Effects of feeding pattern on ghrelin and insulin secretion in pigs.

Ghrelin is a peptide hormone that has been implicated in the regulation of feed intake, but little is known about its secretion in pigs. Hence, the effect of feeding pattern on the regulation of ghrelin secretion was tested. In experiment 1, barrows were allotted randomly into 1 of 2 groups, (1) ad libitum fed (CONT) and (2) limited access to feed (once per day, MEAL). Blood samples were taken through jugular catheters every 15 min for 6 h after 7 d on the experimental feeding regimen. Plasma concentrations of ghrelin and insulin were determined by radioimmunoassay. Ghrelin concentrations in the MEAL pigs were elevated before feeding and declined after feeding (P < 0.01). No pattern in plasma ghrelin concentrations was observed in the CONT pigs, but ghrelin concentrations were lower than in the MEAL group. Insulin concentrations were greater in CONT pigs (P < 0.01) during most of the sampling and increased after feeding in the MEAL pigs (P < 0.01). In experiment 2, the treatments were the same as in experiment 1; however, the amount of feed was increased in the MEAL group so that their daily intake was similar to the CONT pigs. Ghrelin concentrations in the MEAL group were again elevated before the meal and declined afterward (P < 0.01). Insulin but not glucose concentrations were negatively correlated with ghrelin. Once-per-day feeding resulted in increased plasma concentrations of ghrelin, which decreased after feeding. Ghrelin may be involved in the regulation of feed intake in pigs.

p16 expression in psoriatic lesions following therapy with propylthiouracil, an antithyroid thioureylene.

Plaque formation is a characteristic finding in patients with psoriasis and reflects cytokine-induced keratinocyte proliferation and/or impaired apoptosis of keratinocytes. Antithyroid thioureylenes such as propylthiouracil (PTU) and methimazole (MMI) are effective in the treatment of plaque psoriasis. Following PTU and MMI treatment, proliferative cell nuclear antigen (PCNA) expression is significantly reduced, suggesting that these medications have an antiproliferative effect. p16 is an antiapoptotic protein that is present in relative abundance in psoriatic plaques and is believed to play a potential role in the persistent senescence and impaired apoptosis of the keratinocytes in the plaque. This study examined p16 expression in biopsy samples of eight patients with plaque psoriasis given 300 mg of propylthiouracil in divided doses for 3 months. Despite significant clinical and histological improvement with PTU treatment, p16 expression was essentially unchanged, suggesting that the beneficial effect of PTU in psoriasis is not mediated through a decrease in p16 expression. The effect of PTU on other antiapoptotic proteins such as bcl-xL remains to be determined.

Ketosis with enhanced GABAergic tone promotes physiological changes in transcendental meditation.

Transcendental meditation (TM) is a stylized form of physical and mental relaxation which is associated with changes in the secretion and release of several pituitary hormones. The hormonal changes induced by TM mimic the effects of the inhibitory neurotransmitter gamma aminobutyric acid (GABA). It is hypothesized that TM produces changes in pituitary hormone secretion by enhancing hypothalamic GABAergic tone as a result of TM associated ketosis. Ketosis enhances the entry of glutamate, the amino acid substrate of GABA into synaptosomes, making more glutamate available for conversion to GABA through the glutamate decarboxylase pathway.

Leptin and IGF-I levels in unconditioned male volunteers after short-term exercise.

We have previously shown that serum gonadotropins, particularly LH, decline after acute exercise in male volunteers. The mechanism for this decline is unknown. Plasma leptin and IGF-I concentrations were measured in seven male volunteers after acute exercise to exhaustion using the Bruce protocol. Leptin concentrations declined following exercise reaching nadir values 30-120 min after exercise. As anticipated, plasma IGF-I concentrations showed a transient rise immediately after exercise falling thereafter to nadir levels 60-90 min after exercise before returning towards baseline levels. In view of the previously described decline in gonadotropin release after acute exercise, the decline in plasma leptin levels, perhaps related to the rise in IGF-I, may play a role in exercise-induced inhibition of gonadotropin release presumably by inhibition of GnRH secretion.

