Hormonal regulation and cellular localization of fatty acid synthase in human fetal lung.
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Fatty acid synthase (FAS; EC 2.3.1.85) supplies de novo fatty acids for pulmonary surfactant synthesis, and FAS gene expression is both developmentally and hormonally regulated in the fetal lung. To further examine hormonal regulation of FAS mRNA and to determine the cellular localization of FAS gene expression, we cultured human fetal lungs (18-22 wk gestation) as explants for 1-4 days in the absence (control) or presence of glucocorticoid [dexamethasone (Dex), 10 nM] and/or cAMP agents (8-bromo-cAMP, 0.1 mM and IBMX, 0.1 mM). FAS protein content and activity increased similarly in the presence of Dex (109 and 83%, respectively) or cAMP (87 and 111%, respectively), and responses were additive in the presence of both hormones (230 and 203%, respectively). With a rabbit anti-rat FAS antibody, FAS immunoreactivity was not detected in preculture lung specimens but appeared in epithelial cells lining the tubules with time in culture. Dex and/or cAMP markedly increased staining of epithelial cells, identified as type II cells, whereas staining of mesenchymal fibroblasts was very low under all conditions. With in situ hybridization, FAS mRNA was found to be enriched in epithelial cells lining the alveolar spaces, and the reaction product increased in these cells when the explants were cultured with the hormones. The increased FAS mRNA content in the presence of Dex and/or cAMP is primarily due to increased stabilization of mRNA, although Dex alone increased the transcription rate by approximately 30%. We conclude that hormonal treatment of cultured human fetal lungs increases FAS gene expression primarily by increasing stability of the message. The induction of FAS during explant culture and by hormones occurs selectively in type II epithelial cells, consistent with the regulatory role of this enzyme in de novo synthesis of fatty acid substrate for surfactant synthesis in perinatal lungs. (+info)
Immune changes in humans during cold exposure: effects of prior heating and exercise.
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This study examined the immunological responses to cold exposure together with the effects of pretreatment with either passive heating or exercise (with and without a thermal clamp). On four separate occasions, seven healthy men [mean age 24.0 +/- 1.9 (SE) yr, peak oxygen consumption = 45.7 +/- 2.0 ml. kg(-1). min(-1)] sat for 2 h in a climatic chamber maintained at 5 degrees C. Before exposure, subjects participated in one of four pretreatment conditions. For the thermoneutral control condition, subjects remained seated for 1 h in a water bath at 35 degrees C. In another pretreatment, subjects were passively heated in a warm (38 degrees C) water bath for 1 h. In two other pretreatments, subjects exercised for 1 h at 55% peak oxygen consumption (once immersed in 18 degrees C water and once in 35 degrees C water). Core temperature rose by 1 degrees C during passive heating and during exercise in 35 degrees C water and remained stable during exercise in 18 degrees C water (thermal clamping). Subsequent cold exposure induced a leukocytosis and granulocytosis, an increase in natural killer cell count and activity, and a rise in circulating levels of interleukin-6. Pretreatment with exercise in 18 degrees C water augmented the leukocyte, granulocyte, and monocyte response. These results indicate that acute cold exposure has immunostimulating effects and that, with thermal clamping, pretreatment with physical exercise can enhance this response. Increases in levels of circulating norepinephrine may account for the changes observed during cold exposure and their modification by changes in initial status. (+info)
Lack of response to octreotide in Cushing's syndrome due to metastatic adrenocortical carcinoma.
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Functional metastatic adrenocortical carcinoma is an uncommon cause of Cushing's syndrome, which rarely responds to conventional treatment. A patient presenting with Cushing's syndrome secondary to adrenocortical carcinoma underwent surgical resection. Postoperatively, she developed metastatic disease resistant to conventional chemotherapy. Octreotide, a somatostatin analogue which is effective in the treatment of several types of neuroendocrine tumour, was tried to ameliorate her secretory symptoms, but without any therapeutic effect. (+info)
Carcinoid-associated ectopic ACTH syndrome with variable response to octreotide.
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The case is presented of a 31-year-old woman who developed florid clinical and biochemical Cushing's syndrome due to metastatic hepatic carcinoid tumour from a probable pancreatic primary. Hypercortisolaemia was controlled with metyrapone and ketoconazole, but high doses of octreotide failed to affect plasma cortisol and urinary 5-hydroxyindole acetic acid (5HIAA) levels, or prevent rapid tumour growth. Hepatic polystyrene embolisation failed, and she was treated by liver transplantation with initial excellent results, and normalisation of cortisol and 5HIAA levels. Ten months later, however, she relapsed with bony and pelvic tumour recurrence, and high and symptomatic levels of cortisol and 5HIAA. At this time, octreotide in similar doses to those used previously appeared to normalise her biochemically, although she died soon after. This variable responsiveness to octreotide could be related to somatostatin receptor changes, or cyclical tumour secretion patterns. (+info)
Oocyte apoptosis: like sand through an hourglass.
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Although the study of germ cell death is arguably still in its infancy as a field, several recent breakthroughs have provided the fodder for a story, replete with episodes of apparent mass cellular suicide if not murder, that will undoubtedly serve as a research base for many laboratories over the next several years. Death is known to strike the male and female germlines with roughly equal intensity, but the innate feature of male germ cells being self-renewing while those of the female are not places the death of oocytes in a completely different light. Indeed, the functional life span of the female gonads is defined in most species, including humans, by the size and rate of depletion of the precious endowment of oocytes enclosed within follicles in the ovaries at birth. This continuous loss of oocytes throughout life, referred to by many as the female biological clock, appears to be driven by a genetic program of cell death that is composed of players and pathways conserved from worms to humans. It is on this genetic pathway, and the role of its constituent molecules in regulating female germ cell fate, that this review will focus. Emphasis will be placed on those studies using genetic-null or transgenic models to explore the functional requirement of proteins, such as Bcl-2 family members, Apaf-1, and caspases in vertebrates to CED-9, CED-4, and CED-3 in Caenorhabditis elegans, in oocyte survival and death. Furthermore, hypotheses regarding the potential impact of translating what is now known of the oocyte death pathway into new approaches for the clinical diagnosis and management of female infertility and the menopause will be offered as a means to stimulate further research in this new and exciting field. (+info)
An elusive role for glycosylation in the structure and function of reproductive hormones.
