Dim Light Melatonin Onset in Alcohol-Dependent Men and Women Compared with Healthy Controls

Sleep disturbances in alcohol-dependent (AD) individuals may persist despite abstinence from alcohol and can influence the course of the disorder. Although the mechanisms of sleep disturbances of AD are not well understood and some evidence suggests dysregulation of circadian rhythms, dim light melatonin onset (DLMO) has not previously been assessed in AD versus healthy control (HC) individuals in a sample that varied by sex and race. The authors assessed 52 AD participants (mean?±?SD age: 36.0?±?11.0 yrs of age, 10 women) who were 3–12 wks since their last drink (abstinence: 57.9?±?19.3 d) and 19 age- and sex-matched HCs (34.4?±?10.6 yrs, 5 women). Following a 23:00–06:00?h at-home sleep schedule for at least 5 d and screening/baseline nights in the sleep laboratory, participants underwent a 3-h extension of wakefulness (02:00?h bedtime) during which salivary melatonin samples were collected every 30?min beginning at 19:30?h. The time of DLMO was the primary measure of circadian physiology and was assessed with two commonly used methodologies. There was a slower rate of rise and lower maximal amplitude of the melatonin rhythm in the AD group. DLMO varied by the method used to derive it. Using 3 pg/mL as threshold, no significant differences were found between the AD and HC groups. Using 2 standard deviations above the mean of the first three samples, the DLMO in AD occurred significantly later, 21:02?±?00:41?h, than in HC, 20:44?±?00:21?h (t?=??2.4, p?=?.02). Although melatonin in the AD group appears to have a slower rate of rise, using well-established criteria to assess the salivary DLMO did not reveal differences between AD and HC participants. Only when capturing melatonin when it is already rising was DLMO found to be significantly delayed by a mean 18?min in AD participants. Future circadian analyses on alcoholics should account for these methodological caveats. (Author correspondence: daconroy@med.umich.edu)     

Conditions Associated with Circulating Tumor-Associated Folate Receptor 1 Protein in Healthy Men and Women

Background

Serum concentrations of the tumor-associated folate receptor 1 (FOLR1) protein may be a marker for early cancer detection, yet concentrations have also been detected in cancer-free women. We investigated the conditions associated with circulating FOLR1 protein in healthy individuals and sought to clarify the range of normal serum values.

Methods

Sera of cancer-free men and women (N = 60) enrolled in a population-based cohort study in Alberta, Canada were analyzed for FOLR1 protein using an electrochemical luminescence immunoassay. Dietary, lifestyle, medical and reproductive history information was collected by questionnaires. Differences in serum FOLR1 concentrations between groups were assessed by non-parametric tests, and predictors of serum FOLR1 concentrations were estimated using multivariable linear regression.

Results

Median serum FOLR1 concentration was higher in women (491 pg/ml, range = 327–693 pg/ml) than in men (404 pg/ml, range = 340–682 pg/ml), P = 0.001. FOLR1 concentration was also positively associated with vitamin A intake (P = 0.02), and showed positive trends with age and with oral contraceptive hormone use among women and an inverse trend with body mass index. All variables examined explained almost half of the variation in serum FOLR1 (model R² = 0.44, P = 0.04); however, the retention of gender (P = 0.003) and vitamin A intake (P = 0.03) together explained 20% (P = 0.001) of serum FOLR1 variation. No other predictor was significant at P<0.05.

Conclusions

The positive association between serum FOLR1 concentration and female gender independent of an age effect suggests caution against statements to exploit serum FOLR1 for early cancer detection without further understanding the biological underpinnings of these observations. Serum FOLR1 concentrations may be influenced by the steroid retinoic acid (vitamin A) but do not appear to be associated with folate nutritional status. These findings require confirmation in larger independent studies.     

