The loneliness factor in eating disorders: Implications for psychopathology and biological signatures.

OBJECTIVES: Eating disorders (ED) are severe psychiatric conditions. While the biological consequences of EDs are well established, including an increase in inflammatory biomarkers, the influence of psychological factors, such as loneliness, has only recently gained attention in research. Loneliness has been associated with more severe psychopathology in ED patients, while its association with inflammatory biomarkers has only been explored in the general population. For these reasons, we aimed to investigate any possible associations between psychological features, trauma, and inflammatory biomarkers with loneliness in people with ED. METHODS: This study examined the interaction between loneliness, eating psychopathology, and biological markers in people with EDs. A group of 97 female patients with various diagnoses of ED was assessed for loneliness, general and eating psychopathology, traumatic history during childhood, and clinical biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and urinary-free cortisol (UFC). RESULTS: The results indicated that individuals with ED who reported moderate to severe loneliness also displayed greater general psychopathology (p = 0.001), weight concerns (p = 0.007), and physical neglect during childhood (p = 0.006). Furthermore, people with higher levels of loneliness also had higher inflammatory indexes (ESR p = 0.001, CRP p = 0.027) and were positively correlated with markers of stress reaction such as UFC (p < 0.05). CONCLUSION: The findings underscore the importance of considering loneliness in the assessment of individuals with an ED. We observed notable associations between loneliness and increased psychopathology (both general and specific to eating), as well as higher levels of inflammation and childhood physical neglect. Addressing loneliness may contribute to improving overall well-being and potentially support recovery. This consideration encompasses both psychological and physical factors that interplay in the clinical presentation of individuals.

Hypothalamic-pituitary-adrenal axis activity in patients with primary polydipsia compared to healthy controls.

OBJECTIVE: Primary polydipsia is characterized by excessive fluid intake which may suppress vasopressin levels. It is speculated that suppressed vasopressin levels lead to a dysregulated hypothalamic-pituitary-adrenal (HPA) axis as vasopressin co-modulates the HPA axis. However, data are contradictory. The aim of this study was to investigate markers of the HPA axis in patients with primary polydipsia compared to healthy controls. DESIGN: Exploratory analysis combining data from two different prospective observational studies. PATIENTS: We included 34 patients with primary polydipsia (68% females, median aged 29.5 years (interquartile range, IQR: 26.0, 38.8) and 20 healthy controls (55% females, median age 24.0 years [IQR: 22.0, 27.2]). MEASUREMENTS: The main outcome was difference in HPA axis activity assessed using circadian serum and salivary cortisol, 24-h urinary free cortisol and cortisol levels before and after adrenocorticotropic hormone (ACTH) stimulation; vasopressin suppression was assessed measuring fasting copeptin levels between patients with primary polydipsia and healthy controls using Wilcoxon rank-sum test. RESULTS: No difference was seen in circadian serum cortisol levels (p = .9), urinary free cortisol levels (p = .17) and serum cortisol in response to ACTH stimulation (p = .77) between groups. Circadian salivary cortisol levels were significantly lower in patients with primary polydipsia compared to healthy controls with an estimated difference of -3.7 nmol/L (95% CI: -5.5, -1.8 nmol/L, p < .001). Fasting copeptin levels were significantly lower in patients with primary polydipsia compared to healthy volunteers (p < 0.01). CONCLUSION: Our results suggest no difference in HPA axis activity between patients with primary polydipsia and healthy controls. The observed difference in salivary cortisol levels may be linked to a dilution effect in saliva rather than an altered stress axis considering the other findings.

Associations Between Different Cortisol Measures and Adiposity in Children: A Systematic Review and Meta-Analysis.