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The crescendo of events leading first to ovulation and subsequently to birth is orchestrated by a broad repertoire of hormones. The major hormones of the ovulatory cycle are representatives of four hormone classes: neurotransmitters, releasing factors, trophic hormones acting on target tissues, and steroid-like molecules released by the target tissues. The punctuate and staccato rhythm of the neurotransmitters and releasing hormones relentlessly drive the swelling and protracted wave of activity by the luteotrophic and steroid hormones. Carbohydrates alone are notably absent as hormones and the predominant role for glycosylation appears to be the conferment of increased solubility to endocrine molecules, either during their manufacture or by modulating circulatory half-life. Rarely considered examples of the importance of glycosylation in reproductive hormones include adenosine, important for spermatozoan activity, and the hormone-binding globulins, which ensure the aqueous transport of hydrophobic steroids. The archetype glycoprotein hormones, especially human chorionic gonadotrophin (HCG), are discussed more extensively, as the structural and functional roles of carbohydrate in these hormones have been studied exhaustively. Conversely, the direct involvement of HCG and the importance of its carbohydrate for autonomous growth, in both placental invasion and tumorigenesis, has received little attention in the literature. (+info)
Long-term haemodynamic effects of octreotide on postprandial splanchnic hyperemia in humans: a placebo-controlled echo-doppler study.
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BACKGROUND: Octreotide is a potent splanchnic hypotensive somatostatin analogue effective in the treatment of acute variceal bleeding. AIM: To study the effects of octreotide on basal and postprandial splanchnic and systemic haemodynamics, and hormonal changes in humans. METHODS: Twenty-four healthy volunteers were randomized to receive a liquid meal and either octreotide (OCT, 100 microg bolus) or placebo repeatedly every 4 h for 48 h. Splanchnic (Doppler ultrasound) and systemic haemodynamics (non-invasive cardiac monitoring) were assessed for 2 h on four consecutive days: one control day and after doses 1 (0 h), 7 (24 h) and 13 (48 h). RESULTS: The maximum postprandial increases in mean blood velocity of the superior mesenteric artery (SMA-Vmean +72%), portal (PBF +52%) and total hepatic blood flow (HBF +50%) observed in the placebo group, were abolished after the first dose of octreotide (SMA-Vmean -23%, P<0.01; PBF -22%, P<0.01; HBF -21%, P<0.01). Postprandial hyperemia was restored at the end of the 48-h study period, but baseline SMA-Vmean (placebo 40+/-12, OCT 29+/-11 cm/s, P<0.05) and PBF (placebo 1200+/-971, OCT 743+/-449 mL/min, P<0.05) remained significantly lower in the octreotide group. The postprandial decrease of systemic vascular resistance and increase of cardiac index were prevented by octreotide for 48 h. CONCLUSIONS: Repeated 4-hourly bolus injections of octreotide reduce splanchnic blood flow for at least 48 h, but the prevention of food-induced splanchnic hyperemia is short-lasting. (+info)
The effects of oral rabeprazole on endocrine and gastric secretory function in healthy volunteers.
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AIM: To evaluate the short-term effects of rabeprazole 20 mg on endocrine parameters, in particular serum testosterone and cortisol, and on 24 h intragastric pH, H+ activity and nocturnal gastric acid secretion. METHODS: In this double-blind, two-period crossover study, 12 healthy young male volunteers were randomly given oral rabeprazole 20 mg o.m. or placebo for 14 days. There was a washout period of at least 1 week between the two studies. The effects of rabeprazole and placebo on cortisol and testosterone (primary criteria), and on tri-iodothyronine, thyroxine, 17beta-oestradiol, thyroid-stimulating hormone, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, rennin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin and urinary 6-beta hydroxycortisol were compared. Intragastric 24 h pH, 24 h H+ activity and nocturnal gastric acid secretion were determined by pH probe and gastric aspiration. RESULTS: Rabeprazole produced no clinically relevant effects on endocrine function as assessed by measurement of serum testosterone, circadian serum cortisol levels, ACTH-stimulated serum cortisol levels and 17 other endocrine function tests. Rabeprazole significantly increased the 24 h median pH values compared to placebo (on Days 7 and 14 median values ranged from 3.92 to 6.88 with rabeprazole and from 1.48 and 4.22 with placebo, P < 0.001) and significantly decreased the integrated 24 h H+ activity (AUC08--08) from 343 mmol/L/h with placebo to 44 mmol/L/h with rabeprazole (P < 0.001). Following cessation of dosing, intragastric pH levels decreased and H+ activity increased, but acid secretion did not recover completely during the next 72 h. The mean value for nocturnal gastric acid secretion on Days 7 and 8 was 36 mmol/6 h with placebo and 5.6 mmol/6 h with rabeprazole (P < 0.001). Rabeprazole was well tolerated. CONCLUSION: Rabeprazole did not influence endocrine function in healthy young male volunteers during short-term dosing. Rabeprazole substantially increased intragastric pH over a 24 h period and significantly decreased intragastric acidity and nocturnal gastric acid secretion. (+info)