Neuroendocrinology (Neuroendocrinology )

Publisher: Karger

Description

ëNeuroendocrinologyí publishes papers reporting original research in basic and clinical neuroendocrinology. The journal explores the complex interactions between neuronal networks and endocrine glands (in some instances also immune cells) in both central and peripheral nervous systems. Original contributions cover all aspects of the field, from molecular and cellular neuroendocrinology, physiology, pharmacology, and the neuroanatomy of neuroendocrine systems to neuroendocrine correlates of coping behavior or clinical neuroendocrinology. Readers will also benefit from occasional, well-referenced reviews by noted experts which highlight especially active areas of current research.

  • Impact factor
    3.54
  • 5-year impact
    3.63
  • Cited half-life
    0.00
  • Immediacy index
    1.33
  • Eigenfactor
    0.01
  • Article influence
    1.01
  • Website
    Neuroendocrinology website
  • Other titles
    Neuroendocrinology (Online)
  • ISSN
    1423-0194
  • OCLC
    44647673
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Karger

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • On author's server or institutional server
    • Server must be non-commercial
    • Publisher's version/PDF cannot be used
    • Publisher copyright and source must be acknowledged
    • Must link to publisher version
  • Classification
    ​ green

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The neuropeptide RFamide-related peptide-3 (RFRP-3; mammalian ortholog to GnIH) can inhibit LH release and increases feeding, but the regulation and development of RFRP-3 neurons remains poorly characterized, especially in mice. Methods and Results: We first confirmed that peripheral injections of murine RFRP-3 peptide could markedly suppress luteinizing hormone secretion in adult mice, as in other species. Second, given RFRP-3's reported orexigenic properties, we performed double-label in situ hybridization for metabolic genes in Rfrp neurons of mice. While Rfrp neurons did not readily co-express NPY, TRH, or MC4R, a small subset of Rfrp neurons did express leptin receptor in both sexes. Surprisingly, we identified no changes in Rfrp expression or neuronal activation in adult mice after acute fasting. However, we determined that Rfrp mRNA levels in the DMN were significantly reduced in adult Obese (Ob) mice of both sexes. Given the lower Rfrp levels observed in adult Ob mice, we asked whether leptin might also regulate RFRP-3 neuron development. Rfrp gene expression changed markedly over juvenile development, correlating with the timing of the juvenile 'leptin surge' known to govern hypothalamic feeding circuit development. However, the dramatic developmental changes in juvenile Rfrp expression did not appear to be leptin-driven, as the pattern and timing of Rfrp neuron development were unaltered in Ob juveniles. Conclusion: Leptin status modulates RFRP-3 expression in adulthood, but is not required for normal development of the RFRP-3 system. Leptin's regulation of adult RFRP-3 neurons likely occurs via primarily indirect signaling, and may be secondary to obesity, as only a small subset of RFRP-3 neurons express LepRb. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 11/2014;
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    ABSTRACT: Background: The current WHO classification for Neuroendocrine Neoplasms (NEN) of the gastrointestinal tract requires Ki-67 and mitotic index for grading. However both indexes might be conflicting as far as grade is concerned. In this study we investigate which of both indexes is most informative to predict survival. Methods: From 362 patients with NEN of gastrointestinal (n = 148), pancreatic (n = 29), lung (n = 77), unknown primary site (n = 102) and of miscellaneous (n = 6) origin. Follow-up and proliferative indexes were recorded. Results: Survival was clearly correlated with both proliferative indexes (p < 0.001). One hundred nineteen samples (34%) showed discordance in grading between Ki-67 and mitotic index, of which 74 (62%) were biopsies and 45 (38%) were resection specimens (p = 0.001). In 86% of these cases survival matched with the highest proliferative index, which was the Ki-67 index in 87% of these cases. Seventeen cases had a mitotic index of 2 (threshold grade 2) and a Ki-67 index of <3% (grade 1). For these cases survival curve matched that of patients with concordant indexes of grade 1. Conclusion: Grading NEN using two proliferative markers results in discordance between these indexes in one third of cases, more often in biopsy material than in resection specimens. If results are discordant, survival is for the most part associated with the grade of the highest index, for the most part Ki-67. Thus grading with two proliferative indexes is useful as it highlights cases where one of these indexes may be incongruent. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 10/2014;
