Neuroendocrine Hormones Research Articles

Presynaptic Dopamine Dynamics in Striatal Brain Slices with Fast-scan Cyclic Voltammetry

Extensive research has focused on the neurotransmitter dopamine because of its importance in the mechanism of action of drugs of abuse (e.g. cocaine and amphetamine), the role it plays in psychiatric illnesses (e.g. schizophrenia and Attention Deficit Hyperactivity Disorder), and its involvement in degenerative disorders like Parkinson's and Huntington's disease. Under normal physiological conditions, dopamine is known to regulate locomotor activity, cognition, learning, emotional affect, and neuroendocrine hormone secretion. One of the largest densities of dopamine neurons is within the striatum, which can be divided in two distinct neuroanatomical regions known as the nucleus accumbens and the caudate-putamen. The objective is to illustrate a general protocol for slice fast-scan cyclic voltammetry (FSCV) within the mouse striatum. FSCV is a well-defined electrochemical technique providing the opportunity to measure dopamine release and uptake in real time in discrete brain regions. Carbon fiber microelectrodes (diameter of ~ 7 µm) are used in FSCV to detect dopamine oxidation. The analytical advantage of using FSCV to detect dopamine is its enhanced temporal resolution of 100 milliseconds and spatial resolution of less than ten microns, providing complementary information to in vivo microdialysis.

Synaptic regulation of the hypothalamic-pituitary-adrenal axis and its modulation by glucocorticoids and stress.

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been implicated in a range of affective and stress-related disorders. The regulatory systems that control HPA activity are subject to modulation by environmental influences, and stressful life events or circumstances can promote subsequent HPA dysregulation. The brain is a major regulator of the HPA axis, and stress-induced plasticity of the neural circuitry involved in HPA regulation might constitute an etiological link between stress and the development of HPA dysregulation. This review focuses on the synaptic regulation of neuroendocrine corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus, which are the cells through which the brain predominantly exerts its influence on the HPA axis. CRH neuronal activity is largely orchestrated by three neurotransmitters: GABA, glutamate, and norepinephrine. We discuss our current understanding of the neural circuitry through which these neurotransmitters regulate CRH cell activity, as well as the plastic changes in this circuitry induced by acute and chronic stress and the resultant changes in HPA function.

The NLRP3 Inflammasome Promotes Age-Related Thymic Demise and Immunosenescence

The collapse of thymic stromal cell microenvironment with age and resultant inability of the thymus to produce naive Tcells contributes to lower immune-surveillance in the elderly. Here we show that age-related increase in 'lipotoxic danger signals' such as free cholesterol (FC) and ceramides, leads to thymic caspase-1 activation via the Nlrp3 inflammasome. Elimination of Nlrp3 and Asc, a critical adaptor required for inflammasome assembly, reduces age-related thymic atrophy and results in an increase in cortical thymic epithelial cells, Tcell progenitors and maintenance of Tcell repertoire diversity. Using a mouse model of irradiation and hematopoietic stem cell transplantation (HSCT), we show that deletion of the Nlrp3 inflammasome accelerates Tcell reconstitution and immune recovery in middle-aged animals. Collectively, these data demonstrate that lowering inflammasome-dependent caspase-1 activation increases thymic lymphopoiesis and suggest that Nlrp3 inflammasome inhibitors may aid the re-establishment of a diverse Tcell repertoire in middle-aged or elderly patients undergoing HSCT.

