Assessment of Multidimensional Health Care Parameters Among Adults in Japan for Developing a Virtual Human Generative Model: Protocol for a Cross-sectional Study.

BACKGROUND: Human health status can be measured on the basis of many different parameters. Statistical relationships among these different health parameters will enable several possible health care applications and an approximation of the current health status of individuals, which will allow for more personalized and preventive health care by informing the potential risks and developing personalized interventions. Furthermore, a better understanding of the modifiable risk factors related to lifestyle, diet, and physical activity will facilitate the design of optimal treatment approaches for individuals. OBJECTIVE: This study aims to provide a high-dimensional, cross-sectional data set of comprehensive health care information to construct a combined statistical model as a single joint probability distribution and enable further studies on individual relationships among the multidimensional data obtained. METHODS: In this cross-sectional observational study, data were collected from a population of 1000 adult men and women (aged ≥20 years) matching the age ratio of the typical adult Japanese population. Data include biochemical and metabolic profiles from blood, urine, saliva, and oral glucose tolerance tests; bacterial profiles from feces, facial skin, scalp skin, and saliva; messenger RNA, proteome, and metabolite analyses of facial and scalp skin surface lipids; lifestyle surveys and questionnaires; physical, motor, cognitive, and vascular function analyses; alopecia analysis; and comprehensive analyses of body odor components. Statistical analyses will be performed in 2 modes: one to train a joint probability distribution by combining a commercially available health care data set containing large amounts of relatively low-dimensional data with the cross-sectional data set described in this paper and another to individually investigate the relationships among the variables obtained in this study. RESULTS: Recruitment for this study started in October 2021 and ended in February 2022, with a total of 997 participants enrolled. The collected data will be used to build a joint probability distribution called a Virtual Human Generative Model. Both the model and the collected data are expected to provide information on the relationships between various health statuses. CONCLUSIONS: As different degrees of health status correlations are expected to differentially affect individual health status, this study will contribute to the development of empirically justified interventions based on the population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47024.

A biologically active lipid, thromboxane, as a regulator of angiogenesis and lymphangiogenesis.

Thromboxane (TX) and prostaglandins are metabolites of arachidonic acid, a twenty-carbon unsaturated fatty acid, and have a variety of actions that are exerted via specific receptors. Angiogenesis is defined as the formation of new blood vessels from pre-existing vascular beds and is a critical component of pathological conditions, including inflammation and cancer. Lymphatic vessels play crucial roles in the regulation of interstitial fluid, immune surveillance, and the absorption of dietary fat from the intestine; and they are also involved in the pathogenesis of various diseases. Similar to angiogenesis, lymphangiogenesis, the formation of new lymphatic vessels, is a critical component of pathological conditions. The TP-dependent accumulation of platelets in microvessels has been reported to enhance angiogenesis under pathological conditions. Although the roles of some growth factors and cytokines in angiogenesis and lymphangiogenesis have been well characterized, accumulating evidence suggests that TX induces the production of proangiogenic and prolymphangiogenic factors through the activation of adenylate cyclase, and upregulates angiogenesis and lymphangiogenesis under disease conditions. In this review, we discuss the role of TX as a regulator of angiogenesis and lymphangiogenesis, and its emerging importance as a therapeutic target.

Non-restorative Sleep Caused by Autonomic and Electroencephalography Parameter Dysfunction Leads to Subjective Fatigue at Wake Time in Shift Workers.

