Few studies have examined Japanese with regard to the achievement rates for target blood pressure levels, or the relationship between these rates and healthy lifestyle characteristics in patients with hypertension as defined by the newly established hypertension management guidelines (JSH2014). The aim of this study was to elucidate achievement rates and examine healthy lifestyle characteristics associated with achievement status among Japanese.This cross-sectional study, conducted in January-December 2012, examined blood pressure control and healthy lifestyle characteristics in 8,001 Japanese workers with hypertension  who participated in a workplace health checkup. Data were collected from workplace medical checkup records and participants’ self-administered questionnaires. We divided into 5 groups  according to JSH2014. And then, achievement rates were calculated in each group. Multivariate analysis identified healthy lifestyle characteristics associated with “therapeutic failure” of target blood pressure.Target blood pressures were achieved by 60.2% of young, middle-aged, and early-phase elderly patients (G1), 71.4% of late-phase elderly patients (G2), 30.5% of diabetic patients (G3), 33.4% of those with chronic kidney disease (G4), and 66.0% of those with cerebrovascular and/or coronary artery diseases (G5). A body mass index of 18.5–24.9 and non-daily alcohol consumption were protective factors, and adequate sleep was found to contribute to therapeutic success.We found low achievement rates for treatment goals among patients with chronic kidney disease and diabetes mellitus. Maintaining an ideal body weight and adequate alcohol consumption may help with blood pressure control. Lifestyle modification may be necessary for better management of hypertension. Globally, the overall prevalence of higher blood pressure in adults 25 years and older was around 40% in 2008 . This reIn 2014, the Japanese Society of Hypertension (JSH) revised the 2009 version of the Japanese Society of Hypertension Guidelines for Management of Hypertension (JSH2009), and published the JSH2014 –7, and oFew studies have examined Japanese workers with regard to the achievement rates for target blood pressure levels, or the relationship between these rates and healthy lifestyle characteristics in patients with hypertension as defined by the newly established hypertension management guidelines (JSH2014). The present study aimed to elucidate achievement rates for target blood pressure levels and examine the healthy lifestyle characteristics associated with achievement status among Japanese workers.The present cross-sectional study screened 136,770 Japanese individuals who participated in a workplace health checkup conducted by the Tokyo Health Service Association from January to December in 2012 in Tokyo, Japan. Of these, 9,790 who were receiving treatment for hypertension, and 1,789 were excluded due to data missing. Thus 8,001 were included in the present study .2). Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated by calculating the mean of two upper arm blood pressure measurements taken for participants who had been seated for at least five minutes. Serum levels of total cholesterol , high-density lipoprotein cholesterol , low-density lipoprotein cholesterol , and triglycerides  were also measured. LDL-C was estimated using the Friedewald equation [(TC)–(HDL-C)–(TG/5)]  . Glycosy–(TG/5)] .2, adequate sleep duration, daily breakfast consumption, and no snacking between meals [Participants were asked to complete a self-administered questionnaire, which addressed healthy lifestyle characteristics based on Breslow’s seven health practices . These cen meals –13.2 and/or urine test of protein ≥2+ on a scale of (–) to (3+) [From the self-administered questionnaire, we also collected information on participants’ present medical history of diabetes mellitus, cerebrovascular diseases, and coronary artery diseases. The following criteria defined CKD: estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m to (3+) .Results are presented as mean ± standard deviation (SD) for continuous variables or prevalence (%) for categorical variables. Participants were divided into five groups according to categories of JSH2014, and success rates were calculated for each treatment goal as defined by the JSH2014 target values: young, middle-aged, and early-phase elderly patients without diabetes mellitus or CKD (<140/90 mmHg), elderly patients without these diseases (<140/90 mmHg), late-phase elderly patients without diabetes mellitus or CKD (<150/90 mmHg), diabetic patients (<130/80 mmHg), patients with CKD (<130/80 mmHg), and patients with cerebrovascular and/or coronary artery diseases (<140/90 mmHg) [Healthy lifestyle characteristics associated with therapeutic failures were calculated using the odds ratio (OR) and 95% confidence interval (CI) for each item using univariate logistic regression analysis. Following this, factors identified to be significant (P<0.05) by the univariate analysis were entered into the multivariate logistic regression analysis. Late-phase elderly patients without diabetes mellitus or CKD were excluded from the logistic regression analysis, since the number of these participants was relatively small compared to the other groups.For the two-tailed Student’s t-test, P<0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for Social Sciences, version 22 .This survey was conducted in compliance with the Ethical Guidelines for Epidemiological Studies established by the Japanese government , and in Mean participant age (SD) was 57.0 (8.8) years, and 78.8% of the participants were men . Median Multivariate analysis revealed that the factors significantly associated with failure to achieve treatment goals were adequate sleep duration , and a BMI of 18.5–24.9  for young, middle-aged, and early-phase elderly patients without diabetes mellitus or CKD . For diaThe present study examined data from a large number of participants who underwent a workplace health checkup, revealing achievement rates of target blood pressure levels as defined by the newly published Japanese hypertension treatment guidelines. Among our participants, achievement rates were especially low in patients with diabetes mellitus and CKD. In addition, we found that adequate alcohol consumption and maintaining an ideal body weight may improve blood pressure management.We found low achievement rates of target blood pressure levels in those with diabetes mellitus and CKD. The JSH2014 emphasizes that the target blood pressure level for hypertensive patients with diabetes mellitus and/or CKD should be less than 130/80 mmHg, because the incidences of cerebrovascular disease and coronary artery disease increase markedly when these diseases are concomitantly present . A crossThe second potential explanation is a lower awareness of hypertension guidelines in primary care. A study conducted in the United States queried 1,200 primary care physicians via questionnaire, and reported their findings that many physicians have higher blood pressure thresholds for the diagnosis and treatment of hypertension than the 140/90 mmHg criterion recommended by the JNC. This particular study concluded that further improvements in population hypertension control will require behavioral changes among physicians . Althoug2 increment of BMI was 1.16 (1.15–1.17) and 1.13 (1.12–1.14) for men and women, respectively [In the present study, maintaining an ideal BMI and non-excessive alcohol consumption helped to prevent failure to achieve treatment goals. Our data showed that half of our participants were obese and only 29.0% exercised at a frequency of 2 or more times per week. Obesity is a classic risk factor for elevated blood pressure and is also well known as an important risk factor for several lifestyle-related disorders –27. A stectively . In addiectively . The Norectively –30. One ectively . A largeOne somewhat contradictory finding of the present study was the observation that adequate sleep duration was a risk factor for therapeutic failure among young, middle-aged, and early-phase elderly patients without diabetes mellitus or CKD. Several previous reports found an association between sleep quality and blood pressure controls –32. The Our study has several limitations worth noting. First, selection bias may have been present, as participants comprised only those who underwent workplace medical examinations in Tokyo, Japan. As such, these participants may be inherently more aware of health behaviors relative to residents in rural areas. Further analyses which include data from a more diverse cohort are necessary. Second, some key data were not collected, such as information on medications for hypertension. Third, data collection was conducted in 2012. While the draft of the JSH2014 was introduced in 2013, the JSH2014 was established in 2014. Despite the lag, however, the threshold for patients with diabetes mellitus and chronic kidney disease was very similar to that of the JSH2009, so our results may still be applicable. Further studies after 2014 will be needed. Forth, some lifestyle criteria are vague because lifestyle related items were collected from existing questionnaires. Further studies using a questionnaire focused on lifestyle characteristics will be needed. Fifth, the JSH 2014 guideline differs from the majority of guidelines published elsewhere in the world, such as the JNC 8 guideline 2014 (<140/90 mmHg), American and the International Societies of Hypertension guidelines 2014 (<140/90 mmHg), and the 2013 ESH/ESC (the European Society of Hypertension/the European Society of Cardiology) guideline for the management of arterial hypertension (<140/85 mmHg). Thus, it may be required to pay attention applying our results in other countries. Finally, our study employed a cross-sectional analysis to examine lifestyle characteristics, and thus causal relationships between achievement rates and healthy lifestyles cannot be confirmed. Further analyses of follow-up survey data are needed.The present study revealed low achievement rates for treatment goals among hypertensive patients, especially for patients with CKD and diabetes mellitus. With regard to healthy lifestyle characteristics, maintaining an ideal body weight and non-excessive alcohol consumption may contribute to better control of blood pressure levels. Our data indicate the need to focus on these patients and provide instruction regarding lifestyle modification to allow for better management of hypertension according to treatment guidelines.S1 Filekoho@yobouigaku-tokyo.jp).Data are available from the Tokyo Health Service Association Institutional Data Access / Ethics Committee for researchers who meet the criteria for access to confidential data. The data are under the ethical restrictions of the Ethics Committee of the Tokyo Health Service Association ((XLSX)Click here for additional data file.


