Necessary and sufficient conditions of proper estimators based on self density ratio for unnormalized statistical models.

The largest family of density-ratio based estimators is obtained for unnormalized statistical models under the assumption of properness. They do not require normalization of the probability density function (PDF) because they are based on the density ratio of the same PDF at different points; therefore, the multiplicative normalization constant cancels out. In contrast with most existing work, a single necessary and sufficient condition is given here, rather than merely sufficient conditions for proper criteria for estimation. The condition implies that an extended Bregman divergence framework with data-dependent noise (Gutmann & Hirayama, 2011) gives the largest family of proper criteria in the present case. This properness yields consistent estimation as long as some mild conditions are satisfied. The present study shows that the above-mentioned framework gives an "upper bound" for attempts to extend Hyvärinen's score matching and therefore provides a perspective for studies in this direction.

[The Usefulness of Strain Elastography for Determining Liver Fibrosis Stage in Chronic Viral Hepatitis: An Analysis Using Tissue Doppler Imaging with Manual Compression].

BACKGROUND/AIM: Accurate determination of the stage of liver fibrosis is an essential component in choice of treatment and assessment of cancer risk in patients with chronic viral hepatitis. The aim of this study was to evaluate the usefulness of strain elastography based on tissue Doppler imaging for liver fibrosis in chronic viral hepatitis. METHODS: A total of 37 patients with chronic viral hepatitis and 8 healthy volunteers were enrolled. Strain value was measured by using a conventional ultrasound machine that included strain imaging technolo- gy. Strain elastography was performed at the right subcostal area with manual compression. Liver fibrosis stages were assessed by using liver biopsy and compared with strain values. Diagnostic performance of the strain value for fibrosis stage 4, cirrhosis, was determined by performing a receiver-operating characteristics (ROC) curve analysis. RESULTS: Twenty-seven patients were positive for HCV RNA, 9 were positive for HBs antigen, and 1 was positive for both (Fibrosis stage F1, n=11; F2, n=7; F3, n=15; F4, n=4). The strain value of F3 and F4 was 0.066±0.02 and 0.042±0.011, respectively. These strain Values were significantly lower compared to those of healthy volunteers (0.112 ±0.018) (P< 0.05). Using a cutoff value of 0.042, the area under ROC curve was 0.88 for the diagnosis of F4. The sensitivity, specificity, positive predictive value, and negative predictive value were 75%, 92%, 50%, and 94%, respectively. CONCLUSIONS: Strain elastography based on tissue Doppler imaging with manual compression appears to be a useful tool to diagnose cirrhosis in patients with chronic viral hepatitis. [Original].

Renal resistive index correlates with peritubular capillary loss and arteriosclerosis in biopsy tissues from patients with chronic kidney disease.

BACKGROUND: The renal resistive index (RI) is a Doppler-derived measure that reportedly correlates with renal histological changes and renal disease severity and outcome. The aim of this study was to investigate the factors related to the RI elevation in chronic kidney disease (CKD). METHODS: Using Doppler ultrasonography, RIs were determined in 30 patients with CKD, after which they were correlated with interstitial fibrosis, arteriosclerosis, arteriolosclerosis and peritubular capillary (PTC) density. PTC-positive areas were determined based on CD34 immunostaining. Interstitial fibrosis was detected with Masson trichrome staining. All histological markers were assessed using quantitative and semi-quantitative analyses and evaluated statistically using Pearson correlation tests, unpaired t tests and stepwise multiple regression analysis. RESULTS: RI correlated positively with age (r = 0.603, p = 0.0004), systolic blood pressure (r = 0.775, p < 0.0001), diastolic blood pressure (r = 0.575, p = 0.001), interstitial fibrosis (r = 0.381, p = 0.038) and arteriosclerosis (r = 0.520, p = 0.003), and negatively with creatinine clearance (r = -0.471, p = 0.009) and CD34+ (PTC) areas (r = -0.437, p = 0.016). Patients with hypertension or diabetes mellitus showed higher RIs (p < 0.05) than those without the ailments. Multivariate analysis showed PTC and arteriosclerosis to be independent variables correlating with RI (r (2) = 0.321, p < 0.05). CONCLUSIONS: To our knowledge, this is the first report of using RI measurements to evaluate peritubular capillary loss. Our findings indicate that increases in RI are associated with both arteriosclerosis and loss of PTCs.

