Functional characterization of growth hormone releasing hormone and its receptor in amphioxus with implication for origin of hypothalamic-pituitary axis.

Growth hormone-releasing hormone (GHRH) has been widely shown to stimulate growth hormone (GH) production via binding to GHRH receptor GHRHR in various species of vertebrates, but information regarding the functional roles of GHRH and GHRHR in the protochordate amphioxus remains rather scarce. We showed here that two mature peptides, BjGHRH-1 and BjGHRH-2, encoded by BjGHRH precursor, and a single BjGHRHR protein were identified in the amphioxus Branchiostoma. japonicum. Like the distribution profiles of vertebrate GHRHs and GHRHRs, both the genes Bjghrh and Bjghrhr were widely expressed in the different tissues of amphioxus, including in the cerebral vesicle, Hatschek's pit, neural tube, gill, hepatic caecum, notochord, testis and ovary. Moreover, both BjGHRH-1 and BjGHRH-2 interacted with BjGHRHR, and triggered the cAMP/PKA signal pathway in a dose-dependent manner. Importantly, BjGHRH-1 and BjGHRH-2 were both able to activate the expression of GH-like gene in the cells of Hatschek's pit. These indicate that a functional vertebrate-like GHRH-GHRHR axis had already emerged in amphioxus, which is a seminal innovation making physiological divergence including reproduction, growth, metabolism, stress and osmoregulation possible during the early evolution of vertebrates.

The role of nitric oxide and neuroendocrine system in pain generation.

Previous studies have indicated a complex interplay between the nitric oxide (NO) pain signaling pathways and hormonal signaling pathways in the body. This article delineates the role of nitric oxide signaling in neuropathic and inflammatory pain generation and subsequently discusses how the neuroendocrine system is involved in pain generation. Hormonal systems including the hypothalamic-pituitary axis (HPA) generation of cortisol, the renin-angiotensin-aldosterone system, calcitonin, melatonin, and sex hormones could potentially contribute to the generation of nitric oxide involved in the sensation of pain. Further research is necessary to clarify this relationship and may reveal therapeutic targets involving NO signaling that alleviate neuropathic and inflammatory pain.

Gonadotropin-Releasing Hormone (GnRH) and Its Agonists in Bovine Reproduction I: Structure, Biosynthesis, Physiological Effects, and Its Role in Estrous Synchronization.

GnRH is essential for the regulation of mammalian reproductive processes. It regulates the production and release of pituitary gonadotropins, thereby influencing steroidogenesis and gametogenesis. While primarily produced in the hypothalamus, GnRH is also produced in peripheral organs, such as the gonads and placenta. GnRH analogs, including agonists and antagonists, have been synthesized for the reproductive management of animals and humans. This review focuses on the functions of hypothalamic GnRH in the reproductive processes of cattle. In addition to inducing the surge release of LH, the pulsatile secretion of GnRH stimulates the pituitary gland to release FSH and LH, thereby regulating gonadal function. Various GnRH-based products have been synthesized to increase their potency and efficacy in regulating reproductive functions. This review article describes the chemical structures of GnRH and its agonists. This discussion extends to the gene expression of GnRH in the hypothalamus, highlighting its pivotal role in regulating the reproductive process. Furthermore, GnRH is involved in regulating ovarian follicular development and luteal phase support, and estrus synchronization is involved. A comprehensive understanding of the role of GnRH and its analogs in the modulation of reproductive processes is essential for optimizing animal reproduction.

Stress-Induced Oculogyric Crisis in Septo-Optic Dysplasia: Case Report.