Effects of adenosine infusion on renal function, plasma ANP and ADH concentrations and central hemodynamics in anesthetized pigs.

1. The effect of high-dose adenosine administration on atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) release is not completely understood, and data concerning the effect of adenosine on renal and systemic hemodynamics in the pig are lacking. Measurements of central hemodynamics, renal blood flow and urine production were made in anesthetized pigs during infusion of adenosine. The relationship between these parameters and the plasma concentrations of ANP, ADH and renal renin production was examined. 2. Adenosine infusion at the rate of 140 mg/kg per minute resulted in a significant decrease in systolic, diastolic and mean arterial blood pressure as well as pulmonary arterial pressure. However, cardiac output and renal blood flow remained unchanged during adenosine infusion. Likewise, heart rate remained unchanged until the end of infusion when it increased significantly, Plasma ANP and ADH concentrations increased significantly within 30 min after adenosine infusion, reaching peak levels at 30 to 60 min. However, despite the significant decrease in arterial blood pressure, renal renin production did not change significantly. 3. The adenosine-induced rise in ANP, which is normally released by atrial stretch, may represent a direct effect of adenosine on the cardiac myocytes. The increase in ADH may be a result of decreased arterial blood pressure triggering stimulatory signals from the aortic arch and carotid body receptors to hypothalamic-pituitary sites of ADH production/release. Urine flow decreased dramatically within 30 min of adenosine infusion. Thus adenosine infusion at the given rate led to marked reduction in systemic and pulmonary arterial pressures without significant change in cardiac output, heart rate and renal blood flow. This was associated with a marked increase in plasma ANP and ADH levels with no significant change in renal renin production despite a marked reduction in arterial blood pressure. 4. Maintenance of renal blood flow despite marked reduction in perfusion pressure suggests that, at high doses, adenosine induces renal vasodilation in pigs as opposed to a combined afferent and efferent vasoconstriction known to occur under different experimental conditions.

Effects of blood pH and blood lactate on growth hormone, prolactin, and gonadotropin release after acute exercise in male volunteers.

It has recently been found that prevention of the acidosis of anaerobic exercise blocks beta-endorphin release. Because heavy exercise affects secretion of other anterior pituitary hormones, we studied the results of alkali infusion and ingestion upon blood levels of four hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin (PRL). Eight male subjects were studied after either 2 mEq/kg placebo (NaCl) or alkali (NaHCO3) administered before and during exercise to exhaustion. Blood samples were obtained before exercise and then 15, 30, 60, 90, 120, and 180 min postexercise. GH and PRL but not FSH or LH increased significantly postexercise, with a peak at 60 min, and subsequently declined back to baseline by 180 min. Base treatment reduced GH at baseline and postexercise (except at 60 min) and increased PRL significantly, particularly at 60 min. While the precise mechanisms on how acid/base changes affect hormone release remain to be defined, there are possible consequences on gonadal function and substrate availability during exercise.

Serum levels of androstenedione, testosterone and dehydroepiandrosterone sulfate in patients with premature ovarian failure to age-matched menstruating controls.

Serum concentrations of androstenedione, testosterone and dehydroepiandrosterone sulfate (DHEAS) were measured in 29 patients with premature ovarian failure (POF) and an identical number of age-matched normal control subjects. The study was aimed at determining possible differences in androgen concentrations of ovarian and adrenal origin in POF patients and age-matched normal menstruating controls. Serum testosterone and DHEAS concentrations in the 2 populations were not significantly different. The serum androstenedione concentration in the POF patient group (3,077.50 +/- 1,122.33 pmol/l) was significantly lower than in age-matched normal control subjects (4,167.70 +/- 1,381.09 pmol/l, p < 0.005), possibly reflecting the loss of ovarian androstenedione secretion and/or a subtle defect in adrenal steroidogenic capacity.

