Studies of growth regulation in a neuroendocrine cell line

We show that automated external defibrillation training of emergency medical technicians (EMTs) is less time consuming than manual defibrillation training, and hypothesize that both improve survival from sudden cardiac death. Data on 91 cardiac arrests over 27 months among five basic life support services was collected before EMT-defibrillation (EMT-D) training. Subsequently, seven BLS services were trained in EMT-D using either manual difibrillation or automated external defibrillation technology, and 55 sudden cardiac death patients were entered after training. Manual defibrillation required 11 more hours per student in initial training. Survival to hospital discharge improved from two of 91 patients (2.2%) in the series before EMT-D training to nine of 55 patients (16.4%) after EMT-D training (P = .001). Improved survival was correlated with shorter prehospital defibrillation times, 8.84 minutes, when EMTs performed defibrillation versus 16.3 minutes before training when EMTs awaited advanced life support defibrillation (P < .001). To enhance equipment familiarity we allowed EMTs to apply three-lead electrode monitors to all medical/cardiac patients during transport (surveillance). There were six emergency medical service-witnessed "surveillance" arrests and three arrests survived to hospital discharge (50% survival). This group represented 33% of all survivors in the series. We recommend automated external defibrillation training for EMTs. Improved survival in sudden cardiac death cases in well-run emergency medical service systems should result from EMT-D training. Finally, we recommend that routine "surveillance" of high-risk patients during transport by defibrillation-capable EMTs be considered in EMT-D programs, rather than limiting EMT-D only to units capable of rapid "man-down" response.     

Gaseous transmitters and neuroendocrine regulation

Recent work has demonstrated that the brain has the capacity to synthesize impressive amounts of the gases nitric oxide (NO) and carbon monoxide (CO). There is growing evidence that these gaseous molecules function as novel neural messengers in the brain. This article reviews the pertinent literature concerning the putative role of NO and CO as critical neurotransmitters and biological mediators of the neuroendocrine axis. Abundant evidence is presented which suggests that NO has an important role in the control of reproduction due to its ability to control GnRH secretion from the hypothalamus. NO potently stimulates GnRH secretion and also appears to mediate the action of one of the major transmitters controlling GnRH secretion, glutamate. Evidence is presented which suggests that NO stimulates GnRH release due to its ability to modulate the heme-containing enzyme, guanylate cyclase, which leads to enhanced production of the second messenger molecule, cGMP. A physiological role for NO in the preovulatory LH surge was also evidenced by findings that inhibitors and antisense oligonucleotides to nitric oxide synthase (NOS) attenuate the steroid-induced and preovulatory LH surge. CO may also play a role in stimulating GnRH secretion as heme molecules stimulate GnRH release in vitro, an effect which requires heme oxygenase activity and is blocked by the gaseous scavenger molecule, hemoglobin. Evidence is also reviewed which suggests that NO acts to restrain the hypothalamic-pituitary-adrenal (HPA) axis, as it inhibits HPA stimulation by various stimulants such as interleukin-1 beta, vasopressin, and inflammation. This effect fits a proinflammatory role of NO as it leads to suppression of the release of the anti-inflammatory corticosteroids from the adrenal. Although not as intensely studied as NO, CO has been shown to suppress stimulated CRH release and may also function to restrain the HPA axis. Evidence implicating NO in the control of prolactin and growth hormone secretion is also reviewed and discussed, as is the possible role of NO acting directly at the anterior pituitary. Taken as a whole, the current data suggest that the diffusible gases, NO and CO, act as novel transmitters in the neuroendocrine axis and mediate a variety of important neuroendocrine functions.     

The regulation of hippocampal dynorphin by neural/neuroendocrine pathways: models for effects of aging on an opioid peptide system

Previous research has demonstrated increased messenger RNA expression and peptide content in an opioid system localized to hippocampal dentate granule cells in aged rats. This altered regulation of dynorphin was correlated with the emergence of an age-related impairment in spatial learning. Considerable evidence exists for additional effects of aging on systems that provide input to the dynorphin-containing dentate granule cells. Such changes have been well documented for loss of perforant path innervation from entorhinal cortex, deterioration in septohippocampal cholinergic neurons, and high amounts of glucocorticoids that have, among their targets, receptors located in the dentate gyrus. Similar to the effects of aging on hippocampal dynorphin, age-related changes in each of these systems correlate with the severity of spatial learning impairment in aged rats. This raises the possibility that dysregulation of dynorphin in the aged brain is a reactive response to antecedant change(s) in this circuitry, a hypothesis that was examined by separately manipulating in young rats the three neural/neuroendocrine systems identified above. Of the three models examined only removal of the perforant path reproduced the effect of aging on dynorphin in the hippocampal formation. An immunotoxin was used in Experiment 1 to selectively remove septo-hippocampal cholinergic neurons in young rats. No alteration in hippocampal opioid peptides was produced by this treatment. Experiment 2 examined effects of exposure to excess corticosterone. Adrenalectomized rats exhibited a significant decrease in hippocampal dynorphin-A (1-8) content, which was reversed by corticosterone replacement at a concentration approximating normal basal levels. Dynorphin-A (1-8) content, however, was not reliably increased by exposure to excess corticosterone. In contrast, perforant path removal was found to reproduce the effect of aging on dynorphin content; either aspiration of the entorhinal cortex or knife-cut transections of the perforant path reliably increased hippocampal dynorphin content. These results support the conclusion that age-related deterioration in the septohippocampal cholinergic system and evaluated exposure to corticosterone are not sufficient to induce an elevation in hippocampal dynorphin content. Only removal of the perforant path innervation was found to reproduce the elevation in hippocampal dynorphin content observed in aged rats with hippocampal-dependent learning impairment.     

