dilation. Associations were not accounted for by estradiol. Associations were not observed among the older women (age 54-60 years) or for self-reported hot flash frequency, severity, or bother. Among the younger women, hot flashes explained more variance in flow-mediated dilation than standard cardiovascular disease risk factors or estradiol. CONCLUSIONS: Among younger midlife women, frequent hot flashes were associated with poorer endothelial function and may provide information about women's vascular status beyond cardiovascular disease risk factors and estradiol.

Changes in heart rate variability during vasomotor symptoms among midlife women.

OBJECTIVE: Most midlife women report vasomotor symptoms (VMS), yet their physiology remains poorly understood. This study tested whether acute decreases in cardiac vagal control would occur with VMS in a large sample of women monitored during wake and sleep. METHODS: Two hundred and fifteen nonsmoking women aged 40 to 60 years with evidence of VMS were included. Women were free of a history of clinical cardiovascular disease or arrhythmia; or use of insulin, beta blockers, calcium channel blockers, or medications impacting VMS. Women underwent 24 hours of ambulatory monitoring for physiological (sternal skin conductance) and self-report (electronic diary) measurement of VMS; heart rate variability (electrocardiogram); and respiratory rate. Changes in cardiac vagal control as assessed by respiratory sinus arrhythmia during VMS, relative to periods before and after VMS, were tested in linear mixed models. RESULTS: Significant decreases in respiratory sinus arrhythmia were observed during physiologically measured VMS relative to periods preceding (b[SE] = 0.13 (0.004), P < 0.0001) and after the vasomotor symptoms (b[SE] = 0.13 (0.004), P < 0.0001), adjusted for age, race, body mass index, and sleep/wake status. Decreases were observed for women not aware of their VMS, and differences persisted controlling for respiration rate. Interactions indicated that respiratory sinus arrhythmia decreases were most pronounced during sleep and for younger women. CONCLUSIONS: Physiologically measured VMS were accompanied by an inhibition of cardiac vagal control in a large sample of women. Changes were observed irrespective of whether the VMS were reported, were most pronounced during sleep, and were greatest among younger women. These findings contribute to the understanding of vasomotor symptom physiology.

Automated Segmentation of Kidneys from MR Images in Patients with Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: Our study developed a fully automated method for segmentation and volumetric measurements of kidneys from magnetic resonance images in patients with autosomal dominant polycystic kidney disease and assessed the performance of the automated method with the reference manual segmentation method. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Study patients were selected from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease. At the enrollment of the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease Study in 2000, patients with autosomal dominant polycystic kidney disease were between 15 and 46 years of age with relatively preserved GFRs. Our fully automated segmentation method was on the basis of a spatial prior probability map of the location of kidneys in abdominal magnetic resonance images and regional mapping with total variation regularization and propagated shape constraints that were formulated into a level set framework. T2-weighted magnetic resonance image sets of 120 kidneys were selected from 60 patients with autosomal dominant polycystic kidney disease and divided into the training and test datasets. The performance of the automated method in reference to the manual method was assessed by means of two metrics: Dice similarity coefficient and intraclass correlation coefficient of segmented kidney volume. The training and test sets were swapped for crossvalidation and reanalyzed. RESULTS: Successful segmentation of kidneys was performed with the automated method in all test patients. The segmented kidney volumes ranged from 177.2 to 2634 ml (mean, 885.4±569.7 ml). The mean Dice similarity coefficient ±SD between the automated and manual methods was 0.88±0.08. The mean correlation coefficient between the two segmentation methods for the segmented volume measurements was 0.97 (P<0.001 for each crossvalidation set). The results from the crossvalidation sets were highly comparable. CONCLUSIONS: We have developed a fully automated method for segmentation of kidneys from abdominal magnetic resonance images in patients with autosomal dominant polycystic kidney disease with varying kidney volumes. The performance of the automated method was in good agreement with that of manual method.

Automated segmentation of liver and liver cysts from bounded abdominal MR images in patients with autosomal dominant polycystic kidney disease.