Single Oral Dose Pharmacokinetics of Decursin and Decursinol Angelate in Healthy Adult Men and Women

The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (T_max) of 2.1, 2.4 and 3.3 h and mean peak concentration (C_max) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t_1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC_0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h∙nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02114957","term_id":"NCT02114957"}}NCT02114957     

Heart Rate and Heart Rate Variability in Dairy Cows with Different Temperament and Behavioural Reactivity to Humans

From the 1990s, extensive research was started on the physiological aspects of individual traits in animals. Previous research has established two extreme (proactive and reactive) coping styles in several animal species, but the means of reactivity with the autonomic nervous system (ANS) activity has not yet been investigated in cattle. The aim of this study was the characterization of cardiac autonomic activity under different conditions in cows with different individual characteristics. For this purpose, we investigated heart rate and ANS-related heart rate variability (HRV) parameters of dairy cows (N = 282) on smaller- and larger-scale farms grouped by (1) temperament and (2) behavioural reactivity to humans (BRH). Animals with high BRH scores were defined as impulsive, while animals with low BRH scores were defined as reserved. Cardiac parameters were calculated for undisturbed lying (baseline) and for milking bouts, the latter with the presence of an unfamiliar person (stressful situation). Sympathetic tone was higher, while vagal activity was lower in temperamental cows than in calm animals during rest both on smaller- and larger-scale farms. During milking, HRV parameters were indicative of a higher sympathetic and a lower vagal activity of temperamental cows as compared to calm ones in farms of both sizes. Basal heart rate did not differ between BRH groups either on smaller- or larger-scale farms. Differences between basal ANS activity of impulsive and reserved cows reflected a higher resting vagal and lower sympathetic activity of reserved animals compared to impulsive ones both on smaller- and larger-scale farms. There was no difference either in heart rate or in HRV parameters between groups during milking neither in smaller- nor in larger-scale farms. These two groupings allowed to draw possible parallels between personality and cardiac autonomic activity during both rest and milking in dairy cows. Heart rate and HRV seem to be useful for characterisation of physiological differences related to temperament and BRH.     

Effects of Serum Calcium and Magnesium on Heart Rate Variability in Adult Women

The present study was designed to evaluate the association of serum calcium (Ca) and magnesium (Mg) levels with heart rate variability (HRV). One hundred and sixteen adult women were recruited in this cross-sectional study. Serum Ca and Mg levels were measured, and HRV in each time and frequency domain was recorded for 5?min. Mean heart rate and standard deviation of the normal to normal interval (SDNN) and root mean square of differences of successive RR interval (RMSSD) in time domain and total power (TP), low-frequency power (LF), high-frequency power (HF), and LF/HF ratio in frequency domain were compared according to the tertiles of serum Ca and Mg levels and Ca/Mg ratio. The associations between serum Ca and Mg levels and Ca/Mg ratio with HRV were evaluated using regression analyses. Mean heart rate tended to increase from the lowest to the highest tertile of Ca levels (p?=?0.081), whereas it decreased significantly with higher Mg levels (p?=?0.026). Increasing SDNN value was observed from the lowest to the highest tertile of Mg levels (p?=?0.009). SDNN value decreased significantly from the lowest to the highest tertile of Ca/Mg ratio (p?=?0.030). Participants in the lowest tertile of Ca/Mg ratio had significantly higher TP and LF values compared to those in the middle and highest tertiles (p?<?0.05). Decreasing SDNN, TP, and LF values were significantly associated with higher Ca/Mg ratios (p?<?0.05). Associations of serum Mg level and Ca/Mg ratio with HRV could be one of the mechanisms involved in cardiovascular diseases.     