Two hours after ingestion the BJ treatment increased [NO] and decreased SBP. BJ also increased SDNN at rest and at the 40% VO2peak workload, without significant effects on LF. SDNN was significantly greater after the BJ than after the OJ treatment, across the two physical activity conditions and SDNN was (negatively) correlated with SBP. These results suggest that BJ decreases SBP and increases HRV at rest and during aerobic exercise. Similar results in subjects with prehypertension or hypertension could translate to a dietary nitrate treatment for hypertension.Previous studies have shown that beetroot juice (BJ) decreases systolic blood pressure (SBP) and oxygen demand. This study tests the hypothesis that a beetroot juice (BJ) treatment increases heart rate variability (HRV) measured by the average standard deviation of normal-normal electrocardiogram RR intervals (SDNN) and the low frequency (LF), mainly sympathetic, fast Fourier transform spectral index of HRV. The subjects were 13 healthy young adult African-American females. Placebo control orange juice (OJ) and BJ treatments were given on separate days. Blood nitric oxide [NO], SBP and RR intervals were measured at rest and at constant workloads set to 40% and 80% of the predetermined VO Studies have consistently reported a greater prevalence of hypertension in African Americans than in other ethnic groups . Adolescin vivo as an oxidative metabolite of NO itself [Nitric oxide (NO) is a potent endogenous vasodilator  that plaO itself  or ingesO itself , might pO itself , 19. SevO itself –25 folloO itself –22, 24 aThe subjects were 13 healthy normotensive young adult African American females who were physically active but not exercise-trained. None of the subjects were smokers or drinkers and free of any medication intake . The procedures outlined in the study were approved by the Howard University Institutional Human Participants Review Board. Following explaining the study procedures and risks, all subjects gave their written informed consent before commencement of the study. Subjects were instructed to arrive at the laboratory in a rested state, at least three hours postprandial, and to avoid strenuous exercise in the 24 hours preceding each testing session. All tests were performed at the similar time of day.2peak). The progressive exercise test of VO2peak was performed on an electronically braked cycle leg cycle ergometer . The subject performed a three-minute warmup of cycling with no workload, after which the exercise intensity was increased at a rate of 20 W every three minutes until volitional fatigue. The metabolic measure of VO2peak was defined by the VO2 value generated during the last minute of the progressive exercise test. Respiratory measures of expired O2, carbon dioxide, and minute-ventilation were made during the progressive exercise test using a Physio-Dyne Max-II metabolic system . Additionally, in the first visit, the subject’s body composition was measured by the dual energy X-ray absorptiometry method using an Hologic QDR whole body scanner .The study design consisted of the subjects reporting to the laboratory on three occasions, over a 3–7 week period. The first laboratory visit consisted of the subjects performing a progressive exercise test determining peak oxygen uptake  or placebo/control (orange juice) and performed a standardized exercise test on the cycle ergometer. We selected orange juice as the control because it is matched with beetroot juice for calories , carbohydrates (52 g), fat (negligible), and protein (4 g) content and is also similar in texture and is high in antioxidants [2peak, defining low and high levels of physical stress, respectively. Both bouts of submaximal exercise were of 5 min duration. Before the submaximal work bouts, blood pressure, heart rate, and cardiac output were measured. Additionally, venous blood was collected for determination of NO. To limit the confounding influences of menstrual hormonal changes on blood pressure, the females were tested during the luteal phase of their menstrual cycle. Before the exercise bout, the NO concentration in venous blood, blood pressure (BP), heart rate (HR), cardiac output (CO), total peripheral vascular resistance (TPR), and electrocardiogram heart rate variability (HRV) measurements were performed.After measuring VOoxidants . Biotta oxidants , 24, 25.μL) was collected into a tube containing EDTA. To deproteinize the blood, the sample was placed in 300 μL of 20% trichloroacetic acid and centrifuged at 15,000 g for three minutes. Then, 10 μL of a nitrite preservation solution containing 0.8 M ferricyanide, 10 mM-N-ethylmaleimide, and 1% NP-40 was added to the mixture. NO was measured (within 20 minutes of collection) by the amperometric method using an NO electrode system . The electrode was calibrated using a standard nitrite concentration of 50 and 100 nM. The NO recording system has an analog to digital resolution of 24 bit allowing resolution of currents down to 0.1 pA. Assay measurement of NO was performed using the average of duplicate values.A blood sample  automated monitor using R-wave gating and k-sounds for measuring absolute systolic and diastolic blood pressure. Mean arterial pressure (MAP) was estimated by the formula MAP = diastolic blood pressure plus 1/3 pulse pressure. To verify the automated device blood pressure readings, we connected the monitor to a mercury column using a Y-tube connector and assessed the Korotkoff sounds using an audio headphone.−5) = 80 × MAP (mm Hg)/CO (L·min−1).Heart rate and estimate of CO measurements were made using the SORBA model CIC-1000 impedance electrocardiography system, software version 7.2 . The subjects were prepared with four electrodes to measure impedance. The first electrode was placed on the forehead. The second electrode was placed at the base of the neck on the left side, the third at the midaxillary line at the level of the xiphoid process, and the fourth at the midaxillary line at the region of the greater trochanter. Two electrocardiogram (ECG) electrodes were placed on the subject’s right and left arm, respectively. The SORBA system continuously sampled signals for CO using the Kubicek equation  to calcu2peak, using specialized HRV software .The effects of beetroot juice on respiratory sinus arrhythmia and autonomic signaling were measured by the average standard deviation of the normal-normal RR intervals (SDNN) and fast Fourier transform analysis (FFT) of the RR intervals over 5 min during rest and exercise at constant workloads set to 40% and 80% of each subject’s predetermined VOt-tests were used to determine significance of treatment-related differences in cardiac output (CO), heart rate (HR), systolic and diastolic blood pressure , heart rate × systolic blood pressure product (RPP), total peripheral resistance (TPR), average standard deviation of the normal-normal electrocardiogram RR intervals, and the low and high frequency  FFT spectral components of HRV. Linear regression analysis and Pearson’s product-moment correlation coefficient (r) were used to determine the significance of correlations across the control and beetroot juice treatments and the physical activity conditions, as well as across the physical activity conditions for each of the treatments. Differences were considered to be significant at P < 0.05.For statistical analysis paired (two-tailed) Student’s 2peak indicate that the subjects were overweight and exhibited a low level of cardiorespiratory fitness.P < 0.0001).P < 0.05), 40% VO2peak , and 80% VO2peak . DBP tended to be reduced following nitrate-rich beetroot juice at control baseline, 40% VO2peak, and 80% VO2peak workloads, but the differences were not significant. Across the baseline resting and two exercise conditions, SBP was found to be significantly lower after the beetroot juice than after the control orange juice treatment .2peak and 80% VO2peak workloads (P < 0.05). The beetroot juice treatment-related decrements in SBP and TPR were associated with parallel, significant decrements in the heart rate-systolic pressure product (RPP). Across the three conditions, RPP was significantly lower after the beetroot juice than after the control treatment ,.2peak workload. Across the three physical activity conditions, SDNN was significantly higher and HR, SBP, and RPP were significantly lower after the beetroot juice than after the control orange juice treatment . SDNN was significantly correlated with HR , with SBP , and with RPP  across both treatments (orange juice and beetroot juice) and the three conditions .The main finding of this study is that beetroot juice increases SDNN. SDNN is a time-domain HRV measure of the autonomic  influence on HR and was found to be inversely correlated with both SBP and with RPP, an index of myocardial oxygen demand. The significance of larger SDNN associated with the beetroot juice than with the placebo orange juice treatment is demonstrated by other studies wherein SDNN was positively correlated with the LF/HF spectral power ratio. Generally, larger LF/HF indicates greater sympathetic neural signaling, whereas smaller LF/HF indicates greater parasympathetic  autonomic signaling . Our meaIncreased SDNN without a change in LF/HF has been reported following administration of simvastatin to animals subjected to experimental heart failure . Thus, u2peak workload. A beetroot juice treatment-related difference in SDNN was not observed at the 80% VO2peak workload, likely because of insensitivity of the measurement at very high heart rates.In the present study, the larger SDNN associated with the beetroot juice treatment occurred in the absence of treatment-related differences in HR but in the presence of treatment-related decrements in RPP and TPR. These effects were also associated with significant negative (inverse) correlations between SDNN and these variables across the two treatment conditions. Increases in SBP and RPP are common correlates of high sympathetic activity . Thus, tThere is some evidence from prior studies, in experimental animals and in humans, that the dietary nitrate-induced increase in plasma NO played a key role in the beetroot juice treatment-related increases in SDNN. Decreased SDNN has been observed following administration of an inhibitor of neuronally released NO in anesthetized dogs  and highThere are huge stores of nitrate, and nitrite and nitrothiol in cutaneous tissues which function as NO donor molecules. The primary sources of endogenous NO are endothelial, inducible, and neuronal NO synthase, eNOs, iNOS, and nNOS, respectively, and there is substantial evidence that structural and functional changes in these NOS isoforms may modulate HRV measurements. For example, in patients with specific NOS polymorphisms, greater LF/HF is reported in CHF patients , as wellOver the past twenty years, a large database has emerged concerning the effects of inhibitors of NO synthase (NOS) demonstrating that increased bioavailability of NO plays a significant role in the mechanisms related to sympathetic-parasympathetic imbalances. For example, the NOS inhibitor L-NAME is shown to increase the predominance of sympathetic measures of blood pressure variability and baroreceptor reflex sensitivity and higher plasma NO levels are reported in heart failure patients than in control subjects . L-NAME In summary, the results of this study demonstrate that a single beetroot juice treatment may produce significantly larger SDNN at rest and smaller exercise-induced decrement in SDNN, associated with a markedly increased plasma NO concentration in healthy humans. These findings support previous reports that dietary nitrate supplementation with beetroot juice has the potential to decrease blood pressure, vascular resistance, and myocardial oxygen demand in both resting and exercising subjects. The increases in SDNN appear to be indicative of less sympathetic influence on heart rate which might be dependent on NO bioavailability. However, these results should be interpreted cautiously pending verification by more direct measures of sympathetic signaling to the arterial vasculature such as baroreceptor sensitivity and direct microneurography. Because high blood pressure, vascular resistance, myocardial oxygen demand are positively correlated with the severity of cardiovascular disease , beetroo