This study examined associations between hair, salivary, serum, and urinary cortisol concentration with adiposity-related indicators in children, and explored their potential effects modification by age, sex, cortisol measurement method, and country developmental context. We systematically searched PubMed, Web of Science, and Embase for studies examining at least one of the four aforementioned cortisol with objectively measured adiposity-related outcomes in children. Meta-analyses of cross-sectional studies revealed that hair cortisol concentration was associated with fat mass index (FMI)-standard deviation score (SDS)/FMI z-score (pooled-ß = 0.04, 95% CI: 0.01, 0.08) and BMI/BMI z-score (pooled-ß = 0.15, 95% CI: 0.06, 0.25), and these associations were significant among children aged ≤ 12 years (pooled-ß = 0.15, 95% CI: 0.05, 0.26) and >12 years (pooled-ß = 0.13, 95% CI: 0.04, 0.22), children from developed countries (pooled ß = 0.12, 95% CI: 0.03, 0.21) and developing countries (pooled-ß = 0.193, 95% CI: 0.188, 0.198), and in studies extracting cortisol via LC-MS/MS (pooled-ß = 0.18, 95% CI: 0.06, 0.29) but not ELISA (pooled-ß = 0.08, 95% CI: -0.06, 0.22). Meta-analyses of both cohort and cross-sectional studies revealed non-significant associations of morning salivary cortisol concentration and total daily cortisol output with BMI/BMI z-score. Serum cortisol concentration was not associated with BMI or waist circumference. Meta-analysis of urinary cortisol concentration and adiposity was hindered by insufficient data. These findings further corroborate understanding of chronic stress' physiological contribution to increased pediatric obesity risk. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/#recordDetails], identifier [CRD42020215111].

Urinary corticoid to creatinine ratios using IMMULITE 2000 XPi for diagnosis of canine hypercortisolism.

The urinary corticoid to creatinine ratio (UCCR) is one of the most commonly used screening tests for canine hypercortisolism (HC). In this study, a reference interval was established for UCCR using IMMULITE 2000 XPi, the latest chemiluminescence enzyme immunoassay. The diagnostic performance of this method for UCCR in canine HC was also evaluated. The median UCCR was 1.06 × 10-5 (range: 0.28-2.49) for 58 healthy dogs, and an upper reference limit of 1.98 × 10-5 (90% confidence interval: 1.76-2.15) was determined. The median UCCR in the 12 dogs with HC (7.38 × 10-5, range 1.86-29.98) was significantly higher than that in the 16 dogs with mimic-HC (1.59 × 10-5, range 0.47-3.42, P<0.001). The area under the curve for UCCR to differentiate HC dogs from mimic-HC dogs was 0.971, with a sensitivity of 91.7% and specificity of 100% when the cut-off value was set at 3.77 × 10-5. The UCCR of 16 paired urine samples collected at home and in hospital showed that the UCCR of samples collected in the hospital was significantly higher than that of samples collected at home (mean difference 3.30 × 10-5, 95% confidence interval: 0.70-5.90, P=0.001). In summary, we established the upper reference limit for UCCR using IMMULITE 2000 XPi in dogs and confirmed that UCCR is a useful diagnostic test for HC in dogs if urine samples are collected at home.

Five-factor model personality traits and 24-h urinary cortisol in the Baltimore Longitudinal Study of Aging.

Stress is implicated in models of personality and health as a mechanism that explains why traits like conscientiousness and neuroticism are associated with long-term health outcomes. Evidence for an association between personality and cortisol, a biological marker of stress, however, has been inconsistent. This study examined the association between Five-Factor Model personality traits and 24-h urinary cortisol (operationalised as a ratio of urinary free cortisol to creatinine) measured up to 12 times over intervals as long as 30 years in the Baltimore Longitudinal Study of Aging (Mage  = 61.21, SD = 15.46; 49% female). There was a modest association between conscientiousness and lower mean-level cortisol that was attenuated only slightly in the fully-adjusted model. Neuroticism and the other traits were unrelated to cortisol levels, and none of the traits was related to cortisol change over time. The null association for neuroticism suggests that its relation with long-term health may be primarily through pathways other than cortisol. The modest association between conscientiousness and 24-h urinary cortisol replicates a previous finding with a longer-term measure of cortisol measured from hair, which calls for more research on the robustness and replicability of this finding. Cortisol may be one pathway through which conscientiousness is associated with health outcomes.

Detection of Urinary Exosomal HSD11B2 mRNA Expression: A Useful Novel Tool for the Diagnostic Approach of Dysfunctional 11ß-HSD2-Related Hypertension.