Introduction: Oculogyric crisis (OGC) is a dystonic movement disorder of varying durations that manifests as bilateral paroxysmal upward eye deviation accompanied by involuntary blinking, tongue protrusion, and autonomic symptoms. Separately, septo-optic dysplasia (SOD) is a congenital disorder involving hypoplasia of the optic nerve as well as hypothalamic and pituitary abnormalities. In the presented case, we report a case of OGC in the setting of SOD with proposed pathogenesis. Case Presentation: A 27-year-old female presented with a history of SOD (optic nerve hypoplasia and hypopituitarism) with acute, recurrent, painless, bilateral, intermittent, simultaneous tonic conjugate upward eye deviation (i.e., OGC) and dystonic body posturing. She experienced her first episode upon meeting her biological sister for the first time at a loud, crowded public restaurant with continued episodes of OGC increasing in frequency and duration over the subsequent months. She later responded well to treatment with carbidopa/levodopa. Conclusion: Based on our current understanding of OGC, we hypothesize that acute stressful life events in the setting of prior hypothalamic-pituitary axis dysfunction secondary to SOD could lower the threshold for developing OGC. Although most cases of OGC are idiopathic, various etiologies including medications, stress, and hormonal imbalance have been postulated as possible pathogenic mechanisms. We describe a case of SOD with OGC, and based upon our review of the English language ophthalmic literature, we believe that our case is novel.

Alterations in hypothalamic-pituitary axis (HPA) hormones 6 months after cranial radiotherapy in adult patients with primary brain tumors outside the HPA region.

BACKGROUND: Cranial radiotherapy is a common treatment for brain tumors, but it can affect the hypothalamic-pituitary (H-P) axis and lead to hormonal disorders. This study aimed to compare serum levels of HPA hormones before and after cranial radiation. MATERIALS AND METHODS: This study involved 27 adult patients who underwent brain tumor resection before the initiation of radiotherapy, and none had metastatic brain tumors. All participants had the HPA within the radiation field, and their tumors were located in brain areas outside from the HPA. Serum levels of HPA hormones were recorded both before and 6 months after cranial radiotherapy. RESULTS: A total of 27 adult patients, comprising 16 (59.3%) males and 11 (40.7%) females, with a mean age of 56.37 ± 11.38 years, were subjected to evaluation. Six months post-radiotherapy, serum levels of GH and TSH exhibited a significant decrease. Prior to radiotherapy, a substantial and direct correlation was observed between TSH and FSH (p = 0.005) as well as LH (p = 0.014). Additionally, a significant and direct relationship was noted between serum FSH and LH (p < 0.001) before radiotherapy. After radiotherapy, a significant and direct correlation persisted between TSH and FSH (p = 0.003) as well as LH (p = 0.005), along with a significant and direct relationship between serum FSH and LH (p < 0.001). Furthermore, a significant and direct association was identified between changes in serum GH levels and FSH (p = 0.04), as well as between serum LH and FSH (p < 0.001). CONCLUSION: Reduced serum levels of HPA hormones are a significant complication of cranial radiotherapy and should be evaluated in follow-up assessments.

Hypothalamic-pituitary dysfunction in Sturge-Weber syndrome: case report and review of the literature.

OBJECTIVES: Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder that is characterized by a segmental dermatomal facial port-wine stain birthmark and is frequently accompanied by ipsilateral brain and eye abnormalities. We present a case of a patient with SWS who exhibited hypogonadotropic hypogonadism, growth hormone (GH) deficiency, and central hypothyroidism at the age of 20 despite the absence of radiographic findings in the pituitary and hypothalamus. CASE PRESENTATION: A 20-year-old male with SWS with epilepsy and Klippel-Trenaunay syndrome presents with delayed pubertal development, short stature, and obesity. Upon further examination, he was found to have biochemical and clinical evidence of hypogonadism, hypothyroidism, and GH deficiency. A pituitary MRI displayed no abnormalities of the pituitary or hypothalamus. Treatment with testosterone cypionate and levothyroxine was initiated. Despite successful pubertal induction, IGF-1 levels have remained low and treatment with recombinant human growth hormone (rhGH) is now being considered for metabolic benefits. CONCLUSIONS: This case emphasizes the importance of endocrine evaluation and treatment of hormonal deficiencies in patients with SWS despite the absence of radiographic findings.

Postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement in patients with childhood-onset craniopharyngioma.