Obstructive sleep apnea (OSA) is highly associated with hypertension. However, the correlation between hypertension and OSA at different levels of severity and the influence of gender on that correlation are unclear. A total of 996 patients  with OSA were recruited. The influence of gender on the correlation between hypertension and OSA at different stratifications of severity, based on the apnea-hypopnea index (AHI), was fully evaluated together with the major health risk factors obesity, age, and diabetes. Females with OSA were significantly older on average than males with OSA. Moreover, females had milder degrees of OSA on average than the extent of severity seen in males. The proportion of females with diabetes or hypertension was higher than that of males. The proportion of males with hypertension and obesity increased significantly with OSA, and age also increased with OSA. The percentage of females with hypertension at different degrees of OSA severity was stable at about 26% in the mild, moderate, and severe OSA groups. Among females, age was increased significantly in the moderate relative to the mild OSA group. Moreover, the proportion of obese subjects was increased significantly in the severe compared with the moderate OSA group. The proportions of males and females with diabetes were not significantly different among all OSA severity groups. An ordinal multivariate logistic regression analysis confirmed that hypertension, age, and obesity were associated with OSA severity in males, whereas only age and obesity were associated with OSA severity in females. Although the proportion of subjects with hypertension was higher in females with OSA than in males with OSA, the proportion of subjects with hypertension increased as the severity of OSA increased in males but not in females. Obstructive sleep apnea (OSA) is a common respiratory sleep-related disease that involves the cessation or a significant decrease in airflow with breathing effort Normal sleep is a basic physiological process to maintain health by decreasing the body's metabolic rate, sympathetic nervous activity, blood pressure, and heart rate and increasing cardiac vagal tone Hypertension is also a common chronic disease that increases the risks of heart attack, stroke, kidney failure, coronary heart disease, and other serious health problems Current clinical studies have focused mainly on the prevalence of hypertension in OSA patients To determine if the prevalence of hypertension in OSA patients is influenced by gender and how gender may alter the correlation between hypertension and OSA at different levels of severity, 996 OSA patients were recruited to evaluate the association between OSA severity and hypertension, together with major health risk factors such as obesity, age, and diabetes.A total of 1,113 patients with OSA  who visited our Department of Cardiology were recruited sequentially from July 2009 to December 2013. Patients who met one of the following criteria were excluded: treatment with antihypertensive or antidiabetic drugs 1 week prior to data acquisition; treatment with CPAP or other substitution therapies; the presence of sleep disorders other than OSA; and chronic kidney disease or the use of hormone treatment. Ultimately, 966 adult patients  were included in this study.Written informed consent regarding the procedures and for the medical data to be used was obtained from all patients according to the guidelines of the Chinese National Ethics Regulation Committee. The review board of the Center Hospital of Minhang District approved this protocol in accordance with the amended Declaration of Helsinki (reference number: SHMHCH 2009–0009).The patients arrived to our sleep lab in the early evening. Multiple channel PSG  was conducted by full-time technicians. The technicians were responsible for attaching the electrodes and monitoring the patients. Multiple channels of data, including an electroencephalogram, electrooculogram, electromyogram, electrocardiogram, heart rhythm, pressure transducers, oxygen saturation, and chest and upper abdominal wall movement, were recorded. The apnea-hypopnea index (AHI) was calculated by dividing the number of sleep events by the number of hours of sleep. Subjects with an AHI value >5 were defined as having OSA.Waking blood pressure was measured in the morning after overnight monitoring by PSG using a mercury sphygmomanometer. After a 5-min rest, patients in the seated position underwent three measurements at 5-min intervals, and the mean of the three measurements was calculated. Hypertension was defined as a systolic pressure >140 mmHg or diastolic pressure >90 mmHg according to American Society of Hypertension guidelines Fasting blood samples were also collected in the morning after monitoring by PSG. Serum glucose concentrations were measured with a Hitachi H-7600 Autoanalyzer . Diabetes was defined as a combination of a fasting plasma glucose level of ≥7.0 mmol/L, a previous diabetes diagnosis, or treatment with an anti-diabetic medication 1 week before measurement.2 or waist circumference/hip circumference ratio >0.90 for males and >0.86 for females were defined as obese.Age and sex data were collected before PSG. Anthropometric data were measured in light clothing and bare feet. Neck circumference was measured at the level of the cricothyroid membrane while the subject was standing, waist circumference was measured midway between the lower costal margin and iliac crest, and hip circumference was measured as the maximum girth at the greater trochanters. The mean of two measurements was used to calculate the subject's body mass index (BMI) and waist circumference/hip circumference ratio. Patients with a BMI >30 kg/m2 test according to the characteristics of the data distribution. P-values <0.05 were considered significant.Descriptive statistics were performed first; categorical variables are presented as frequencies (%), and non-normally distributed variables are summarized as medians and interquartile ranges. Differences in the baseline characteristics among groups were examined by the Kruskal-Wallis H test, one-way analysis of variance, Fisher's exact test, or the χIn the multivariate analysis, an ordinal logistic regression was performed with backward selection of variables. The AHI was used as a dependent variable; raw AHI values were inputted into the ordinal logistic regression model to evaluate the correlations between OSA severity and risk factors. Independent variables of diabetes, obesity, and hypertension were included in the ordinal logistic regression model as binary variables. The independent variable age was inputted into the ordinal logistic regression model as a continuous variable. Factors significant in the ordinal logistic regression model were tested in a stepwise multivariate model as independent variables. The level of statistical significance was set to 0.05. The statistical analysis was performed using STATA 8.0 statistical software .p = 0.0258). The proportion of female OSA patients with hypertension (26.3%) was higher than that of male patients (20.5%) (p = 0.0513).Of 966 patients with OSA who met the inclusive criteria were included in the analysis, 776 were males and 190 were females . The average age of the female patients (54±12 years) was significantly higher than that of the male patients (44±17 years). The severity of OSA in the male patients  was generally greater than that in the female patients . Of the male patients, 6.1% (47/776), 12.8% (99/776), and 20.5% (159/776) had diabetes, obesity, and hypertension, respectively. Of the female patients, 10.5% (20/190), 16.8% (32/190), and 26.3% (50/190) had diabetes, obesity, and hypertension, respectively. The proportion of female OSA patients with diabetes (10.5%) was significantly higher than that of male patients (6.1%) (The patients were stratified into mild (n = 220), moderate (n = 219), and severe (n = 337) OSA groups according to their AHI value, and the proportions with hypertension, diabetes, and obesity were plotted against the AHI stratification. The proportions of subjects with hypertension, diabetes, and obesity in the mild, moderate, and severe OSA groups were 12.3, 22.4, and 24.6%; 5.5, 5.5, and 6.8%; and 7.7, 13.7, and 15.4%, respectively . The proThe 190 female patients were also stratified into mild, moderate, and severe OSA groups according to their AHI value. There were 64, 52, and 74 patients with mild, moderate, and severe OSA, respectively. The proportions of females with hypertension and diabetes in the mild, moderate, and severe OSA groups were 26.6, 25.0, and 27.0% and 9.4, 13.5, and 9.5%, respectively . AlthougObesity, age, and diabetes are the main confounding factors in the correlation between OSA and hypertension. An ordinal multivariate logistic regression analysis was conducted to eliminate the confounding effects of these factors on the above proportion distributions and to reveal the correlation between hypertension and OSA severity in male and female patients. As shown in Population-based studies have identified an independent correlation between a higher AHI value and increased blood pressure The key challenge in deciphering OSA-associated risk factors, including hypertension, is appropriately accounting for the many confounding variables, particularly obesity and age Reports indicate that as many as 50% of patients with hypertension have concomitant OSA Sex affects the incidence of the disease, OSA being more prevalent in males than in females The proportion of subjects with hypertension was higher in females than males with OSA The proportion of subjects with hypertension increased as the severity of OSA increased in males but not in females.