Objective: Apparent mineralocorticoid excess (AME) is an autosomal recessive disorder caused by the 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) enzyme deficiency, traditionally assessed by measuring either the urinary cortisol metabolites ratio (tetrahydrocortisol+allotetrahydrocortisol/tetrahydrocortisone, THF+5αTHF/THE) or the urinary cortisol/cortisone (F/E) ratio. Exosomal mRNA is an emerging diagnostic tool due to its stability in body fluids and its biological regulatory function. It is unknown whether urinary exosomal HSD11B2 mRNA is related to steroid ratio or the HSD11B2 662 C>G genotype (corresponding to a 221 A>G substitution) in patients with AME and essential hypertension (EH). Aim of the Study: To detect and quantify HSD11B2 mRNA from urinary exosomes in samples from family members affected by AME and EH, and to evaluate the relationship between exosomal HSD11B2 mRNA, steroid ratio, 662C>G genotype, and hypertension. Methods: In this observational case-control study, urinary steroid ratios and biochemical parameters were measured. Urinary exosomes were extracted from urine and exosomal HSD11B2 mRNA was quantified by Droplet Digital PCR (ddPCR). B2M (ß-2 microglobulin) gene was selected as the reference housekeeping gene. Results: Among family members affected by AME, exosomal urinary HSD11B2 mRNA expression was strictly related to genotypes. The two homozygous mutant probands showed the highest HSD11B2 mRNA levels (median 169, range 118-220 copies/µl) that progressively decreased in 221 AG heterozygous with hypertension (108, range 92-124 copies/µl), 221 AG heterozygous normotensives (23.35, range 8-38.7 copies/µl), and wild-type 221 AA subjects (5.5, range 4.5-14 copies/µl). Heterozygous hypertensive subjects had more HSD11B2 mRNA than heterozygous normotensive subjects. The F/E urinary ratio correlated with HSD11B2 mRNA copy number (p < 0.05); HSD11B2 mRNA strongly decreased while THF+5αTHF/THE increased in the two probands after therapy. In the AME family, HSD11B2 copy number correlated with both F/E and THF+5αTHF/THE ratios, whereas in EH patients, a high F/E ratio reflected a reduced HSD11B2 mRNA expression. Conclusions: HSD11B2 mRNA is detectable and quantifiable in urinary exosomes; its expression varies according to the 662 C>G genotype with the highest levels in homozygous mutant subjects. The HSD11B2 mRNA overexpression in AME could be due to a compensatory mechanism of the enzyme impairment. Exosomal mRNA is a useful tool to investigate HSD11B2 dysregulation in hypertension.

Perioperative stress dose steroid management of children with classical congenital adrenal hyperplasia: Too much or too little?

BACKGROUND: Children with congenital adrenal hyperplasia (CAH) are at risk for adrenal crises in the perioperative period and require higher doses of glucocorticoids. However, there are no specific protocols detailing the appropriate stress dosing required for children with CAH undergoing surgery with anesthesia. OBJECTIVE: To evaluate CAH patients using our current hydrocortisone stress dose surgical protocol. We hypothesized that current clinical protocols may overestimate the endogenous response to perioperative stress. STUDY DESIGN: 14 children with CAH scheduled to have genital surgery and a control group of 10 unaffected children scheduled to have cardiac or urologic surgery (of a similar duration) were evaluated in a prospective observational study. Urinary free cortisol (UFC) and urinary 17-hydroxycorticosteroids (17-OHCS) per body surface area were measured in the postoperative period. RESULTS: UFC levels were significantly higher in CAH patients (115.8 ± 24.6 nmol/m2) than in controls (26.5 ± 12.2 nmol/m2), P < 0.05.17-OHCS levels were also higher in CAH patients than in controls (6.5 ± 0.5 nmol/m2 vs. 3.4 ± 0.5 nmol/m2), P < 0.05). CONCLUSION: In the immediate postoperative period, urinary cortisol and its metabolites are significantly higher in pediatric CAH patients receiving stress dose corticosteroids compared to controls. Results suggest that the amount of hydrocortisone given during our stress dose protocol may be higher than physiologic needs. Future dynamic studies are needed to determine appropriate perioperative and postoperative cortisol requirements in pediatric CAH patients in order to develop optimal stress dose regimens.

Bridging environment, physiology and life history: Stress hormones in a small hibernator.

Our knowledge of the perception of stress and its implications for animals in the wild is limited, especially in regard to mammals. The aim of this study was therefore to identify sex specific effects of reproductive activity, body mass, food availability and hibernation on stress hormone levels in the edible dormouse (Glis glis), a small mammalian hibernator. Results of our study reveal that reproductive activity and pre-hibernation fattening were associated with high cortisol levels in both sexes. During the mating season, in particular individuals with low body masses had higher stress levels. Elevated levels of cortisol during pre-hibernation fattening were even higher in females that had formerly invested into reproduction compared to non-reproductive females. Previously observed impairments on health parameters and reduced survival rates associated with reproduction emphasize the functional relevance of high stress hormone levels for fitness. Prolonged food limitation, however, did not affect stress levels demonstrating the ability of dormice to predict and cope with food restriction.