CATALYTIC RECEPTORS

CATALYTIC RECEPTORS

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Current diagnostic tools cannot predict clinical failure and androgen-independent disease progression for patients with prostate cancer (PC). The survival signaling pathways of prostate cells play a central role in the progression of tumors to a neuroendocrine (NE) phenotype. NE cells demonstrate attributes that suggest that they are an integral part of the signaling cascade leading to castration-resistant PC. In this study, making use of in vitro neuroendocrine differentiation (NED) of human LNCaP and mouse TRAMP-C2 cells after androgen withdrawal, and of the transgenic adenocarcinoma of mouse prostate (TRAMP) model, we characterized a sequence of molecular events leading to NED and identified a number of markers that could be detectable by routine analyses not only in castration resistant PC but also in hormone naïve PC at the time of initial diagnosis. We found that NED associates with AKT activation that in turn regulates heterogeneous nuclear ribonucleoprotein K (hnRNP K), androgen receptor (AR) and β-catenin levels. Addition of molecules targeting membrane-bound receptors and protein kinases blocks NE differentiation in LNCaP and TRAMP-C2 cells. The extent of AKT phosphorylation and hnRNP K, AR and β-catenin levels may have a potential value as prognostic indicators discriminating between androgen-responsive and unresponsive cells and could be used as molecular targets to monitor the anti-tumor action of new therapeutic protocols based on antireceptor agents and/or neuroendocrine hormone antagonists.

Neuroendocrine modulation of GH-IGF1 axis function

Pulsatility and circadian rhythmcity characterize neuroendocrine hormone secretion. Melatonin is secreted at night by the pineal gland and its circadian rhythm of secretion influences many biological rhythms. The rhythm of CRH and ACTH secretion produces the rhythm of cortisol secretion with peak secretion in the morning. GRH and GH are secreted with circadian rhythmicity with higher levels during the night, but IGF1 production remains steady during the 24-hour period. In this paper we have considered a possible role of reciprocal hormone modulation of the hypothalamic-pituitary-adrenal axis, hypothalamic-pineal axis and GH-IGF1 axis function in humans. Melatonin, cortisol, GH and total IGF1serum levels were determined on blood samples obtained every four hours for 24 hours from 10 healthy males, aged 36–51 (mean age ± SEM 44.3 ± 1.02, body mass index ± SEM 25.2 ± 0.45). We correlated hormone serum levels at each sampling time and evaluated the presence of circadian rhythmicity of hormone secretion. Pearson Product Moment Correlations showed that at 1000 h melatonin correlated negatively with IGF1 (t = −2.112, p = 0.02), cortisol correlated positively with GH (t = 7.471, p < 0.001), and at 2200 h melatonin correlated negatively with IGF1 (t = −2.206, p = 0.03). A clear circadian rhythm was validated for the time-qualified changes of melatonin and GH secretion (with acrophase at night), for cortisol serum levels (with acrophase in the morning), but not for total IGF1 serum level changes. We conclude that melatonin and cortisol may modulate GH-IGF1 axis function

Chronobiologic study of neuro-endocrine axis hormone sequence signalling in healthy men

The neuro-endocrine system function is characterized by a large number of circadian processes that signal each other in sequence with different rhythm phases over 24 h. The morning peak of cortisol secretion and the nightly peak in melatonin secretion are well-known physiological phenomena. Thyroid-stimulating hormone (TSH) secretion shows higher levels at night, whereas free thyroxine (FT4) levels do not seem to change with circadian rhythmicity. Similarly, growth hormone (GH) is secreted with higher levels at night, but insulin-like growth factor (IGF)-1 production shows only minor fluctuations over 24 h. In order to look for rhythmicity and phasing (acrophase, Ø) in the dynamics of variation over 24 h, we investigated adrenal and pineal gland, pituitary-thyroid axis, and GH-IGF-1 axis secretions of cortisol, melatonin, TSH, FT4, GH and total IGF-1 in serum levels every 4 h for 24 h from 11 healthy men, age: 35–53 years. Circadian rhythmicity was evaluated for original values and for the fractional variation (FV) between single time point values that was calculated to evaluate the percentage change in rise and fall. A 24 h cosine significantly described the circadian waveform for serum levels in cortisol, melatonin, TSH and GH (Ø = 07:48 h, 01:35 h, 23:32 h, 00:00 h, respectively), while a 12 h cosine significantly described two peaks for serum levels in FT4 (Ø = 09:44 h and 21:44 h, P = 0.038), and in IGF-1 (Ø = 07:40 h and 19:40 h, P = 0.013). A 24 h cosine also significantly described the circadian waveform for FV of cortisol (02:00 h), melatonin (22:29 h), FT4 (05:14 h), and GH (21:19 h), while a 12 h cosine significantly described two peaks for FV of TSH (04:28 h for fall and 16:28 h for rise), whereas FV of IGF-1 did not show a rhythmic pattern. Thus, maximal FV estimated by 24 h Øs preceded maximal serum levels by ∼6 h for cortisol and TSH, ∼5 h for FT4, ∼3 h for melatonin, ∼2.5 h for GH, and ∼1 h for IGF-1. When comparing 24 h Øs for serum levels of hormone pairs, the peak for melatonin preceded that for cortisol by 6 h, the peak for TSH preceded the first peak of FT4 by 10.5 h, and the peak for GH preceded that for IGF-1 by 8 h. When comparing FV pairs, the peak for melatonin surge preceded that for cortisol by ∼3.5 h, the peak for TSH surge preceded that for FT4 by ∼13 h, and the peak for GH rise preceded that for IGF-1 ∼10 h. In conclusion, the neuro-endocrine system function is characterized by circadian organization, with individual components showing different phasic patterns of time-related variations, and this array of rhythms undoubtedly underlies the maintenance of stable, but rhythmic and thus predictive, homeostatic processes in the human body.