Sleep is a physiological state that plays important role in the recovery of fatigue. However, the relationship between the physiological status of sleep and subjective fatigue remains unknown. In the present study, we hypothesized that the non-recovery of fatigue at wake time due to non-restorative sleep might be ascribed to changes in specific parameters of electroencephalography (EEG) and heart rate variability (HRV) in poor sleepers. Twenty healthy female shift-working nurses participated in the study. Subjective fatigue was assessed using the visual analog scale (VAS) at bedtime and wake time. During sleep on the night between 2 consecutive day shifts, the EEG powers at the frontal pole, HRV based on electrocardiograms, and distal-proximal gradient of skin temperature were recorded and analyzed. The results indicated that the subjects with high fatigue on the VAS at wake time exhibited (1) a decrease in deep non-rapid eye movement (NREM) (stageN3) sleep duration in the first sleep cycle; (2) a decrease in REM latency; (3) a decrease in ultra-slow and delta EEG powers, particularly from 30 to 65 min after sleep onset; (4) a decrease in the total power of HRV, particularly from 0 to 30 min after sleep onset; (5) an increase in the very low frequency component of HRV; and (6) a smaller increase in the distal-proximal gradient of skin temperature, than those of the subjects with low fatigue levels. The correlational and structural equation modeling analyses of these parameters suggested that an initial decrease in the total power of HRV from 0 to 30 min after sleep onset might inhibit the recovery from fatigue during sleep (i.e., increase the VAS score at wake time) via its effects on the ultra-slow and delta powers from 30 to 65 min after sleep onset, stageN3 duration in the first sleep cycle, REM latency, and distal-proximal gradient of skin temperature. These findings suggest an important role of these physiological factors in recovery from fatigue during sleep, and that interventions to modify these physiological factors might ameliorate fatigue at wake time.

Age-related changes in gingival blood flow parameters measured using laser speckle flowmetry.

Previous studies have suggested a possible relationship between age-related changes to human gingival hemodynamics and periodontal disease. However, firmly establishing this has been difficult because of a lack of suitable tools. Our study investigated whether a non-invasive laser speckle flowgraphy (LSFG)-based 2-dimensional technique could be used to assess maxillary anterior gingival blood flow under resting conditions. In total, 124 healthy male volunteers aged between 22 and 69 years were included in the study and delineated into young (Y; 22-37 years, n = 45), middle-aged (M; 38-53 years, n = 43), and elderly groups (E; 54-69 years, n = 36). The differences in gingival hemodynamics were compared among age groups and pulse waveform analysis performed to calculate blood flow indices, mean blur rate (MBR), gingival vascular conductance (MBR/mean blood pressure [MBP]), and three pulse waveform parameters (acceleration time index [ATI], falling rate, and blowout time [BOT]). Although no statistically significant differences were observed in the MBR of the three age groups, vascular conductance (MBR/MBP) was lower in groups M and E compared to group Y and correlated negatively with age. ATI and falling rates were also significantly higher in group E relative to group Y, whereas average BOT was significantly lower. All of the assessed parameters correlated with age. These data suggest that there are age-related decreases in the ability to maintain blood flow in the human maxillary anterior gingiva under resting conditions which may impact the likelihood of periodontal disease.

Thermotherapy to the facial region in and around the eyelids altered prefrontal hemodynamic responses and autonomic nervous activity during mental arithmetic.

To investigate neural mechanisms of local thermotherapy to reduce mental stress, participants were required to perform mental arithmetic after treatment by a heat- and steam-generating sheet on the facial eyelid region while hemodynamic activity and ECGs were monitored. The results indicated that thermotherapy decreased hemodynamic activity in the anterior dorsomedial prefrontal cortex (aDMPFC) involved in sympathetic activity. Consistently, thermotherapy increased parasympathetic activity while it decreased sympathetic activity. Furthermore, thermotherapy increased hemodynamic activity in the dorsolateral prefrontal cortex (DLPFC) during mental arithmetic. These hemodynamic responses in the DLPFC during mental arithmetic were negatively correlated with that in the aDMPFC during thermotherapy. The results suggest that thermotherapy in the facial eyelid region is useful to ameliorate mental fatigue through its effects on the prefrontal cortex.

Effects of direct cedrol inhalation into the lower airway on brain hemodynamics in totally laryngectomized subjects.

A previous study reported that when cedrol (odorant) is inhaled directly through the lower airway of the trachea, it decreases the sympathetic nervous activity and blood pressure in totally laryngectomized subjects (Umeno et al., 2008). In the present study, totally laryngectomized subjects were asked to inhale cedrol into the lower airway in the same manner and its effects on regional cerebral blood flow (rCBF) were analyzed. Our results indicated that hippocampal rCBF was bilaterally increased during cedrol inhalation as compared to the inhalation of blank air. These results provide the first evidence that an odorant in the lower airway modulates autonomic activity via the central nervous system.

Application of a heat- and steam-generating sheet increases peripheral blood flow and induces parasympathetic predominance.