Thyroid axis and adrenal activity in 28 day survivor and nonsurvivor dogs involved in recent road traffic accidents: A cohort study of 420 dogs.

The objective of this retrospective cohort study was to determine the impact of a recent trauma on thyroid axis and adrenal activity in dogs and to assess the usefulness of urinary cortisol-to-creatinine ratio (UCCR), basal serum thyroid-stimulating hormone (TSH), total thyroxine (tT4), and free thyroxine (fT4) concentrations in predicting outcome in dogs traumatized by a road traffic accident (RTA). An RTA exposed group of 210 dogs was evaluated within 24  hours of the trauma. Their data were compared with data from a matched group of dogs with other diagnoses. UCCR was positively correlated with the trauma severity and was higher in the exposed group than in the nonexposed group (median 101.500 vs. 21.02; p < 0.0001). tT4 values were statistically similar between the two groups, but were correlated with a trauma score, while TSH (median = 0.050 vs. 0.080 ng/mL; p < 0.0001) and fT4 (median = 15.850 vs. 17.950 pmol/L; p = 0.0037) were significantly lower for the exposed group. Nonsurvivors in comparison to survivors presented and higher median UCCR (181.800 vs. 93.850 respectively; p = 0.020), and a lower serum fT4 (12.700 vs. 16.500 pmol/L, respectively; p = 0.0046). A similar pattern had been observed for tT4. TSH levels were not predictive of survival. This study provides insights into the endocrine characteristics of dogs suffering from acute trauma. UCCR was higher while fT4 and TSH were both lower in RTA-injured dogs than in dogs affected by other conditions. Furthermore low fT4 and tT4, and a high UCCR could be useful prognostic factors in dogs affected by RTA trauma.

Hyperarousal in insomnia: pre-sleep and diurnal cortisol levels in response to chronic zolpidem treatment.

OBJECTIVES: To determine whether cortisol levels, both diurnal and pre-sleep, would vary as a function of MSLT and would be reduced by nightly placebo versus zolpidem 10 mg. METHODS: DSM-IVR diagnosed subjects with insomnia (N = 95), aged 32-70 yrs, having no other sleep disorder, unstable medical or psychiatric diseases or drug dependency served. On a screening MSLT 27 had MSLTs <10 min (Lo) and 42 > 15 min (Hi). Participants took 10 mg zolpidem or placebo, double-blind, nightly for 12 months. In months one and 12 urine was collected over 24 h in 8 hr-aliquots and assayed for cortisol (Ward Laboratories, Ann Arbor, MI). Saliva samples were collected 35 min before bedtime and the 30 min drug administration in month one and eight, and analyzed for cortisol levels (Salimetrics, State College, PA). RESULTS: Pre-sleep salivary cortisol was higher in insomniacs than controls, but did not differ as a function of MSLT. Nightly zolpidem reduced pre-sleep cortisol relative to placebo on month one and eight, with no month effects or interaction. Diurnal (0700-1500 h) urinary cortisol was higher overall in the Hi vs Lo MSLT subjects with insomnia, was stable across months, and was not reduced with zolpidem. CONCLUSIONS: Hyperarousal among subjects with insomnia as operationalized by MSLT is associated with higher diurnal urinary cortisol than those without hyperarousal, but not differential pre-sleep salivary cortisol. Zolpidem relative to placebo reduced pre-sleep salivary cortisol in all subjects, but not diurnal urinary cortisol. CLINICAL TRIAL: Safety and Efficacy of Chronic Hypnotic Use: http://www.clinicaltrials.gov NCT01006525.

Co-twin relationship quality as a moderator of genetic and environmental factors on urinary cortisol levels among adult twins.

