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An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics.
Sheldon, CA, Kwon, YJ, Liu, GT, McCormack, SE
Pediatric research. 2015;(2):282-9
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Abstract
Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues.
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On criticism in bio-medical research--a tribute to Uffe Ravnskov.
Folkow, B
Scandinavian cardiovascular journal : SCJ. 2008;(4):240-3
Abstract
The great importance of criticism in science--and its ups-and-downs due to human prejudices and emotions--is discussed in a historical perspective. Towards such a background, attempts are made to evaluate present controversies concerning the widely assumed cause-effect relations between diet-adipositas per se and disorders, like diabetes 2 and atherosclerosis. Seen from a physiological angle, it appears that the real culprits are to a great extent of a different nature, though easily overlooked in e.g. mass screenings. Thus, the human brain reacts to the many mental challenges of modern hectic-competitive life with the same protective response patterns as seen in all mammals, i.e. with defeat- and/or defence-reactions. Here the hypothalamic-hypophyseal-glucocorticoid axis, respectively the hypothalamic-sympatho-adrenomedullary one, serves to support the associated behavioural expressions. Experiments in group-living mammals show how mentally induced prolonged engagements of these neuro-endocrine links end up in serious metabolic and organ-system disturbances, also if factors like diet are kept unchanged. To this comes that in 'civilized' man the respective behavioural expressions are commonly suppressed, whereby most 'inside' neuro-hormonally induced changes occur in vain. An aggravating component is inherent in generally dwindling physical activity, implying that the many bodily and mental advantages of regular exercise are much reduced. Towards such a background, it appears strange that 'The metabolic syndrome' and its sequalae are not even more common today.
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The hypothalamic-pituitary-adrenal-axis in the regulation of energy balance.
Nieuwenhuizen, AG, Rutters, F
Physiology & behavior. 2008;(2):169-77
Abstract
Human (visceral) obesity is associated with alterations hypothalamus-pituitary-adrenal (HPA) axis functioning. It is however not completely clear whether the HPA axis is causally or co-incidentally related to (visceral) obesity. This review summarizes supporting data of an involvement of the HPA axis in the development of (visceral) obesity. First, several DNA polymorphisms related to HPA axis functioning are correlated to the development of obesity. Second, chronic elevation of circulatory glucocorticoid concentrations, as in Cushing's disease, results in increased abdominal adiposity. Third, (visceral) obesity is associated with a diminished capacity of cortisol to suppress its own secretion. HPA axis functioning might affect energy balance through affecting energy intake. Both CRH and cortisol influence physiological, central mechanisms involved in the regulation of food intake. Still, general activation of the HPA axis has shown to have inconsistent effects on food intake in humans. This inconsistency may partially be explained by gender differences, individual differences in the functioning of the HPA axis, as well as differences in attitude towards eating. In particular, women with high scores on dietary restraint are prone to stress-induced hyperphagia. Dietary restraint scores, in turn, are positively correlated to basal and dexamethasone-suppressed cortisol levels, indicating a complex dual relationship between stress, HPA axis functioning, attitude towards eating and the risk for stress-induced hyperphagia. In the Western society, with chronically high ambient levels of stress and the availability of high caloric foods, this relationship may imply a risk for the development of (visceral) obesity and the metabolic syndrome.
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Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis.
Beck-Peccoz, P, Persani, L, Calebiro, D, Bonomi, M, Mannavola, D, Campi, I
Best practice & research. Clinical endocrinology & metabolism. 2006;(4):529-46
Abstract
Forty years have elapsed since the first description of a syndrome of resistance in the hypothalamic-pituitary-thyroid axis, i.e., resistance to thyroid hormone action. In the last two decades many other types of resistance have been discovered, including resistance to the action of thyrotropin-releasing hormone (TRH), of thyroid-stimulating hormone (TSH), and of thyroid hormones (THs); the latter can be due not only to thyroid hormone receptor defects but also to alteration in genes encoding TH-specific transporters or components involved in metabolic pathways of THs. Moreover, alteration in genes encoding for second messengers may cause forms of resistance other than those due to receptor mutations, the most important one being that of an inactivating mutation in the G-protein alpha-subunit leading to TSH resistance in the setting of pseudohypoparathyroidism type 1a. Recognition of these rare thyroid disorders is of great importance not only for informed genetic counselling but also for avoiding diagnostic mistakes that may lead to incorrect and potentially dangerous treatments.
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The hypothalamic-pituitary-adrenal axis activity in obesity and the metabolic syndrome.
Pasquali, R, Vicennati, V, Cacciari, M, Pagotto, U
Annals of the New York Academy of Sciences. 2006;:111-28
Abstract
A hypothetical role of glucocorticoids in human obesity has been suggested since the abdominal obesity phenotype and syndromes of endogenous or exogenous hypercortisolism share several clinical, metabolic, and cardiovascular similarities. An emerging body of evidence indicates that both neuroendocrine dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as peripheral alterations of cortisol metabolism may play a role in the pathophysiology of abdominal obesity. Major alterations of the HPA axis in vivo may be identified in different ways. They include evaluation of hormone concentrations: (a) in basal conditions, in blood, urine, or saliva samples; (b) during dynamic studies following stimulation with different neuropeptides or psychological stress challenges, or suppression with inhibiting agents of the HPA axis at different levels; and (c) after mixed meals or meals containing different nutrient compositions. In addition, alteration of peripheral cortisol metabolism can be detected by direct measurement of cortisol metabolites in urine, although this is a matter of more complex investigation. Alterations of the HPA axis in abdominal obesity are associated with insulin resistance, which suggests a direct responsibility of these hormonal alterations in the susceptibility of affected patients to develop both metabolic and cardiovascular diseases. According to available data, no single marker probably has the power to detect subtle alterations of the HPA axis in conditions, such as the abdominal obesity and the metabolic syndrome. On the contrary, they indicate the need for multiple parameters. At present, evaluation of urinary free cortisol, particularly during the night-time, and salivary-free cortisol appear to be promising for these purposes, whereas dynamic tests should be reserved for specific clinical settings, involving well-characterized patients.