Objective: Hypothalamic-pituitary axis dysfunction is a common complication in post-operative craniopharyngioma(CP) patients, and it greatly impacts the long-term quality of life of such patients. To better understand the effects of postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement therapy in patients with childhood CP, we assessed approximately 200 patients with childhood-onset CP postoperatively. Methods: Clinical details of patients with childhood-onset CP who underwent sellar tumor resection in Beijing Children's Hospital and Beijing Tiantan Hospital from 2018 to 2019 were retrieved retrospectively. The participants were followed up to assess the effects of post-operative long-term hormone replacement therapy and assess the tumor recurrence rate. Results: The median age of admission was 8.1 (1.8, 14.3) years. Headache (45.5%), visual impairment (39.5%), and nausea (33.0%) were the most common clinical manifestations. ACP accounted for 95% of all CP cases. The incidence of central adrenal insufficiency and central hypothyroidism within the first week after surgery was 56.2% and 70.3%, respectively. At the same time 85.5% of the patients required at least one dose of desmopressin to control urine output. Total survival and tumor recurrence rates were 98.6% and 26.1%, respectively, with a median follow-up time of 29.7 (19.0, 40.3) months. During the follow-up period, 28.1% patients met the diagnostic criteria for short stature, while 54.4% fit the criteria for obesity. In addition, 94.4% of the patients were taking at least one kind of hormone substitution, and 74.7% were taking three or more. The prevalence of levothyroxine, glucocorticoid, desmopressin, and growth hormone replacement therapy was 87.3%, 77.5%, 78.9% and 31.0%, respectively. The proportion of patients treated with the substitutive combination of levothyroxine, hydrocortisone, and desmopressin was 54.9%. Conclusion: This study is a large-sample systematic postoperative endocrine function evaluation of patients with childhood-onset CP. Due to the high prevalence of post-operative hypothalamic-pituitary dysfunction, patients with CP usually require long-term multiple hormone substitution therapy. Individualized management and accurate hormone replacement dosage for postoperative childhood-onset CP patients are of great importance.

A Rare Case of Myxedema Coma Precipitated by a Single Dose of Haloperidol in a Patient With Paranoid Schizophrenia.

Myxedema coma is a rare and potentially life-threatening condition that occurs when severe hypothyroidism is untreated or inadequately managed. It is characterized by a rapid drop in mental status, hypothermia, respiratory failure, hypotension, and other symptoms of severe metabolic dysfunction. The condition primarily affects older women with a history of thyroid dysfunction but can occur in any age or gender group. A common trigger for this condition is seen with a drop in atmospheric temperatures or during the cold winter months. However, a rare, poorly documented trigger is recent antipsychotic use in severe hypothyroid states. The diagnosis of myxedema coma requires prompt recognition and treatment, as delays can result in significant morbidity and mortality which is the objective of this case report.

The hidden hedgehog of the pituitary: hedgehog signaling in development, adulthood and disease of the hypothalamic-pituitary axis.

Hedgehog signaling plays pivotal roles in embryonic development, adult homeostasis and tumorigenesis. However, its engagement in the pituitary gland has been long underestimated although Hedgehog signaling and pituitary embryogenic development are closely linked. Thus, deregulation of this signaling pathway during pituitary development results in malformation of the gland. Research of the last years further implicates a regulatory role of Hedgehog signaling in the function of the adult pituitary, because its activity is also interlinked with homeostasis, hormone production, and most likely also formation of neoplasms of the gland. The fact that this pathway can be efficiently targeted by validated therapeutic strategies makes it a promising candidate for treating pituitary diseases. We here summarize the current knowledge about the importance of Hedgehog signaling during pituitary development and review recent data that highlight the impact of Hedgehog signaling in the healthy and the diseased adult pituitary gland.

Melatonin modulates the hypothalamic-pituitary neuroendocrine axis to regulate physiological color change in teleost fish.

