Physiological behavior during stress anticipation across different chronic stress exposure adaptive models.

Anticipation of stress induces physiological, behavioral and cognitive adjustments that are required for an appropriate response to the upcoming situation. Additional research examining the response of cardiopulmonary parameters and stress hormones during anticipation of stress in different chronic stress adaptive models is needed. As an addition to our previous research, a total of 57 subjects (16 elite male wrestlers, 21 water polo player and 20 sedentary subjects matched for age) were analyzed. Cardiopulmonary exercise testing (CPET) on a treadmill was used as the laboratory stress model; peak oxygen consumption (VO2) was obtained during CPET. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol, alpha-melanocyte stimulating hormone (alpha-MSH) and N-terminal-pro-B type natriuretic peptide (NT-pro-BNP) were measured by radioimmunometric, radioimmunoassay and immunoassay sandwich technique, respectively, together with cardiopulmonary measurements, 10 minutes pre-CPET and at the initiation of CPET. The response of diastolic blood pressure and heart rate was different between groups during stress anticipation (p = 0.019, 0.049, respectively), while systolic blood pressure, peak VO2 and carbon-dioxide production responses were similar. ACTH and cortisol increased during the experimental condition, NT-pro-BNP decreased and alpha-MSH remained unchanged. All groups had similar hormonal responses during stress anticipation with the exception of the ACTH/cortisol ratio. In all three groups, ΔNT-pro-BNP during stress anticipation was the best independent predictor of peak VO2 (B = 36.01, r = 0.37, p = 0.001). In conclusion, the type of chronic stress exposure influences the hemodynamic response during anticipation of physical stress and the path of hormonal stress axis activation. Stress hormones released during stress anticipation may hold predictive value for overall cardiopulmonary performance during the stress condition.

LAY SUMMARYThe study revealed differences in hormonal and hemodynamic responses during anticipation of stress between athletes and sedentary participants. Stress hormones released during stress anticipation may hold predictive value for overall cardiopulmonary performance during the stress condition.

Cardiopulmonary assessment of patients diagnosed with Gaucher's disease type I.

BACKGROUND: Understanding the basis of the phenotypic variation in Gaucher's disease (GD) has proven to be challenging for efficient treatment. The current study examined cardiopulmonary characteristics of patients with GD type 1. METHODS: Twenty Caucasian subjects (8/20 female) with diagnosed GD type I (GD-S) and 20 age- and sex-matched healthy controls (C), were assessed (mean age GD-S: 32.6 ± 13.1 vs. C: 36.2 ± 10.6, p > .05) before the initiation of treatment. Standard echocardiography at rest was used to assess left ventricular ejection fraction (LVEF) and pulmonary artery systolic pressure (PASP). Cardiopulmonary exercise testing (CPET) was performed on a recumbent ergometer using a ramp protocol. RESULTS: LVEF was similar in both groups (GD-S: 65.1 ± 5.2% vs. C: 65.2 ± 5.2%, p > .05), as well as PAPS (24.1 ± 4.2 mmHg vs. C: 25.5 ± 1.3 mmHg, p > .05). GD-S had lower weight (p < .05) and worse CPET responses compared to C, including peak values of heart rate, oxygen consumption, carbondioxide production (VCO2 ), end-tidal pressure of CO2 , and O2 pulse, as well as HR reserve after 3 min of recovery and the minute ventilation/VCO2  slope. CONCLUSIONS: Patients with GD type I have an abnormal CPET response compared to healthy controls likely due to the complex pathophysiologic process in GD that impacts multiple systems integral to the physiologic response to exercise.

Alpha-melanocyte-stimulating hormone during exercise recovery has prognostic value for coronary artery disease.