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    ABSTRACT: Intestinal gluconeogenesis is a recently described function in intestinal glucose metabolism. In particular, the intestine contributes around 20-25% of total endogenous glucose production during fasting. Intestinal gluconeogenesis appears to regulate energy homeostasis via a neurally-mediated mechanism linking the entero-hepatic portal system with the brain. The periportal neural system is able to sense glucose produced by intestinal gluconeogenesis in the portal vein walls, which sends a signal to the brain to modulate energy and glucose homeostasis. Dietary proteins mobilize intestinal gluconeogenesis as a mandatory link between the sensing of these proteins in the portal vein and their well-known effect of satiety. Comparably, dietary soluble fibers exert their anti-obesity and anti-diabetic effects via the induction of intestinal gluconeogenesis. Finally, intestinal gluconeogenesis might be involved in the rapid metabolic improvements in energy homeostasis induced by gastric bypass surgeries of obesity. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 10/2014;
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    ABSTRACT: Background: Mixed AdenoNeuroEndocrine Carcinomas (MANECs) of the gastrointestinal tract are rare neoplasms characterized by coexisting exocrine and neuroendocrine neoplastic components. MANECs' histogenetic classification and molecular characterization remain unclear, significantly affecting the identification of innovative therapeutic options for these tumors. Methods: In this study, the exocrine and neuroendocrine components of 6 gastrointestinal MANECs were microdissected and subjected to the simultaneous mutation assessment in selected regions of 54 cancer-associated genes, using Ion Torrent semiconductor-based next-generation sequencing (NGS). Sanger sequencing and immunohistochemistry were used as validation of the mutational status. Results: A total of 20 driver gene somatic mutations were observed among the 12 neoplastic components investigated. In 11 of 12 (91.7%) samples at least one mutation was detected; 7 samples (58.3%) were found to have multiple mutations. TP53 gene mutations were the most frequent genetic alterations observed in the series, occurring in 11/12 samples (91.7%). Somatic mutations in other genes were detected at lower frequencies: ATM, CTNNB1, ERBB4, JAK3, KDR, KRAS, RB1. Conclusions: Five of the six MANECs presented an overlapping mutational profile in both components, suggesting a monoclonal origin of the two MANEC components. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 10/2014;
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    ABSTRACT: Delta-like 1 homologue (DLK1; also called preadipocyte factor 1; Pref1) is an epidermal growth factor (EGF) repeat-containing transmembrane protein that is cleaved by tumour necrosis factor-α-converting enzyme to generate a biologically active soluble form. DLK1 is involved in the differentiation of several cell types, including adipocytes. Lack of the dlk1 gene results in adiposity and polymorphism within the gene encoding DLK1 is associated with human obesity. The dlk1 gene is expressed in restricted areas of the adult brain, with an enrichment of cell bodies expressing DLK1 mRNA in the hypothalamus. Antibodies to DLK1 were used to study the cellular localization and chemical identity of DLK1-immunoreactive neuronal cell bodies in rat hypothalamus. DLK1 immunoreactivity was demonstrated in the cell soma and dendrites of cell bodies in the suprachiasmatic, supraoptic, paraventricular, dorsomedial, arcuate nuclei and in the perifornical/lateral hypothalamic area. In the arcuate nucleus (Arc), DLK1 immunoreactivity was mainly seen in many neurons of the ventromedial and to lesser extent in its ventrolateral division. Double-labeling showed that 93.7% of orexigenic agouti-related peptide (AgRP) and 94.1% of neuropeptide Y (NPY) neurons located in the ventromedial part of the Arc were DLK1-positive, whereas 36.1% of anorexigenic pro-opiomelanocortin (POMC) and 34.6% of cocaine- and amphetamine-regulated transcript (CART) neurons of the Arc contained DLK1 immunoreactivity. DLK1 mRNA was down-regulated in the hypothalamus of fasted animals. Presence of DLK1 in the majority of orexigenic Arc NPY/AgRP neurons and regulation of DLK1 mRNA by nutritional challenge, suggests that DLK1 has a role in hypothalamic regulation of body weight control. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 10/2014;