Melatonin (MT) is a crucial neuroendocrine regulator of various physiological activities in vertebrates, especially in circadian or seasonal rhythm control. In the present study, the large yellow croaker (Larimichthys crocea), a marine bony fish with circadian body color change behavior, is chosen for functional investigation on teleost MT signaling systems that remain uncharacterized. All five melatonin receptors (LcMtnr1a1, LcMtnr1a2, LcMtnr1b1, LcMtnr1b2, and LcMtnr1c) were significantly activated by MT, triggering extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation through different G protein coupling signaling pathways, with exclusive Gαi-dependency for LcMtnr1a2 and LcMtnr1c, and Gαq-dependency for two LcMtnr1b paralogs, whereas LcMtnr1a1 activated Gαi and Gαs dual-dependent signaling pathways. A comprehensive model of the MT signaling system in the hypothalamic-pituitary neuroendocrine axis was further constructed based on ligand-receptor interaction analysis using single-cell RNA-seq data, as well as spatial expression patterns of Mtnrs and related neuropeptides in central neuroendocrine tissues. A novel regulatory pathway of MT/melanin-concentrating hormone (MCH) and MT/(tachykinin precursor 1 (TAC1)+corticotropin-releasing hormone (CRH))/melanocyte-stimulating hormone (MSH) was discovered that functions in chromatophore mobilization and physiological color change and was further validated by pharmacological experiments. Together, our findings define multiple intracellular signaling pathways mediated by L. crocea melatonin receptors and provide the first in-depth evidence that uncover the upstream modulating roles of the MT signaling system in the hypothalamic-pituitary neuroendocrine axis of a marine teleost species, particularly in chromatophore mobilization and physiological color change.

Meta-analysis of serological biomarkers at hospital admission for the likelihood of developing delirium during hospitalization.

Importance: Identifying biomarkers that, at hospital admission, predict subsequent delirium will help to focus our clinical efforts on prevention and management. Objective: The study aimed to investigate biomarkers at hospital admission that may be associated with delirium during hospitalization. Data sources: A librarian at the Fraser Health Authority Health Sciences Library performed searches from 28 June 2021 to 9 July 2021, using the following sources: Medline, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, and the Database of Abstracts of Reviews and Effects. Study selection: The inclusion criteria were articles in English that investigated the link between serum concentration of biomarkers at hospital admission and delirium during hospitalization. Exclusion criteria were single case reports, case series, comments, editorials, letters to the editor, articles that were not relevant to the review objective, and articles concerning pediatrics. After excluding duplicates, 55 studies were included. Data extraction and synthesis: This meta-analysis followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocol. Independent extraction, with the consensus of multiple reviewers, was used to determine the final studies included. The weight and heterogeneity of the manuscripts were calculated using inverse covariance with a random-effects model. Main outcomes and measures: Differences in mean serum concentration of biomarkers at hospital admission between patients who did and did not develop delirium during hospitalization. Results: Our search found evidence that patients who developed delirium during hospitalization had, at hospital admission, significantly greater concentrations of certain inflammatory biomarkers and one blood-brain barrier leakage marker than patients who did not develop delirium during hospitalization (differences in the mean: cortisol: 3.36 ng/ml, p < 0.0001; CRP: 41.39 mg/L, p < 0.00001; IL-6: 24.05 pg/ml, p < 0.00001; S100ß 0.07 ng/ml, p < 0.00001). These differences were independent of other confounding variables such as the patient's severity of illness. A significantly lower serum concentration, at hospital admission, of acetylcholinesterase (difference in the means -0.86 U/ml, p = 0.004) was also associated with an increased vulnerability to developing delirium during hospitalization. Conclusion and relevance: Our meta-analysis supports the hypothesis that patients with hypothalamic-pituitary axis dysfunction, increased blood-brain barrier permeability, and chronic overload of the cholinergic system, at hospital admission, are more vulnerable to developing delirium during hospitalization.

Subacute high-refined carbohydrate diet leads to abnormal reproductive control of the hypothalamic-pituitary axis in female rats.