PURPOSE: Alpha-melanocyte-stimulating hormone (alpha-MSH) has proven cardiovascular effects and plays a significant role as an endogenous countermeasure to ischemia-reperfusion injury. The aim of the current study was to examine the response of alpha-MSH during exercise in patients diagnosed with coronary artery disease (CAD) and evaluate its value in the assessment of severity and prognosis. METHODS: Forty subjects with documented CAD (i.e., lesions on coronary angiography ≥ 50%) were included. Cardiopulmonary exercise testing (CPET) on a treadmill (TM) and recumbent ergometer (RE) were performed on two visits, 2-4 days apart, during 2 months of coronary angiography; subsequently, the subjects were followed up for 32 ± 10 months. At rest, at peak CPET, and after 3 min of recovery, plasma levels of alpha-MSH were measured by enzyme-linked immunosorbent assay technique. RESULTS: Mean ejection fraction was 56.7 ± 9.6%. Alpha-MSH similarly increased from rest to peak CPET on both modalities. There were no significant differences in alpha-MSH values during testing in patients with 1,2- and 3-vesel CAD, nor in patients with a SYNTAX score 0.05). Among CPET and hormonal parameters, ∆alpha-MSH recovery/peak during RE CPET was the best predictor of cardiac event occurrence (chi-square 6.67, HR = 0.51, CI = 0.25-1.02, p = 0.010). CONCLUSION: ∆alpha-MSH recovery/peak during RE CPET has predictive value for CAD prognosis, demonstrating involvement of alpha-MSH in CAD and a link between stress hormones and cardiac events.

The alpha-melanocyte stimulating hormone is related to heart rate during exercise recovery.

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a part of the hormonal stress system with proven cardiovascular effects. Heart rate recovery (HRR) following exercise is strongly correlated to overall fitness and future adverse cardiovascular events. The current study examined the predictive value of alpha-MSH for HRR following exercise testing.Cardiopulmonary exercise testing (CPET) on a treadmill was used to measure HR and oxygen consumption (V̇O2) in 16 elite male wrestlers (W), 21 water polo player (WP) and 20 sedentary subjects (C) matched for age. Plasma levels of alpha-MSH were measured by radioimmunoassay technique in four phases of CPET: 1) 10 min pre-CPET at rest; 2) at the initation of CPET; 3) at peak CPET; and 4) at the third minute of recovery. The WP group had significantly higher HRR compared to than W and C groups, who did not have significantly different values. Significant difference in alpha-MSH measurements and patterns during CPET between groups was not observed (p > 0.05). When combining all three groups, we observed a significant correlation between V̇O2 recovery and alpha-MSH recovery/peak (r = -0.3, p = 0.022). HRR and ΔHRR/peak significantly correlated with alpha-MSH at all four measurment points (r = -0.4; p < 0.01 for all). On multiple regression analysis, which included anthropometric and hormonal measures, the best independent predictor of HRR and ΔHRR/peak was alpha-MSH during recovery (B = -1.0, -0.5; SE = 0.3, 0.1; CI = -1.5 to -0.4, -0.7 to -0.2; p = 0.001 respectively). In conclusion, alpha-MSH measured during exercise recovery holds predictive value for HRR and ΔHRR/peak, suggesting a contributing role to integrative regulation of overall cardiopulmonary performance. CONDENSED ABSTRACT: Present study examined the predictive value of alpha-melanocyte stimulating hormone (alpha-MSH) for heart rate recovery (HRR) in elite male wrestlers, water polo players and sedentary subjects matched for age. Alpha-MSH measured during exercise recovery holds predictive value for HRR and ΔHRR/peak, suggesting a contributing role to integrative regulation of overall cardiopulmonary performance.

ARMC5 Alterations in Patients With Sporadic Neuroendocrine Tumors and Multiple Endocrine Neoplasia Type 1 (MEN1).