The clinical significance of abnormal diurnal blood pressure variation in healthy late middle-aged and older adults.

Objective. A fall in nocturnal blood pressure (BP) is generally observed in normotensive subjects as well as in those with mild to moderate essential hypertension, regardless of the level of daytime BP. Among elderly hypertensive subjects, extreme-dippers with a marked nocturnal fall in BP as well as non-dippers with nocturnal fall absence are at increased risk for cardiovascular and cerebrovascular complications. However, the relationship between these abnormal diurnal BP variation patterns in normotensive elderly subjects has not been investigated. Methods. We classified 45 healthy late middle-aged and older adults into three groups according to the nocturnal systolic BP fall pattern examined by 24-h ambulatory BP monitoring (dipper, non-dipper and extreme-dipper), and compared the parameters of initial atherosclerosis, endothelial function and autonomic function. As a parameter of atherosclerotic factors, the intima-media thickness (IMT) of the carotid artery was examined, and as a parameter of endothelial function, brachial artery endothelium-dependent flow-mediated dilation (FMD) was ultrasonographyically measured. Autonomic function was assessed by power spectral analysis of heart rate variability (HRV). Results. No difference was observed in the severity of IMT between the three groups. The percent change of FMD in subjects in the extreme-dipper group was significantly lower than that of subjects in the dipper group, indicating that extreme-dippers in healthy elderly subjects may be associated with endothelial dysfunction. Also, HRV due to sympathetic modulation of subjects in the extreme-dipper group was significantly higher than that of subjects in the dipper and non-dipper groups, suggesting the activation of sympathetic tone. Conclusion. In healthy elderly subjects, the extreme-dipper type may reflect a decrease in endothelial function, i.e. initial stage atherosclerosis, rather than the dipper type.

Associations between trait anxiety, insulin resistance, and atherosclerosis in the elderly: a pilot cross-sectional study.

Anxiety has been shown to be associated with cardiovascular disease. Atherosclerosis is responsible for the vast majority of cardiovascular events. Recent evidence is accumulating to show that insulin resistance (IR) plays a central role in determining the clinical manifestations of established atherosclerotic lesions. The current preliminary study aimed to investigate the associations between trait anxiety, IR, and atherosclerotic progression in healthy elderly subjects with normal fasting glucose and without metabolic syndrome. Thirty-five healthy elderly subjects (19 males and 16 females, mean age 64.5+/-4.7 years) were enrolled in this study. Trait anxiety was measured using a questionnaire corresponding to the trait anxiety scale taken from the State and Trait Anxiety Inventory. The homeostasis model assessment (HOMA-R) and plasma leptin-to-adiponectin ratio (L/A ratio), which are convenient IR indexes calculated from fasting blood sampling, were examined. As measurements of atherosclerotic progression, we performed two ultrasound methods, namely brachial artery flow-mediated dilation (FMD), an endothelial function assessment quantitatively reflecting the endothelium-dependent vasodilation responses following hyperemia, and measurement of carotid intima-media thickness (IMT). The severity of trait anxiety was positively associated with HOMA-R and L/A ratio, and negatively associated with the percent change of brachial artery FMD (%FMD). HOMA-R and L/A ratio were positively associated with carotid IMT, and L/A ratio was negatively associated with %FMD. These data showed the associations between trait anxiety, IR indexes and endothelial dysfunction or atherosclerotic progression. This pilot study, with a cross-sectional design, supports the promising role of IR for clarifying the pathophysiological mechanism by which anxiety contributes to an increasing risk of atherosclerosis.