Blood pressure (BP) variability is associated with target organ damage in hypertension and diabetes. The 24 h ambulatory blood pressure monitoring (24 h-ABPM) has been proposed as an evaluation for BP variability using several indexes .We evaluated the association between BP variability measured by 24 h-ABPM indexes and echocardiographic variables in a cross-sectional study in 305 diabetic-hypertensive patients.n = 148) and high (n = 157) variability groups. Office SBP and systolic 24 h-ABPM were higher in the high variability group . Time-rate index, SD and CV of SBP, were higher in high variability group . Time-rate index was not independently associated with the echocardiography’s variables in multiple linear model when adjusting for age, 24 h-ABPM, diabetes duration and HbA1c. The multiple linear regression model revealed that the significant and independent determinants for septum thickness, relative wall thickness and posterior wall thickness (parameters of left ventricular hypertrophy) were: age  and 24 h-SBP (p < 0.001 in the three parameters).Two groups were defined by the median (0.55 mmHg/min) of time-rate systolic BP (SBP) index and classified as low or high variability. Age was 57.3 ± 6.2 years, 196 (64.3 %) were female. Diabetes duration was 10.0 (5.0–16.2) years, HbA1c was 8.2 ± 1.9 %. Baseline clinical characteristics were similar between low (BP variability estimated by 24 h-ABPM is not independently associated with echocardiographic parameters in diabetic-hypertensive patients. Observational studies had consistently shown the continuous relationship between office systolic and diastolic blood pressure (BP) and cardiovascular events . Indeed,Methods of out-of-office BP measurement such as 24 h ambulatory BP monitoring (24 h-ABPM) evaluated in general population or in hypertensive-based longitudinal studies also showed a close relationship between BP elevation and cardiovascular risk . Other pConsidering the high cardiovascular risk profile  and the This is a cross-sectional study conducted in the outpatient clinic of a tertiary hospital , from April 2010 to December 2011. The data came from a larger study that aimed to assess cardiovascular risk in diabetic hypertensive patients through non-invasive methods –20. The 2 cancer, arrhythmias  that could interfere with BP measurement and 24 h-ABPM recordings. According to these criteria, 351 patients were included  ≥ 35 kg/m,Patients who met the inclusion criteria and agreed to participate underwent a demographic and clinical baseline data collection, including the assessment of duration of diabetes and hypertension and its known chronic complications, smoking habits, previous cardiovascular diseases, medication in use, BMI, and office BP levels.Blood pressure was measured after 15 min of rest with an automatic sphygmomanometer . High office BP levels were defined as office BP higher than 140/90 mmHg.n = 327) underwent 24 h-ABPM  on an usual working day, performed at up to four months after the initial evaluation . Readings were obtained automatically at 15-min intervals during the day and at 20-min intervals during the night for the duration of the 24 h-ABPM period. Cuff size was chosen according to arm circumference. Daytime was defined as the interval between 06:00–22:00 h and nighttime was the interval between 22:00–06:00 h. Individuals with less than 6 and 18 measures during the night and the day periods, respectively (n = 24) were excluded from further analysis. All individuals were instructed to rest or sleep during the nighttime and to maintain their usual activities during daytime. Based on the results of the 24 h-ABPM, the mean 24 h-SBP and diastolic BP (DBP) were calculated for each patient. We calculated three different parameters of SBP variability: the standard deviation of mean (SD), coefficient of variation (CV = SD/mean pressure × 100%) and rate of change in SBP over time (mmHg/min), defined as the first derivative values of SBP by time (time-rate index). This index allows the calculation of the sum of angular coefficients and aims to measure how fast or how slow and which direction SBP values change. The measure was calculated using the following formula [Among the 351 selected individuals, 93.1 %  and N is the number of recordings.In the formula, n = 345) of patients by a single investigator, usually on the same day of the 24 h-ABPM. Images were obtained using a commercially available instrument  equipped with a 4 MHz transducer, according to the recommendations of the American Society of Echocardiography, [Echocardiography was performed in 98.3 % . Serum total cholesterol and triglycerides were measured by enzymatic-colorimetric methods , and High-density lipoprotein (HDL) cholesterol by a homogeneous direct method . Low-density lipoprotein (LDL) cholesterol was calculated using Friedewald’s formula [Fasting blood samples were collected for laboratory analysis using commercial kits. Plasma glucose was evaluated by a glucose oxidase method, serum creatinine by Jaffé’s reaction, and glycated hemoglobin (HbA1c) by ion-exchange HPLC  and HbA1c were included in models. Continuous variables are expressed as mean ± SD or median and interquartile range. Categorical variables are expressed as number (%).The comparison groups were defined by the median of time-rate index of 24 h-SBP and classified as low and high variability of time-rate index: values ≤ 0.54 mmHg/min or ≥ 0.55 mmHg/min, respectively. Comparisons were tested by Pearson’s chi-square test, Student’s Sample size calculation was based upon the mean differences in two echocardiographic variables of septum and E/E’, between low and high variability. Considering the 1:1 proportion in low and high variability groups, a SD of 0.17 cm, an alpha error of 5 %, and power of 90 % to detect a 10 % increase in the septum, the sample size estimation was 124 patients (62 in each group). For the E/E’ ratio we considered a SD of 3.6, considering the same proportion, alpha error and power to detect a 15 % of difference between groups, the sample size estimation was 162 patients (81 in each group).P values < 0.05 (two-tailed) were considered to be statistically significant. Statistical Package for Social Science  version 18.0 was used for the analyses.Logarithmic transformation was applied to albuminuria before parametric tests were applied. A total of 305 patients was evaluated. The characteristics of the subjects studied, grouped as low and high variability (time-rate index of 24 h-SBP) are presented in Table P = 0.006) higher in the high variability as compared to the low variability group, as well as mean and daytime SBP of 24 h-ABPM . The time-rate index of 24 h-SBP was higher in the high variability group as compared to the low variability group , such as the other parameters of variability, SD SBP  and CV of SBP  were higher in the group of high variability when compared to the group of low variability.Office BP recordings and 24 h-ABPM parameters are presented in Table Echocardiographic measurements are presented in Table p = 0.025; p = 0.010; p = 0.032, respectively) and 24 h-SBP (p < 0.001 in the three parameters). Considering the parameters of diastolic function, age was the only variable that was significantly associated with isovolumetric relaxation time (IVRT) and E/E’ ratio.The time-rate index of SBP was not associated with the echocardiography’s variables in multiple linear model when adjusting for age, 24 h-SBP, duration of diabetes (years) and HbA1c  and diastolic function (IVRT and E/E’) were age and 24 h-SBP, and the only parameter associated with diastolic function (IVRT and E/E’) was age.Cross-sectional and longitudinal studies showed a positive association between BP variability and cardiovascular risk in pure hypertensive patients. The identification of higher risk patients through variables beyond the absolute values of BP could have practical applications. High risk patients with high BP variability could be chosen to have lower BP targets. Moreover, there is some evidence of a class difference effect between antihypertensive drugs in the within-individual visit-to-visit variability of BP. This potential effect on BP variability could be the guide to an optimal antihypertensive treatment in higher risk patients . In a prThe association of time-rate index of SBP with echocardiographic parameters was previously studied by Zakopoulos et al. in a cross-sectional study. They demonstrated that a 0.1 mmHg/min increase in the daytime rate of SBP variation was associated with an increment of 7.087 g  in the left ventricular mass . Short-tvs 14.5 mmHg; p = 0.041 and SD of mean DBP, 11.5 mmHg vs 9.6 mmHg; p = 0.042). A prospective study in patients with type 2 diabetes has shown that nighttime BP variability estimated by SD of the nighttime SBP and DBP was an independent predictor of future incidence of cardiovascular events [Diabetes is associated with higher values of short-term BP variability . Ozawa er events . Howeverr events , 33. UnfIn the present study we analyzed the relationship of short-term BP variability and echocardiographic parameters in a high risk sample. Diabetic hypertensive patients have approximately twice the risk of developing cardiovascular events when compared to purely hypertensive patients. Moreover, 56 % of our sample had history of previous cardiovascular disease, the median duration of diabetes was 10 years, the mean HbA1c was 8.2 ± 1.9 % and almost 60 % had left ventricular hypertrophy. This high-risk profile of the subjects evaluated can explain our negative results, as parameters of BP variability may not add cardiovascular risk information beyond age or BP values in such a high risk sample.Certain limitations of the present study should be acknowledged. Firstly, we quantified the rate of BP changes using discontinuous 24 h-ABPM techniques, which cannot adequately assess short-lasting BP fluctuations and can only provide some insight into slow and relatively ‘long-term’ BP oscillations. Secondly, the echocardiographic phenotypes assessed are not in fact endpoints. However, in longitudinal studies, these echocardiographic abnormalities have been associated with hard outcomes. Several studies have also confirmed the prognostic significance of left ventricular hypertrophy and diastolic dysfunction , 35. TheIn conclusion, in a diabetic hypertensive high risk sample, BP variability estimated by time-rate índex of SBP was not independently associated with echocardiographic parameters of left ventricular hypertrophy or diastolic function. The use of BP variability for risk stratification beyond the absolute level of BP in this clinical setting should be questioned. Prospective studies in diabetic hypertensive patients with hard outcomes could better confirm our findings.