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    ABSTRACT: Kisspeptin-Gpr54 signaling is critical for regulating the activity of gonadotropin releasing-hormone (GnRH) neurons in mammals. Previous studies have shown that the negative feedback mechanism is disrupted in global Gpr54-null mutants. The present investigation aimed to determine (1) if a lack of cyclical estrogen exposure of the GnRH neuronal network in the life-long hypogonadotropic Gpr54-null mice contributed to their failed negative feedback mechanism, and (2) the cellular location of disrupted kisspeptin-Gpr54 signaling. Plasma luteinizing hormone (LH) concentrations were determined in individual adult female mice when intact, following ovariectomy (OVX), and in response to an acute injection of 17β-estradiol (E2). Control mice exhibited a characteristic rise in LH after OVX that was suppressed by acute E2. Global Gpr54-null mice failed to exhibit any post-OVX increase in LH or response to E2. Adult female global Gpr54-null mice given a cyclical regimen of estradiol for three cycles prior to OVX also failed to exhibit any post-OVX increase in LH or response to E2. To address whether Gpr54 signaling at the GnRH neuron itself was necessary for the failed response to OVX in global Gpr54 null animals, adult female mice with a GnRH neuron-selective deletion of Gpr54 were examined. These mice also failed to exhibit any post-OVX increase in LH or response to E2. These experiments demonstrate defective negative feedback in global Gpr54-null mice that cannot be attributed to a lack of prior exposure of the GnRH neuronal network to cyclical estradiol. The absence of negative feedback in GnRH neuron-selective Gpr54-null mice demonstrates the necessity of direct kisspeptin signaling at the GnRH neuron for this mechanism to occur. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 10/2014;
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    ABSTRACT: Purpose: To evaluate the effect of combined (68)Ga and (18)F-FDG PET/CT on treatment management for patients with pancreatic NET (PNET). Methods: Between January 2012 and April 2014, 49 consecutive patients with cytological and/or histological proven diagnosis of PNET underwent combined (68)Ga and (18)FDG PET/CT on the same day. Results: There were 21 males and 28 females with a median age of 59 years. (68)Ga imaging achieved disease detection in 48 out of 49 cases and (18)FDG PET/CT in 36 of 49 cases. These results corresponded to sensitivities of 98% for (68)Ga versus 73% for (18)FDG PET/CT. Patients with NET-G1/NET-G2 had positive (68)Ga and negative (18)FDG in 13 cases whereas both (68)Ga and (18)FDG PET/CT were positive in 27. Patients with NEC-G3 were both (68)Ga and (18)FDG PET/CT positive in 7 cases and only (18)FDG positive in one case. Another NEC G3 patient was only (68)Ga PET/CT positive. The median Ki67 was 7% for (68)Ga PET/CT positive tumors and 10% for tumors with both (68)Ga and (18)FDG PET/CT positive (p = 0.130). Half of patients with a prevalent uptake of 18FDG (n = 7) had a NEC G3 compared with the 12% of patients with a prevalent uptake of 68Ga (p = 0.012). There were no significant differences between patients with positive (68)Ga and those with positive (18)FDG as regards of treatment choice. Conclusions: The association of (18)FDG slightly increases sensitivity of (68)Ga PET/CT alone in the diagnosis of PNET. A combined dual tracer PET/CT does not influence the choice of treatment strategy. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 10/2014;
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    ABSTRACT: Introduction: Recent data indicate that there is a link between depression and diabetes and that excess glucocorticoids may play an underlying role in the pathogenesis of both of these diseases. The aim of the present study was to determine whether there are any alterations in glucose, glycogen, glucose transporters, insulin, insulin receptors or corticosterone concentrations in the hippocampus and frontal cortex in a prenatal stress rat model of depression. Methods: Male rats whose mothers had been subjected to stress and control animals were subjected to the Porsolt test to verify the experimental model. Next, some of the rats were subjected to acute stress and/or were administered