Relationship between prorenin, IGF-I, IGF-binding proteins and retinopathy in diabetic patients.

Plasma prorenin and renin, serum insulin-like growth factor I (IGF-I) and IGF-binding protein (IGFBP-2 and IGFBP-3) concentrations were measured in 22 randomly selected male and female patients with insulin-dependent diabetes mellitus (IDDM) or non-IDDM (NIDDM). Plasma prorenin concentration was significantly elevated in patients with proliferative retinopathy (1869.5 +/- 785.0 mUL-1, mean +/- SEM) compared to patients with nonproliferative retinopathy (325.5 +/- 73.2 mUL-1, P < 0.003) and those without retinopathy (318.6 +/- 47.3 mUL-1, P < 0.007). Similarly, serum insulin-like growth factor-I (IGF-I) concentration in patients with proliferative retinopathy (126.3 +/- 21.5 micrograms L-1) was significantly higher than in patients with nonproliferative retinopathy (126.3 +/- 14.85 micrograms L-1, P < 0.004) and without retinopathy (135.2 +/- 37.26, P < 0.05). There was moderately strong positive correlation between plasma prorenin and serum IGF-I concentrations (r = 0.56, P < 0.01). Plasma prorenin concentration was uninfluenced by change in renal function (creatinine clearance, serum creatinine or BUN), but IGF-I levels were inversely related to creatinine clearance (r = 0.67, P < 0.002). There was no demonstrable relationship between IGF-binding proteins and prorenin or renin concentrations. In view of some overlap between plasma prorenin and serum IGF-I concentrations in diabetic patients with proliferative and nonproliferative retinopathy, measurement of both markers may be more useful in predicting the development of proliferative retinopathy in patients with diabetes mellitus than either measurement alone.

Relationship between serum estradiol concentration and IGF-I, IGF-II and IGF-binding proteins in patients with premature ovarian failure on short-term estradiol therapy.

OBJECTIVE: Insulin-like growth factors (IGFs) exert stimulatory effects on follicular growth and development, and early embryogenesis. In view of this, we studied the effect of short-term estradiol treatment, as used in preparing the uterus for embryo implantation, on the serum concentrations of IGFs and their binding proteins (IGFBP) in patients with premature ovarian failure (POF). PATIENTS AND METHODS: Twenty-four patients with POF, enrolled in an assisted reproduction program, were treated with increasing doses of estradiol up to 8 mg daily for 6 weeks. Blood was sampled for measurement of serum estradiol, IGF-I, IGF-II, and IGFBP 1, 2 and 3 at various times during estradiol treatment. RESULTS: There was no significant correlation between serum estradiol concentrations and the serum concentrations of IGF-I and IGF-II. As expected, IGF-I and IGF-II concentrations in serum correlated positively with the serum concentration of IGFBP-3, the major IGF-binding protein in serum. CONCLUSION: The results of this study suggest that estradiol therapy as used to prepare the uterus for implantation has no significant effect on serum IGF-I and IGF-II concentrations, and therefore probably does not influence, via an IGF-mediated mechanism, the success of implantation and early embryonic development.

Serum hormonal concentrations following transcendental meditation--potential role of gamma aminobutyric acid.

Transcendental mediation (TM) is a stylized form of physical and mental relaxation which is associated with changes in the secretion and release of several pituitary hormones. The hormonal changes induced by TM mimic the effects of the inhibitory neurotransmitter gamma aminobutyric acid (GABA). It is hypothesized that TM produces changes in pituitary hormone secretion by enhancing hypothalamic GABAergic tone, and its anxiolytic effects by promoting GABAergic tone in specific areas of the brain. This mechanism is similar to the effects of synthetic anxiolytic and tranquilizing agents such as benzodiazepines that bind to components of the GABA-A (GABAA) receptor. TM, therefore, may produce relaxation by enhancing the effects of an endogenous neurotransmitter analogous to the effects of endorphins in runners who reportedly experience a 'runner's high'.