Low tidal volume ventilation improves the outcomes of acute respiratory distress syndrome (ARDS). However, no studies have investigated the use of a rescue therapy involving mechanical ventilation when low tidal volume ventilation cannot maintain homeostasis. Inverse ratio ventilation (IRV) is one candidate for such rescue therapy, but the roles and effects of IRV as a rescue therapy remain unknown.We undertook a retrospective review of the medical records of patients with ARDS who received IRV in our hospital from January 2007 to May 2014. Gas exchange, ventilation, and outcome data were collected and analyzed.2/FiO2 from 76 ± 27 to 208 ± 91 mmHg without circulatory impairment. The mean duration of IRV was 10.5 days, and all survivors were weaned from mechanical ventilation and discharged. The 90-day mortality rate was 38.5 %. Univariate analysis showed that the duration of IRV was associated with the 90-day mortality rate. No patients were diagnosed with pneumothorax.Pressure-controlled IRV was used for 13 patients during the study period. Volume-controlled IRV was not used. IRV was initiated on 4.4 ventilation days when gas exchange could not be maintained. IRV significantly improved the PaOPressure-controlled IRV provided acceptable gas exchange without apparent complications and served as a successful bridge to conventional treatment when used as a rescue therapy for moderate to severe ARDS. A retrospective review of the clinical records of all patients with ARDS treated in the ICU of our institution from January 2007 to May 2014 was undertaken. All patients diagnosed with ARDS according to the Berlin definition  was calculated, and the timing of initiation of IRV, duration of IRV, total duration of ventilation, and 28- and 90-day mortality were also collected. Arterial blood pressure and heart rate before and after the initiation of IRV and the incidence of pneumothorax were collected to assess the adverse effects.We recorded age, sex, body weight, underlying diseases, presumed cause of ARDS, indications for IRV, acid–base balance, serum lactate concentration, acute physiological and chronic health evaluation (APACHE) II score at ICU admission, mechanical ventilation parameters, and Murray score before switching to IRV. The arterial partial pressure of oxygen to fraction of inspired oxygen  of <90 %] persisted even when the Pplat reached 30 cmH2O with a fraction of inspired oxygen of >0.6, the ventilator mode was switched to APRV or IRV with the aim of achieving an adequate mean airway pressure and thus maintaining acceptable and stable oxygenation. The APRV parameters were set according to a previous review , and PEEP were adjusted to avoid respiratory acidosis and maintain a pH of >7.25. Cardiac ultrasonography was performed daily to evaluate the right ventricular function. The Richmond agitation-sedation scale score  according to our procedures for acute hypoxemic respiratory failure. Briefly, the expiratory tidal volume and the Pplat were limited <8 ml/kg predicted body weight and 30 cmH Habashi . When APStatistical analyses were performed using JMP 9 . The significance of the categorical variables was calculated using Fisher’s exact test. A t test was used to compare quantitative variables, which were presented as either mean ± standard deviation or proportion (%). Univariate analysis was performed to screen variables associated with the 90-day mortality rate. A p value of <0.05 was considered statistically significant.Of 116 patients with ARDS screened during the study period, 13 patients had received IRV and were included in the analysis; their characteristics are summarized in Table 2O, respectively. The mean highest PEEP in APRV before IRV was 29.0 ± 4.0 cmH2O. The ventilation frequency during IRV was 31–57 breaths/min. The changes in Pplat, PEEP and ventilation frequency over time are shown in Table The mean Pplat and PEEP in ACV before IRV were 29.4 ± 3.3 and 12.4 ± 3.5 cmHHypoxemia and acidosis was improved over time after IRV Table . The timFive patients were in shock status when IRV was introduced. Patient 1 became hemodynamically unstable on initiation of IRV and was successfully treated with volume resuscitation and administration of vasopressors. The remaining four patients did not require any additional resuscitation. Mean blood pressure was stable in the first 24 h after the initiation of IRV  or esophageal pressure. An inspiratory to expiratory ratio of 2:1 was used in the study, but the effect of this ratio on the outcomes is unclear. We were unable to establish whether IRV reduced lung injury because we did not measure the biomarkers associated with VILI and did not routinely perform lung biopsy. Finally, the feasibility of volume-controlled IRV is unknown because we did not use it.Pressure-controlled IRV provided acceptable oxygenation without major complications, suggesting that pressure-controlled IRV is feasible as a rescue therapy in patients with ARDS that do not respond to conventional treatment. Further studies are warranted to confirm the efficacy and safety of pressure-controlled IRV as a rescue therapy for moderate to severe ARDS.


Impaired glucose tolerance (IGT) is a pre-diabetic state of hyperglycemia that is associated with insulin resistance, increased risk of type II diabetes, and cardiovascular pathology. Recently, investigators hypothesized that decreased vagus nerve activity may be the underlying mechanism of metabolic syndrome including obesity, elevated glucose levels, and high blood pressure.In this pilot randomized clinical trial, we compared the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) and sham taVNS on patients with IGT. 72 participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham taVNS treatment groups. In addition, 30 IGT adults were recruited as a control population and not assigned treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All treatments were self-administered by the patients at home after training at the hospital. Patients were instructed to fill in a patient diary booklet each day to describe any side effects after each treatment. The treatment period was 12 weeks in duration. Baseline comparison between treatment and control group showed no difference in weight, BMI, or measures of systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc).F(2) = 5.79, p = 0.004). In addition, we found that taVNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham taVNS. Compared with the no-treatment control group, patients receiving taVNS significantly differed in measures of FPG (F(2) = 10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the course of the 12 week treatment period.100 participants completed the study and were included in data analysis. Two female patients  dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham taVNS, taVNS significantly reduced the two-hour glucose tolerance (Our study suggests that taVNS is a promising, simple, and cost-effective treatment for IGT/ pre-diabetes with only slight risk of mild side-effects. Pre-diabetes, defined as impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) or both, represents an intermediate state between normal glucose homeostasis and diabetes . IGT is Current opinion suggests that pre-diabetes should be treated either with lifestyle interventions, which target obesity and physical inactivity, and/or with pharmacological intervention based on anti-diabetic drugs, in order to prevent progression to diabetes . For botIn recent years, investigators have proposed the hypothesis that adequate vagus nerve activity can reduce the risk of metabolic syndromes such as obesity, elevated glucose level and blood pressure . Thus, iMore recently, investigators have implemented transcutaneous auricular vagus nerve stimulation (taVNS) in replacement of the classic VNS method to treat disorders such as epilepsy  and deprIn this study, we performed a pilot randomized clinical trial to test the efficacy of taVNS in IGT patients.This study was registered at the Chinese Cochrane Centre, International Clinical Epidemiology Network Resource and Training Center (ChiCTR-TRC-12002522). The Institutional Ethics Committee of the China Academy of Chinese Medical Sciences approved this study. All clinical investigative procedures were conducted according to the principles expressed in the Declaration of Helsinki. All patients and healthy controls signed a consent form prior to initiation of study procedures.IGT outpatients were recruited from the China Academy of Chinese Medical Sciences acupuncture hospital for a randomized clinical trial to test the efficacy of taVNS. Subject recruitment and all study procedures were completed between November 2009 and December 2010.In order to monitor the natural fluctuation of glucose tolerance in IGT patients, an additional 30 IGT patients were recruited from free clinics in the community through advertisements in the local newspaper and posters. Patients in the no-treatment control group were required to fulfill the same inclusion criteria as patients who were randomized to receive treatment. Recruitment for the control population took place during the same period of time as for the two treatment groups. The control population was included to explore the variation of patient glucose levels under normal life conditions for 12 weeks without treatment.All patients met the World Health Organization (WHO) standard diagnosis of IGT , and adda. Patients between 20 and 70 years of ageb. Levels of FPG less than 7.0 mmol/L and levels of 2hPG between 7.8 and 11.1 mmol/L at the time of enrollmentc. Ability and willingness to provide informed consentd. No history of serious infections in the previous month.Individuals were excluded from participation if they fulfilled any of the following exclusion criteria:a. Risk of serious cardiovascular and hematopoietic system disease, or other serious primary diseases or mental illnessesb. Pregnant or lactating womenc. Use of hypoglycemic western medicine or insulin treatmentd. Failure to cooperate during the treatment periode. History of alcohol dependency or use of illicit drugs.This study was designed as a single blind randomized controlled trial (RCT). After screening, 72 IGT participants were randomly assigned to either the transcutaneous auricular vagus nerve stimulation group (taVNS) or sham taVNS group (randomization sequence created using SAS System 7.0). All randomization assignments were pre-packed in envelopes and consecutively numbered for each participant according to the randomization schedule. All participants were blinded to their treatment modality and received the randomly-assigned intervention, as described in the envelope, until the end of the study.After group randomization, all patients received training at the hospital regarding how to use the Transcutaneous Electrical Nerve Stimulator device to apply stimulation. All subsequent treatments were self-administered by the patients at home. Patients were also instructed to complete a patient diary booklet each day to describe any side effects corresponding with or temporally related to treatment. The investigators checked all booklets at the 6 and 12-week assessments.The points for taVNS are located in the auricular concha area where there is rich vagus nerve branch distribution Figure .taVNS was applied using a Huatuo ear vagus nerve stimulator