We previously reported that female rats placed on a diet containing refined carbohydrates (HCD) resulted in obesity and reproductive abnormalities, such as high serum LH concentration and abnormal ovarian function. However, the impacts at the hypothalamic-pituitary (HP) function, specifically regarding pathways linked to reproductive axis modulation are unknown. In this study, we assessed whether subacute feeding with HCD results in abnormal reproductive control in the HP axis. Female rats were fed with HCD for 15 days and reproductive HP axis morphophysiology was assessed. HCD reduced hypothalamic mRNA expression (Kiss1, Lepr, and Amhr2) and increased pituitary LHß+ cells. These changes likely contribute to the increase in serum LH concentration observed in HCD. Blunted estrogen negative feedback was observed in HCD, with increased kisspeptin protein expression in the arcuate nucleus of the hypothalamus (ARH), lower LHß+ cells and LH concentration in ovariectomized (OVX)+HCD rats. Thus, these data suggest that HCD feeding led to female abnormal reproductive control of HP axis.

The microbiome-gut-brain axis in epilepsy: pharmacotherapeutic target from bench evidence for potential bedside applications.

The gut-brain axis augments the bidirectional communication between the gut and brain and modulates gut homeostasis and the central nervous system through the hypothalamic-pituitary-adrenal axis, enteroendocrine system, neuroendocrine system, inflammatory and immune pathways. Preclinical and clinical reports showed that gut dysbiosis might play a major regulatory role in neurological diseases such as epilepsy, Parkinson's, multiple sclerosis, and Alzheimer's disease. Epilepsy is a chronic neurological disease that causes recurrent and unprovoked seizures, and numerous risk factors are implicated in developing epilepsy. Advanced consideration of the gut-microbiota-brain axis can reduce ambiguity about epilepsy pathology, antiepileptic drugs, and effective therapeutic targets. Gut microbiota sequencing analysis reported that the level of Proteobacteria, Verrucomicrobia, Fusobacteria, and Firmicutes was increased and the level of Actinobacteria and Bacteroidetes was decreased in epilepsy patients. Clinical and preclinical studies also indicated that probiotics, ketogenic diet, faecal microbiota transplantation, and antibiotics can improve gut dysbiosis and alleviate seizure by enhancing the abundance of healthy biota. This study aims to give an overview of the connection between gut microbiota, and epilepsy, how gut microbiome changes may cause epilepsy, and whether gut microbiome restoration could be used as a treatment for epilepsy.

The impact of prolonged, maternal iodine exposure in early gestation on neonatal thyroid function.

Context: Hysterosalpingography (HSG) using oil-soluble contrast medium (OSCM) improves pregnancy rates but results in severe and persistent iodine excess, potentially impacting the fetus and neonate. Objective: To determine the incidence of thyroid dysfunction in newborns conceived within six months of OSCM HSG. Design: Offspring study of a prospective cohort of women who underwent OSCM HSG. Setting: Auckland region, New Zealand (2020-2022). Participants: Offspring from the SELFI (Safety and Efficacy of Lipiodol in Fertility Investigations) study cohort (n=57). Measurements: All newborns had a dried blood spot card for TSH measurement 48 hours after birth as part of New Zealand's Newborn Metabolic Screening Programme. Forty-one neonates also had a heel prick serum sample at one week to measure thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Maternal urine iodine concentration (UIC) and TSH in the six months after OSCM HSG were retrieved from the SELFI study for analyses. Primary outcome: Incidence of hypothyroidism in the neonatal period. Results: There was no evidence of primary hypothyroidism on newborn screening (TSH 2-10 mIU/L). All neonates tested at one week had normal serum TSH, FT4, and FT3 levels. However, increasing maternal peak UIC levels during pregnancy were associated with lower TSH levels (p= 0.006), although also associated with lower FT4 levels (p=0.032). Conclusions: While pre-conceptional OSCM HSG in women did not result in neonatal hypothyroidism, gestational iodine excess was associated with a paradoxical lowering of neonatal TSH levels despite lower FT4 levels. These changes likely reflect alterations in deiodinase activity in the fetal hypothalamic-pituitary axis from iodine excess. Trial registration: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000738921, identifier 12620000738921.

How cancer hijacks the body's homeostasis through the neuroendocrine system.