Liver and liver cyst volume measurements are important quantitative imaging biomarkers for assessment of disease progression in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD). To date, no study has presented automated segmentation and volumetric computation of liver and liver cysts in these populations. In this paper, we proposed an automated segmentation framework for liver and liver cysts from bounded abdominal MR images in patients with ADPKD. To model the shape and variations in ADPKD livers, the spatial prior probability map (SPPM) of liver location and the tissue prior probability maps (TPPMs) of liver parenchymal tissue intensity and cyst morphology were generated. Formulated within a three-dimensional level set framework, the TPPMs successfully captured liver parenchymal tissues and cysts, while the SPPM globally constrained the initial surfaces of the liver into the desired boundary. Liver cysts were extracted by combined operations of the TPPMs, thresholding, and false positive reduction based on spatial prior knowledge of kidney cysts and distance map. With cross-validation for the liver segmentation, the agreement between the radiology expert and the proposed method was 84% for shape congruence and 91% for volume measurement assessed by the intra-class correlation coefficient (ICC). For the liver cyst segmentation, the agreement between the reference method and the proposed method was ICC = 0.91 for cyst volumes and ICC = 0.94 for % cyst-to-liver volume.

Correlation of protease-activated receptor-1 with differentiation markers in squamous cell carcinoma of the head and neck and its implication in lymph node metastasis.

PURPOSE: Protease-activated receptor-1 (PAR-1) is a G-protein-coupled receptor that contributes to multiple signal transduction pathways. Although the functions of PAR-1 in many normal cells, such as platelets and astrocytes, have been well studied, its roles in cancer progression and metastasis have not been fully elucidated, and studies to date appear contradictory. EXPERIMENTAL DESIGN: To clarify the function of PAR-1 in metastasis of squamous cell carcinoma of the head and neck (SCCHN), we examined PAR-1 expression in clinical specimens by immunohistochemistry and in SCCHN cell lines by immunoblotting. Furthermore, par-1 cDNA-transfected SCCHN cell lines were also used to verify PAR-1-mediated pathway. RESULTS: The metastatic tumors showed a lower percentage of PAR-1-positive cells (46%) and lower levels of PAR-1 expression (median weight index = 10) than node negative primary tumors (80% and median weight index = 60, respectively). In addition, expression level of PAR-1 positively correlated with levels of keratinocyte differentiation markers keratin-1, -10, and -11. Additional studies using sense and antisense par-1 cDNA-transfected SCCHN cell lines illustrated that the presence of PAR-1 was required for the expression of involucrin, a keratinocyte differentiation marker. PAR-1 expression also contributes to activation of the mitogen-activated protein kinase (MAPK) pathway. Blocking MAPK activation by a mitogen-activated protein/extracellular signal-regulated kinase inhibitor, not by a phosphatidylinositol 3'-kinase inhibitor, reduced level of involucrin, suggesting that regulation of involucrin by PAR-1 is partially through the MAPK signaling pathway. CONCLUSIONS: Our study suggests that PAR-1 signaling induces differentiation markers in SCCHN cells, and its expression is conversely correlated with cervical lymph node metastasis.

Segmentation of individual renal cysts from MR images in patients with autosomal dominant polycystic kidney disease.

OBJECTIVE: To evaluate the performance of a semi-automated method for the segmentation of individual renal cysts from magnetic resonance (MR) images in patients with autosomal dominant polycystic kidney disease (ADPKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This semi-automated method was based on a morphologic watershed technique with shape-detection level set for segmentation of renal cysts from MR images. T2-weighted MR image sets of 40 kidneys were selected from 20 patients with mild to moderate renal cyst burden (kidney volume < 1500 ml) in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). The performance of the semi-automated method was assessed in terms of two reference metrics in each kidney: the total number of cysts measured by manual counting and the total volume of cysts measured with a region-based thresholding method. The proposed and reference measurements were compared using intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: Individual renal cysts were successfully segmented with the semi-automated method in all 20 cases. The total number of cysts in each kidney measured with the two methods correlated well (ICC, 0.99), with a very small relative bias (0.3% increase with the semi-automated method; limits of agreement, 15.2% reduction to 17.2% increase). The total volume of cysts measured using both methods also correlated well (ICC, 1.00), with a small relative bias of <10% (9.0% decrease in the semi-automated method; limits of agreement, 17.1% increase to 43.3% decrease). CONCLUSION: This semi-automated method to segment individual renal cysts in ADPKD kidneys provides a quantitative indicator of severity in early and moderate stages of the disease.