Effect of orally administered antithyroid thioureylenes on PCNA and P53 expression in psoriatic lesions.

BACKGROUND: Antithyroid thioureylenes are effective agents in the oral and topical treatment of patients with chronic plaque psoriasis. METHOD: The effect of oral treatment with 6-n-propyl 2-thiouracil (propylthiouracil, PTU) and 2-mercapto 1-methyl imidazole (methimazole, MMI) on proliferating cell nuclear antigen (PCNA), and p53 protein expression was studied in patients with stable plaque psoriasis. RESULTS: Following treatment with PTU and MMI, PCNA staining in psoriatic epidermis was significantly decreased. P53 was minimally expressed in untreated lesions, and treatment with PTU and MMI did not enhance p53 expression in the psoriatic lesions. CONCLUSIONS: Since PCNA is a marker of cellular proliferation and p53 inhibits cellular cycling, some of the beneficial effects of PTU and MMI in psoriasis may depend on the ability of the drugs to impair cellular turnover, perhaps by binding to the triiodothyronine (T3) receptor. These effects may be in addition to the previously described effects of PTU and MMI as immune modulators and free radical scavengers.

A controlled trial of topical propylthiouracil in the treatment of patients with psoriasis.

BACKGROUND: Propylthiouracil (PTU, 6-n-propyl 2-thiouracil) is an antithyroid thioureylene, which, in addition to its ability to decrease thyroid hormone synthesis, also has immune modulatory and free radical scavenging abilities. We have previously shown that oral PTU and another antithyroid thioureylene are effective in the treatment of plaque psoriasis. OBJECTIVE: The current study was performed to determine the efficacy of topical PTU in psoriasis. METHODS: Topical PTU and placebo were administered, in a double-blind fashion, three times daily for 4 to 8 weeks to nine volunteers with long-standing plaque psoriasis. The patients had biopsy specimens of their lesions taken at the start and end of the study. Clinical response was monitored with a scoring system based on scale, erythema, and thickness of the plaques. Complete blood cell count and thyroid function studies were obtained in each patient at the beginning and at 2-week intervals thereafter until completion of the study. RESULTS: Topically applied PTU produced significant clearing of the lesions (clinical scores 8.0 +/- 0.6 vs 3.7 +/- 0.3, p < 0.0001 at 4 weeks, and 4.0 +/- 0.6, p < 0.02 at 8 weeks); two patients demonstrated nearly complete clearing. Placebo-treated and untreated "control" areas showed no significant change during the study. None of the subjects had hypothyroidism or cytopenia. CONCLUSION: Topical applied PTU is effective in the treatment of patients with stable plaque psoriasis and has low toxicity.

Serum ICAM-1 concentrations in patients with psoriasis treated with antithyroid thioureylenes.

Serum concentrations of intercellular adhesion molecule-1 (ICAM-1), a marker of early T-cell activation were measured in 14 patients with stable plaque psoriasis who received treatment for 8 weeks with the antithyroid thioureylenes, propylthiouracil (PTU) or methimazole (MMI) which have been previously shown to produce significant improvement in such patients. Baseline serum concentrations of ICAM-1 were significantly higher in the patients with psoriasis compared with normal control volunteers. Following therapy with either PTU (300 mg daily) or MMI (40 mg daily) serum ICAM-1 concentrations did not decline significantly. Since ICAM-1 expression on vascular endothelium increases in active psoriasis, and is postulated to promote T-cell migration to and retention at these sites, it is hypothesized that the beneficial therapeutic effects of thioureylenes in psoriasis occur distal to the events that lead to lymphocyte migration to vascular structures in the dermis.

Exercise and gonadal function.