TENS-200) developed by Suzhou manufacture of Medical Device and Material , where we expect no vagus nerve distribution Figure  based onAll procedures performed in the sham taVNS treatment group were identical to those performed for the taVNS group, with the exception of the altered location of stimulations.All patients in the no-treatment control group were recruited from community free clinics that provide free physical exams, including blood glucose testing. No taVNS or sham taVNS treatments were applied.The primary outcome measure of this study is the change in 2hPG levels measured at baseline, 6-weeks, and 12-weeks. Secondary outcomes include changes in FPG levels, HbAlc levels, BMI (Body Mass Index) and blood pressure (assessed at baseline and 12-weeks). All measures of blood glucose were measured by the Glucose Oxidase method .Our analyses were based on the intention-to-treat principle. Statistical analysis was performed using SPSS 19.0 Software . Repeated measurements were applied to compare primary and secondary outcomes. First, we compared the taVNS and sham taVNS groups; then, we separately compared real and sham taVNS with the no-treatment control population, to further assess and isolate the treatment effects of taVNS and sham taVNS.A total of 102 participants completed the study , range: 33–68). Two female patients (one in the taVNS group and one in the sham taVNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. All other participants reported following all treatment instructions with a reported compliance rate of 98.04%. Figure t(70) = 1.51, p = 0.14), weight (t(70) = −0.83, p = 0.41) systolic blood pressure (t(70) = 1.42, p = 0.16), diastolic blood pressure (t(70) = 0.22, p = 0.16), or BMI (t(70) = 64.07, p = 0.61) at baseline  =3.29, p = 0.07). Measures of FPG (t(70) = 0.3, p = 0.77), 2hPG (t(70) = 1.96, p = 0.054) and HbAlc (t(70) = 1.12, p = 0.27) similarly did not differ between groups at baseline.Comparison by Independent Samples t-test showed that the two groups did not differ in age (F(2) = 5.79, p = 0.004)  = 2.48, p = 0.093) and HbAlc (F(1) = 0.23, p = 0.63) did not differ significantly between the taVNS and sham taVNS groups over time in both crude analysis and after adjusting for age, gender, and BMI  indicated a significant difference in 2hPG between groups over the course of the experiment  Figure . After aF(1) = 4.21, p = 0.044). In the taVNS group, systolic blood pressure dropped from 123.69 ± 14.14 (mean ± SD) to 118.64 ± 13.34, while in the sham taVNS group, systolic blood pressure remained at 119 ± 12. No significant differences were observed for changes in diastolic blood pressure (F(1) = 0.75, p = 0.39) or BMI (F(1) = 0.069, p = 0.79).Further analysis of other secondary outcomes indicated that the taVNS and sham taVNS groups differed significantly in systolic blood pressure over time  = 1.95, p = 0.15), weight (F(2) = 0.85,p = 0.43), diastolic blood pressure (F(2) = 1.05, p = 0.37), gender distribution  = 3.29, p = 0.2), or BMI (F(2) = 2.96, p = 0.057) at baseline. Measures of FPG (F(2) = 2.86, p = 0.06), 2hPG (F(2) = 2.03, p = 0.14) and HbAlc (F(2) = 1, p = 0.37) also did not differ between groups at baseline. There was, however, a significant difference in systolic blood pressure (F(1) = 1.02, p = 0.01).Analysis of variance indicated that the three experimental groups did not differ in age (F(2) = 10.62, p < 0.001), 2hPG (F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) between groups over the course of the 12 weeks. All effects remained significant after adjusting for age, gender, and BMI (Table Repeated measures ANOVA between the taVNS and no-treatment control indicated significant differences in FPG (MI Table .F(1) = 0.99, p = 0.32). diastolic blood pressure (F(1) = 1.27, p = 0.27), or BMI (F(1) = 0.003, p = 0.96) over time.Analysis of other secondary outcomes, with comparison between the taVNS and no-treatment control groups, indicated that there were no significant differences between the two groups in systolic blood pressure (FGG(1.72) = 10.51, p < 0.001) and HbAlc (F(1) = 5.94, p = .018) over the course of the experiment. Measures of both 2hPG and HbAlc increased over the 12 weeks in the control group, and decreased over the course of the 12 weeks in the sham taVNS treatment group. After controlling for age, gender, and BMI, only the effect for change in 2hPG remained significant (Table Repeated measures ANOVA between the sham taVNS and no-treatment control groups showed that the two groups differed significantly in their levels of 2hPG (F(1) = 1.44, p = 0.24), diastolic blood pressure (F(1) = 0.047, p = 0.83), or BMI (F(1) = 0.024, p = 0.88) over time.Analysis of other secondary outcomes between the sham taVNS and no-treatment control indicated that there were no significant differences between the two groups in systolic blood pressure  = 4.21, p = 0.044) as compared with controls who received no treatment. Taken together, our results suggest that taVNS demonstrates potential use as a preventive treatment for pre-diabetes or IGT.As the epidemic of diabetes continues to rise, it becomes essential to develop and implement cost-effective preventative therapeutic strategies . In thisThe metabolic syndrome, which includes a constellation of risk factors such as obesity, elevated lipids, and elevated glucose and blood pressure, has increasingly drawn attention from investigators; this syndrome is regarded as both a disease and a risk factor for other major diseases such as cardiovascular disease and Alzheimer’s disease (AD) . These dPrevious studies have suggested that the vagus nerve plays an important role in maintaining metabolic homeostasis. These studies further suggest that efferent vagus nerve-mediated cholinergic signaling controls immune function and proinflammatory responses via the inflammatory reflex. Deregulation of metabolism and immune function are associated with chronic inflammation, which acts as a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus ,16.In a previous study, investigators  found thAnatomical studies have shown that the ear is the only place on the surface of the human body where there is afferent vagus nerve distribution . Thus, direct stimulation of the afferent nerve fibers on the ear can regulate the activity of the vagus nerve, which can further regulate metabolic homeostasis. In this study, we found that taVNS reduced both IGT and systolic blood pressure. This result suggests that taVNS has the potential for use as a therapeutic method for IGT and pre-diabetes, as well as potentially for other metabolic syndromes.In this study, we found that both taVNS and sham taVNS significantly reduced the 2-hour glucose tolerance and levels of HbAlc, indicating that sham taVNS could also produce a significant, and desirable, modulatory effect on glucose levels. We speculate that this may be due to the strong electrical stimulation at the sham point extending to the adjacent area of the ear, where there is vagus nerve distribution. In addition, sham taVNS may produce these placebo effects by influencing patient lifestyle. Patients were asked to apply the postprandial treatment twice daily, which might have reminded them to pay more attention to food intake and levels of daily activity.There are several limitations in this study. First, treatments in the study were self-administered by the patients, and thus patient compliance may have influenced the observed results. To enhance compliance, all patients were required to complete daily entries into a diary that was checked during assessments. More importantly, however, this self-administration method provides direct evidence for the feasibility of wide application of the method used within the study. This shows promise in significantly reducing the expenses associated with such a treatment. Secondly, the treatment was only 12 weeks in duration, thus the results obtained only represent its short or mid-term effects. Further study is warranted to evaluate the long-term effects of this treatment option. Thirdly, we only measured blood glucose level at three time points  for statistic analysis. Since blood glucose levels may be affected by the food intake of the previous day, a more frequent measurement in the future study may provide more reliable information for the influence of treatment on blood glucose level. Finally, the no-treatment control group was not included in the randomization scheme, as were the other two treatment groups. The participants constituting the control group were also recruited from a different population. However, the purpose of this group was to add another layer of control to explore the effects of the different treatments; thus, it should not influence the conclusions of this study.In summary, this pilot study demonstrates that taVNS can significantly reduce two-hour glucose tolerance and systolic blood pressure. As a simple, cost-effective therapeutic method with mild side effects, it demonstrates great potential in the treatment of pre-diabetes and associated metabolic disorders.The authors declare that they have no competing interests.PJR designed the trail and was the principal clinical research investigator. PJR, FH, wrote the manuscript with JK. XL generated the random allocation sequence. FH, HM, CHW, XL, XZ, JXD were in charge of the recruitment and treatment of patients in the hospital and collected the data. FH prepared the figures. JK, SC and RBS were responsible for the data analysis and edited the manuscript with BZ. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6882/14/203/prepub


Inflammatory blood count biomarkers may improve recurrence risk stratification and inform long-term prognosis of cancer patients. Here, we quantify the prognostic impact of blood-based biomarkers on recurrence risk and long-term survival in a large cohort of gastrointestinal stroma tumor (GIST) patients after curative surgery.One-hundred-forty-nine consecutive GIST patients were followed-up for a median period of 4.8 years. Local recurrence, distant metastasis, and death occurred in 9, 21, and 31 patients, respectively. Time-to-event and competing risk analysis were applied to study the association between haemoglobin (Hb) level, white blood cell count (WBC), neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR) with risk of local or distant recurrence (RR), recurrence free survival (RFS), and overall survival (OS).A low Hb (p = 0.029), and elevations in the parameters WBC (p = 0.004), NLR (p = 0.015) and dNLR (p = 0.037) were associated with a poor OS in GIST patients in multivariate analysis. Moreover, a low Hb (p = 0.049) and an elevated WBC (p = 0.001), NLR (p = 0.007), dNLR (p = 0.043) and PLR (p = 0.024) were independently associated with decreased RFS after adjusting for Miettinen score. However, only an increase of dNLR/NLR showed a significant association to higher RR (p = 0.048). Inclusion of NLR or PLR to Miettinen risk score did not reasonably improve the clinical risk prediction of 2-year RFS.Low Hb, elevated WBC, elevated dNLR, and elevated PLR are independent prognostic factors for a worse clinical outcome in GIST patients after curative resection. Gastrointestinal stroma tumors (GIST) are mesenchymal malignancies that represent the most frequent subtype of sarcomas and are usually characterized by mutations in the KIT and PDGFRA