Stress and quality of life in psoriasis: an update

Psoriasis is a chronic, relapsing, cutaneous condition with 1-2% prevalence in the general population. There are many factors involved in the induction and/or exacerbation of psoriasis of which stress is a well-known trigger factor in the appearance or exacerbation of psoriasis. Stress reaction in patients with psoriasis is probably mediated by the hypothalamic-pituitary-adrenal relationship with immunologic effects. Stress response involves increased levels of neuroendocrine hormones and autonomic neurotransmitters. Psychological stress or an abnormal response to stressors has been found to modify the evolution of skin disorders such as psoriasis. It can also have substantial psychological, and psychosocial impact on a patient's quality of life. Treatment regimens include stress-reduction strategies, such as biofeedback, meditation, yoga, and self-help approaches. This review focuses the relationship between psoriasis and stress, especially relating to psychosocial, psychological, and emotional stress aspects.

Effect of α-melanocyte stimulating hormone on human dermal fibroblasts: preliminary identification of protein expression

Objective To evaluate the effect of this neuroendocrine hormone on protein expression by treating the human dermal fibroblasts with a-melanocyte stimulating hormone (α-MSH ).Methods Thehuman dermal fibroblasts was cultured, and the total protein of the fibroblasts were separated with immobilized pH gradient-based two-dimensional gel electrophoresis (2-DE). After Coomassie bright blue staining, gel images were acquired by Image-scanner and then analyzed with the PDQuest software. 2-DE maps of fibroblasts were established. Partial differently expressed protein spots were incised from gels and digested by trypsin in-gel. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and MSDB database searching by Mascot? software were used for protein identification. Results Well-resolved, reproducible 2-DE patterns of dermal fibroblasts treated with and without crMSH were obtained. 8 differently expressed protein spots were detected, among which 8 obtained peptide mass fingerprints (PMF) by MALDI-TOF-MS analysis. Among these proteins, of particular interest were five proteins annexin I, HSP27 and lamin A, etc. Conclusions Proteins expressed by human dermal fibroblasts treated with or without crMSH are different, and some of the differently expressed proteins involve apoptosis, intracellular signal transduction and framework construction and so on, which may be associated with anti-fibrosis effects of (a)-MSH on human dermal fibroblasts. Key words: a-melanocyte stimulating hormone; Fibroblasts; Electrophoresis; Proteomics