Toxicity and neuroendocrine regulation of the immune response: a model analysis

Various models have been proposed for the regulation of the primary immune response. Most of the models focus on the ability of the immune system to control a multiplying pathogen, and take into account the cross-regulations between different immune components. In the present study, we integrate the immune system in the general physiology of the host and consider the interaction between the immune and neuroendocrine systems. In addition to pathogen growth and toxicity, our four-variable model takes into account the toxic consequences for the organism of the immune response itself, as well as a neuro-hormonal retro-control of this immune response. Formally, the dynamics of the model is first explored on the basis of a discrete caricature, with special emphasis on the role of the constitutive feedback loops for determining the essential dynamical behavior of the system. This logical analysis is then completed by a classical continuous approach using differential equations. From a biological point of view, our model accounts for four stable regimes which can be described as "pathogen elimination/organism healthy", "pathogen elimination/ organism death", "pathogen growth/organism death" and "chronic infection". The size of the basins of attraction of these different regimes varies as a function of some crucial parameters. Our model allows moreover to interpret the interplay between pathogen immunogenicity and neuro-hormonal feedback, the effects of stress on immunity and the toxic shock syndrome, in terms of transitions among the steady states.     

Effects of growth hormone on neuroendocrine function

Although the role of growth hormone (GH) in the control of reproductive functions is not well understood, there is considerable evidence that the states of both GH deficiency and GH excess are typically associated with reproductive deficits. To identify the possible involvement of functional alterations in the hypothalamic-pituitary system in producing these deficits, we are studying neuroendocrine function related to reproduction in transgenic animals overexpressing GH, in animals with congenital GH deficiency, and in animals with selective immunoneutralization of GH. The results indicate that GH acts on the hypothalamus to alter dopaminergic and noradrenergic control of prolactin and gonadotropin release. Life-long elevation of GH levels outside the physiological ranges disrupts feedback control of luteinizing hormone (LH) release by gonadal streroids. Plasma LH and follicle-stimulating hormone (FSH) levels and feedback control of LH release are also abnormal in GH-deficient animals indicating that physiological levels of endogenous GH are normally involved in the control of gonadotropin release. Differences between the effects of bovine vs. human GH in transgenic mice and differential effects of GH deficiency in mice and rats should facilitate identification of the mechanisms involved in the actions of GH on the hypothalamic-pituitary system.     

Peripheral circulation regulation in patients with the neuroendocrine metabolic form of hypothalamic syndrome

Peripheral circulation and regulating hormonal (renin-angiotensin-aldosterone system) and electrolytic (plasma sodium and potassium) factors were studied in 102 patients with the hypothalamic syndrome neuroendocrine metabolic form administered pathogenetic therapy with antiserotonin and dopaminergic drugs as well as routine therapy. Blood plasma sodium vasopressin and aldosterone levels were found increased, arterial vessel reactivity in the forearm reduced, and venous circulation disordered in these patients. Routine therapy failed to normalize electrolytes and hormonal parameters and was conducive to a still more marked reduction of arterial vessel reactivity. Peritol therapy resulted in a reduction of vasopressin concentration and normalization of blood plasma sodium and aldosterone, as well as in improvement of the myogenic mechanisms of vascular tone regulation and normalization of venous circulation parameters. A course of parlodel therapy lead to normalization of blood plasma levels of vasopressin, aldosterone, and sodium but no changes in the regional vessels were observed.     

Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours

Circulating neuron-specific enolase (NSE) and chromogranin A (CgA) were measured in 128 patients with neuroendocrine tumours (NET) to compare their sensitivity and specificity, to investigate factors associated with elevated serum levels and to determine the usefulness of these markers in the follow-up of NET patients. NSE (Cispack NSE, Cis Bio International, Gif-sur-Yvette, France; normal <12.5 microg l(-1)), and chromogranin A (CgA-Riact, Cis Bio International, normal <100 microg l(-1)) were measured in 128 patients without renal insufficiency. There were 99 patients with gastroenteropancreatic (GEP) NET, 19 with medullary thyroid carcinoma and ten with phaeochromocytoma. Fifty-three patients with non-NET were studied as controls. Serum NSE and CgA levels were elevated in 48 (38%) and 76 (59%) of the 128 NET patients respectively. In all groups of NET patients, CgA proved to be more sensitive than NSE. NSE and CgA had a specificity of 73% and 68% respectively. Immunostaining for NSE was positive in three out of eight controls with elevated CgA levels, whereas immunostaining for CgA and synaptophysin was negative in all cases. Elevated CgA levels were significantly associated with two independent parameters, namely the presence of other secretions (P = 0.0001) and a heavy tumour burden (P = 0.001). Elevated NSE levels were exclusively associated with poor tumour differentiation (P = 0.01). Among six patients with NET followed for 11-37 months, CgA appeared to be a better marker of tumour evolution than NSE. We suggest that CgA ought to be the only general marker screened in NET patients.     

Vascular and neuroendocrine components in altered blood pressure regulation after surgical repair of coarctation of the aorta

STUDY OBJECTIVE: To investigate potential vascular and neuroendocrine determinants of altered blood pressure (BP) regulation in patients previously operated on for aortic coarctation. DESIGN, SETTING AND PATIENTS: We prospectively re-evaluated 45 patients operated on for aortic coarctation at Strasbourg University Hospital over a 13-year period. Four of these patients were less than 2 years old at the time of the operation and four were older than 20 years. Patient age and time since the operation were on average 21+/-13 years and 8+/-3 years, respectively. Surgery consisted of a resection with end-to-end anastomosis for 18 patients, angioplasty (8), prosthesis (4) or sub-clavian flap (15). RESULTS: Despite repair of the coarctation, about 40% of the patients showed an abnormal BP status at rest. The majority of these patients had uncomplicated borderline hypertension. The orthostasis test as well as the BP circadian rhythm were frequently abnormal. While the ankle/arm systolic pressure index measured at rest was generally within the normal range, diminished carotid-femoral pulse wave velocity was observed. Plasma adrenaline and aldosterone levels were elevated in about 50% of the patients examined. CONCLUSIONS: These new findings suggest that there are 'cause and effect' relationships between aortic structural and functional vascular abnormalities, and augmented plasma adrenaline and aldosterone in some patients after coarctation repair. These phenomena are likely to be involved in altered BP regulation and might result in recurrent hypertension.     

Effects of chronic nicotine treatment and withdrawal on hypothalamic proopiomelanocortin gene expression and neuroendocrine regulation

Considerable evidence suggest that some responses to smoking and nicotine are mediated by forebrain beta-endorphinergic opioid mechanisms. It has also been demonstrated that nicotine stimulates rat tuberoinfundibular dopaminergic activity. Since we have proposed that interactions between mediobasohypothalamic (MBH) dopaminergic and beta-endorphinergic mechanisms have a key role in neuroendocrine integration, we investigated the effects of chronic nicotine treatment and withdrawal on: (1) MBH concentrations of proopiomelanocortin (POMC, precursor for beta-endorphin biosynthesis) mRNA; (2) MBH concentrations of tyrosine hydroxylase (TH, rate limiting enzyme in catecholamine biosynthesis) mRNA; (3) corresponding serum prolacin, corticosterone, luteinizing hormone (LH), and testosterone concentrations. POMC and TH mRNA levels were measured by RNase protection/solution hybridization assay; serum hormone levels were measured by radioimmunoassay. Adult male rats received subcutaneous injections of either nicotine or saline during the dark period of each day on an increasing frequency (1-3 injections/day) and dosage (0.4-0.5 mg nicotine/kg body weight) schedule over 4 weeks. The rats were sacrificed after 4 weeks treatment and at 1, 3, 7, 14 and 21 days withdrawal. Chronic daily nicotine administration induced significant changes in serum corticosterone, serum prolactin, MBH TH mRNA, and MBH POMC mRNA concentrations that tended to persist through day 3 of withdrawal; serum prolactin and MBH POMC mRNA concentrations were suppressed whereas serum corticosterone and MBH TH mRNA concentrations were stimulated. None of the parameters were significantly different from control levels following 7 or more days of withdrawal from nicotine, except for a significant decrease of MBH POMC mRNA concentrations on day 21. Chronic daily nicotine or withdrawal did not significantly alter serum LH or testosterone concentrations. These results suggest that chronic nicotine inhibited POMC gene expression and thus, probably, biosynthesis of beta-endorphin and other opiomelanocortins. We hypothesize that suppression of forebrain beta-endorphin synthesis in response to long-term nicotine exposure produces a chronically opioid deficient condition which may play an important role in maintaining nicotine self-administration and in mediating some changes during the nicotine withdrawal syndrome.