glucose. Glucose, glycogen, corticosterone, insulin, insulin receptors (IR), phospho-IR and glucose transporters (GLUT1, GLUT3 and GLUT4) concentrations were assayed. Results: Prenatally stressed rats exhibited glucose and glycogen concentrations in both investigated brain structures that exceeded those of the control animals. Prenatal stress also increased the levels of glucose transporters - GLUT1 in both tissues and GLUT4 in the frontal cortex. The changes in the prenatally stressed rats were more prominent in the animals that were subjected to stress or glucose loading in adulthood. Conclusion: In conclusion, the increase in carbohydrate brain concentrations evoked by prenatal stress may result from changes in the amounts of glucose transporters, especially GLUT1. Moreover, the obtained results support the hypothesis that stress during the perinatal period permanently increases the sensitivity of brain tissue to factors that act in adulthood. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 10/2014;
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    ABSTRACT: Background: This study was designed to evaluate the role of heat-shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90-inhibitor, have not been examined. Material and Methods: The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signalling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemsistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets, isolated from treated and untreated RIP1Tag2 mice. Results: HSP90 blockade impaired constitutive and growth factor-induced signalling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose-dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000) and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant down-regulation in the islet cell tumors of Rip1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site, in vivo. Conclusion: This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 10/2014;
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    ABSTRACT: Exposure to stressors such as footshock leads to increased expression of multiple inflammatory factors, including the pro-inflammatory cytokine interleukin-1 (IL-1) in the brain. Studies have indicated that there are sex differences in stress reactivity, suggesting that the fluctuation of gonadal steroid levels across the estrous cycle may play a regulatory role in the stress-induced cytokine expression. The present studies were designed to investigate the role of estrogen (E2) and progesterone (Pg) in regulating the cytokine response within the paraventricular nucleus of the hypothalamus (PVN) through analysis of gene expression with real-time RT-PCR. Intact, cycling female rats showed a stress-induced increase in PVN IL-1 during the diestrus, proestrus, and estrus stages. During the metestrus stage, no change in IL-1 levels was seen following footshock; however ER-β levels did increase. Ovariectomy resulted in an increase in PVN IL-1, which was attenuated by treatment with estradiol benzoate (10 or 50 µg), indicating an E2- mediated anti-inflammatory effect. Ovarectomized rats treated with Pg (500 or 1,250 µg) showed no alteration in IL-1 levels, however Pg did up-regulate ER-β gene expression. The results from the current study implicate a potential mechanism through which high availability of endogenous Pg during the metestrus stage increases ER-β sensitivity, which in turn attenuates the PVN IL-1 response to stress. Thus, the interaction between gonadal steroid hormones and their central receptors throughout the estrous cycle may exert a powerful inhibitory influence on neuroimmune consequences of stress. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 10/2014;
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    ABSTRACT: Neuronal populations that synthesize kisspeptin (KP), neurokinin B (NKB) and substance P (SP) in the hypothalamic infundibular nucleus of humans are partly overlapping. These cells are important upstream regulators of gonadotropin-releasing hormone (GnRH) neurosecretion. Homologous neurons in laboratory animals are thought to modulate episodic GnRH secretion primarily via influencing KP receptors on the hypophysiotropic fiber projections of GnRH neurons. To explore the structural basis of this putative axo-axonal communication in humans, we analyzed the anatomical relationship of KP-immunoreactive (IR), NKB-IR and SP-IR axon plexuses with hypophysiotropic GnRH fiber projections. Immunohistochemical studies were carried out on histological samples from postmenopausal women. The neuropeptide-IR axons innervated densely the portal capillary network