During oncogenesis, cancer not only escapes the body's regulatory mechanisms, but also gains the ability to affect local and systemic homeostasis. Specifically, tumors produce cytokines, immune mediators, classical neurotransmitters, hypothalamic and pituitary hormones, biogenic amines, melatonin, and glucocorticoids, as demonstrated in human and animal models of cancer. The tumor, through the release of these neurohormonal and immune mediators, can control the main neuroendocrine centers such as the hypothalamus, pituitary, adrenals, and thyroid to modulate body homeostasis through central regulatory axes. We hypothesize that the tumor-derived catecholamines, serotonin, melatonin, neuropeptides, and other neurotransmitters can affect body and brain functions. Bidirectional communication between local autonomic and sensory nerves and the tumor, with putative effects on the brain, is also envisioned. Overall, we propose that cancers can take control of the central neuroendocrine and immune systems to reset the body homeostasis in a mode favoring its expansion at the expense of the host.

The link between post-traumatic stress disorder and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous, multisystem autoimmune disorder characterized by unpredictable disease flares. Although the pathogenesis of SLE is complex, an epidemiologic link between posttraumatic stress disorder (PTSD) and the development of SLE has been identified, suggesting that stress-related disorders alter the susceptibility to SLE. Despite the strong epidemiologic evidence connecting PTSD and SLE, gaps remain in our understanding of how the two may be connected. Perturbations in the autonomic nervous system, neuroendocrine system, and at the genomic level may cause and sustain immune dysregulation that could lower the threshold for the development and propagation of SLE. We first describe shared risk factors for SLE and PTSD. We then describe potential biological pathways which may facilitate excessive inflammation in the context of PTSD. Among those genetically predisposed to SLE, systemic inflammation that accompanies chronic stress may fan the flames of smoldering SLE by priming immune pathways. Further studies on the connection between trauma and inflammation will provide important data on pathogenesis, risk factors, and novel treatments for SLE.

Endocrine Evaluation and Homeostatic Model Assessment in Patients with Cornelia de Lange Syndrome.

Objective: The aim of this study was to expand knowledge about endocrine disorders in individuals with Cornelia de Lange syndrome (CdLS), a rare developmental genetic disorder with anomalies in multiple organs and systems. Methods: Hormone levels, clinical scores, anthropometric measurements, and molecular analysis were assessed in 24 individuals with CdLS. Results: Hyperprolactinemia was the most common endocrine disorder. Three patients showed subclinical hypothyroidism. In the gonadotropic axis, mildly delayed puberty was observed, as well as genital anomalies, such as cryptorchidism. Despite short stature, levels of insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 were normal, on average. Three prepubertal individuals without risk factors had higher than normal values for the homeostatic model assessment of insulin resistance (HOMA-IR) and for insulinemia, suggesting insulin resistance. Furthermore, two adults had elevated BMIs associated with HOMA-IR values over the cut-off values. Conclusion: CdLS can lead to dysregulation of the endocrine system, particularly in patients with high HOMA-IR values and insulinemia who are at risk of insulin resistance. Therefore, clinical follow-ups with hormonal assessments are proposed for individuals with CdLS.

The late effects of cranial irradiation in childhood on the hypothalamic-pituitary axis: a radiotherapist's perspective.

Brain tumours make up nearly one-third of paediatric malignancies. Over time, advancements in oncological treatments like radiotherapy have helped reduce normal-tissue toxicity when treating cancers in the brain. However, clinicians are still facing a trade-off between treatment efficacy and potential side effects. The aim of this review is to address the late effects of cranial irradiation on the neuroendocrine system and to identify factors that make patients more vulnerable to radiation-induced endocrine sequelae. Radiation damage to the hypothalamic-pituitary axis, which orchestrates hormone release, can lead to endocrinopathy; up to 48.8% of children who have undergone cranial irradiation develop a hormone deficiency. This may lead to further health complications that can appear up to decades after the last treatment, lowering the patients' quality of life and increasing long-term costs as lifelong hormone replacement therapy may be required. Growth hormone deficiency is the most common sequelae, followed by either thyroid or gonadotropic hormone deficiency. Adrenocorticotropic hormone deficiency tends to be the least common. Identified factors that increase the risk of late endocrine deficiency include total radiation dose, age at treatment, and time since last treatment. However, as there are various other factors that may potentiate the damage, a universal solution proven to be most effective in sparing the endocrine tissues is yet to be identified. Until then, accounting for the identified risk factors during treatment planning may in some cases help reduce the development of endocrine sequelae in childhood cancer survivors.