Adiponectin multimer distribution, not absolute amount of plasma, correlates with depression severity in healthy elderly subjects.

Adiponectin is an adipocyte-specific secretory protein that circulates in serum as three oligomeric complexes known as the high, medium and low molecular weight form (HMW, MMW and LMW). HMW adiponectin has been suggested to be a better predictor of metabolic variables, and it was recently reported that the ratio of HMW to total adiponectin or to LMW, not the absolute amount of plasma adiponectin, might be crucial in determining insulin sensitivity. Insulin resistance (IR) is considered to be a primary component of vascular risk factors. Although the association of depression with atherosclerotic vascular diseases has been well documented, the contribution of IR to the evolution and progression of depression-associated vascular morbidity and mortality remains unknown. The current preliminary study showed that the ratio of HMW to total adiponectin or to LMW, not the absolute amount of plasma adiponectin, was negatively associated with depression severity in healthy elderly subjects without metabolic syndrome. This pilot study supports a promising role of adiponectin multimer distribution for clarifying the pathophysiological mechanism by which depression is associated with increased risk for IR, leading to cardiovascular disease, metabolic syndrome or type 2 diabetes.

The association between anger-related personality trait and cardiac autonomic response abnormalities in elderly subjects.

Cardiac autonomic response abnormality associated with trait anger has been recognized to elevate blood pressure in daily life, leading to atherosclerotic progression and cardiovascular disease. To clarify the relationship between anger-related personality traits and cardiac autonomic response in healthy elderly subjects, 54 volunteers consisting of 30 male (mean age 62.2+/-5.4) and 24 female (mean age 58.4+/-4.6) subjects underwent testing of heart rate variability (HRV) with head-up tilt. For the evaluation of trait anger, we used a questionnaire corresponding to the trait anger score taken from the State and Trait Anger Expression Inventory. Furthermore, we measured carotid intima-medial thickness (IMT) to evaluate atherosclerotic progression in subjects with anger trait. In female subjects, higher trait anger was positively associated with elevated carotid IMT and the suppression of HRV vagal attenuation from the supine to head-up position, and negatively associated with the HRV sympathetic activity in the head-up position and also with the HRV sympathetic response from the supine to head-up position. In male subjects, trait anger was not significantly associated with carotid IMT or any HRV component with or without head-up tilt testing. We conclude that a simple noninvasive measure, short-term HRV with head-up tilt testing, could be a useful method to investigate the association between cardiac autonomic imbalance and increased risk of atherosclerosis associated with trait anger in healthy elderly subjects.

[The association between autonomic response status and the changes in EEG activity during mental arithmetic task].

Mental arithmetic (MA) tasks have been reported to induce an increase in blood pressure and heart rate by enhancing sympathetic activity. However, there are individual differences in the change of autonomic nervous activity during MA task. In the present study, we quantitatively analyzed EEG changes and autonomic nervous activity using heart rate variability (HRV) during MA task in 38 healthy young volunteers. They were classified into two groups, stress responders and non-responders, according to whether both LF/HF and blood pressure increased above the baseline or not in response to MA. Then autonomic and EEG changes were compared between the two groups. The MA task induced an increase in slow beta power in the stress responders, whereas it induced a decrease in slow beta power in the stress non responders. Further evaluation showed a significant positive correlation between the percent change from the baseline in slow alpha power and that in LF/HF. These results suggest that there are correlations between the autonomic response in an individual and EEG power changes during MA tasks.

Association between trait anxiety and endothelial function observed in elderly males but not in young males.