Exercise is associated with release of a number of pituitary and hypothalamic hormones and a decline in the concentration of luteinizing hormone (LH). Follicle stimulating hormone (FSH) is generally not influenced by exercise. Serum inhibin concentrations, which are reciprocally influenced by serum FSH concentrations, are increased in some animals but are unchanged after acute exercise in human males. Teleologically, the decline in gonadotrophic hormone (LH) secretion after exercise may be geared to enhance individual survival over species propagation in times of stress, analogous to the postulated 'fight or flight' reaction. The decrease in gonadotrophic hormone (LH) secretion is believed to be due to changes in gonadotrophin releasing hormone (GnRH) pulse frequency and amplitude, particularly in women, who often develop amenorrhoea. Males have less dramatic changes in their hypothalamic-pituitary-gonadal axis, although a significant decrease in serum testosterone in physically conditioned males can usually be demonstrated. In this update possible mechanisms for the decline in gonadotrophin secretion with exercise are briefly discussed.

Effect of propylthiouracil and methimazole on serum levels of interleukin-2 receptors in patients with psoriasis.

BACKGROUND: We have previously reported clinical improvement in patients with psoriasis who received orally administered antithyroid thioureylenes, propylthiouracil (PTU), and methimazole (MMI). The antithyroid drugs are believed to exert immunomodulatory effects based on the results of studies in patients with Graves' disease, the only disease in which they are clinically used. The potential of these drugs to mediate clinical improvement in patients with psoriasis by reducing expression of the interleukin-2 receptor (IL2R), a marker of early T and B cell activation, was addressed in the present study. METHODS: Baseline serum concentrations of IL2R were measured by an enzyme-linked immunosorbant assay (ELISA) in 15 patients with stable plaque psoriasis and in the same patients after 8 weeks of oral therapy with either 300 mg of propylthiouracil (n = 7) or 40 mg methimazole (n = 8) given daily. Baseline values were compared with normal controls. RESULTS: Serum IL2R concentrations in the psoriatic patients were significantly higher than in normal controls. After treatment with PTU or MMI, IL2R serum concentrations were not significantly reduced either in the group as a whole or separately in the PTU and MMI treated patients. CONCLUSIONS: Since elevated serum concentrations of IL2R often reflect T and B cell activation, and elevated IL2R serum levels are seen in several autoimmune diseases, it is speculated that the beneficial effect of thioureylenes in patients with psoriasis is mediated by some mechanism(s) other than reduction of IL2R expression in activated lymphocytes.

Propylthiouracil in psoriasis: results of an open trial.

BACKGROUND: Propylthiouracil (PTU) is an antithyroid thioureylene that has immune modulatory and free radical scavenging abilities. In view of the immunomodulatory effects of PTU, we decided to study the therapeutic response of patients with psoriasis to oral PTU. OBJECTIVE: Our purpose was to study the effect of oral PTU in patients with stable plaque psoriasis. METHODS: Oral PTU, 100 mg, was administered every 8 hours for 8 weeks to 10 patients with long-standing psoriasis. Skin biopsy specimens were taken from the lesions before and at the end of the study. Clinical response was monitored with the Psoriasis Area and Severity Index scoring system. Histologic scores were graded with a 5-point grading scale. Complete blood cell count was obtained at the beginning and at the end of the study. Thyroid-stimulating hormone (TSH) was obtained at the beginning and every 2 weeks thereafter until completion of the study. RESULTS: Three patients dropped out of the study. Of the remaining seven, two showed near-complete resolution of their psoriatic lesions, whereas the remainder showed moderate improvement in their clinical scores. Histologic scores were significantly improved in the group with all but one patient showing improvement or no change. Thyroid function tests were unchanged in all but one patient who showed a slight increase in serum TSH at the sixth week of therapy. CONCLUSION: Because of its low toxicity relative to other oral treatments of psoriasis, PTU may have a role in the treatment of patients with this disorder.