in the postinfundibular eminence. Subsets of the fibers formed descending tracts in the infundibular stalk, some reaching the neurohypophysis. KP-IR, NKB-IR and SP-IR plexuses intermingled, and established occasional contacts, with hypophysiotropic GnRH fibers in the postinfundibular eminence and through their lengthy course while descending within the infundibular stalk. Triple-immunofluorescent studies also revealed considerable overlap between the KP, NKB and SP signals in individual fibers, providing evidence that these peptidergic projections arise from neurons of the mediobasal hypothalamus. These neuroanatomical observations indicate that the hypophysiotropic projections of human GnRH neurons in the postinfundibular eminence and the descending GnRH tract coursing through the infundibular stalk to the neurohypophysis are exposed to neurotransmitters/neuropeptides released by dense KP-IR, NKB-IR and SP-IR fiber plexuses. Localization and characterization of axonal neuropeptide receptors will be required to clarify the putative autocrine and paracrine interactions in these anatomical regions. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 09/2014;
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    ABSTRACT: Introduction: The 'diurnal slope' of salivary cortisol has been used as a measure of stress and circadian function in a variety of reports with several detailing its association with cancer progression. The relationship of this slope, typically a negative value from high morning concentrations to low evening concentrations, to the underlying daily variation in total plasma cortisol throughout the 24-hour cycle, however, has never been reported. Methods: To examine the relationship between diurnal salivary cortisol slope and the underlying pattern of plasma cortisol in individuals with cancer, we examined a cohort of women with advanced breast cancer (n = 97) who had saliva and plasma collected during a modified 24-hour, constant posture protocol. Results: We found that steepness of the diurnal slope of salivary cortisol was correlated with the amplitude of plasma cortisol rhythm when the slope was calculated from samples taken at wake+30 min and 9PM (r = -0.29, p > 0.05). Other variants of salivary slope calculations were not significantly correlated with the amplitude of the plasma cortisol rhythm. Diurnal salivary cortisol slope steepness was not correlated with the time between habitual waking and the computed circadian peak of cortisol, but there was a correlation between diurnal slope steepness and the time between habitual waking and the time of the awakening spike of morning cortisol (r's<-0.23, p's<0.05). Conclusion: It therefore appears that in women with advanced breast cancer, diurnal salivary cortisol slope primarily represents aspects of the cortisol awakening response in relation to evening levels more than the circadian rhythm of total plasma cortisol. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 09/2014;
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    ABSTRACT: Background: Whether patients with small (<2 cm), sporadic non-functioning pancreatic endocrine tumors (NF-PETs) should directly undergo pancreatic surgery or should be followed longitudinally to detect growth and malignancy still has to be defined. Study Design: Based on the pertinent literature of the past decade, a Markov model was developed to investigate this issue. In the wait-and-see strategy arm, surgery was performed if the tumor attained a size ≥2 cm or surpassed 20% of the initial size. In a Monte Carlo probabilistic analysis, 100 hypothetical patients undergoing a wait-and-see strategy were compared to 100 patients directly undergoing surgery, with the aim of investigating the efficacy and cost-effectiveness of the two strategies. Results: During the post-diagnostic lifetime, 63 NF-PETs in the wait-and-see group showed significant growth and underwent surgery: 38 were Stage I, 10 were Stage II, 15 were stage III and none were Stage IV. In the base-case scenario, the mean life expectancy and quality-adjusted life expectancy were found to be superior after immediate surgery (26.1 years and 11.8 quality-adjusted life-years [QALYs]) than with the wait-and-see strategy (22.1 years and 8.3 QALYs) as the consequence of ageing during the wait-and-see follow-up which increased mortality due to surgery, when surgery was needed. The model was sensitive to starting age and length of follow-up; in particular, for patients >65 years of age, the two strategies provided similar results but the wait-and-see strategy was more cost-effective. Conclusions: The wait-and-see strategy for NF-PETs <2 cm represents a reasonable approach only in patients over 65 years of age; otherwise, immediate surgery is preferable. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 09/2014;