BACKGROUND AND OBJECTIVES: Endothelial function plays a key role in determining the clinical manifestations of atherosclerosis. Recent reports have shown that healthy elderly subjects with higher trait anxiety tend to have heightened risks of atherosclerotic lesions and cardiovascular disease. The present study was intended to examine whether an association exists between trait anxiety and endothelial function in healthy young and elderly subjects. METHODS: This study examined 26 young male and 30 elderly male subjects using brachial artery flow-mediated dilation (FMD) - a non-invasive ultrasound method - to evaluate endothelial function by measuring the dilation responses of vascular smooth muscle to the nitric oxide produced by endothelial cells following hyperemia. RESULTS: A significant negative correlation was observed between the State and Trait Anxiety Inventory (STAI)-trait score as a parameter of anxiety and the percentage change of FMD (%FMD) in the elderly subjects, but not in the young subjects. The elderly subjects showed significantly lower %FMD than the young subjects. CONCLUSION: These results suggest the possibility that trait anxiety is a predisposing risk factor for cardiovascular damage that might, over a long period, induce atherosclerotic lesions.

Interactions among higher trait anxiety, sympathetic activity, and endothelial function in the elderly.

Negative psychological characteristics have been recognized as independent risk factors of cardiovascular disease (CVD). The purpose of this study was to evaluate the influence of depression and anxiety on cardiac autonomic function and endothelial function in healthy elderly subjects. Forty-six healthy elderly volunteers (mean age 60.8 years) were enrolled in this study. Cardiac autonomic function was assessed by spectral analysis of heart rate variability (HRV) with the head-up tilt test. Brachial artery endothelium-dependent flow-mediated dilation (FMD) was measured using high-resolution ultrasound. A significant positive correlation was observed between the State and Trait Anxiety Inventory (STAI)-trait score as a parameter of anxiety and HRV sympathetic modulation in the supine position (baseline), and a significant negative correlation between this score and the head-up-induced HRV sympathetic response from the baseline. The STAI-trait score also showed a significant negative correlation with the percent change of FMD (%FMD). Analysis using structural equation modeling showed that higher trait anxiety reduced %FMD via abnormalities of sympathetic activity. On the other hand, psychometric parameters of depression were not associated with any HRV component or %FMD. These results suggest that there are specific interactions among higher trait anxiety, abnormalities of sympathetic activity, and endothelial dysfunction. This finding may be useful in clarifying the pathophysiological mechanism by which anxiety is associated with increased risks for atherosclerosis and CVD.

Multifractal analysis of deep white matter microstructural changes on MRI in relation to early-stage atherosclerosis.

Multifractal analysis based on generalized concepts of fractals has been applied to evaluate biological tissues composed of complex structures. This type of analysis can provide a precise quantitative description of a broad range of heterogeneous phenomena. Previously, we applied multifractal analysis to describe heterogeneity in white matter signal fluctuation on T2-weighted MR images as a new method of texture analysis and established Deltaalpha as the most suitable index for evaluating white matter structural complexity (Takahashi et al. J. Neurol. Sci., 2004; 225: 33-37). Considerable evidence suggests that pathophysiological processes occurring in deep white matter regions may be partly responsible for cognitive deterioration and dementia in elderly subjects. We carried out a multifractal analysis in a group of 36 healthy elderly subjects who showed no evidence of atherosclerotic risk factors to examine the microstructural changes of the deep white matter on T2-weighted MR images. We also performed conventional texture analysis, i.e., determined the standard deviation of signal intensity divided by mean signal intensity (SD/MSI) for comparison with multifractal analysis. Next, we examined the association between the findings of these two types of texture analysis and the ultrasonographically measured intima-media thickness (IMT) of the carotid arteries, a reliable indicator of early carotid atherosclerosis. The severity of carotid IMT was positively associated with Deltaalpha in the deep white matter region. In addition, this association remained significant after excluding 12 subjects with visually detectable deep white matter hyperintensities on MR images. However, there was no significant association between the severity of carotid IMT and SD/MSI. These results indicate the potential usefulness of applying multifractal analysis to conventional MR images as a new approach to detect the microstructural changes of apparently normal white matter during the early stages of atherosclerosis.

White coat phenomenon, anxiety and endothelial function in healthy normotensive elderly subjects.