proto-oncogenes –4. GISTsThe introduction of imatinib in the treatment of GIST has revolutionized GIST patients’ outcome by reducing the risk of local and distant recurrence and improving overall survival. Tyrosine kinase inhibitors (TKI) are now standard treatment in metastatic GIST, and in the adjuvant setting, patients at intermediate or high risk of recurrence, should be considered for adjuvant treatment with imatinib –11. At pThis retrospective analysis included data from 149 consecutive patients who were treated at the Division of Clinical Oncology and the Division of General Surgery, Medical University of Graz, between 1997 and 2014. All patients suffered from histologically confirmed GIST, and had a basic blood count available at the date of diagnosis. All clinico-pathological data were retrieved from our in-house medical records, as well as from pathology records from the Institute of Pathology at our institution. The preoperative blood cell count was obtained within 7 days before surgery and performed for routine clinical practice within the general routine laboratory of our hospital, the Barmherzigen Brüder Hospital or the Elisabethinen Hospital in Graz. Patients with signs of systemic inflammation related to infection at time of diagnosis were excluded from the study population. The LMR was calculated from the routinely performed preoperative blood cell count as the absolute count of lymphocytes divided by the absolute count of monocytes. The PLR and NLR were calculated as the absolute count of platelets or neutrophils divided by the absolute count of lymphocytes, respectively. The derived neutrophil-lymphocyte-ratio (dNLR) was calculated as the absolute neutrophil count / (absolute leukocyte count–absolute neutrophil count) . Follow-All statistical analyses were performed using Stata . Continuous variables were reported by medians (25th– 75th percentile), whereas count data were summarized using absolute frequencies and percentages. Spearman’s rank-based correlation coefficient, rank-sum tests, and chi-squared tests were applied to study the association between two continuous variables, between one continuous and one categorical variable, and between two categorical variables, respectively. Median follow-up was estimated with the method of Schemper & Smith . OS was One-hundred-forty-nine patients with histologically-confirmed GIST were included in the analysis. All of these 149 patients underwent surgery with curative intent, and none of the patients had evidence of distant metastasis at the time of surgery. The median age at surgery was 65.5 years , and only 9 patients (6.0%) were lost-to-follow-up during the study period. More than 80% of the patient population was followed for more than 1 year. The 9 patients that were lost-to-follow-up were followed for a median interval of 5.7 years. Thirty-one (20.8%) patients died during follow-up. The Kaplan-Meier 1-, 2-, 5-, and 10-year overall survival rates were 95.7% (95%CI: 90.7–98.1), 92.5% (95%CI: 86.4–95.9), 78.4%, (95%CI: 68.7–85.5) and 58.5% (95%CI: 42.6–71.4), respectively . The KapAmong clinical variables, higher age at entry (Hazard ratio (HR) per 5 years increase = 1.32, 95%CI: 1.10–1.58, p = 0.003) and a SPM at baseline or before , and after adjusting for age at study entry, SPM at or before baseline was associated with a 2.4-fold increase in the risk of death . In multivariable analysis adjusting for age and SPM, the associations between an increased risk of all-cause-mortality and a low Hb (p = 0.029), a high white blood count (p = 0.004), a high lymphocyte and monocyte count , and a high NLR/dNLR (p = 0.015) and a high PLR (p = 0.05) prevailed .In univariable competing risk analysis of recurrence risk , a higher tumor size (p<0.001), a higher mitotic rate (p<0.001) and a moderate/high Miettinen score (p<0.001) were predictors of progression risk. In detail, in patients with a “no risk”, “very low risk”, and “low risk” Miettinen score, the proportion of patients who recurred was below 5%. Conversely, 22% and 42.5% of patients with a “moderate risk” or “high risk” Miettinen score experienced recurrence, respectively. In competing risk regression, the model predicted that in comparison to patients with a “no to low Risk” Miettinen score, patients with a moderate risk score have a 9.7 times higher risk of recurrence (p = 0.008), and patients with a high risk score have an 18.3 times higher risk of recurrence (p<0.001). Among the investigated blood-based biomarkers, a higher NLR (p = 0.036), dNLR  patients entered the study before the introduction of adjuvant imatinib to our center. Because trials have shown that imatinib is associated with a strong reduction in the risk of recurrence and death, we examined the impact of the imatinib era on the association between inflammatory biomarkers and recurrence-free survival. We did this by fitting an interaction between the selected biomarkers and a binary variable indicating whether a patient entered our study cohort prior or after the introduction of adjuvant imatinib to our center: Treatment era did not interact with inflammatory markers in any of the conducted analyses , which sIn the present study we examined the clinical course of 149 patients with GIST after curative surgery and found a significant association between low Hb levels, an elevated WBC, NLR, dNLR and decreased OS. For RFS, we identified a low haemoglobin level, an elevated WBC, as well as an elevated NLR, dNLR and PLR as parameters that were significantly associated with poor outcome. Of all studied variables, only elevated dNLR was associated with a higher RR after adjusting for Miettinen score. This initially suggested that this parameter may be used to improve the prediction of disease relapse in this patient population. However, we could then show that the inclusion of NLR or PLR to Miettinen risk score did not reasonably improve the clinical risk prediction of RFS. Notably, SPMs appear to contribute significantly to survival outcome in patients with GIST.Adjuvant imatinib influences the risk of GIST recurrence over time. The risk of recurrence is high during the first two years after surgery and patients are at a relatively small risk of relapse while therapy is ongoing; however, the risk after finishing therapy with imatinib is substantially increasing. It seems that imatinib delays the risk of recurrence in „high risk”operated GIST patients . In our The bi-directional association between inflammation and cancer progression has already been established, and knowledge about the cancer-immune-system-interaction is becoming increasingly important in the era of checkpoint-blockade immunotherapy. Our study group previously investigated the role of blood-based inflammatory biomarkers such as the NLR, PLR, dNLR or LMR in a variety of tumor entities including soft tissue sarcomas (STS), where we demonstrated their role as independent prognostic factors for an adverse survival experience , 30–32. Additionally, we found that the age at study entry and SPM are independent predictors of an adverse survival experience in patients with surgically-resected GIST. When we included both neutrophil and lymphocyte count into a multivariable model with age and SPM, both neutrophil and lymphocyte count remained associated with reduced OS. This suggests that neutrophilia and lymphocytosis may represent separate pathobiologic features of an immune process leading to a higher risk of death. Interestingly, SPM diagnosed at or before baseline emerged as a strong adverse risk factor for OS but not for RFS. This discrepancy between OS and RFS can be explained by the observation that the SPM variable does not appear to be associated with any of the GIST-specific outcomes such as local recurrence and distant metastasis, but rather with a general impairment in overall survival.There are several limitations to be taken into account. Potential confounding factors such as moderate local or systemic infection, ischemia, acute coronary syndrome, metabolic syndrome, diabetes mellitus and renal or hepatic dysfunction that might affect the white blood cell counts or the haemoglobin level have not been systematically assessed in this study. Finally, the event rate of local recurrence was quite low, which may have led us to “miss” relevant associations between blood-based biomarkers and this endpoint. Moreover, because of the retrospective design of the study we cannot fully exclude a selection bias in our study cohort.In conclusion, we found that a low Hb level and an elevated WBC, NLR, dNLR and PLR were independently associated with reduced RFS, whereas a low Hb level and an elevated white blood cell count, NLR and dNLR showed a significant association with worse OS in multivariate analysis. However, only dNLR remained statistically significant associated with the tumor-specific endpoint RR. Furthermore, we demonstrated that the addition of the investigated blood-based biomarkers NLR and PLR to Miettienen score revealed no benefit regarding prediction of recurrence and mortality risk. LMR was not associated with clinical outcome in our study population. Synoptically, this paper clarifies the association between blood-based biomarkers and tumor-specific and survival endpoints occurring during long-term follow-up of patients with GIST treated with primary curative surgery.S1 FigBoth functions were estimated using the Kaplan-Meier product limit estimator.(TIF)Click here for additional data file.S2 FigThe risk of all three endpoints was estimated using cumulative incidence functions accounting for all-cause mortality as a competing risk.(TIF)Click here for additional data file.S1 TableReported are Spearman’s correlation coefficients with p-values in round brackets. P-values are from a hypothesis test which tests the null hypothesis that the correlation coefficient is zero. Abbreviations: WBC–white blood cell counts, ANC–neutrophil counts, ALC–lymphocyte counts, AMC–monocyte counts, NLR–neutrophil lymphocyte ratio, dNLR–derived NLR, LMR–lymphocyte monocyte ratio, PLR–platelet lymphocyte ratio.(DOCX)Click here for additional data file.S2 TableResults are from Cox models. Abbreviations: HR–hazard ratio, 95%CI– 95% confidence interval, p–p-value, HPF–high power field, g/dL–grams per deciliter, G/L–giga per liter, NLR–neutrophil lymphocyte ratio, dNLR–derived NLR, LMR–lymphocyte monocyte ratio, PLR–platelet lymphocyte ratio.(DOCX)Click here for additional data file.S3 TableResults are from Fine & Gray models. Abbreviations: HR–hazard ratio, 95%CI– 95% confidence interval, p–p-value, HPF–high power field, g/dL–grams per deciliter, G/L–giga per liter, NLR–neutrophil lymphocyte ratio, dNLR–derived NLR, LMR–lymphocyte monocyte ratio, PLR–platelet lymphocyte ratio.(DOCX)Click here for additional data file.S4 TableResults are from Cox models. Abbreviations: HR–hazard ratio, 95%CI– 95% confidence interval, p–p-value, g/dL–grams per deciliter, G/L–giga per liter, NLR–neutrophil lymphocyte ratio, dNLR–derived NLR, LMR–lymphocyte monocyte ratio, PLR–platelet lymphocyte ratio.(DOCX)Click here for additional data file.S5 TableAbbreviations: HR–hazard ratio, 95%CI– 95% confidence interval, p–p-value, g/dL–grams per deciliter, NLR–neutrophil lymphocyte ratio, dNLR–derived NLR, LMR–lymphocyte monocyte ratio, PLR–platelet lymphocyte ratio.(DOCX)Click here for additional data file.