To promote the practical application of a Japanese traditional medical treatment, such as hot compresses, we developed a plaster-type warming device consisting of a heat- and steam-generating sheet (HSG sheet). First, we tested its effects when applied to the anterior abdominal wall or lumbar region of women complaining of a tendency towards constipation. Application of the sheet to either region produced a feeling of comfort in the abdomen, as assessed by a survey of the subjects. The significant increases in the total hemoglobin observed in these regions suggested an increase in peripheral blood flow, and significant increases in the HF component on ECG and in the amplitude of gastric motility suggested parasympathetic predominance. We concluded that application of the HSG sheet improves the peripheral hemodynamics and autonomic regulation, induces a feeling of comfort in the abdomen, and provides a beneficial environment for the improvement of gastrointestinal movements.

Significant correlation between autonomic nervous activity and cerebral hemodynamics during thermotherapy on the neck.

Although local thermotherapy reduces mental stress and neck stiffness, its physiological mechanisms are still not fully understood. We speculated that local thermotherapy exerts its effect, in addition to its direct peripheral effects, through the central nervous system that is involved in controlling stress responses. In the present study, we investigated the effects of a heat- and steam-generating (HSG) sheet on cerebral hemodynamics and autonomic nervous activity using near-infrared spectroscopy (NIRS) and the electrocardiograms (ECGs). Thirteen healthy young female subjects participated in this study. HSG or simple (control) sheets were repeatedly applied to the neck for 120 s with 180 s intervals of rest between applications. During the experiment, brain hemodynamic responses (changes in Oxy-Hb, Deoxy-Hb, and Total-Hb) and autonomic nervous activity based on heart rate variability (HRV) were monitored. Subjective perception of neck stiffness and fatigue was significantly improved after application of the HSG sheet. NIRS findings indicated that the application of HSG sheets decreased Oxy-Hb concentration in the anterior-dorsal region of the medial prefrontal cortex (adMPFC), while increasing parasympathetic nervous activity and decreasing sympathetic nervous activity. Furthermore, changes in Oxy-Hb in the adMPFC were significantly and negatively correlated with those in parasympathetic nervous activity during application of the HSG sheet. These findings suggest that application of the HSG sheet to the neck region induced mental relaxation and ameliorated neck stiffness by modifying activity of the adMPFC.

Effects of direct cedrol inhalation into the lower airway on autonomic nervous activity in totally laryngectomized subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Relationships between smell sensation and autonomic changes have been studied extensively. However, the possibility that odorants may also act on the lung and lower airway remains unknown. WHAT THIS STUDY ADDS: The present results provide the first evidence that the lung and lower airway exert an inhibitory influence on the cardiovascular system in response to Cedrol (odorant) in the air under physiological conditions. AIMS: Previous studies reported that Cedrol (odorant) inhalation (CI) induced changes in autonomic balance and baroreceptor sensitivity (BRS) in both healthy subjects and anosmic patients. This suggests that Cedrol may act on the lower airway, and that the pulmonary system may exert an inhibitory influence on the cardiovascular system. METHOD: To test the above possibility, vaporized Cedrol (64.0 +/- 7.7 10(-9)m) or blank air was directly inhaled through the lower airway from a hole in the trachea, but not through the upper airway, using totally laryngectomized subjects. During the experiment, ECG, systolic (SBP) and diastolic (DBP) blood pressures were measured. Sympathetic and parasympathetic nervous activity was estimated by spectral analyses of variability in these parameters (heart rate variability (HRV), SBP variability (SBPV) and DBP variability (DBPV)). BRS was computed from transfer gain between SBP and the R-R interval of the ECG. RESULTS: SBP and DBP significantly decreased during CI, although there were no significant differences in HR and respiratory rate. BRS significantly increased during CI. The low frequency components of SBPV and DBPV (indices for sympathetic activity) significantly decreased during CI, while high frequency components of HRV (an index for parasympathetic activity) significantly increased. CONCLUSIONS: The present experiment using totally laryngectomized patients replicated the similar results in healthy subjects who inhaled Cedrol through the nose, suppression of sympathetic outflow and increase in parasympathetic outflow. These results demonstrated that Cedrol acts on the lower airway and pulmonary system, and suggest a new target for drug therapy of hypertension.

Overseas survey of the effect of cedrol on the autonomic nervous system in three countries.