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    ABSTRACT: Background/Aims: Stress exacerbates neuron loss in many CNS injuries via the actions of adrenal glucocorticoid (GC) hormones. For some injuries, this GC-endangerment of neurons is accompanied by greater immune cell activation in the CNS, a surprising outcome given the potent immunosuppressive properties of GCs. Methods: To determine whether the effects of GCs on inflammation contribute to neuron death or result from it, we tested whether non-steroidal anti-inflammatory drugs could protect neurons from GCs during kainic acid excitotoxicity in adrenalectomized male rats. We next measured GC effects on (i) chemokine production (CCL2, CINC-1), (ii) signals that suppress immune activation (CX3CL1, CD22, CD200, and TGF-b), and (iii) NF-kB activity. Results: Concurrent treatment with minocycline but not indomethacin prevented GC-endangerment. GCs did not substantially affect CCL2, CINC-1, or baseline NF-kB activity, but they did suppress CX3CL1, CX3CR1, and CD22 expression in the hippocampus, factors that normally restrain inflammatory responses. Conclusions: These findings demonstrate that cellular inflammation is not necessarily suppressed by GCs in the injured hippocampus; instead, GCs may worsen hippocampal neuron death, at least in part, by increasing the neurotoxicity of CNS inflammation. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 09/2014;
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    ABSTRACT: Background: The latest WHO classification for neuroendocrine neoplasms (NEN) of the gastrointestinal tract defines grade according to Ki-67 and mitotic indices. Some have questioned the reproducibility and thus the reliability of Ki-67 assessment. We therefore investigated the accuracy of this proliferation marker in NEN. Methods: The Ki-67 index of tumor specimens of NEN (n = 73) was assessed by two pathologists as in routine practice with eyeballing and twice by image analysis using ImageJ freeware at different magnifications. Results were correlated with overall survival. Results: The intraclass correlation coefficient (ICC) between pathologists was 0.88. The ICC for the measurements using image analysis was 0.85. The ICC between all four measurements (pathologists and ImageJ) was 0.80. If the Ki-67 index was translated to grade as prescribed by the current WHO classification (<3% = grade 1, 3-20% = grade 2, >20% = grade 3), kappa was between 0.61 and 0.75. Grades based on pathologist scoring were often (16-29%) higher than grades assigned by image analysis (p < 0.001). Grade was significantly correlated with survival (p < 0.0001) irrespective of the way Ki-67 was assessed. Conclusion: Assessment of the Ki-67 index by eyeballing correlates remarkably well with the Ki-67 index as calculated by image analysis and is therefore an accurate parameter. Moreover, it is significantly related to survival irrespective of the method used. Yet if the Ki-67 index is translated to grade, the grade should be interpreted with caution due to values around threshold levels. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 08/2014;
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    ABSTRACT: A pivotal event in the onset of puberty in humans is the re-emergence of pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamic neurons. Pathways governing GnRH ontogeny and physiology have been discovered by studying animal models and humans with reproductive disorders. Recent human studies implicated the activation of the kisspeptin and its cognate receptor (KISS1- KISS1R), and the inactivation of the MKRN3 in the premature reactivation of the GnRH secretion, causing central precocious puberty (CPP). MKRN3, an imprinted gene located in the long arm of chromosome 15, encodes makorin ring finger protein 3 that is involved with ubiquitination and cell signaling. MKRN3 protein is derived only from RNA transcribed from the paternally inherited copy of the gene due to maternal imprinting. Currently, MKRN3 defects represent the most frequent known genetic cause of familial CPP. In this review, we explore the clinical, hormonal and genetic aspects of children with sporadic or familial CPP caused by mutations in the kisspeptin and MKRN3 systems, essential genetic factors for pubertal timing. © 2014 S. Karger AG, Basel.
    Neuroendocrinology 08/2014;