CONTEXT: Adrenal lesions are frequent among patients with sporadic neuroendocrine tumors (spNETs) or multiple endocrine neoplasia type 1 (MEN1). Armadillo repeat-containing 5 (ARMC5)-inactivating variants cause adrenal tumors and possibly other neoplasms. OBJECTIVE: The objective of this work is to investigate a large cohort spNETs or MEN1 patients for changes in the ARMC5 gene. PATIENTS AND METHODS: A total of 111 patients, 94 with spNET and 17 with MEN1, were screened for ARMC5 germline alterations. Thirty-six tumors (18 spNETs and 18 MEN1 related) were collected from 20 patients. Blood and tumor DNA samples were genotyped using Sanger sequencing and microsatellite markers for chromosomes. ARMC5 and MEN1 expression were assessed by immunohistochemistry. RESULTS: In 76 of 111 (68.4%) patients, we identified 16 different ARMC5 germline variants, 2 predicted as damaging. There were no differences in the prevalence of ARMC5 variants depending on the presence of MEN1-related adrenal lesions. Loss of heterozygosity (LOH) at chromosome 16p and ARMC5 germline variants were present together in 23 or 34 (67.6%) tumors; in 7 of 23 (30.4%) their presence led to biallelic inactivation of the ARMC5 gene. The latter was more prevalent in MEN1-related tumors than in spNETs (88.9% vs 38.9%; P = .005). LOH at the chromosome 16p (ARMC5) and 11q (MEN1) loci coexisted in 16/18 MEN1-related tumors, which also expressed lower ARMC5 (P = .02) and MEN1 (P = .01) proteins compared to peritumorous tissues. CONCLUSION: Germline ARMC5 variants are common among spNET and MEN1 patients. ARMC5 haploinsufficiency or biallelic inactivation in spNETs and MEN1-related tumors suggests that ARMC5 may have a role in modifying the phenotype of patients with spNETs and/or MEN1 beyond its known role in macronodular adrenocortical hyperplasia.

Acute Response to Endurance Exercise Stress: Focus on Catabolic/anabolic Interplay Between Cortisol, Testosterone, and Sex Hormone Binding Globulin in Professional Athletes.

BACKGROUND: Endocrine system plays a major role in both permissive and regulatory activities in order to adequately respond to physical stress of exercise. But level and direction of activation depend on many factors and are not easily interpreted. METHODS: We tested a group of male professional athletes (21 water polo players and 15 wrestlers), together with 20 sedentary controls matched by age. All participants took a continuous progressive exercise stress test on a treadmill until exhaustion and plateau of oxygen consumption (VO2). Blood samples for cortisol, sex hormone binding globulin (SHBG) and testosterone were drawn in four time points: baseline (B), start of the test (S), point of maximal strain (MAX) and in the 3rd minute of recovery period (R). RESULTS: Cortisol levels significantly increased in both groups, but the response between S and MAX was more pronounced in controls (p=0.036). The athletes had significantly higher levels of cortisol in all points in test, except during R (p=0.118), when their cortisol levels gradually started to decline. Significant increase in total testosterone was in great deal a consequence of increase in SHBG level (p<0.01 for both). Consequently, calculated free testosterone significantly decreased during test (p=0.008), and the drop was more pronounced in athletes. This was in concordance with significant correlation between SHBG and cortisol level demonstrated in athletes, but not in controls. CONCLUSIONS: It seems that high intensity endurance exercise favors catabolic response, but the level of response highly depends on a previous level of training.

Novel Mutations in Serbian MEN1 Patients: Genotype-phenotype Correlation.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome characterized by the occurrence of primary hyperparathyroidism (PHPT), pituitary adenoma (PA) and pancreatic neuroendocrine tumor (pNET). Whether the underlying mutations in MEN1 gene predict clinical presentation of affected heterozygotes or not, is still a matter of a debate. METHODS: Clinical and genetic analysis of 90 consecutive MEN1 patients was performed in a retrospective, single - center study. RESULTS: MEN1 mutation was found in 67 (74.4%) patients belonging to 31 different families. Twenty nine different heteozygous mutations were found, including 6 novel point mutations (W220G, 941delG, 1088del7, 1184insA, 1473del10, 1602del17) and one large deletion of exon 8. Truncating mutations predicted development of pNETs (OR=5.8, 95% CI 1.7 - 19.7%) and PHPT (OR=4.3, 95% CI 1.5 - 12.4%). CONCLUSIONS: Large number of novel mutations among MEN1 patients confirmed previously reported data. PNETs and PHPT were more frequent in patients with truncating mutations.