Physiological stress reactivity in pediatric cancer survivors treated with chemotherapy.

Children who experience early life stress demonstrate changes to their stress responses, which may modulate long-term health. Childhood cancer presents significant stress during diagnosis, treatment, and survivorship. We hypothesized that children who have completed chemotherapy treatment for ALL will demonstrate altered hormone patterns in response to a stressor compared with healthy controls. Twelve pediatric ALL survivors and 12 healthy controls completed the Trier Social Stress Test. Salivary samples, heart rate, and self-report ratings of stress were collected at baseline, pretest, and posttest. Between group comparison showed baseline (interleukin [IL]-8) was significantly higher in the survivor group versus controls (survivors: 89.9, 40.1-544.9 pg ml-1 ; controls: 30.7, 5.6-241.9 pg ml-1 , p = .001) as was peak (IL-8) (survivors: 147.1, 71.6-1177.6 pg ml-1 ; controls: 75.5, 28.6-698.6 pg ml-1 ). Peak salivary alpha-amylase (sAA) concentration was significantly lower in the survivor group (survivors: 69.3, 19.4-195.5 U ml-1 ; controls: 91.2, 27.7-213.7 U ml-1 ; p = .04). Repeated measures ANOVA revealed significant main effects for time on cortisol (F(2.35, 50.81)  = 5.9, p < .01), sAA (F(1.56, 33.17)  = 6.6, p < .01), stress ratings (F(3.42, 88.14)  = 53.4, p < .001), and heart rate (F(8, 83)  = 16.8, p < .05). Significant main effects for group were observed for IL-8 (F(1, 23)  = 8.2, p < .01) and tumor necrosis factor-α (F(1, 23)  = 6.8, p < .05). Significant interaction effects for group × time were found for sAA (F(5, 106)  = 2.8, p < .05). Our results indicate that childhood ALL survivors have similar responses to stress as healthy controls, but lower sympatho-adrenal-medullary reactivity. Therefore, altered stress regulation may present a pathway modulating long-term health in this population.

PACAP/GCGa Is an Important Modulator of the Amphioxus CNS-Hatschek's Pit Axis, the Homolog of the Vertebrate Hypothalamic-Pituitary Axis in the Basal Chordates.

The Hatschek's pit in the cephalochordate amphioxus, an invertebrate deuterostome basal to chordates is suggested to be the functional homolog structure of the vertebrate adenohypophysis based on anatomy and expression of homologous neuroendocrine genes. However, the endocrine potential of the cephalochordate Hatschek's pit remains to be demonstrated as well as the physiological actions of the secreted neuropeptides. In this study, we have explored the distribution and characterize the potential function of the amphioxus PACAP/GCG precursor, which is the ortholog of the hypothalamic PACAP neuropeptide in vertebrates. In amphioxi, two PACAP/GCG transcripts PACAP/GCGa and PACAP/GCGbc that are alternative isoforms of a single gene with different peptide coding potentials were isolated. Immunofluorescence staining detected their expression around the nucleus of Rohde, supporting that this structure may be homologous of the neurosecretory cells of the vertebrate hypothalamus where abundant PACAP is found. PACAP/GCGa was also detected in the infundibulum-like downgrowth approaching the Hatschek's pit, indicating diffusion of PACAP/GCGa from the CNS to the pit via the infundibulum-like downgrowth. Under a high salinity challenge, PACAP/GCGa was upregulated in amphioxi head and PACAP/GCGa treatment increased expression of GHl in Hatschek's pit in a dose-dependent manner, suggesting that PACAP/GCGa may be involved in the regulation of GHl via hypothalamic-pituitary (HP)-like axis similar as in the vertebrates. Our results support that the amphioxus Hatschek's pit is likely to be the functional homolog of pituitary gland in vertebrates.