Unique Interaction Pattern for a Functionally Biased Ghrelin Receptor Agonist

Based on the conformationally constrained D-Trp-Phe-D-Trp (wFw) core of the prototype inverse agonist [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]substance P, a series of novel, small, peptide-mimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers connecting the D-Trp-Phe-D-Trp motif with the important C-terminal carboxyamide group, 40 nm agonism potency was obtained and also in one case (wFw-Isn-NH(2), where Isn is isonipecotic acid) ~80% efficacy. However, in contrast to all previously reported ghrelin receptor agonists, the piperidine-constrained wFw-Isn-NH(2) was found to be a functionally biased agonist. Thus, wFw-Isn-NH(2) mediated potent and efficacious signaling through the Gα(q) and ERK1/2 signaling pathways, but in contrast to all previous ghrelin receptor agonists it did not signal through the serum response element, conceivably the Gα(12/13) pathway. The recognition pattern of wFw-Isn-NH(2) with the ghrelin receptor also differed significantly from that of all previously characterized unbiased agonists. Most importantly, wFw-Isn-NH(2) was not dependent on GluIII:09 (Glu3.33), which otherwise is an obligatory TM III anchor point residue for ghrelin agonists. Molecular modeling and docking experiments indicated that wFw-Isn-NH(2) binds in the classical agonist binding site between the extracellular segments of TMs III, VI, and VII, interacting closely with the aromatic cluster between TMs VI and VII, but that it does so in an opposite orientation as compared with, for example, the wFw peptide agonists. It is concluded that the novel peptide-mimetic ligand wFw-Isn-NH(2) is a biased ghrelin receptor agonist and that the selective signaling pattern presumably is due to its unique receptor recognition pattern lacking interaction with key residues especially in TM III.

Characterizing an Animal Model of Anorexia Nervosa

Anorexia Nervosa is a condition of severe under-nutrition characterized by alterations in multiple neuroendocrine axes. PURPOSE: To investigate the temporal changes in body composition and neuroendocrine hormones in food restricted rats, with and without access to running wheels, over a four week period. METHODS: Sixteen, 12 wk old, female Wistar rats were randomly divided into four groups: Control (C), Control/Wheel-Running (C/WR), Starved (S), and Starved/Wheel-Running (SWR). C animals were fed ad libitum, while S were food restricted with the goal of achieving 75% of body mass within the first two weeks with a maintenance phase for the final two weeks. Wheel running activity and food intake were measured constantly through-out the study, and IGF-1, leptin (ELISA) and body composition (DXA, GE Lunar Prodigy) were measured at baseline (B) and once a week ending at 4 weeks (T4). RESULTS: SWR animals demonstrated a rapid loss of body fat (BF) (B = 43.4±5.3g, T4 = 6.6±5.0g) tracked by significant decreases in both leptin (B = 12.5±1.48ng/mL, T4 = 1.8±0.12ng/mL) and IGF-1 (B = 184±13.2ng/mL, T4 = 44±5.8ng/mL). S animals demonstrated similar reductions in BF (B = 37.8g±3.8, T4 = 5.9g±2.4), leptin (B = 7.5±1.3ng/mL, T4 = 2.0±0.3ng/mL) and IGF-1 (B = 196±20.3ng/mL, T4 = 67±7.9ng/mL). C and CWR animals grew to roughly 110%-115% of their original body mass over the study and demonstrated similar increases in IGF-1 (C: B = 181.5±22.9ng/mL, T4 = 244±14.4ng/mL; CWR: B = 180±13.2ng/mL, T4 = 246±21.6ng/mL). However, despite an increase in body mass, wheel running resulted in a reduction in BF (CWR: B = 42.4±6.6g, T4 = 33.3±3.9g) while C animals gained BF (B = 38.2±9.83g, T4 = 46.9±10.1g). In both cases, leptin changed in parallel with BF (CWR: B = 16.4±1.6ng/mL±, T4 = 10.3±0.9ng/mL; C: B = 5.37±0.3ng/mL, T4 = 14.3±3.2ng/mL. CONCLUSION: These data demonstrate that changes in leptin occur rapidly upon initiation of food restriction tracking losses in BF, while adaptations in IGF-1 parallel changes in lean tissue. Wheel running did not prohibit weight gain in ad lib fed animals and resulted in modest reductions in body fat suggesting that investigation of a refeeding program for the food restricted animals that includes exercise is warranted and might not be counter-productive as previously thought.

