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.

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.

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.

Recurrent spontaneous abortions, Hashimoto thyroiditis and alopecia totalis: response to anticoagulation and intravenous immunoglobulin therapy.

INTRODUCTION: Although numerous studies indicated a link between antithyroid antibodies and recurrent spontaneous abortions (RSA), consensus on the treatment of this condition is still lacking. CASE REPORT: We present a case of a 35-year-old pregnant woman (gestation week 4) with primary hypothyroidism, total alopecia, high level of positive antithyroid antibodies, and history of two recurrent spontaneous abortions in early pregnancy. Along with L-thyroxin substitution, intravenous human immunoglobulin (IVIg) combined with anticoagulation and antiaggregation therapy was introduced. During pregnancy her scalp hair completely re-grew, and following gestation week 39 she delivered healthy female child. CONCLUSION: Thyroid antibodies could contribute to previous recurrent abortions in our patient. It is suggested that in older primiparas with Hashimoto thyroiditis and history of RSA, a combined treatment with IVIg, anticoagulation and antiaggregation therapy should be considered.

Glucocorticoid receptor and molecular chaperones in the pathogenesis of adrenal incidentalomas: potential role of reduced sensitivity to glucocorticoids.

Glucocorticoid (GC) sensitivity depends on glucocorticoid receptor (GR) and heat shock proteins (Hsps). We investigated whether common GR genes (ER22/23EK, N363S, Bcl I, and 9ß) and adrenocorticotropin receptor promoter polymorphisms influence susceptibility for unilateral adrenal incidentaloma (AI), plus GR and Hsp expression in tumorous (n = 19), peritumorous (n = 13) and normal adrenocortical (n = 11) tissues. Patients (n = 112), population-matched controls (n = 100) and tumor tissues (n = 32) were genotyped for these polymorphisms. Postdexamethasone serum cortisol was higher in patients (p < 0.001). GR gene variants, larger allele of Bcl I (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.7-5.1; p < 0.001] and minor allele of 9ß (OR 3.0; 95% CI 1.6-5.7; p < 0.001) were independent predictors of AI. In patients, the first allele is linked with larger tumors (p = 0.002) and the latter with higher postdexamethasone cortisol levels (p = 0.025). Both allele carriers had lesser waist circumference (p = 0.02), similar adrenocorticotropin and higher basal (p = 0.024) and postdexamethasone cortisol concentrations (p < 0.001). Tumorous and constitutional genotypes were similar. GR-D is the major receptor isoform in normal adrenal cortex by Western blotting. Loss of other receptor isoforms, decrease in immunostaining for GR (p < 0.0001), underexpression of chaperones (p ≤ 0.01) and the presence of inducible Hsp70 were found in adenomas. In conclusion, GR gene variants, C allele of Bcl I and minor allele of 9ß, are associated with AIs. Their concurrent presence in patients reduces GC sensitivity. Normal adrenal cortex preferentially expresses GR-D. In adenomas, the lack of other GR isoforms and underexpression of heat shock proteins perhaps permanently impair GC signaling, which could promote dysregulated cortisol production and tumor growth. The innate GC sensitivity probably modifies these effects.

Similar developmental patterns of ghrelin- and glucagon-expressing cells in the human pancreas.