OBJECTIVE: The white coat phenomenon (WCP) is a blood pressure (BP) elevation specifically observed in the clinical setting. Though WCP has been suggested to associate with emotional responses such as anxiety or with cardiovascular complications, its pathogenesis and clinical significance are unclear. We studied the possible association between WCP and anxiety or vascular function in normotensive elderly subjects without major cardiovascular risk factors. METHODS: As a parameter of anxiety, the State and Trait Anxiety Inventory (STAI) was used. WCP was evaluated by calculating the difference between the clinic BP and mean daytime ambulatory BP. As parameters of vascular function, brachial artery endothelium-dependent flow-mediated dilation (FMD) and the endothelium-independent dilation response to sublingual glyceryl trinitrate (GTN) were measured using high-resolution ultrasound. RESULTS: Using confounding factors as covariates, no association was observed between WCP and the STAI-trait or STAI-state score. There was a significant negative association between WCP and the percent change of FMD but no association between WCP and the percent change of GTN. CONCLUSION: WCP in the healthy normotensive elderly subjects may reflect a decrease in endothelial function, i.e. initial stage atherosclerosis, rather than anxiety.

[Changes in autonomic function and EEG power during mental arithmetic task and their mutual relationship].

Meditation is a specific consciousness state in which deep relaxation and increased internalized attention coexist. Autonomic nervous activity during meditation was reported to be characterized by decreased sympathetic activity and increased parasympathetic activity. And concerning EEG power, slow alpha power and fast theta power increased during meditation. On the other hand, mental arithmetic (MA) tasks have been reported to induce an increase in blood pressure and heart rate with enhanced sympathetic activity. However, changes in autonomic nervous activity and EEG power during MA tasks and their mutual relationship have not been adequately studied. In the present study, we quantitatively analyzed the changes in autonomic nervous activity using heart rate variability (HRV) and EEG power during MA task in 30 healthy volunteers. MA task induced significant increases in normalized LF, LF/HF ratio (as a sympathetic index), and a decrease in normalized HF (as a parasympathetic index). On the other hand, significant decrease in EEG power (slow theta: 4-6 Hz and fast alpha: 10-13 Hz in the posterior region and fast theta: 6-8 Hz and slow alpha: 8-10 Hz in all the regions) were induced by MA task. Further evaluation of these changes showed a negative correlation between the change rates (with the control resting condition as the baseline) in fast alpha power and that in LF/HF. These results suggest that specific correlated relationships exist between the change in autonomic nervous activity and EEG power depending on the difference in mental task (i.e., meditation or MA).

Changes in EEG and autonomic nervous activity during meditation and their association with personality traits.

Meditation is the attainment of a restful yet fully alert physical and mental state practiced by many as a self-regulatory approach to emotion management, but the psychophysiological properties and personality traits that characterize this meditative state have not been adequately studied. We quantitatively analyzed changes in psychophysiological parameters during Zen meditation in 20 normal adults, and evaluated the results in association with personality traits assessed by Cloninger's Temperament and Character Inventory (TCI). During meditation, increases were observed in fast theta power and slow alpha power on EEG predominantly in the frontal area, whereas an increase in the normalized unit of high-frequency (nuHF) power (as a parasympathetic index) and decreases in the normalized unit of low-frequency (nuLF) power and LF/HF (as sympathetic indices) were observed through analyses of heart rate variability. We analyzed the possible correlations among these changes in terms of the percent change during meditation using the control condition as the baseline. The percent change in slow alpha EEG power in the frontal area, reflecting enhanced internalized attention, was negatively correlated with that in nuLF as well as in LF/HF and was positively correlated with the novelty seeking score (which has been suggested to be associated with dopaminergic activity). The percent change in fast theta power in the frontal area, reflecting enhanced mindfulness, was positively correlated with that in nuHF and also with the harm avoidance score (which has been suggested to be associated with serotonergic activity). These results suggest that internalized attention and mindfulness as two major core factors of behaviors of mind during meditation are characterized by different combinations of psychophysiological properties and personality traits.