To clarify the influences of ethnic and regional characteristics, and differences in perception on the cedrol effect on autonomic nerve activity, we compared women in their 20s-40s in Norway, Thailand, and Japan. A questionnaire survey of sense of stress and sleep conditions was performed at the same time. The degree of perceived stress, using a 30-item checklist, was highest in Japanese women. The mean stress score exceeded 5.0 in Japanese women, significantly higher than in Thai women (p<0.05) and Norwegian women (p<0.01). Sleeping time was shortest in Japanese women in all generations among the three countries. As the index of autonomic nervous activity, the miosis rate (ratio of pupil-diameter variation after light stimulus to initial pupil diameter) in pupillary light reflex was measured before and after cedrol inhalation. The miosis rate significantly increased after cedrol exposure compared to that before exposure in all three countries, suggesting that the parasympathetic nervous system became dominant. These findings suggested that cedrol produces a sedative effect in people of the three countries despite differences in the ethnic and living environments.

Application of heat- and steam-generating sheets to the lumbar or abdominal region affects autonomic nerve activity.

Effects of applying a heat- and steam-generating (HSG) sheet on peripheral hemodynamics and autonomic nerve activity were examined. An HSG sheet was applied to the lumbar or abdominal region. Measurements included skin temperature at the lumbar and abdominal regions and the fingertip, total hemoglobin, tissue oxygen saturation ratio (StO2), pupillary light reflex, changes in ECG R-R interval blood pressure and percutaneous electrogastrography (EGG). A heat-generating sheet without steam was used as the control. Based on the present findings, application of the HSG sheet to the lumbar or abdominal region may improve peripheral hemodynamics and inhibit sympathetic nerve activity, resulting in parasympathetic nerve activity dominance.

Autonomic responses during inhalation of natural fragrance of Cedrol in humans.

It is well known that odors affect behaviors and autonomic functions. Previous studies reported that some compounds in cedar wood essence induced behavioral changes including sedative effects. In the present study, we analyzed cardiovascular and respiratory functions while subjects were inhaling fumes of pure compound (Cedrol) which was extracted from cedar wood oil. Vaporized Cedrol (14.2+/-1.7 microg/l, 5 l/min) and blank air (5 l/min) were presented to healthy human subjects (n=26) via a face mask, while ECGs, heart rate (HR), systolic blood pressure (SBP), diastolic BP (DBP), and respiratory rates (RR) were monitored. Statistical analyses indicated that exposure to Cedrol significantly decreased HR, SBP, and DBP compared to blank air while it increased baroreceptor sensitivity. Furthermore, respiratory rate was reduced during exposure to Cedrol. These results, along with the previous studies reporting close relationship between respiratory and cardiovascular functions, suggest that these changes in respiratory functions were consistent with above cardiovascular alterations. Spectral analysis of HR variability indicated an increase in high frequency (HF) component (index of parasympathetic activity), and a decrease in ratio of low frequency to high frequency components (LF/HF) (index of sympathovagal balance) during Cedrol inhalation. Furthermore, Cedrol inhalation significantly decreased LF components of both SBP and DBP variability, which reflected vasomotor sympathetic activity. Taken together, these patterns of changes in the autonomic parameters indicated that Cedrol inhalation induced an increase in parasympathetic activity and a reduction in sympathetic activity, consistent with the idea of a relaxant effect of Cedrol.

Relationship between physical parameters and blood flow in human facial skin.

We evaluated the association between the cutaneous blood flow and the three-dimensional morphology of the skin by measuring various aspects of blood flow (resting blood flow, mean blood flow during cooling, minimum blood flow during cooling, mean blood flow after cooling, and maximum blood flow after cooling) of the cheeks and foreheads of 40 healthy women (aged 60-77 years). We also analyzed the three-dimensional morphology of the skin surface (sWa, sWp, sWt, sWq) in replicas obtained from foreheads, cheeks, and other sites on the faces of those subjects. In addition, we measured the skin elasticity and water content of the stratum corneum on the cheeks of those women. No correlation was observed between the parameters of the blood flow and the surface morphology of the forehead. On the cheek, however, significant negative correlations were observed between those parameters. Among the blood flow parameters, the resting blood flow and the mean blood flow during cooling showed particularly high correlations. Concerning the surface morphology parameters, high correlations were observed in parameters related to local changes such as sWp and sWt. None of the cutaneous properties examined (including the skin elasticity and water content of the stratum corneum) correlated with the blood flow or the surface morphology parameters of the cheek. Facial wrinkles are classified into linear grooves, which develop at the corner of the eye and on the forehead, and glyphic wrinkles, which develop as deep grooves in areas such as the cheek. These results suggest that a reduction in blood flow is one of the putative causes of local irregularities observed in the cheek, that is, the glyphic wrinkles, of elderly women.