It is a challenge for the human body to maintain stable blood pressure while standing. The body’s failure to do so can lead to dizziness or even fainting. For decades it has been postulated that the vestibular organ can prevent a drop in pressure during a position change – supposedly mediated by reflexes to the cardiovascular system. We show – for the first time – a significant correlation between decreased functionality of the vestibular otolith system and a decrease in the mean arterial pressure when a person stands up. Until now, no experiments on Earth could selectively suppress both otolith systems; astronauts returning from space are a unique group of subjects in this regard. Their otolith systems are being temporarily disturbed and at the same time they often suffer from blood pressure instability. In our study, we observed the functioning of both the otolith and the cardiovascular system of the astronauts before and after spaceflight. Our finding indicates that an intact otolith system plays an important role in preventing blood pressure instability during orthostatic challenges. Our finding not only has important implications for human space exploration; they may also improve the treatment of unstable blood pressure here on Earth. Movements and position changes are followed by a series of physiological changes in the human body. One of them is the maintenance of stable blood pressure during a position change. However, its underlying mechanism is still not fully understood. It is crucial to keep a sufficient blood flow to the brain at all times. The inability to do so is called Orthostatic Intolerance (OI), which causes a drop in blood pressure. The main cause of orthostatic hypotension is today attributed to an excessive fall of cardiac output or a defect vasoconstrictor mechanismThe sympathetic nervous system (SNS), which is responsible for cardiac regulation, has been pointed out as a key factor in blood pressure control3The vestibular organs, located in the inner ears, sense rotations by means of three semi-circular canals, and they sense linear accelerations, including gravity, by means of the otoliths. Together with information provided by the visual and proprioceptive system, the vestibular organs ensure gaze stabilization and balance as well as orientation and navigation. This task is so fundamental to life on Earth that most animals have a highly specialized vestibular system, the mammalian one being very similar across many species.Early animal studies suggest that the vestibular system plays an important role in the activation of the SNS356789101112133. Based on the information from the otoliths, the activation of the SNS increases pre-emptively before an actual drop in blood pressure is detected, constituting a feed-forward mechanism. For instance, the baroreceptors are not activated until an actual blood pressure drop is measured in the carotid arteries. Hence, they initiate a feed-backward mechanism with a latency of 1.2–1.4 sVestibular signals have been shown to affect mainly the sympathetic outflow to the blood vessels. In fact, all the activated nerves contain vasoconstrictor efferents16A few later studies show that the same theory might be applicable to humans3516171819A majority of the astronauts returning from a long-term exposure to microgravity suffer from OI during the first days after their return2124Similarly to the cardiovascular system, the otoliths are also forced, during spaceflight, to adapt to a situation where there is no longer a preferred direction given by the acceleration of gravityIn view of this phenomenon, we hypothesized that the otoliths play a key role in OI, affecting the astronauts during their first days after spaceflight. The goal of our study has been to investigate if a suppressed otolith system affects the ability to regulate blood pressure upon standing, on return from space. In this way we could study the link between the vestibular and the cardiovascular system to elucidate the VSR.In order to study the VSR, we needed to evaluate brainstem-mediated reflexes that were based on information from the vestibular system, in particular ocular counter-rolling (OCR). OCR is an otolith-mediated reflex that serves as a compensatory eye movement. It is generated when we tilt our head sideways , turn around a corner or undergo off-axis centrifugationSimilarly, the cardiovascular system can be quantified by specific parameters. Mean arterial pressure (MAP) is one of the most important parameters resulting from the cardiac and cardiovascular control mechanisms. Indeed, MAP is considered to be the perfusion pressure seen by the organs and is directly influenced by stroke volume (SV), heart rate (HR), systemic vascular resistance (SVR) and central venous pressure (CVP):As a result, MAP can be considered the output of the overall cardiovascular system. The goal is to maintain an appropriate perfusion of all organs via action on the cardiac function  and the vascular system . However, HR and heart rate variability (HRV) are also markers of the autonomic control of the cardiovascular system.Our primary outcomes in this study are the values of the OCR, the MAP and their correlation.Gagarin Cosmonaut Training Centre (Star City) near Moscow, Russia. A group of 12 male  cosmonauts from the Russian Space Agency (Roscosmos) and one from European Space Agency (ESA)  took part in the study. The astronauts were tested before and after a 6-month stay in the International Space Station (ISS). The preflight data were based on two baseline experiments that were conducted on average 66 (SD = 26) days before launch. The postflight data consist of one experiment performed in the early days  after return back to earth, and another experiment performed 9–10 days  after return. The two experiments will be denoted as “early postflight” and “late postflight”. Due to medical and administrative issues we were not able to test all the astronauts on the same day after return.We conducted our experiments in the To quantify the effect of microgravity on the vestibular otolith system and on the cardiovascular system respectively, two separate tests were performed. During the first test the astronaut was subjected to centrifugation to induce the otolith parameter Ocular Counter-Rolling (OCR). Similarly to eliciting an otolith reflex by centrifugation, the cardiovascular system control mechanism can be elicited by an operational tilt test. The second test was meant to put the cardiovascular system under orthostatic stress and evaluate its reaction. The responses evaluated were MAP, HR and HRV. Moreover, the autonomic control of the HR and the reactivity of the cardiovascular system were evaluated with the analysis of total power of HRV, as well as LF (low frequency) and HF (high frequency) components separately. The latter is also known as respiratory sinus arrhythmia (RSA), a marker of vagal modulation of HR. The RR-interval (RRI), used in HRV computation, was also computed as:As RRI is used for the analysis of HRVVisual and Vestibular Investigation System (VVIS), a small centrifuge  before putting the table in an upright position for the second measurement in standing position. In the same way as when analysing the OCR, we compared the preflight data for the cardiac and blood pressure control with the postflight data. Measurements were performed during a 60 seconds long recording. For supine position the measurement took place between the 4th and 5th minute of the protocol and for the upright position between the 9th and 10th minute during a passive tilt of 60 degrees. The difference between cardiac and blood pressure control during standing and supine position, as well between pre- and post-flight, served as a measurement of the cardiovascular function, the so-called By comparing the OCR before and after spaceflight, we could study the effect of prolonged microgravity on the otolith system. Similarly, we could estimate the impact of prolonged microgravity on the cardiovascular system by assessing the reaction to the standing position. The final step was to check for correlation between the Our current study on astronauts who spent six months in space, offered a unique opportunity to investigate the impact of a deconditioned otolith system on blood pressure and cardiac autonomic control. In addition, it allowed us to study a temporarily hampered VSR in humans in an unprecedented way.Comparison of pairwise preflight data with postflight data, for each astronaut individually, resulted in a statistically significant decrease of  0.018).  MAP is r 0.018).  In all tFurther on, the HR (presented as RRI), HF and the total power of HRV , did notPulse pressure was significantly decreased (p < 0.05) on the second experiment after spaceflight. On late postflight it was back at the same level as before flight (BDC), indicating a full recovery from the microgravity effect, just as OCR. No significant changes were observed in the supine posture. A decrease is observed on the first experiment after spaceflight (R + 2), but not significant due to the low number of subject tested that day (n = 5) .We have investigated what the effect is of a defect otolith system on the ability to regulate blood pressure during a position change. Our goal has been to elucidate a hampered VSR, the link between the vestibular and cardiovascular system. That it is a suppression of the otolith inputs to the brain instead of a stimulation of the activity has been the key to our study. Other studies have so far, only pointed toward an increase of the VSR during stimulation, instead of evaluating the effect of a suppression of the vestibular system. To the best of our knowledge, this is the closest anyone has come so far to show a relation between a suppression of the otolith response and a parallel decrease of blood pressure control in humans. We are convinced that this is a unique dataset revealing the link between the otoliths and blood pressure control mechanisms. A correlation by itself is not the shear proof of causality but together with the rest of our findings it strongly suggest that there is one. In addition, our conclusion is also based on results from earlier research studies showing that a defect otolith system could affect the ability to control the blood pressureA decreased OCR and a depression of all blood pressure and cardiac control parameters were observed during the first days after return from space. After ten days the OCR was back at the same level as before flight. This indicates that the otolith deficiency is temporary. The MAP showed the same type of recovery as the OCR  after reA decrease in pulse pressure could theoretically be the cause of a lower stimulation of the baroreceptors. This could in turn induce a sympathetic activation (which is what we observe), and therefore end in a better blood pressure control (maintenance of MAP). However, to explain the observed decreased MAP control, the pulse pressure data should then demonstrate an increased pulse pressure after spaceflight. An increased pulse pressure could elicit a peripheral vasodilatation, responsible for the observed decrease in MAP. But this is not what we found. On the contrary, we measured a decrease in pulse pressure after spaceflight, something that is very unlikely to explain the decreased MAP on return.As the standing values were taken 10 minutes after the tilt, we can stress the evidence that a sympathetic activation, on early postflight, was not able to counteract the decrease in MAP. MAP still remained lower than normal. However, late postflight, we observed a similar sympathetic activation as early postflight (similar decrease in HR and in HF) but MAP returned back to normal. For the OCR we saw the same recovery pattern as for the MAP, a full recovery at late postflight. Therefore our data suggest that the return back to normal values of blood pressure control is to due the VSR. Rather than due to the central autonomic control of the cardiovascular system, which remains under a high sympathetic activation. We speculate that, when the otolith function returns back to normal, the VSR helps preventing a blood pressure drop that the activation of the sympathetic system can not do alone.The finding that a decreased ability to maintain blood pressure upon standing is correlated with a decreased otolith response do not only has important implications for human space exploration. The acquired knowledge possibly suggests looking at OI problems also from a vestibular point of view. Currently, the cardiovascular clinical approach to OI does not consider a vestibular component, but this is understandable since only recently the evaluation of the otolith system has become more readily available to the clinicians. Nevertheless, for the future, we anticipate that the current findings may spur interdisciplinary research regarding a vestibulo-sympathetic reflex. Besides these important applications, we consider our finds to be of fundamental scientific interest, since they strengthens the evidence of a fundamental physiological otolith-sympathetic reflex (VSR) in humans.All participants provided written informed consent prior to their participation. The study protocol was designed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the ESA and the Antwerp University Hospital.How to cite this article: Hallgren, E. et al. Dysfunctional vestibular system causes a blood pressure drop in astronauts returning from space. Sci. Rep.5, 17627; doi: 10.1038/srep17627 (2015).