Heart Rate Variability Profiles and Exposure Therapy Treatment Outcome in Flight Phobia

The goal of this study was to explore why certain patients in a previous study on exposure therapy for flight phobia did not experience an improvement in their conditions. Participants from a treatment study (N = 45) were selected according to post-treatment results and divided into two groups: the unsatisfactory treatment outcome group (UTO, N = 10) and the satisfactory treatment outcome group (STO, N = 10). The differences between these two groups prior to receiving exposure therapy were analyzed at the behavioral, physiological, and cognitive levels. The UTO participants had been avoiding flying longer than the STO phobics. Following Thayer and Lane’s neurovisceral model of emotion regulation, heart rate variability was analyzed at two levels: tonic and phasic. Low frequency and high frequency (HF) power were calculated in the frequency domain and Sample Entropy was computed in the time domain. The tonic HF power of the UTO group was higher than the STO group’s tonic HF power. In the phasic level, while the STO group’s HF power decreased under exposure and subsequently returned to baseline level, the UTO group demonstrated a more rigid pattern. Finally, the STO group reported higher emotional involvement than the UTO group when they were shown a sample of the therapy. Based on these results, the challenge of matching exposure therapy to each patient’s profile is discussed.     

Different Effects of Adrenergic Beta-receptor Blockade on Heart Rate Response to Mental Stress,Catecholamines, and Exercise

The magnitude and duration of effect of a single 40-mg oral tablet of oxprenolol on the tachycardias associated with motor-car driving, isoprenaline infusion, and walking were compared against placebo in six normal people by a double-blind study. The tachycardias due to driving and isoprenaline were both conspicuousy reduced for over eight hours; the magnitude and duration of the reduction in exercise tachycardia was substantially less. Thus relatively small doses of beta-receptor antagonists will suppress the increase in heart rate induced by mental stress or catecholamines with relatively little effect on the response to everyday exercise. Possibly smaller doses of these drugs would relieve emotionally-induced anginal pain and tachycardia.     

Multilocus Heterozygosity and Coronary Heart Disease: Nested Case-Control Studies in Men and Women

BackgroundGeneralized allelic heterozygosity has been proposed to improve reproductive fitness and has been associated with higher blood pressure, but its association with chronic disease is not well characterized.MethodsUsing the Affymetrix Genome-Wide Human 6.0 array, we performed whole genome scans in parallel case-control studies of coronary heart disease (CHD) nested in the Health Professionals Follow-up Study and Nurses’ Health Study. We examined ~700,000 single nucleotide polymorphisms (SNPs) in 435 men with incident CHD and 878 matched controls and 435 women with incident CHD with 931 matched controls. We examined the relationship of genome-wide heterozygosity with risk of incident of CHD and with baseline levels of cardiovascular risk factors.ResultsIn both cohorts, approximately 227650 (SD 2000) SNPs were heterozygous. The number of heterozygous SNPs was not related to risk of CHD in either men or women (adjusted odds ratios per 2000 heterozygous SNPs 1.01 [95% confidence interval, 0.91-1.13] in women and 0.94 [0.84-1.06] in men). We also found no consistent associations of genome-wide heterozygosity with levels of lipids, inflammatory markers, adhesion molecules, homocysteine, adiponectin, or body-mass index.ConclusionsIn these parallel nested case-control studies, we found no relationship of multilocus heterozygosity with risk of CHD or its major risk factors. Studies in other populations are needed to rule out associations with lower levels of heterozygosity.     

Campodimele Study: Blood Pressure and Heart Rate Pattern in Clinically Healthy Elderly Subjects

Noninvasive ambulatory blood pressure (BP) monitoring is a developing method in clinical practice. Its interpretation needs reference standards stratified by age and gender. This study addresses ambulatory BP monitoring in elderly people with the purpose of quantifying the discrete and periodic variability of BP pattern over a 24-h period. The ABPM was performed in 92 clinically healthy subjects (45 men and 47 women) ranging in age from 76 to 102 years. The results refer to the time-qualified mean values with their dispersion, to the circadian rhythm with its parameters, and to the daily baric impact (BI) with its variability. The conclusion is drawn that BP preserves its nychtohemeral variability and circadian rhythmicity despite old age. The daily BP mean level and BI in older people in good health are comparable with those of young subjects, suggesting that humans surviving into old age are characterized by a eugenic control of their pressure regimen.     