Previous research has indicated that genetic and environmental factors shape physiological activity. Cortisol levels, in particular, have received significant attention, with studies indicating substantive heritability estimates across various sampling techniques. A related line of research has indicated that genetic and environmental factors that explain variability in cortisol levels may vary across context and experiences by way of gene-environment interactions (G × Es). Despite these findings, a limited number of studies have examined the extent to which interpersonal relationships may operate as a moderator. The current study focused on co-twin relationship quality as a source of moderation, as twins are more likely to have contact with one another and to form close, interpersonal relationships with their co-twin relative to singleton siblings. Using a sample of 298 adult twins from the National Survey of Midlife Development in the United States (MIDUS), we examined the extent to which genetic and environmental factors that explain variability in urinary cortisol levels varied across levels of co-twin relationship quality. The heritability of cortisol levels was greater and nonshared environmental influences were lower at greater levels of relationship quality. These findings suggest that the heritability of cortisol may vary across context, and positive relationships with others may moderate such factors.

Influence of calving difficulty on dry matter intake immediately after calving of dairy cows.

We investigated the influence of calving difficulty on dry matter intake (DMI) in Holstein cows immediately after calving using 15 pregnant heifers and 15 multiparous cows. DMI was measured for 6 days after calving. Calving difficulty was evaluated with a calving score, and urinary cortisol was measured. The calving score was higher in the first lactation heifers than in the multiparous cows. The average DMI 6 days after calving was lower in the first lactation heifers than in the multiparous cows. The urinary cortisol concentration at 4 days after calving was higher in the first lactation heifers than in the multiparous cows and was positively associated with the calving score. The DMI was negatively associated with the calving score and the urinary cortisol concentration at 4 days after calving and was positively associated with the average milk yield 6 days after calving and the serum calcium concentration at 3 days after calving. We conclude that DMI immediately after calving is influenced not only by nutrient requirements of cows but also stress derived from calving, and the low DMI in the first lactation heifers is due to the lower energy requirement and high susceptibility to the stress compared with multiparous cows.

Twenty-four hour urinary cortisol excretion and the metabolic syndrome in prednisolone-treated renal transplant recipients.

Chronic prednisolone treatment in renal transplant recipients (RTR) causes metabolic abnormalities, which cluster in the metabolic syndrome (MS). It also suppresses the hypothalamic-pituitaryadrenal (HPA)-axis. We investigated whether HPA-axis suppression, as measured by 24h urinary cortisol excretion, is associated with presence of the MS and its individual components, in outpatient RTR with a functioning graft for >1year. Urinary cortisol was measured in 24h urine, using LC-MS/MS (LOQ 0.30nmol/L). We included 563 RTR (age 51±12years; 54% male) at median 6.0 [IQR, 2.6-11.5] years post-transplantation. MS was present in 439/563 RTR (78%). Median 24h urinary cortisol excretion was 2.0 [IQR, 0.9-5.1]nmol/24h. Twenty-four hour urinary cortisol excretion was independently associated with MS presence (OR=0.80 [95% CI, 0.66-0.98], P=0.02). It was also independently associated with bodyweight (st.ß=-0.11, P=0.007), waist circumference (st.ß=-0.10, P=0.01), BMI (st.ß=-0.14, P=0.001), fasting triglycerides (st.ß=-0.15, P=0.001), diabetes (st.ß=-0.12, P=0.005), and number of antihypertensives used (st.ß=-0.13, P=0.003). Suppressed HPA-axis activity, as reflected by decreased 24h urinary cortisol excretion, is associated with higher prevalence of MS and its individual components (i.e. central obesity, dyslipidemia, diabetes, hypertension) in prednisolone-treated RTR. Assessment of 24h urinary cortisol excretion by LC-MS/MS may be a tool to monitor metabolic side-effects of prednisolone in RTR.

Effects of urinary cortisol levels and resting heart rate on the risk for fatal and nonfatal cardiovascular events.