Evaluation of the use of an integration-type laser-Doppler flowmeter with a temperature-loading instrument for measuring skin blood flow in elderly subjects during cooling load: comparison with younger subjects.

An integration-type laser-Doppler flowmeter, equipped with a temperature-load instrument, for measuring skin blood flow (ILD-T), and analytical parameters developed in a previous study were used to compare changes in the skin blood flow in the forehead and cheek in elderly subjects (in their 60s and 70s) with those in younger subjects (in their teens to 50s). Age-related differences in skin blood flow in the forehead and cheek in response to cooling were evaluated in 90 healthy women in their teens to 70s (mean age: 17.2 +/- 0.33 years for teenagers; 24.3 +/- 0.76 years for those aged 20-29 years; 34.8 +/- 1.12 years for those aged 30-39 years; 43.3 +/- 0.78 years for those aged 40-49 years; 53.8 +/- 1.13 years for those aged 50-59 years; 63.5 +/- 0.55 years for those aged 60-69 years; 72.2 +/- 0.70 years for those aged 70-79 years). The measurement was performed continuously for 5 min: for 1 min at a sensor temperature of 30 degrees C, for 2 min after the setting of the sensor temperature had been changed to 10 degrees C, and for 2 min after the temperature setting had been cancelled. The parameters analyzed were (1) skin temperature in a resting state before measurement ( T(rest)), (2) mean skin blood flow in 1 min at a sensor temperature of 30 degrees C ( F(30 degrees C)), (3) minimum skin blood flow at a sensor temperature of 10 degrees C ( F(min)), (4) slope of the blood flow plot during the period from the beginning of cooling at 10 degrees C to F(min) ( S(fall)), (5) time required for the sensor temperature to reach 10 degrees C (Delta t(s)), (6) maximum skin blood flow during the period from the end of cooling to the end of measurement ( F(max)), (7) slope of the blood flow plot during the period from F(min) to F(max) ( S(rise)), (8) rate of decrease of the skin blood flow during cooling: FDR = ( F(min)/ F(30 degrees C))x100, (9) recovery rate of the skin blood flow after the end of cooling: FRR = ( F(max)/ F(30 degrees C))x100. When correlations among the above nine parameters were evaluated by combining all age groups, significant correlations ( P < 0.01) were observed between F(30 degrees C) and F(min), F(30 degrees C) and F(max), F(30 degrees C) and S(fall), F(min) and F(max), and F(max) and S(rise) in the forehead. In the cheek, significant correlations ( P < 0.01) were observed in all these combinations except between F(max) and S(rise). When these analytical parameters were compared among the age groups, F(30 degrees C), T(rest), F(max), and S(rise) decreased significantly ( P < 0.02 for F(30 degrees C) and T(rest), P < 0.01 for F(max) and S(rise)) and S(fall) increased significantly ( P < 0.03) in the forehead with aging. However, no significant change with aging was observed in FDR, Delta t(s), F(min), and FRR. In the cheek, FDR increased significantly ( P < 0.03), and S(rise) decreased significantly ( P < 0.01) with aging. However, no significant change with aging was observed in F(30 degrees C), T(rest), F(max), S(fall), Delta t(s), F(min), and FRR. Thus, the decrease in the skin blood flow during cooling showed no marked quantitative change with age, but, with aging, the rate of this decrease was clearly reduced in the forehead. In the cheek, on the other hand, the skin blood flow decreased markedly with aging, but no clear change was observed in the rate of this decrease. By using ILD-T and examining various parameters obtained, the skin hemodynamics in the forehead and cheek during cooling from 30 degrees C to 10 degrees C could be analyzed, and differences in the hemodynamics between the forehead and cheek and between elderly and younger individuals were clarified. This instrument is expected to be clinically useful.