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Journal: Neuroendocrinology

167

Aim: To determine the effect of a 12-month intent-to-treat tesosterone replacement therapy (TRT) trial on QTa interval variability (QTaVI) in hypogonadal (HG) men with spinal cord injury (SCI). Method: A prospective, controlled, 12-month TRT trial was completed in twenty-two healthy, chronic, non-ambulatory men with SCI. Based on serum T concentration, subjects were designated as HG (≤11.3 nmol/l) or eugonadal (EG, ≥11.4 nmol/l). Digital 3-lead electrocardiograms were performed. Heart rate (RR), heart rate variability [(HRV), including total power (TP(RR)), low frequency (LF(RR)) and high freguency (HF(RR))], QTa, QTe, and RT intervals, QTC (Bazett), QTVN, and QTaVI were calculated and evaluated at baseline and 12 months. Lipoprotein profiles (triglycerides, total cholesterol, low density and high-density lipoproteins) were obtained at the respective time points. Results: Based on serum T concentration, 13 subjects were designated as HG and 11 EG. During the trial, there were no group differences for RR, QTa, QTe or RT intervals, QTC, TP(RR), HF(RR), or lipoproteins. The HG was older (p < 0.05) and LF(RR) was lower (p < 0.05) at baseline. At baseline, QTaVI was significantly greater in HG compared to EG [-0.17 (0.92) vs. -1.07 (0.90); p < 0.05]. After TRT, this group difference was no longer present [-0.44 (0.87) vs. -0.65 (0.85)] and the change in HG was significant (p < 0.05). Conclusion: Hypogonadism in men with SCI was associated with elevated QTaVI at baseline. After 12 months of physiological TRT, the QTaVI improved in association with raising T into the normal range. These findings occurred independently from the prolongation of the QT interval.

Concepts: Cholesterol, Cardiology, Lipoprotein, Lipoproteins, Cardiac electrophysiology, Testosterone, QT interval, Hypogonadism

26

In monogamous mammals, fathers play an important role in the development of the brain and typical behavior in offspring, but the exact nature of this process is not well understood. In particular, little research has addressed whether the presence or absence of paternal care alters levels of hippocampal glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF), and basal levels of serum corticosterone (CORT) and adrenocorticotropin (ACTH). Here, we explore this concept using socially monogamous mandarin voles (Microtus mandarinus), a species in which fathers display high levels of paternal care toward their pups. Our immunohistochemical study shows that paternal deprivation (PD) significantly decreased levels of GR and BDNF protein in the CA1 and CA2/3 of the hippocampus. In the dental gyrus, decreases in GR and BDNF induced by PD were evident in females but not in males. Additionally, Elisa results show that PD significantly up-regulated levels of serum CORT and ACTH in females, but not males. These findings demonstrate that paternal deprivation alters HPA axis activity in a sex-specific way. The changes in stress hormones documented here may be associated with alteration in hippocampal BDNF and GR levels. © 2014 S. Karger AG, Basel.

Concepts: Brain, Cerebrum, Cortisol, Neurotrophin, Brain-derived neurotrophic factor, Nerve growth factor, Adrenal cortex, Glucocorticoid receptor

24

Computed-tomography (CT) scan is the current standard cross-sectional imaging modality for neuroendocrine tumor (NET) work-up. Diffusion-weighted magnetic resonance imaging (DW-MRI) has proven to be more sensitive than standard sequences to diagnose liver metastases; whole-body DW-MRI may be more sensitive than whole-body MRI. Clinical implications have not yet been assessed. Thus, we evaluated radiological and clinical contributions of liver and whole-body DW-MRI to manage NETs.

Concepts: Cancer, Oncology, Spin, Brain tumor, Nuclear magnetic resonance, Magnetic resonance imaging, Radiology, Neuroendocrine tumor

8

The increased prevalence and high comorbidity of metabolic syndrome and mental health disorders have prompted investigation into the potential contributing mechanisms. There is a bidirectional association between metabolic syndrome and mental health disorders including schizophrenia, bipolar disorder, depression, anxiety, attention deficit/hyperactivity disorder, and autism spectrum disorders. Medication side effects and social repercussions are contributing environmental factors, but there are a number of shared underlying neurological and physiological mechanisms that explain the high comorbidity between these two disorders. Inflammation is a state shared by both disorders, and it contributes to disruptions of neuroregulatory systems, including the serotonergic, dopaminergic, and neuropeptide Y systems, as well as dysregulation of the hypothalamic-pituitary-adrenal axis. Metabolic syndrome in pregnant women also exposes the developing fetal brain to inflammatory factors that predispose the offspring to metabolic syndrome and mental health disorders. Due to the shared nature of these conditions, treatment should address aspects of both mental health and metabolic disorders. Additionally, interventions need to be developed that can interrupt the transfer of increased risk of the disorders to the next generation. © 2013 S. Karger AG, Basel.