BACKGROUND AND AIMS: Higher cortisol levels are associated with cardiovascular mortality in the elderly. It is unclear whether this association also exists in a general population of younger adults and for non-fatal cardiovascular events. Likewise, resting heart rate is associated with cardiovascular mortality, but fewer studies have also considered non-fatal events. The goal of this study was to investigate whether twenty-four-hour urinary cortisol (24-h UFC) levels and resting heart rate (RHR) predict major adverse fatal and non-fatal cardiovascular events (MACE) in the general population. METHODS: We used data from a subcohort of the PREVEND study, a prospective general population based cohort study with a follow-up of 6.4 years for 24-h UFC and 10.6 years for RHR. Participants were 3432 adults (mean age 49 years, range 28-75). 24-h UFC was collected and measured by liquid chromatography-tandem mass spectrometry. RHR was measured at baseline in a supine position for 10 min with the Dinamap XL Model 9300. Information about cardiovascular events and mortality was obtained from the Dutch national registry of hospital discharge diagnoses and the municipal register respectively. RESULTS: 24-h UFC did not significantly increase the hazard of MACE (hazard ratio = 0.999, 95% confidence interval = 0.993-1.006, p = 0.814). RHR increased the risk for MACE with 17% per 10 extra heart beats per minute (hazard ratio = 1.016, 95% confidence interval = 1.001-1.031, p = 0.036) after adjustment for conventional risk factors. CONCLUSIONS: In contrast to 24-h UFC, RHR is a risk marker for MACE in the general population.

The 10:00-11:00 pm urine cortisol/creatinine ratio. An alternative to late-night salivary cortisol for the diagnosis of Cushing's syndrome.

The aim of this study was to investigate interchangeability of two tests to diagnose Cushing's syndrome. We compared 10:00-11:00 PM urinary free cortisol/creatinine ratio (UFC/Cr) with late night 11:00 PM salivary cortisol (LNSC) in normal and obese controls vs. patients with Cushing's syndrome. Mean UFC/Cr did not differ between 69 normal and 62 obese controls (9.9 ± 7.9 vs. 9.7 ± 9.3) whereas 116 Cushing's patients had significantly higher values (277.0 ± 318.0; z: -11.1 and -10.2, respectively; p < 0.001). LNSC was 1.9 ± 1.2 nmol/l in 44 normal and 2.5 ± 1.6 in 45 obese subjects with no differences between them, but was significantly higher in 47 Cushing's patients (24.8 ± 23.3; z: -7.22 and -6.96, respectively, p < 0.001). Comparison of UFC/Cr and LNSC in samples obtained simultaneously showed that UFC/Cr was 12.0 ± 8.7 ng cortisol/mg creatinine in 34 normal, 12.3 ± 8.9 in 40 obese and 319.5 ± 333.4 in 35 CS subjects (p < 0.001 vs. normal and obese), whereas LNSC was 1.8 ± 1.2 nmol/l in normal, 2.6 ± 1.7 in obese and 24.6 ± 17.4 in CS patients (p < 0.001 vs. normal and obese); ROC curves showed comparable high sensitivity and specificity figures for the diagnosis of CS. We concluded that UFC/Cr test is easy to perform, readily available in routine laboratories, has high sensitivity and specificity, and offers a valuable alternative to LNSC in the study of Cushing's syndrome.

Variation in maternal urinary cortisol profiles across the peri-conceptional period: a longitudinal description and evaluation of potential functions.