VHL Dependent Expression of REDD1 and PDK3 Proteins in Clear-cell Renal Cell Carcinoma.

BACKGROUND: Sporadic clear-cell renal cell carcinoma (ccRCC) is associated with mutations in the VHL gene, upregulated mammalian target of rapamycin (mTOR) activity and glycolytic metabolism. Here, we analyze the effect of VHL mutational status on the expression level of mTOR, eIF4E-BP1, AMPK, REDD1, and PDK3 proteins. METHODS: Total proteins were isolated from 21 tumorous samples with biallelic inactivation, 10 with monoallelic inactivation and 6 tumors with a wild-type VHL (wtVHL) gene obtained from patients who underwent total nephrectomy. The expressions of target proteins were assessed using Western blot. RESULTS: Expressions of mTOR, eIF4EBP1 and AMPK were VHL independent. Tumors with monoallelic inactivation of VHL underexpressed REDD1 in comparison to wtVHL tumors (P = 0.042), tumors with biallelic VHL inactivation (P < 0.005) and control tissue (P = 0.004). Additionally, REDD1 expression was higher in tumors with VHL biallelic inactivation than in control tissue (P = 0.008). Only in wt tumor samples PDK3 was overexpressed in comparison to tumors with biallelic inactivation of VHL gene (P = 0.012) and controls (P = 0.016). In wtVHL ccRCC, multivariate linear regression analysis revealed that 97.4% of variability in PDK3 expression can be explained by variations in AMPK amount. CONCLUSION: Expressions of mTOR, eIF4EBP1 and AMPK were VHL independent. We have shown for the first time VHL dependent expression of PDK3 and we provide additional evidence that VHL mutational status affects REDD1 expression in sporadic ccRCC.

Long-acting FC-fusion rhGH (GX-H9) shows potential for up to twice-monthly administration in GH-deficient adults.

OBJECTIVE: Hybrid Fc-fused rhGH (GX-H9) is a long-acting recombinant human growth hormone (GH) under clinical development for both adults and children with GH deficiency (GHD). We compared the safety, pharmacokinetics and pharmacodynamics of weekly and every other week (EOW) dosages of GX-H9 with those of daily GH administration in adult GHD (AGHD) patients. DESIGN: This was a randomized, open-label, active-controlled and dose-escalation study conducted in 16 endocrinology centers in Europe and Korea. METHODS: Forty-five AGHD patients with or without prior GH treatment were enrolled. Patients with prior GH treatments were required to have received the last GH administration at least 1 month prior to randomization. Subjects were sequentially assigned to treatment groups. Fifteen subjects were enrolled to each treatment group and randomly assigned to receive either GX-H9 or Genotropin (4:1 ratio). GX-H9 dosage regimens for Groups 1, 2 and 3 were 0.1 mg/kg weekly, 0.3 mg/kg EOW and 0.2 mg/kg EOW, respectively. All Genotropin-assigned subjects received 6 µg/kg Genotropin, regardless of treatment group. Main outcome analyses included measurements of serum insulin-like growth factor 1 (IGF-I), safety, pharmacokinetics, pharmacodynamics and immunogenicity. RESULTS: Mean GX-H9 peak and total exposure increased with an increase in dose after a single-dose administration. The mean IGF-I response was sustained above baseline over the intended dose interval of 168 h for the weekly and 336 h for the EOW GX-H9 groups. Safety profiles and immunogenicity were not different across the treatment groups and with Genotropin. CONCLUSIONS: GX-H9 has the potential for up to twice-monthly administration.

Cognitive functioning and quality of life in patients with Hashimoto thyroiditis on long-term levothyroxine replacement.