The pancreas appears to be a major source of ghrelin during fetal development, but the ontogeny of ghrelin cells in the human pancreas and their developmental relationship with α- and ß-cells remain largely unknown. In the present study, we examined the dynamics of ghrelin cell growth, colocalization of ghrelin with major pancreatic hormones and defined the similarities and differences among developmental patterns of ghrelin-, glucagon- and insulin-expressing cells in the human pancreas. To this end, paraffin-embedded pancreatic tissue sections from human embryos and fetuses were assessed by immunohistochemistry. Ghrelin-positive cells were first detected in the pancreas of 11-week-old fetuses. With advancing gestational age, both ghrelin- and glucagon-expressing cells were increasingly observed at the periphery of the developing islets, whereas insulin-containing cells were typically found in the islet core. Double immunohistochemistry showed that ghrelin-expressing cells were clearly separate from insulin-, somatostatin- and pancreatic polypeptide-containing cells. In contrast, cells coexpressing ghrelin and glucagon were sporadically detected during both the early and late fetal periods. Furthermore, morphometric analysis revealed a similar trend in the volume density of ghrelin- and glucagon-positive cells, and a contrasting pattern in ß-cell density at specific time points during the development of the human pancreas. This study demonstrates that the developmental pattern of ghrelin cells, although clearly distinct, is quite similar to that of glucagon-expressing cells. The obtained findings indicate a close lineage relationship between these cell populations, a functional relationship between their secretory products and an auto/paracrine mode of ghrelin-glucagon interaction in pancreatic development.

Clinical and pathological tools for identifying microsatellite instability in colorectal cancer.

AIM: To assess practical accuracy of revised Bethesda criteria (BGrev), pathological predictive model (MsPath), and histopathological parameters for detection of high-frequency of microsatellite instability (MSI-H) phenotype in patients with colorectal carcinoma (CRC). METHOD: Tumors from 150 patients with CRC were analyzed for MSI using a fluorescence-based pentaplex polymerase chain reaction technique. For all patients, we evaluated age, sex, family history of cancer, localization, tumor differentiation, mucin production, lymphocytic infiltration (TIL), and Union for International Cancer Control stage. Patients were classified according to the BGrev, and the groups were compared. The utility of the BGrev, MsPath, and clinical and histopathological parameters for predicting microsatellite tumor status were assessed by univariate logistic regression analysis and by calculating the sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values. RESULTS: Fifteen out of 45 patients who met and 4 of 105 patients who did not meet the BGrev criteria had MSI-H CRC. Sensitivity, specificity, PPV, and NPV for BGrev were 78.9%, 77%, 30%, and 70%, respectively. MSI histology (the third BGrev criterion without age limit) was as sensitive as BGrev, but more specific. MsPath model was more sensitive than BGrev (86%), with similar specificity. Any BGrev criterion fulfillment, mucinous differentiation, and right-sided CRC were singled out as independent factors to identify MSI-H colorectal cancer. CONCLUSION: The BGrev, MsPath model, and MSI histology are useful tools for selecting patients for MSI testing.

Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10.

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

Modulation of aldosterone release by epidural analgesia impacts brain natriuretic peptide: a link to stress cardiomyopathy? Pilot study.

OBJECTIVE: Data pertaining to whether stress-induced aldosterone release is associated with cardiac disorders are lacking. This study was designed to compare whether the modulation of intra-operative aldosterone release by epidural analgesia had an effect on the brain natriuretic peptide (BNP) levels. DESIGN, PATIENTS, MEASUREMENTS: A study was pilot prospective, open label randomized one. Patients were randomized to one of two anaesthesia protocols: group 1 included 13 patients who received general anaesthesia, and group 2 included 12 patients who received combined general anaesthesia and epidural analgesia. Study protocol was by completed 25 male patients, median age 56 years, without significant comorbidities, who underwent radical cystectomy because of urinary bladder tumour. Serum aldosterone, BNP, cortisol (measured by radioimmunoassay), adrenocorticotropine hormone (ACTH) (by solid-phase ELSA), blood chemistry, complete blood count and vital signs were compared preoperatively, intra-operatively and at postoperative days (POD) 1 and 7. RESULTS: Hemodynamics was stable in both groups. Group 1 showed threefold serum aldosterone, (P = 0·001) 20-fold ACTH (P = 0·003) and twofold cortisol (P = 0·001) increases intra-operatively, unlike group 2. Both groups had a twofold BNP increase in POD 1 that remained above normal on POD 7 only in group 1 (P = 0·02; P = 0·019 vs group 2). CONCLUSION: Alleviation of aldosterone release by epidural analgesia modulated the postoperative serum BNP pattern in patients with a low risk for cardiac diseases who underwent noncardiac surgery.