STUDY QUESTION: How do women's first morning urinary cortisol levels, a marker of stress axis activity, vary during the peri-conceptional period (the 12 weeks around conception)? SUMMARY ANSWER: First morning urinary cortisol follows an overall increasing trajectory across the peri-conceptional period, interrupted by 2 week-long decreases during the week preceding conception and the fifth week following conception. WHAT IS KNOWN ALREADY: Later gestational stages (i.e. second and third trimesters) are characterized by increasing levels of circulating cortisol. This increase is hypothesized to constitute a response to the energy demands imposed by fetal growth, and the development of energy reserves in preparation for nursing and performing regular activities while carrying pregnancy's extra weight and volume. STUDY DESIGN, SIZE, DURATION: This study is based on a data set collected as part of a longitudinal, naturalistic investigation into the interactions between the stress (hypothalamic-pituitary-adrenal axis (HPAA)) and reproductive (hypothalamic-pituitary-gonadal axis (HPGA)) axes. Biomarkers of HPAA and HPGA function were quantified in first morning urinary specimens collected every other day from 22 healthy women who conceived a pregnancy during the study. We analyzed the longitudinal within- and between-individual variation in first morning urinary cortisol levels across the 12-week peri-conceptional period. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recruited from two rural, aboriginal, neighboring communities in Guatemala. Cortisol, estradiol and progesterone metabolites (estrone-3-glucuronide and pregnanediol glucuronide, respectively) and hCG levels were quantified in first morning urinary specimens using immunoassays to determine time of conception and confirm pregnancy maintenance. Linear mixed-effects models with regression splines were used to evaluate the magnitude and significance of changes in cortisol trajectories. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, maternal first morning urinary cortisol increased from 6 weeks prior to conception (geometric mean ± SD = 58.14 ± 36.00 ng/ml) to 6 weeks post-conception (89.29 ± 46.76 ng/ml). The magnitude of the increase between the pre- and post-conception periods varied significantly between women (likelihood ratio test statistic = 8.0017, P = 0.005). The peri-conceptional period is characterized by an increasing cortisol trajectory (+1.36% per day; P = 0.007) interrupted by a week-long decline immediately prior to conception (-4.02% per day; P = 0.0013). After conception cortisol increased again (+1.73% per day; P = 0.0008) for 4 weeks, fell in the fifth week (-6.60% per day; P = 0.0002) and increased again in post-conceptional week 6 (+8.86% per day; P = 0.002). Maternal urinary cortisol levels varied with sex of the gestating embryo. During gestational week 2, mothers carrying female embryos (N = 10) had higher mean cortisol levels than those carrying male embryos (N = 9) (t(17) = 2.28, P = 0.04). LIMITATIONS, REASONS FOR CAUTION: Our results are based on a relatively small sample (n = 22) of women. However, our repeated-measures design with an average of 27 ± 8 (mean ± SD) data points per woman strengthens the precision of estimates resulting in high statistical power. Additionally, our study population's high degree of ethnic and cultural homogeneity reduces the effects of confounders compared with those found in industrialized populations. This higher level of homogeneity also increases our statistical power. However, since there may be small differences in absolute cortisol values among ethnic groups, the social and biological background of our sample may affect the generalizability of our results. General patterns of HPAA activity, however, are expected to be universal across women. Finally, as there is, to the best of our knowledge, no evidence to the contrary, we assumed that urinary cortisol levels reflect HPAA activity and that changes in gonadal steroids across the menstrual cycle do not affect the levels of free cortisol measured in urine. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first longitudinal profile of basal maternal HPAA activity across the peri-conceptional period. A basic understanding of the normative (basal as opposed to stress-induced) changes in HPAA activity across this period is needed to accurately assess women's stress at this juncture. Importantly, changes in HPAA activity are likely to play a critical role in ovulation, fertilization, implantation, placentation and embryonic programing. Thus, this novel information should aid in the development of interventions aimed at preventing or moderating undesired effects of maternal physiological stress during the peri-conceptional period on reproductive outcomes as well as embryonic development. STUDY FUNDING/COMPETING INTERESTS: This research was funded by a CIHR IGH Open Operating grant (CIHR 106705) to P.A.N. and L.Z.; a Simon Fraser University (SFU) President's Start-up grant, a Community Trust Endowment Fund grant through SFU's Human Evolutionary Studies Program and a Michael Smith Foundation for Health Research Career Investigator Scholar Award to P.A.N.; an NSERC Discovery grant to L.Z.; a CIHR Post-Doctoral Fellowship to C.K.B. and an NSERC Undergraduate Student Research Award to H.M. and J.C.B. The funding agencies had no role in the design, analysis, interpretation or reporting of the findings. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Rank-dependent grooming patterns and cortisol alleviation in Barbary macaques.

Flexibly adapting social behavior to social and environmental challenges helps to alleviate glucocorticoid (GC) levels, which may have positive fitness implications for an individual. For primates, the predominant social behavior is grooming. Giving grooming to others is particularly efficient in terms of GC mitigation. However, grooming is confined by certain limitations such as time constraints or restricted access to other group members. For instance, dominance hierarchies may impact grooming partner availability in primate societies. Consequently specific grooming patterns emerge. In despotic species focusing grooming activity on preferred social partners significantly ameliorates GC levels in females of all ranks. In this study we investigated grooming patterns and GC management in Barbary macaques, a comparably relaxed species. We monitored changes in grooming behavior and cortisol (C) for females of different ranks. Our results show that the C-amelioration associated with different grooming patterns had a gradual connection with dominance hierarchy: while higher-ranking individuals showed lowest urinary C measures when they focused their grooming on selected partners within their social network, lower-ranking individuals expressed lowest C levels when dispersing their grooming activity evenly across their social partners. We argue that the relatively relaxed social style of Barbary macaque societies allows individuals to flexibly adapt grooming patterns, which is associated with rank-specific GC management.

Awake/sleep cortisol levels and the development of posttraumatic stress disorder in injury patients with peritraumatic dissociation.