Prolactin: Does it exert an up-modulation of the immune response in Trypanosoma cruzi-infected rats?

During the course of infection by Trypanosma cruzi, the host immune system is involved in distinct, complex interactions with the endocrine system, and prolactin (PRL) is one of several hormones involved in immunoregulation. Although intensive studies attempting to understand the mechanisms that underlie Chagas’ disease have been undertaken, there are still some pieces missing from this complex puzzle. Because data are scarce concerning the role of PRL involvement in Chagas’ disease and taking into account the existence of crosstalk between neuroendocrine hormones and the immune system, the current study evaluates a possible up-regulation of the cellular immune response triggered by PRL in T. cruzi-infected rats and the role of PRL in reversing immunosuppression caused by the parasitic infection. The data shown herein demonstrate that PRL induces the proliferation of T lymphocytes, coupled with an activation of macrophages and the production of nitric oxide (NO), leading to a reduction in the number of blood trypomastigotes during the peak of parasitemia. During the acute phase of T. cruzi infection, an enhancement of both CD3+CD4+ and CD3+CD8+ T cell populations were observed in infected groups, with the highest numbers of these T cell subsets found in the infected group treated with PRL. Because NO is a signaling molecule involved in a number of cellular interactions with components of the immune system and the neuroendocrine system, PRL can be considered an alternative hormone able to up-regulate the host's immune system, consequently lowering the pathological effects of a T. cruzi infection.

Antiphase signalling in the neuroendocrine-immune system in healthy humans

Background Any quantity varying in the spatial-temporal dimension may be considered as a signal. Human lymphocyte cell surface molecules and subsets present circadian variation and this variation may represent a kind of signalling in the neuroendocrine-immune system. We have analyzed the dynamics of variation of specific lymphocyte subsets in healthy humans. Subjects and methods In our study, lymphocyte subpopulation analyses were performed and cortisol, melatonin, GH and TSH serum levels were measured on blood samples collected every 4 h for 24 hours from eleven healthy men, ages 35–53 years (mean = 44 ± 6 SD). Results A clear circadian rhythm was validated for CD8 and cortisol with acrophase during the day and for CD3, CD4, melatonin, GH and TSH with acrophase at night. Cross-correlation showed that CD3 correlated positively with CD4 ( ρ = 0.67, P < 0.05) and negatively with CD8 ( ρ = −0.41, P < 0.05), CD4 correlated positively with melatonin ( ρ = 0.90, P < 0.05), GH ( ρ = 0.92, P < 0.05) and TSH ( ρ = 0.71, P < 0.05), negatively with CD8 ( ρ = −0.90, P < 0.05) and cortisol ( ρ = −0.18, P < 0.05), CD8 correlated positively with cortisol ( ρ = 0.38, P < 0.05). Discussion The different profiles of nyctohemeral changes of lymphocyte cell surface molecules and specific lymphocyte subsets realize different relationships with the neuroendocrine hormones and might represent a way of signal transmission among the multiple components of the neuroendocrine-immune system.

Melatonin as a central molecule connecting neural development and calcium signaling

Melatonin (MEL) is a neuroendocrine hormone secreted by the pineal gland in association with the suprachiasmatic nucleus and peripheral tissues. MEL has been observed to play a critical role in the reproductive process and in the fetomaternal interface. Extrapineal synthesis has been reported in mammalian models during pregnancy, especially by the placenta tissue. MEL can regulate intracellular processes (e.g., G-proteins) and the activity of second messengers (e.g., cAMP, IP(3,) Ca(2+)). During neurodevelopment, these activities regulated by melatonin have an important role as an intracellular signaling for gene expression regulation. To review the role of MEL in neurodevelopment, we built interactome networks of different proteins that act in these processes using systems biology tools. The analyses of interactome networks revealed that MEL could modulate neurodevelopment through the regulation of Ca(2+) intracellular levels and influencing BMP/SMAD signaling, thus affecting neural gene responses and neuronal differentiation.