Concepts: Pregnancy, Autism, Mental disorder, Asperger syndrome, Borderline personality disorder, Bipolar disorder, Major depressive disorder, Mental illness diagnosis by DSM and ICD

2

Neurons of the cerebellar cortex contain a circadian oscillator with circadian expression of clock genes being controlled by the master clock of the suprachiasmatic nucleus (SCN). However, the signaling pathway connecting the SCN to the cerebellum is unknown. Glucocorticoids exhibit a prominent SCN-dependent circadian rhythm and high levels of the glucocorticoid receptor have been reported in the cerebellar cortex; we therefore hypothesized that glucocorticoids may control rhythmic expression of clock genes in the cerebellar cortex. We here applied a novel methodology by combining electrolytic lesion of the SCN with implantation of a micropump programmed to release corticosterone in a circadian manner mimicking the endogenous hormone profile. By use of this approach, we were able to restore the corticosterone rhythm in SCN lesioned male rats. Clock gene expression in the cerebellum was abolished in rats with a lesioned SCN, but exogenous corticosterone restored the daily rhythm in clock gene expression in the cerebellar cortex, as revealed by quantitative real-time PCR and radiochemical in situ hybridization for detection of the core clock genes Per1, Per2 and Arntl. On the other hand, exogenous hormone did not restore circadian rhythms in body temperature and running activity. RNAscope in situ hybridization further revealed that the glucocorticoid receptor colocalizes with clock gene products in cells of the cerebellar cortex, suggesting that corticosterone exerts its actions by binding directly to receptors in neurons of the cerebellum. However, rhythmic clock gene expression in the cerebellum was also detectable in adrenalectomized rats, indicating that additional control mechanisms exist. These data show that the cerebellar circadian oscillator is influenced by SCN-dependent rhythmic release of corticosterone.

2

Background: We evaluated the activity and safety profile of (177)Lu-DOTATATE peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced G1-G2 pancreatic neuroendocrine tumors (P-NETs). Patients and Methods: Fifty-two consecutive patients were treated at two different therapeutic dosages of 18.5 GBq or 27.8 GBq in five cycles, according to the patient’s kidney function and bone marrow reserve, which are known to be the critical organs in PRRT. Results: Twenty-six patients received a mean full dosage (FD) of 25.5 GBq (range 20.7-27.8) and 26 a mean reduced dosage (RD) of 17.8 GBq (range 11.1-19.9). Both therapeutic dosages resulted in antitumor activity (Disease Control Rate in the entire case series 81%), with 12% complete response (CR), 27% partial response (PR) and 46% stable disease (SD) in the FD group, whereas we observed 4% CR, 15% PR and 58% SD in the RD group. Median progression-free survival (PFS) was not reached in the FD group and was 20 months in the RD group. No major acute or delayed hematological toxicity occurred. Conclusion: Lu-PRRT showed antitumor activity in advanced P-NETs even at a reduced total activity of 18.5 GBq. However, PFS was significantly longer (p = 0.05) after a total activity of 27.8 GBq, which can thus be considered the recommended dosage in eligible patients.

Concepts: Immune system, Cancer, Oncology, Bone marrow, Chemotherapy, Neuroendocrine tumor, Somatostatin, Radionuclide

1

To date, research findings are inconsistent about whether neuroanatomy in transgender persons resembles that of their natal sex or their gender identity. Moreover, few studies have examined the effects of long-term, cross-sex hormonal treatment on neuroanatomy in this cohort. The purpose of the present study was to examine neuroanatomical differences in transgender persons after prolonged cross-sex hormone therapy.

Concepts: Gender, Gender identity, Sexual orientation, Transgender, Homosexuality

1

The recent description of infertility in humans with loss-of-function mutations in genes for neurokinin B (NKB) or its receptor (NK3R) has focused attention on the importance of this tachykinin in the control of GnRH secretion. In a number of species, NKB neurons in the arcuate nucleus also produce two other neuropeptides implicated in the control of GnRH secretion: (1) kisspeptin, which is also essential for fertility in humans, and (2) dynorphin, an inhibitory endogenous opioid peptide. A number of characteristics of this neuronal population led to the hypothesis that they may be responsible for driving synchronous release of GnRH during episodic secretion of this hormone and there is now considerable evidence to support this hypothesis in sheep and goats. In this article, we briefly review the history of work on the NKB system in sheep and then review the anatomy of NKB signaling in the sheep. We next describe evidence from a number of species that led to development of a model for the role of these neurons in episodic GnRH secretion. Finally, we discuss recent experiments in sheep and goats that tested this hypothesis and led to a modified version of the model, and then broaden our focus to briefly consider the possible roles of NKB in other species and systems. © 2013 S. Karger AG, Basel.

Concepts: Nervous system, DNA, Protein, Hypothalamus, Mutation, Chromosome, Neurotransmitter, Opioid peptide

0

Aversion to environmental cues of predators is an integral part of defensive behaviors in many prey animals. It enhances their survival and probability of future reproduction. At the same time, animals cannot be maximally defended because imperatives of defense usually tradeoff with behaviors required for sexual reproduction like display of dominance and production of sexual pheromones. Here we approach this tradeoff through the lens of arginine vasopressin neurons within the posterodorsal medial amygdala of mice. This neuronal population is known to be involved in sexual behaviors like approach to sexually salient cues. We show that chemogenetic partial ablation of this neuronal population increases aversion to predator odors. Moreover, overexpression of arginine vasopressin within this population is sufficient to reduce aversion to predator odors. The loss of fear of the predator odor occurs in parallel with increased recruitment of arginine vasopressin neurons within the posterodorsal medial amygdala. These observations suggest that arginine vasopressin neurons in the medial aspect of the extended amygdala are a proximate locus for the reduction in innate fear during life stages dominated by reproductive efforts.

0

In peripheral tissues, the lipid droplet (LD) organelle links lipid metabolism, inflammation and insulin resistance. Little is known about the brain LDs.