Differences in the time of day that cortisol is sampled and failure to consider the impact of peritraumatic dissociation have been hypothesized as factors possibly contributing to the inconsistent findings in research examining associations between cortisol levels soon after trauma exposure and the subsequent development of posttraumatic stress disorder (PTSD). The present study examined associations between urinary cortisol levels during wake and sleep times soon after a serious injury and the subsequent development of PTSD in adult patients reporting low or high peritraumatic dissociative (PD) symptoms. Thirty-nine injury patients (20 with high and 19 with low PD symptoms) provided a 15-hour (6 PM to 9 AM) urine sample at 3-weeks post-injury and completed the Clinician Administered PTSD Scale at a 7-week follow-up. Participants collected their urine during wake and sleep times separately. Results showed that in the total sample and in the high PD group, wake, but not sleep, cortisol levels were lower in patients who developed PTSD compared to those who did not. A multiple linear regression analysis revealed a significant main effect of PD and a non-significant interaction between wake cortisol and PD in predicting PTSD symptom severity. In addition, results showed that PD was a better predictor of PTSD symptom severity than wake cortisol levels. These results were consistent with prior research indicating lower afternoon/evening cortisol levels in PTSD and strong associations between PD and PTSD, but did not support the existence of subgroups of PTSD patients (dissociators versus non-dissociators) who may differ in basal cortisol levels.

Stroke-induced immune depression-a randomized case control study in Kashmiri population of North India.

BACKGROUND: Stroke leads to transient immunedepression, which leads to increased incidence of poststroke infections. Because infection is one of the most common causes of increased mortality in patients with stroke, this study was undertaken to document immunedepression after stroke in our population. METHODS: A case-controlled study wherein 39 patients with acute ischemic stroke in the age group of 18 and 60 years without any evidence of previous immunedepression were included. Interleukin 6 (IL-6) and interleukin 10 (IL-10) levels were checked in plasma in both the groups on day 3 and day 45. Also Cortisol and epinephrine levels were checked in the urine samples collected on day 3 and day 8. RESULTS: No significant difference was seen between the IL-6 and the IL-10 levels in samples collected on day 3 between the controls and cases, whereas Cortisol and norepinephrine were significantly raised in samples collected on day 3 in cases who developed infection as compared with controls. CONCLUSIONS: The higher levels of urinary cortisol and norepinephrine were observed in patients with stroke who developed infections, which indirectly reflected increased amount of stroke related stress. Furthermore, the levels of plasma IL-6 and IL-10 were also elevated in the same group of patients, which means transformation of immunecompetence to immunedepression, which is responsible for higher mortality. Subsequently on recovery from infection the plasma levels of interleukins and urinary cortisol and norepinephrine did not show any difference, which indirectly means recovery of the immune system on recovery from acute stage of stroke. Mortality in the patients with infection was increased than controls.

Growth velocity reduced with once-daily fluticasone furoate nasal spray in prepubescent children with perennial allergic rhinitis.

BACKGROUND: The effect of fluticasone furoate nasal spray (FFNS) on growth in prepubescent children has not been evaluated. OBJECTIVE: To characterize the difference in mean prepubescent growth velocities, as determined by stadiometry, between patients treated continuously for 1 year with FFNS 110 mcg once daily and placebo nasal spray. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group 76-week safety study. Nasal symptom assessments were used as a measure of adherence. Eligible patients were ages 5 to <8.5 years at screening and had at least a 1-year clinical history and diagnosis of perennial allergic rhinitis, including a positive skin test or specific IgE to an appropriate perennial allergen within the past year. RESULTS: One hundred eighty-six patients in the FFNS group and 187 patients in the placebo group completed the entire 52-week treatment period. During treatment, the least squares mean growth velocity was 5.19 cm/y for the FFNS group and 5.46 cm/y for the placebo group; mean difference, -0.270 cm/y (95% CI, -0.48 to -0.06 cm/y). Other safety assessments, including 24-hour urinary cortisol excretion, were comparable between the treatment groups. Daily reflective total nasal symptom scores declined similarly in both the FFNS and placebo groups. CONCLUSION: Once-daily treatment with FFNS over 52 weeks in prepubescent children resulted in a small reduction in growth velocity compared with placebo. Clinicians will need to balance the reduction in growth observed with FFNS to its potential for clinical benefit.