Nutrigenomics analyze of expression of extracellular leptin receptor by the following essential oil monitoring at the avian models

Leptin gene was identified in 1994 by positional cloning. His mutation is considered extreme obesity surface phenotype and infertility in ob/ob mice. Most of the research, which followed the discovery of this hormone, focused on the role of leptin in regulating body weight, in order to clarify the pathophysiology of obesity. Many research results show that leptin is not only important in regulating food intake and energy balance, but also performs functions such as metabolic and neuroendocrine hormone. Using herbs and essential oils depends on their antimicrobial activity. Most plants have favorable multifunctional properties, which are the specific content of bioactive components. Some authors characterize fytogénne substance such as natural substancese plant origin, which leave no residues in animal products and is not necessary to keep the trade period before slaughter animals. Analyses suggest that the structural function of the receptor exists as a dimer constructively in the plasma membrane. Each receptor dimer pair is reversibly bound to one molecule of leptin. When bound, signaling pathways are responsible for beginning the activation receptor associated Janus kinase 2 (JAK2) and tyrosine phosphorylation of two key residues in the intracellular part of receptor.

Salmonella Typhi sense host neuroendocrine stress hormones and release the toxin haemolysin E

Salmonella enterica serovar Typhi (S. typhi) causes typhoid fever. We show that exposure of S. typhi to neuroendocrine stress hormones results in haemolysis, which is associated with the release of haemolysin E in membrane vesicles. This effect is attributed to increased expression of the small RNA micA and RNA chaperone Hfq, with concomitant downregulation of outer membrane protein A. Deletion of micA or the two-component signal-transduction system, CpxAR, abolishes the phenotype. The hormone response is inhibited by the β-blocker propranolol. We provide mechanistic insights into the basis of neuroendocrine hormone-mediated haemolysis by S. typhi, increasing our understanding of inter-kingdom signalling.

Signalling pathways and the host-parasite relationship: Putative targets for control interventions against schistosomiasis

A better understanding of how schistosomes exploit host nutrients, neuro-endocrine hormones and signalling pathways for growth, development and maturation may provide new insights for improved interventions in the control of schistosomiasis. This paper describes recent advances in the identification and characterisation of schistosome tyrosine kinase and signalling pathways. It discusses the potential intervention value of insulin signalling, which may play an important role in glucose uptake and carbohydrate metabolism in schistosomes, providing the nutrients essential for parasite growth, development and, notably, female fecundity. Significant progress has also been made in the characterisation of other schistosome growth factor receptors, such as transforming growth factor beta receptor and epidermal growth factor receptor, and in our understanding of their roles in the host-parasite molecular dialogue and parasite development. The use of parasite signal transduction components as novel vaccine or drug targets may prove invaluable in prevention, treatment and control strategies to combat schistosomiasis.

Effects of low level manganese exposure on the serum neuroendocrine hormones in the welders