OBJECTIVE: Intrinsic imperfections of thyroid hormone replacement therapy may affect long-term general well-being. In patients with Hashimoto thyroiditis (HT), cognitive functioning may be affected via altered thyroid hormones action as well as by the autoimmune process. The aim of this study was to evaluate cognitive function and quality of life (QoL) in patients on long-term levothyroxine replacement for HT in relation to thyroid function tests and TPO (thyroid-peroxidase) antibody (TPOAb) status. DESIGN: Retrospective cross-sectional study. PATIENTS AND MEASUREMENTS: One-hundred-and thirty patients with HT on long-term levothyroxine replacement and 111 euthyroid control subjects. Both groups were divided into two age subgroups, 20-49 years (N = 59 vs N = 79) and > 50 years (N = 71 vs N = 32). Evaluation included biochemical and neuropsychological tests, evaluating attention, global cognitive status, verbal and working memory, executive function, depression and anxiety, and quality of life. We used ANOVA and partial correlations to test for significant associations. RESULTS: FT4 (free-thyroxine), FT3 (free-triiodothyronine) levels and FT3/FT4 ratio were not different between patients and controls. Mean TSH (thyroid-stimulating hormone) was normal in all subjects but significantly higher in the patients (20-49 yrs:3.64 ± 2.74 vs 1.93 ± 1.10, >50 yrs:3.93 ± 2.84 vs 1.91 ± 0.90). Antibodies (TgAb,TPOAb) were higher in patients. Global cognitive function (MMSE-Mini mental state examination), conceptual tracking (TMT-Trail Making Test:A/B), verbal divergent thinking (like Phonemic fluency test), and anxiety and depression scores were significantly worse in patients vs controls. QoL was impaired in patients. there was a significant negative correlation between antibodies (TPOAb, TgAb) and quality in life (total SF36 score). CONCLUSION: Patients on long-term levothyroxine replacement show persistent impairments in both cognitive functioning and general well-being.

PTSD and depressive symptoms are linked to DHEAS via personality.

BACKGROUND: Research results on dehydroepiandrosterone sulfate ester (DHEAS) in post-traumatic stress disorder (PTSD) are inconsistent. We hypothesized that personality traits could be the confounders of DHEAS levels and disease symptoms, which could in part explain the discrepancy in findings. METHOD: This study was a part of a broader project in which simultaneous psychological and biological investigations were carried out in hospital conditions. 380 male subjects were categorized in four groups: A) current PTSD (n = 132), B) lifetime PTSD (n = 66), C) trauma controls (n = 101), and D) healthy controls (n = 81), matched by age. RESULTS: The level of DHEAS is significantly lower in the current PTSD group than in trauma controls. All groups significantly differ in personality traits Disintegration and Neuroticism (current PTSD group having the highest scores). DHEAS is related to both PTSD and depressive symptoms; however, Structural Equation Model (SEM) shows that the relations are indirect, realized via their confounder - personality trait Disintegration. CONCLUSIONS: According to our project results, DHEAS is the second putative biomarker for trauma-related disorders that fails to fulfil this expectation. It appears to be more directly related to personality than to the disease symptoms (the first one being basal cortisol). Our data promote personality as a biologically based construct with seemingly important role in understanding the mental health status.

Stress hormones at rest and following exercise testing predict coronary artery disease severity and outcome.