Campodimele Study: Blood Pressure and Heart Rate Pattern in Clinically Healthy Elderly Subjects

Noninvasive ambulatory blood pressure (BP) monitoring is a developing method in clinical practice. Its interpretation needs reference standards stratified by age and gender. This study addresses ambulatory BP monitoring in elderly people with the purpose of quantifying the discrete and periodic variability of BP pattern over a 24-h period. The ABPM was performed in 92 clinically healthy subjects (45 men and 47 women) ranging in age from 76 to 102 years. The results refer to the time-qualified mean values with their dispersion, to the circadian rhythm with its parameters, and to the daily baric impact (BI) with its variability. The conclusion is drawn that BP preserves its nychtohemeral variability and circadian rhythmicity despite old age. The daily BP mean level and BI in older people in good health are comparable with those of young subjects, suggesting that humans surviving into old age are characterized by a eugenic control of their pressure regimen.     

A Pilot Study on the Effects of Heart Rate Variability Biofeedback in Patients with Depression and in Healthy Subjects

Decreased vagal activity and increased sympathetic arousal have been proposed as major contributors to the increased risk of cardiovascular mortality in patients with depression. It was aim of the present study to assess the feasibility of using heart rate variability (HRV) biofeedback to treat moderate to severe depression. This was an open-label study in which 14 patients with different degrees of depression (13 f, 1 m) aged 30 years (18–47; median; range) and 12 healthy volunteers attended 6 sessions of HRV biofeedback over two weeks. Another 12 healthy subjects were observed under an active control condition. At follow up BDI was found significantly decreased (BDI 6; 2–20; median 25%–75% quartile) as compared to baseline conditions (BDI 22;15–29) in patients with depression. In addition, depressed patients had reduced anxiety, decreased heart rate and increased HRV after conduction of biofeedback (p < 0.05). By contrast, no changes were noted in healthy subjects receiving biofeedback nor in normal controls. In conclusion, HRV biofeedback appears to be a useful adjunct for the treatment of depression, associated with increases in HRV.     

Cardio-Respiratory Reference Data in 4631 Healthy Men and Women 20-90 Years: The HUNT 3 Fitness Study

Purpose

To provide a large reference material on key cardio-respiratory variables in a healthy population of Norwegian men and women aged 20–90 years.

Methods

Sub maximal and peak levels of cardio-respiratory variables were measured using cardiopulmonary exercise testing during treadmill running.

Results

The highest peak ventilation among men (141.9±24.5 L·min⁻¹) and women (92.0±16.5 L·min⁻¹) was observed in the youngest age group (20–29 years, sex differences p<0.001) with an average 7% reduction per decade. The highest tidal volumes were observed in the 30–39 and 40–49 year age groups among men (2.94±0.46 L) and women (2.06±0.32 L) (sex differences p<0.001), with a subsequent average 6% reduction per decade. Ventilatory threshold and respiratory compensation point were observed at approximately 77% and 87% of peak oxygen uptake (VO_2peak) among men and women, respectively. The best ventilatory efficiency (EqVCO_2Than) was observed in the youngest age group (20–29 years) in both men (26.2±2.8) and woman (27.5±2.7) (sex differences p<0.001) with an average 3% deterioration in ventilatory efficiency per decade.

Conclusion

This is the largest European reference material of cardio-respiratory variables in healthy men and women aged 20–90 years, establishing normal values for, and associations between key cardio-respiratory parameters. This will be useful in clinical decision making when evaluating cardiopulmonary health in similar populations.     

Wireless Fetal Heart Rate Monitoring in Inpatient Full-Term Pregnant Women: Testing Functionality and Acceptability