To study the effects of low level manganese (Mn) exposure on the serum neuroendocrine hormones levels of the welders. The exposure group consisted of 41 male welders, 40 male workers without exposing to harmful agents served as controls. The serum contents of prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (TST) and thyroid stimulating hormone (TSH) of 81 subjects were detected by chemiluminescence immunoassay. The geometric mean value of airborne Mn concentrations was 0.03 mg/m(3) (0.003 - 0.519 mg/m(3)) in the welding circumstances. The levels of Mn in red blood cells (RBCs) and urinary Mn of the exposure group were significantly higher than those of control group (P < 0.01). The contents of serum LH and TSH of the exposure group were 2.89 ± 0.69 mIU/ml and 1.45 ± 0.56 uIU/ml, which were significantly lower than those (3.82 ± 1.61 mIU/ml and 2.19 ± 1.28 µIU/ml) of control group (P < 0.01). The serum contents of LH, FSH and TSH of the group exposed to Mn for < 5 years were significantly lower than those of the control group, The serum TST level of the group exposed to Mn for < 5 years was significantly higher than those of the control group and group exposed to Mn for 5 ∼ years, the serum FSH level of the group exposed to Mn for < 5 years was significantly lower than that of the group exposed to Mn for 10 years (P < 0.05 or P < 0.01). The serum contents of LH and TSH of the group exposed to Mn for 5 ∼ years were significantly lower than those of the control group (P < 0.05 or P < 0.01). The serum contents of PRL, LH and TSH of the group exposed to Mn for 10 years were significantly lower than those of the control group (P < 0.05). There was negative correlation between blood (RBC) Mn and urinary Mn (r = -0.310, P < 0.05), also there was negative correlation between serum PRL and serum TST (r = -0.409, P < 0.01), the positive correlation between serum LH and serum FSH was observed (r = 0.361, P < 0.05). The results of present study showed that the long exposure to low level of Mn may decrease the levels of serum PRL, LH and TSH in workers occupationally exposed to Mn, which can influence the metabolism of neuroendocrine hormones to certain extent.

Incidental diagnosis of pancreatic neuroendocrine tumors.

190 Background: Pancreatic neuroendocrine tumors are often discovered incidentally during radiologic or endoscopic examinations. The incidence of incidental detection is unknown. It is also unclear whether patients with incidentally discovered, asymptomatic tumors should be treated similarly to patients who present with tumor-related symptoms. Methods: A database of 425 patients with pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center was developed. Patient charts were reviewed to assess whether their diagnosis was incidental or prompted by tumor-related symptoms such as pain, jaundice, or neuroendocrine hormone secretion. The frequency of “incidentalomas” was categorized by TNM stage (AJCC, 7th edition). Overall survival was stratified by “incidental” versus “symptomatic” diagnosis. Results: Among 425 patients with histologically proven pancreatic neuroendocrine tumors, 112 patients (26%) had tumors that were discovered incidentally. The majority of stage I tumors (55%) were incidentally discovered. Among patients with stage IV tumors, 20% were detected incidentally (Table). Median survival of patients with incidentally discovered tumors was 103 months versus 84 months in patients who were symptomatic at diagnosis. Conclusions: A sizeable fraction of patients with pancreatic neuroendocrine tumors are diagnosed incidentally during evaluations for other conditions or unrelated symptoms. The majority of patients with stage I tumors are incidentally diagnosed. The increased incidence of pancreatic neuroendocrine “incidentaloms” may be contributing to improving survival rates in this disease. This study highlights the necessity of developing guidelines for management of patients with incidentally discovered, early-stage tumors. [Table: see text] No significant financial relationships to disclose.

Altered levels of circulating insulin and other neuroendocrine hormones associated with the onset of schizophrenia

Recently, we showed that the circulating levels of insulin-related peptides and the secretory granule protein chromogranin A were increased in small cohorts of first onset schizophrenia patients. Assuming that this effect was associated with impaired insulin signalling, we investigated the possibility that secretion of other hormones is also affected in schizophrenia. Multiplex immunoassay analysis of 21 hormones and hormone-related molecules was carried out using sera from 236 first and recent onset schizophrenia patients and 230 matched controls. Serum concentrations of insulin and chromogranin A were increased in schizophrenia subjects, consistent with our previous study. In addition, we found elevated concentrations of pancreatic polypeptide, prolactin, progesterone and cortisol, and decreased levels of growth hormone. We also found that growth hormone levels were decreased in post-mortem pituitaries obtained from chronic schizophrenia patients. It will be important to determine whether any of these molecules are involved in the pathosphysiology of schizophrenia or if they reflect the associated insulin resistance. We conclude that function of multiple components of the hypothalamic-pituitary-adrenal-gonadal axis may be affected in schizophrenia. This could have important implications for future biomarker discovery efforts and personalized medicine strategies based on patient stratification for the treatment of this debilitating disorder.