OBJECTIVES: Despite considerable knowledge regarding the importance of stress in coronary artery disease (CAD) pathogenesis, its underestimation persists in routine clinical practice, in part attributable to lack of a standardized, objective assessment. The current study examined the ability of stress hormones to predict CAD severity and prognosis at basal conditions as well as during and following an exertional stimulus. MATERIALS AND METHODS: Forty Caucasian subjects with significant coronary artery lesions (≥50%) were included. Within 2 months of coronary angiography, cardiopulmonary exercise testing (CPET) on a recumbent ergometer was performed in conjunction with stress echocardiography (SE). At rest, peak and after 3 min of recovery following CPET, plasma levels of cortisol, adrenocorticotropic hormone (ACTH) and NT-pro-brain natriuretic peptide (NT-pro-BNP) were measured by immunoassay sandwich technique, radioimmunoassay, and radioimmunometric technique, respectively. Subjects were subsequently followed a mean of 32 ± 10 months. RESULTS AND DISCUSSION: Mean ejection fraction was 56.7 ± 9.6%. Subjects with 1-2 stenotic coronary arteries (SCA) demonstrated a significantly lower plasma cortisol levels during CPET compared to those with 3-SCA (p < .05), whereas ACTH and NT-pro-BNP were not significantly different (p > .05). Among CPET, SE, and hormonal parameters, cortisol at rest and during CPET recovery demonstrated the best predictive value in distinguishing between 1-, 2-, and 3-SCA [area under ROC curve 0.75 and 0.77 (SE = 0.11, 0.10; p = .043, .04) for rest and recovery, respectively]. ΔCortisol peak/rest predicted cumulative cardiac events (area under ROC curve 0.75, SE = 0.10, p = .049). CONCLUSIONS: Cortisol at rest and following an exercise test holds predictive value for CAD severity and prognosis, further demonstrating a link between stress and unwanted cardiac events.

Tuberous sclerosis complex protein 1 expression is affected by VHL Gene alterations and HIF-1α production in sporadic clear-cell renal cell carcinoma.

Alterations in von Hippel-Lindau gene (VHL) do not determine deregulation of hypoxia-inducible factors (HIFs) in clear-cell renal carcinoma (ccRCC). Their effects on tuberous sclerosis proteins (TSC1/2) and heat shock protein 90 (Hsp90) expressions in sporadic ccRCC are unknown. Therefore, we analyze the impact of VHL alterations and HIF-α production on the expression of TSC proteins and Hsp90 in these tumors. Alterations in VHL gene region exhibited 37/47 (78.7%) tumors. Monoallelic inactivation (intragenic mutation or LOH) was found in 10 (21.3%) and biallelic inactivation (intragenic mutation plus LOH) in 27 (57.4%) ccRCCs. Tumorous expression of HIF-α mRNAs, HIF-α, Hsp90 and TSC2 were VHL independent; TSC2 was underexpressed in all tumors by immunostaining (P<0.001). Immunoblotting revealed that TSC1 production was lower in tumors with monoallelic VHL inactivation than in control (P=0.01) and tissues with biallelic VHL inactivation (P=0.019), while tumors lacking HIF-1α (16/47) concurrently overexpressed HIF-2α and underexpressed TSC1 in comparison to controls (P=0.01 for both) and HIF-1α positive tumors (P=0.015 and P=0.050). Significant portion of variability (56.4%) in tumor diameter was explained by oscillations in nuclear grade, and TSC1 and HIF-2α expression in VHL altered tumors. In conclusion, while TSC2 is broadly downregulated in sporadic ccRCC, TSC1 expression is reduced in two subsets of these tumors, those with monoallelic VHL gene inactivation and those with concurrent low HIF-1α and high HIF-2α expression. Hence, the involvement of nuclear grade, TSC1 and HIF-2α in the progression of VHL altered tumors, implies the interplay between pVHL and TSC1.

Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis.

Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamic-pituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations.

Exercise capacity is not impaired after acute alcohol ingestion: a pilot study.