We tested functionality and acceptability of a wireless fetal monitoring prototype technology in pregnant women in an inpatient labor unit in the United States. Women with full-term singleton pregnancies and no evidence of active labor were asked to wear the prototype technology for 30 minutes. We assessed functionality by evaluating the ability to successfully monitor the fetal heartbeat for 30 minutes, transmit this data to Cloud storage and view the data on a web portal. Three obstetricians also rated fetal cardiotocographs on ease of readability. We assessed acceptability by administering closed and open-ended questions on perceived utility and likeability to pregnant women and clinicians interacting with the prototype technology. Thirty-two women were enrolled, 28 of whom (87.5%) successfully completed 30 minutes of fetal monitoring including transmission of cardiotocographs to the web portal. Four sessions though completed, were not successfully uploaded to the Cloud storage. Six non-study clinicians interacted with the prototype technology. The primary technical problem observed was a delay in data transmission between the prototype and the web portal, which ranged from 2 to 209 minutes. Delays were ascribed to Wi-Fi connectivity problems. Recorded cardiotocographs received a mean score of 4.2/5 (± 1.0) on ease of readability with an interclass correlation of 0.81(95%CI 0.45, 0.96). Both pregnant women and clinicians found the prototype technology likable (81.3% and 66.7% respectively), useful (96.9% and 66.7% respectively), and would either use it again or recommend its use to another pregnant woman (77.4% and 66.7% respectively). In this pilot study we found that this wireless fetal monitoring prototype technology has potential for use in a United States inpatient setting but would benefit from some technology changes. We found it to be acceptable to both pregnant women and clinicians. Further research is needed to assess feasibility of using this technology in busy inpatient settings.     

The Effect of Bright/Dim Light Exposure During the Daytime on Rectal Temperature and Plasma Glucose Concentration in Healthy Women

The aim of our present study was to establish if there are any changes in core temperature and plasma glucose concentration during exposure to bright (5000 lx) and dim (100 lx) light. Ten healthy women (age: 19.6 ± 1.66 years) were studied in climatic chamber in which ambient temperature and relative humidity were maintained at 26°C and 60% RH, respectively. Rectal temperature was measured every 5 min and blood samples for determination of glucose were collected every 2 h. Each participant took part in both sessions in bright light and dim light conditions on different days with an interval of at least 1 day. Our results have shown that glucose concentration increases in bright light conditions as compared to dim light conditions but it remains within the normal range values for healthy subjects. On the other hand, there is a slight but significant decrease in rectal temperature in bright light in comparison to dim light conditions. The findings showing the decreased rectal temperature with concomitant increase in glucose concentration observed in bright light conditions might be explained by the mechanism involving melatonin action as shown previously by Aizawa and Tokura (1999).     

The Effect of Bright/Dim Light Exposure During the Daytime on Rectal Temperature and Plasma Glucose Concentration in Healthy Women

The aim of our present study was to establish if there are any changes in core temperature and plasma glucose concentration during exposure to bright (5000 lx) and dim (100 lx) light. Ten healthy women (age: 19.6 ± 1.66 years) were studied in climatic chamber in which ambient temperature and relative humidity were maintained at 26°C and 60% RH, respectively. Rectal temperature was measured every 5 min and blood samples for determination of glucose were collected every 2 h. Each participant took part in both sessions in bright light and dim light conditions on different days with an interval of at least 1 day. Our results have shown that glucose concentration increases in bright light conditions as compared to dim light conditions but it remains within the normal range values for healthy subjects. On the other hand, there is a slight but significant decrease in rectal temperature in bright light in comparison to dim light conditions. The findings showing the decreased rectal temperature with concomitant increase in glucose concentration observed in bright light conditions might be explained by the mechanism involving melatonin action as shown previously by Aizawa and Tokura (1999).     

Circadian Variations of Heart Rate and Premature Beats in Healthy Subjects and in Patients with Previous Myocardial Infarction

Chronobiological analysis of the circadian variations of heart rate, ventricular and atrial ectopies, was carried out on 11 patients with previous myocardial infarction matched with 11 controls. Individual circadian rhythms in heart rate were seen in all the control subjects but only in 6 patients with previous myocardial infarction. The behaviour of the individual circadian rhythms of premature beats was not significantly different between the two groups. A significant group rhythm in ectopies was not demonstrated, nevertheless a trend to higher frequency of arrhythmias during the activity span was detected. These results do not allow to postulate a circadian pattern of arrhythmias common to all the subjects examined. Therefore, the individual circadian behaviour of premature atrial and ventricular beats should be recognized for monitoring antiarrhythmic therapy. A significant group rhythm in heart rate was demonstrated for the two populations studied and linear discriminant analysis showed that the amplitude of this rhythm was significantly lower in patients than in controls. Possibly, myocardial infarction may affect the sinus node function producing a “flattened” range of heart rates during the 24 hours.     