Assessment of the left ventricular chamber stiffness in athletes.

Since diastolic dysfunction is an early sign of the heart disease, detecting diastolic disturbances is predicted to be the way for early recognizing underlying heart disease in athletes. So-called chamber stiffness index (E/e')/LVDd was predicted to be useful in distinguishing physiological from pathological left ventricular hypertrophy, because it was shown to be reduced in athletes. It remains unknown whether it is reduced in all athletic population. Standard and tissue Doppler were used to assess cardiac parameters at rest in 16 elite male wrestlers, 21 water polo player, and 20 sedentary subjects of similar age. In addition to (E/e')/LVDd index, a novel (E/e')/LVV, (E/e')/RVe'lat indices were determined. Progressive continuous maximal test on treadmill was used to assess the functional capacity. VO(2) max was the highest in water polo players, and higher in wrestlers than in controls. LVDd, LVV, LVM/BH(2.7) were higher in athletes. Left ventricular early diastolic filling velocity, deceleration and isovolumetric relaxation time did not differ. End-systolic wall stress was significantly higher in water polo players. RV e' was lower in water polo athletes. Right atrial pressure (RVE/e') was the highest in water polo athletes. (E/e'lat)/LVDd was not reduced in athletes comparing to controls (water polo players 0.83 ± 0.39, wrestlers 0.73 ± 0.29, controls 0.70 ± 0.28; P = 0.52), but (E/e's)/RVe'lat better distinguished examined groups (water polo players 0.48 ± 0.37, wrestlers 0.28 ± 0.15, controls 0.25 ± 0.16, P = 0.015) and it was the only index which predicted VO(2) max. In conclusion, intensive training does not necessarily reduce (E/e'lat)/LVDd index. A novel index (E/e's)/RVe'lat should be investigated furthermore in detecting diastolic adaptive changes.

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.

Assessment of p27 (cyclin-dependent kinase inhibitor 1B) and aryl hydrocarbon receptor-interacting protein (AIP) genes in multiple endocrine neoplasia (MEN1) syndrome patients without any detectable MEN1 gene mutations.

OBJECTIVE: Germline mutations in the MEN1 gene predispose to the multiple endocrine neoplasia (MEN1) syndrome; however, approximately 10-20% of patients with MEN1 do not have a detectable MEN1 mutation. A rat strain with multiple endocrine tumours, a phenotypic overlap of both MEN1 and MEN2, has been reported to have a homozygous germline p27 (CDKN1B) mutation. Recently, two MEN1 mutation-negative MEN1 syndrome patients have been identified to harbour a germline CDKN1B mutation. The recently identified gene AIP can also cause familial isolated pituitary adenoma, but no other specific tumour is associated with this syndrome. The objective of this study was to evaluate the possible contribution of CDKN1B and AIP germline mutations in a cohort of MEN1 mutation-negative MEN1 syndrome patients. PATIENTS: Eighteen sporadic and three familial cases of MEN1 mutation-negative MEN1 syndrome were studied (18 pituitary adenomas, 12 hyperparathyroidism, 10 neuroendocrine tumours including 2 ACTH-secreting lesions and one adrenal nodular hyperplasia). Clinical data and genomic DNA were analysed for mutations in the CDKN1B and AIP genes. RESULTS: There were no mutations in the coding region or exon/intron junction of the CDKN1B and AIP genes in any patient. Although we have a limited number of patients in our cohort, our data is consistent with others in the literature suggesting that CDKN1B and AIP mutations are extremely rare in MEN1 syndrome. CONCLUSION: Our results suggest that mutations in the CDKN1B and AIP genes are relatively uncommon in MEN1 mutation-negative MEN1 syndrome patients.

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.

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.