Brain death

Summary Following the research of Giessen Neurosurgery on primary and secondary lesions of the hypothalamo-pituitary system and the brainstem over a period of more than 30 years, cerebral failure and death does not represent a uniform syndrome but consists of several, well characterized syndromes of irreversible hypothalamo-pituitary, mesencephalic and bulbar failure. The specific syndromes are described in detail. The diagnosis is based on establishing complete irreversible damage of specific vital basal functions such as hypothalamo-pituitary transmission, water-and electrolyte metabolism, temperature regulation, circulation and respiration. The common feature of all types is the irreversible break-down of the complex central neurogenous and/or neurohumoral regulatory system. The permanent and irreversible loss of central regulation and modulation means at the same time the complete cessation of the specific human cortical function, the death of the whole brain. Only in bulbar failure with primary irreversible cessation of respiration artificial respiration can maintain the autonomous functions of the heart for a limited time. It is indicated when organ explantation is to be considered. Complete and irreversible isolated loss of cortical function abolishes the normal human life, but does not mean death of the remaining vegetating human being.Presented at the meeting of the Working Group of the Pontificia Academia Scientiarum on The artificial prolongation of life and the exact determination of the moment of death, Vatican City, October 19–21, 1985.Dedicated to Prof. Dr. Jean Brihaye at the occasion of his 65th anniversary.     

Sex-specific effects of isolation stress and consumption of palatable diet during the prepubertal period on metabolic parameters

Objectives

Social isolation during the prepubertal period may have long-term effects on metabolism. The exposure to stressful events is associated with increased palatable food intake, constituting reward-based eating. However, palatable food consumption in early life may lead to metabolic alterations later in life. We investigated whether isolation stress during early life can lead to metabolic alterations in male and female rats with or without exposure to a palatable diet.

Methods

Animals were stressed by isolation during one week after weaning, with or without exposure to a palatable diet.

Results

Stress and palatable diet induced increased caloric consumption. In females, there was a potentiation of consumption in animals exposed to stress and palatable diet, reflected by increased weight gain and triacylglycerol levels in juveniles, as well as increased adiponectin levels. Most of the effects had disappeared in the adults. Different effects were observed in males: in juveniles, stress increased unacylated ghrelin levels, and hypothalamic neuropeptide Y (NPY). Subsequently, adult males that were exposed to a palatable diet during prepuberty showed increased body weight and retroperitoneal fat deposition, increased glycemia, and decreased plasma adiponectin and hypothalamic NPY. Exposure to stress during prepuberty led to increased adrenals during adulthood, decreased LDL-cholesterol and increased triacylglycerol levels.

Conclusion

Isolation stress and consumption of palatable diet changes metabolism in a sex-specific manner. Prepuberty female rats were more prone to stress effects on food consumption, while males showed more long-lasting effects, being more susceptible to a metabolic programming after the consumption of a palatable diet.     

Involvement of the paraventricular (PVN) and arcuate (ARC) nuclei of the hypothalamus in the central noradrenergic regulation of liver cytochrome P450

The present study was aimed at assessing the influence of noradrenergic innervation of the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the brain hypothalamus on cytochrome P450 expression in the liver. DSP-4, a neurotoxin specific to noradrenergic nerve terminals, was administrated locally into the PVN or ARC. One week after neurotoxin injection, the levels of neurotansmitters (noradrenaline/dopamine/serotonin) were measured in the middle part of the hypothalamus, hormone concentrations were estimated in blood plasma, and the activity and the protein levels of CYP isoforms were measured in the liver. A significant decrease in noradrenaline level in the hypothalamus was observed after DSP-4 injection into the PVN or ARC. The levels of dopamine or serotonin remained unchanged or slightly lowered. Simultaneously, significant changes in the plasma concentration of growth hormone were found; its elevation in PVN-lesioned rats and a drop in ARC-lesioned ones. There were no changes in the plasma concentration of the thyroid hormones or corticosterone. The activity and protein levels of isoforms CYP2C11, CYP3A and CYP2A rose in the liver of PVN-lesioned rats, but the activity and protein level of CYP2C11 fell in ARC-lesioned animals such a tendency being also observed in the case of CYP3A. Our study shows that noradrenergic innervation of the PVN and ARC of the hypothalamus exerts an opposite effect on the regulation of cytochrome P450 in the liver. These findings may be important for pharmacological experiments and pharmacotherapy with neuroactive drugs, since cytochrome P450 is responsible for the metabolism of steroids and the majority of drugs.     

Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroid-stimulating hormone and thyroxine

The optimal strategy in neonatal screening for congenital hypothyroidism is still a subject of controversy. In Kanagawa Prefecture in Japan, simultaneous thyroid-stimulating hormone (TSH) and T4/fT4 determination has been used, while the results of our program may provide valuable information. Cumulative findings were analysed to determine the type and frequency of thyroid disorders in infants detected by simultaneous TSH and T4/fT4 determination, and the TSH and T4/fT4 screening strategy was validated. A total of 1284130 neonates were screened between October 1979 and September 1997 and infants followed because of low T4/fT4 without elevated TSH (T4 < 51.5 nmol/L or fT4 < 9 pmol/L and TSH < 15 mU/L) were retrospectively analysed. The first survey was carried out within 6 mo of birth and the second in 1998; 258 infants were diagnosed with congenital hypothyroidism at the first medical evaluation, 15 of them with hypothalamo-pituitary hypothyroidism. However, in the second survey, only 8 children were confirmed as having hypothalamo-pituitary hypothyroidism, therefore the incidence detected by the present strategy was 1/160516. Of 8 children with hypothalamo-pituitary hypothyroidism, mental retardation was prevented in 3 owing to early treatment. CONCLUSIONS: Simultaneous measurement of TSH and T4/fT4 is a useful strategy for detecting hypothalamo-pituitary hypothyroidism, but more studies are needed to show the cost-benefits of using this strategy.     

Chronic central neuropeptide Y infusion in normal rats: status of the hypothalamo-pituitary-adrenal axis, and vagal mediation of hyperinsulinaemia

Summary Neuropeptide Y in the hypothalamus is a potent physiological stimulator of feeding, and may contribute to the characteristic metabolic defects of obesity when hypothalamic levels remain chronically elevated. Since corticosterone and insulin are important regulators of fuel metabolism, the longitudinal effects of chronic (6 days) intracerebroventricular infusion of neuropeptide Y in normal rats on the hypothalamo-pituitary-adrenal axis and on insulin secretion were studied. Neuropeptide Y-infused rats were either allowed to eat ad libitum, or were pair-fed with normophagic control rats. Neuropeptide Y increased the basal plasma concentrations of adrenocorticotropic hormone and corticosterone during the first 2 days of its intracerebroventricular infusion and increased cold stress-induced plasma adrenocorticotropic hormone concentrations. After 4–6 days of central neuropeptide Y infusion, however, basal plasma adrenocorticotropic hormone and corticosterone concentrations were no different from control values (except in ad libitum-fed rats in which corticosteronaemia remained elevated), they were unaffected by the stress of cold exposure, and the hypothalamic content of corticotropin-releasing factor immunoreactivity was significantly decreased. A state of hyperinsulinaemia was present throughout the 6 days of intracerebroventricular neuropeptide Y infusion, being more marked in the ad libitum-fed than in the pair-fed group. The proportions of insulin, proinsulin, and conversion intermediates in plasma and pancreas were unchanged. Hyperinsulinaemia of the pair-fed neuropeptide Y-infused rats was accompanied by muscle insulin resistance and white adipose tissue insulin hyperresponsiveness, as assessed by the in vivo uptake of 2-deoxyglucose. Finally, bilateral subdiaphragmatic vagotomy prevented both the basal and the marked glucose-induced hyperinsulinaemia of animals chronically infused with neuropeptide Y, demonstrating that central neuropeptide Y-induced hyperinsulinaemia is mediated by the parasympathetic nervous system. [Diabetologia (1997) 40: 1269–1277] Received: 7 May 1997 and in revised form: 24 July 1997     

Neuroanatomical characterization of endogenous opioids in the bed nucleus of the stria terminalis