The usage of alcohol is widespread, but the effects of acute alcohol ingestion on exercise performance and the stress hormone axis are not fully elucidated.We studied 10 healthy white men, nonhabitual drinkers, by Doppler echocardiography at rest, spirometry, and maximal cardiopulmonary exercise test (CPET) in two visits (2-4 days in between), one after administration of 1.5 g/kg ethanol (whisky) diluted at 15% in water, and the other after administration of an equivalent volume of water. Plasma levels of NT-pro-BNP, cortisol, and adrenocorticotropic hormone (ACTH) were also measured 10 min before the test, at maximal effort and at the third minute of recovery. Ethanol concentration was measured from resting blood samples by gas chromatography and it increased from 0.00 ±â€Š0.00 to 1.25 ±â€Š0.54‰ (P < 0.001). Basal echocardiographic and spirometric parameters were normal and remained so after acute alcohol intake, whereas ACTH, cortisol, and NT-pro-BNP nonsignificantly increased in all phases of the test. CPET data suggested a trend toward a slight reduction of exercise performance (peak VO2 = 3008 ±â€Š638 vs. 2900 ±â€Š543 ml/min, ns; peak workload = 269 ±â€Š53 vs. 249 ±â€Š40 W, ns; test duration 13.7 ±â€Š2.2 vs. 13.3 ±â€Š1.7 min, ns; VE/VCO2 22.1 ±â€Š1.4 vs. 23.3 ±â€Š2.9, ns). Ventilatory equivalent for carbon dioxide at rest was higher after alcohol intake (28 ±â€Š2.5 vs. 30.4 ±â€Š3.2, P = 0.039) and maximal respiratory exchange ratio was lower after alcohol intake (1.17 ±â€Š0.02 vs. 1.14 ±â€Š0.04, P = 0.04). In conclusion, we showed that acute alcohol intake in healthy white men is associated with a nonsignificant exercise performance reduction and stress hormone stimulation, with an unchanged exercise metabolism.

The Occurrence of Subclinical Hypercortisolism and Osteoporosis in Patients with Incidentally Discovered Unilateral and Bilateral Adrenal Tumors.

BACKGROUND: Adrenal incidentalomas (AI) are clinically silent adrenal masses that are detected incidentally during imaging procedures performed for unrelated diseases. The aim of this study was to investigate the prevalence of sub-clinical hypercortisolism (SH) and associated co-morbidities in patients with unilateral AI (UAI) and bilateral AI (BAI). METHODS: We evaluated 152 patients, 105 (69.1%) with UAI and 47 (30.9%) with BAI. SH was diagnosed in the presence of serum cortisol levels after 1 mg dexamethasone suppression test (DST) or after 2-day low-dose DST (LDDST) > 50 nmol/L with at least one of the following parameters: midnight serum cortisol > 208 nmol/L, 24-h urinary free cortisol > 245 nmol/24 h, or ACTH < 10 ng/L. Bone mineral density (BMD) was measured at lumbar spine (LS) and femoral neck (FN). RESULTS: Age, BMI, and waist circumference were comparable, and diabetes, hypertension and dyslipidemia occurred with similar frequency in both groups. The overall prevalence of SH was 20.5% based on post-1 mg DST, and 20.0% based on post-LDDST cortisol levels, and it was more prevalent in BAI than UAI patients (31.1% vs 15.2%, respectively, p=0.026). LS BMD was lower in BAI than in UAI patients (0.96±0.14 vs 0.87±0.15, p=0.002). There were no differences in FN BMD. The prevalence of osteoporosis was higher in BAI compared to UAI patients (37.1% vs 15.9%, respectively, p=0.011). CONCLUSIONS: Patients with BAI had higher prevalence of SH and osteoporosis than those with UAI. Frequency of other co-morbidities was similar. This may be due to the higher degree of autonomous cortisol secretion or different tissue-specific sensitivity to glucocorticoids.

Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms.

The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34(+) cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34(+) cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

Posttraumatic and depressive symptoms in ß-endorphin dynamics.