Cardiovascular Risk Factors Have Larger Impact on Endothelial Function in Self-Reported Healthy Women than Men in the HUNT3 Fitness Study

Background

Several studies suggest that cardiovascular risk factors comprising the metabolic syndrome have larger effects on the development of cardiovascular disease in women than in men. A recent study in self-reported healthy subjects demonstrated a marked gender difference in endothelial dysfunction that may be an important precursor of manifest cardiovascular disease. The aim of the present study was to determine whether the association between endothelial function and cardiovascular risk factors is different in self-reported healthy women compared to self-reported healthy men.

Methods and Results

Associations between endothelial function (flow mediated dilation, FMD, of the brachial artery measured by ultrasound), anthropometric variables, peak oxygen uptake (VO_2peak), blood pressure, serum lipids, blood glucose and a questionnaire on general health and lifestyle including smoking status were studied by logistic and linear regression in 2 528 women and 2 211 men aged 20–89 years, free from self-reported cardiovascular disease. In women with hyperglycemia, endothelial dysfunction (FMD ≤0%) occurred twice as frequently as in male counterparts. The presence of the metabolic syndrome, high blood pressure and low VO_2peak increased the prevalence of endothelial dysfunction more in women than in men.

Conclusion

Endothelial dysfunction is more strongly associated with cardiovascular risk factors in self-reported healthy women than in self-reported healthy men. This finding could explain why the metabolic syndrome, and especially hyperglycemia, is associated with higher cardiovascular risk and a worse prognosis in women.     

Plasma Phospholipid Fatty Acid Concentration and Incident Coronary Heart Disease in Men and Women: The EPIC-Norfolk Prospective Study

Background

The lack of association found in several cohort studies between dietary saturated fat and coronary heart disease (CHD) risk has renewed debate over the link between dietary fats and CHD.

Methods and Findings

We assessed the relationship between plasma phospholipid fatty acid (PFA) concentration and incident CHD using a nested case control design within a prospective study (EPIC-Norfolk) of 25,639 individuals aged 40–79 years examined in 1993–1997 and followed up to 2009. Plasma PFA concentrations were measured by gas chromatography in baseline samples retrieved from frozen storage. In 2,424 men and women with incident CHD compared with 4,930 controls alive and free of cardiovascular disease, mean follow-up 13 years, saturated PFA (14:0, 16:0,18:0) plasma concentrations were significantly associated with increased CHD risk (odds ratio [OR] 1.75, 95% CI 1.27–2.41, p<0.0001), in top compared to bottom quartiles (Q), and omega-6 polyunsaturated PFA concentrations were inversely related (OR 0.77, 0.60–0.99, p<0.05) after adjusting for age, sex, body mass index, blood pressure, smoking, alcohol intake, plasma vitamin C, social class, education, and other PFAs. Monounsaturated PFA, omega-3 PFA, and trans PFA concentrations were not significantly associated with CHD. Odd chain PFA (15:0, 17:0) concentrations were significantly inversely associated with CHD (OR 0.73, 0.59–0.91, p<0.001, Q4 versus Q1). Within families of saturated PFA or polyunsaturated PFA, significantly heterogeneous relationships with CHD were observed for individual fatty acids.

Conclusions

In this study, plasma concentrations of even chain saturated PFA were found to be positively and omega-6 polyunsaturated PFA inversely related to subsequent coronary heart disease risk. These findings are consistent with accumulating evidence suggesting a protective role of omega-6 fats substituting for saturated fats for CHD prevention. Please see later in the article for the Editors'' Summary