Numerous neuroanatomical data indicate that the bed nucleus of the stria terminalis (BST) provides an interface between cortical and amygdaloid neurons, and effector neurons modulating motor, autonomic and neuroendocrine responses. Distinct divisions of the BST may be involved in stress response, homeostatic regulation, nociception, and motivated behaviors. Endogenous opioid peptides and receptors are expressed in the BST, but their exact distribution is poorly characterized. The present study used in situ hybridization in order to characterize the endogenous opioid system of the BST, focusing on both enkephalin and dynorphin neuropeptides, as well as their respective receptors (mu, delta, and kappa opioid receptors). We report that preprodynorphin mRNA is observed in distinct nuclei of the BST, namely the fusiform, oval and anterior lateral nuclei. In contrast, there is a widespread expression of preproenkephalin mRNA in both anterior and posterior divisions of the BST. Similarly, mu and kappa opioid receptors are broadly expressed in the BST, whereas delta opioid receptor mRNA was observed only in the principal nucleus. For further characterization of enkephalin-expressing neurons of the BST, we performed a double fluorescent in situ hybridization in order to reveal the coexpression of enkephalin peptides and markers of GABAergic and glutamatergic neurons. Although most neurons of the BST are GABAergic, there is also a modest population of glutamatergic cells expressing vesicular glutamate transporter 2 (VGLUT2) in specific nuclei of the BST. Finally, we identified a previously unreported population of enkephalinergic neurons expressing VGLUT2, which is principally located in the posterior BST.     

Somatostatin levels in the central nervous system of the Snell dwarf mouse; is somatostatin excess the primary molecular defect in the dw/dw dwarfism?

The Snell dwarf mouse (dw/dw) shows significantly decreased somatostatin levels in the hypothalamus whereas more or less increased somatostatin concentrations are observed in any central extrahypothalamic sites studied. These opposite results in hypothalamus and extrahypothalamic areas may be linked to the apparently distinct neurohormonal and neuromodulatory functions of somatostatin in the brain. They also provide arguments for the assumption of a primary somatostatin excess which could be related to the dwarf mutation. In hypothalamus, the severe defect in growth hormone of the dwarf mutant may rapidly lead, by failure of a pituitary retro-control, to a reduction in the presumed initially elevated somatostatin levels. In central extrahypothalamic sites, known to escape to GH retro-action, higher somatostatin levels remain.     

Dysgenesis of the Corpus Callosum and Hypopituitarism

ABSTRACT. A high resolution CT scan demonstrated the unexpected finding of dysgenesis of the corpus callosum in addition to the expected finding of pituitary hypoplasia in three children who presented with growth failure secondary to hypopituitarism. Several of the clinical features reported in association with dysgenesis of the corpus callosum may be ascribed to hypo-thalamo-pituitary dysfunction. These children emphasize the need to assess the endocrine function of patients with midline structural defects. It should not be assumed that the clinical manifestations are related solely to the anatomical abnormality.     

Dexamethasone Suppression Test in Autistic Children

Abstract: A dexamethasone suppression test (DST) was carried out on autistic and other handicapped children to investigate the function of the hypothalamo-pituitary adrenal axis (HPA-axis). The subjects were 19 autistic children consisting of 11 relatively well-developed and eight poorly-developed children. The control groups were 26 normal volunteers, 19 patients with schizophrenia and 15 children with mental retardation (MR) or minimal brain dysfunction (MBD). The DST procedures followed the Carroll method. As a result, all of the normal volunteers and 19 schizophrenic patients showed normal response (suppressor). Nine of the 11 well-developed autistic children exhibited suppressor, while all of the poorly-developed children showed an abnormal response (non-suppressor). Nine of the 10 children with MR and all of the five children with MBD were suppressor. These results suggest that there might be a dysfunction in the HPA-axis of the poorly-developed autistic children.     

Sexual function in women with hypothalamo-pituitary disorders

The extent to which hypothalamo-pituitary disorders in women affect sexual desire and sexual functions was investigated. Sexual functions and sexual appreciation were assessed in a comprehensive interview of 48 women with well-defined hypothalamo-pituitary disorders. Data about sex life were correlated to blood hormone levels and diagnosis. In most of the women (64.8%), the first clinical symptom indicating a hypothalamo-pituitary dysfunction began in the age group 16 to 35. In 43 patients (89.6%), the initial symptom was menstrual irregularities. Altogether 45 (93.8%) of the women declared that they had or had had significant sexual problems. Two of the three women who did not report sexual problems had never had intercourse. Thirty-eight (79.2%) of the women had developed a lack of or a considerable decrease in sexual desire. Problems with lubrication or orgasm were reported by 31 (64.6%) and 33 (68.7%) of the women, respectively. Normal menstrual pattern, young age, and intrasellar tumor growth correlated better with normal sexual desire and sexual functions than did normal prolactin levels and normal testosterone levels. However, at the time of interview, only 7 women had hyperprolactinemia. Serum testosterone values correlated significantly only with masturbation.