A disturbed beta-endorphin system can be a part of the post-traumatic stress disorder (PTSD) and depression allostasis. Study subjects (N=392) included those with PTSD and/or (stress-induced) depression, and healthy controls with and without traumas. The aim of the study was to examine the network of relations centered around plasma beta-endorphin. The network included anxiety (as a personality trait), traumatic events, pain, aggressiveness, depressive symptoms, and three clusters of PTSD symptoms: intrusions, avoidance, and hyperarousal. Beta-endorphin was represented by individual mean from 13 time points (BEmean), reflecting the total amount of the peripherally secreted hormone, and the coefficient of variation (BEvar), calculated as the ratio of standard deviation to the mean, reflecting the hormone׳s dynamics. BEvar correlated with all other variables, BEmean had no correlations. Structural equation modeling (SEM) was used to examine all interrelations (including their directions) of BEvar and the state/trait variables in the context of their entirety. The model revealed that hyperarousal and anxiety were the only direct agents of peripheral beta-endorphin fluctuations, mediating the effects of other variables. Traumatic events and intrusions act on BEvar via hyperarousal, while depressive symptoms, avoidance, and pain act via anxiety. Hyperarousal should be emphasized as the main agent not only because its effect on BEvar is larger than that of anxiety, but also because it increases anxiety itself (via avoidance and pain). All influences on BEvar are positive and they indicate long-term (sensitizing) effects (as opposed to direct stimulation, for example, by acute pain, anger, etc.). Relations apart from beta-endorphin are also discussed.

Metformin effects on malignant cells and healthy PBMC; the influence of metformin on the phenotype of breast cancer cells.

The aim of research was to determine the effects of maximally therapeutically achievable concentrations of metformin on malignant cells and healthy peripheral blood mononuclear cells (PBMC). Eight patients with T2D or hyperglycemia and nine healthy volunteers were included in the study. For determination of the influence of metformin on the phenotype of breast carcinoma, 1,410 patients with surgically removed tumors were included. From this group 37 breast cancer patients had DM type 2 or hyperglycemia and were pretreated with metformin alone or sometimes in combination with other antidiabetic drugs. Our results proved that metformin at low concentrations induced mild decrease in survival of malignant cells and PBMC stimulated for proliferation, but it didn't affect survival of resting PBMC. The effects of plasma of hyperglycemic patients who were under metformin therapy on autologous PBMC-induced decrease in survival of MDA-MB-361 cells, was noticeable in some patients. Metformin pretreatment for 24 h of HER2+ MDA-MB-361 cells, which were subsequently treated for 48 h with Herceptin, induced additional decline in cell survival. The analysis of influence of metformin on phenotype of breast cancer cells revealed significantly lower number of diabetic cancer patients treated with metformin with overexpressed HER2+ tumors (p < 0.013), while the number of patients with ER+PR+ tumors was not significantly changed (p < 0.832). In conclusion, therapeutically used concentrations of metformin exhibit mild cytotoxic action on malignant and dividing normal cells pointing to its preferred role in malignant and autoimmune diseases. The use of metformin was associated with pronounced decrease in HER2 overexpressing tumors.

GR gene BclI polymorphysm changes the path, but not the level, of dexamethasone-induced cortisol suppression.

BACKGROUND: The hypothalamo-pituitary-adrenocortical (HPA) axis self-regulation is achieved via cortisol binding to mineralocorticoid (MR) and glucocorticoid receptors (GR). It is often disturbed in mental disorders, particularly in those where traumatic stress has been implicated, such as posttraumatic stress disorder and depression. Although dexamethasone suppression test (DST) is often used as diagnostic aid, the findings still vary. In search of the factors influencing the DST outcome, we examined the glucocorticoid receptor (GR) gene BclI polymorphism. METHODS: A total of 229 male subjects were classified into three BclI groups: two groups with homozygous carriers (of the G allele, N=108, and of the C allele, N=26), and one with heterozygous carriers (N=95). Multiple hierarchical linear regression analysis was done, where the dependent variable was the dexamethasone-induced cortisol suppression, and predictors included receptor variables. The interactions of the count of 'G׳s with the predictors were introduced to single out the effects of the G allele. RESULTS: The means of all studied variables, including suppression, are statistically the same in the three groups. However, the mechanism of suppression involves MRs only in the G allele carriers. LIMITATIONS: The subjects were selected by criteria suited for the aim of the large project whose part is this study, hence the relatively small number of CC carriers. Also, we did not assess MR functional properties that would probably sharpen the results. CONCLUSION: Our finding that MRs participate in cortisol suppression in the G allele carriers suggests that research aimed at refining HPA axis-based therapy might require its adjustment for such patients.