Paraneoplastic Syndromes

MedlinePlus

... cortisone or prednisone, high-dose intravenous immunoglobulin, or irradiation. Plasmapheresis, a process that cleanses antibodies from the ... cortisone or prednisone, high-dose intravenous immunoglobulin, or irradiation. Plasmapheresis, a process that cleanses antibodies from the ...

CORTISONE IN TREATMENT OF BRONCHIAL ASTHMA

PubMed Central

Harris, Marvin S.

1951-01-01

Twenty patients with intractable asthma were treated with cortisone on various dosage schedules. Results indicated that a rapid improvement in the asthmatic state may be expected in four to five days with high level dosage of the hormone—usually a total dose exceeding 200 mg. per day at the beginning. If treatment is discontinued after a week, relapse usually will occur within a period of eight days. If small doses are given two or three times weekly, following initial response, relapse may not occur for 20 or 30 days. The interspersed administration of ACTH during an attempt to discontinue cortisone apparently was of no value. It therefore appears that cortisone control of intractable asthma is dependent on large dosage until clinical improvement is obtained, then approximately 100 mg. two or three times a week for maintenance of a reasonable state of health. PMID:14848726

Parotid fluid cortisol and cortisone

PubMed Central

Katz, Fred H.; Shannon, Ira L.

1969-01-01

Parotid fluid corticosteroids, substantially comprised of cortisol and cortisone, were previously demonstrated to rise to far greater levels 4 hr after administration of ACTH than they did in the third trimester of pregnancy, although the plasma total corticosteroid concentrations were similar in these two states. It was therefore suggested that only nonproteinbound corticosteroid gains access to parotid fluid. In the present study parotid fluid cortisol and cortisone and plasma dialyzable cortisol concentrations have been measured in normal men before and 2 hr after 40 U ACTH, and, in another group, before and after 10 days of diethystilbestrol (5 mg daily). Total plasma cortisol rose from a mean of 6.3 to 17.9 μg/100 ml after ACTH and from 14.6 to 39.4 mg/100 ml after the estrogen. However parotid fluid cortisol plus cortisone rose from 0.8 to 2.6 μg/100 ml after ACTH and to only 2.2 after estrogen. This rise resembled that of the plasma dialyzable cortisol (control 0.4, ACTH 1.8, estrogen 1.2 μg/100 ml) rather than the increase in total plasma cortisol which was over twice as high after estrogen as after ACTH. Thus parotid fluid corticosteroids seem to be a good measure of nonprotein-bound corticosteroid, the cortisol available to the cell. The total amount of cortisol plus cortisone excreted is approximately constant, independent of parotid fluid flow rate. Cortisone exceeds cortisol in parotid fluid in the basal state, but after ACTH the situation is reversed. PMID:4305375

Stability of Cortisol and Cortisone in Human Breast Milk During Holder Pasteurization.

PubMed

van der Voorn, Bibian; de Waard, Marita; Dijkstra, Lisette R; Heijboer, Annemieke C; Rotteveel, Joost; van Goudoever, Johannes B; Finken, Martijn J J

2017-12-01

Human donor milk is the feeding of choice for preterm infants, when own mother's milk is not available. Holder pasteurization is necessary to secure the safety of donor milk, although it can affect milk quality by reduction of nutritional and bioactive components. Recently, research has focused on the potential role of breast milk glucocorticoids for infant development. At this moment, it is unknown whether pasteurization affects milk glucocorticoid levels. Therefore, we assessed whether Holder pasteurization, the most frequently used method nowadays, reduces breast milk cortisol and cortisone levels, using breast milk samples from 30 women who delivered at term. We found tight correlations between pre- and postpasteurization levels of cortisol (R = 0.99) and cortisone (R = 0.98), and good agreement in Passing and Bablok regression analysis. In conclusion, cortisol and cortisone in human term breast milk are not significantly affected by Holder pasteurization.

Decreased OxLDL uptake and cholesterol efflux in THP1 cells elicited by cortisol and by cortisone through 11β-hydroxysteroid dehydrogenase type 1.

PubMed

Ledda, Angelo; González, Marina; Gulfo, José; Díaz Ludovico, Ivo; Ramella, Nahuel; Toledo, Juan; Garda, Horacio; Grasa, Mar; Esteve, Montserrat

2016-07-01

Data about glucocorticoids role in the development of atherosclerosis are controversial showing different effects in human than in experimental animal models. Atherosclerosis is the result of a chronic inflammatory response to an injured endothelium where an uncontrolled uptake of OxLDL by macrophages triggers the development of foam cells, the main component of fatty streaks in atherosclerotic plaque. There are few data about the direct effect of glucocorticoids in macrophages of atherosclerotic plaque. The aim of the study was to elucidate the role of glucocorticoids in the development of foam cells in atherosclerosis initiation. For this purpose we used THP1 cells differentiated to macrophages with phorbol esters and incubated with OxLDL alone or with cortisol or cortisone. THP1 cells were also incubated with cortisone plus an inhibitor of 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) activity to determine the role of this enzyme on glucocorticoid action in this process. Ours results showed that cortisol and cortisone decreased significantly the inflammation promoted by OxLDL, and also diminished the expression of genes involved in influx and efflux of cholesterol resulting in a reduced lipid accumulation. Likewise cortisol and cortisone decreased 11βHSD1 expression in THP1 cells. The presence of the inhibitor of 11βHSD1 abolished all the effects elicited by cortisone. Our results indicate a direct effect of glucocorticoids on macrophages braking atherosclerosis initiation, reducing pro-inflammatory markers and OxLDL uptake and cholesterol re-esterification, but also inhibiting cholesterol output. These effects appear to be mediated, at least in part, by 11βHSD1 activity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

STUDIES ON THE ANTIPYRETIC ACTION OF CORTISONE IN PYROGEN-INDUCED FEVER

PubMed Central

Atkins, Elisha; Allison, Fred; Smith, Mary Ruth; Wood, W. Barry

1955-01-01

The mode of action of cortisone as an antipyretic has been studied in rabbits challenged with intravenous injections of bacterial pyrogens. The fever induced by pyromen or dextran was found to be markedly suppressed when cortisone was administered in liberal amounts (25 mg. twice daily) for 3 days prior to the challenge. Although the cortisone effectively blocked the febrile response to both pyrogens, it failed to influence the transient but marked leucopenia which characteristically precedes the onset of fever. The antipyretic action of the drug also was shown to bear no relation to the activity of the serum factor recently demonstrated by Farr, Grant, and others to be involved in the production of pyrogen-induced fever. In preliminary experiments with typhoid vaccine as the inciting pyrogen, the presence of serum factor activity in normal blood and its absence in the blood of pyrogen-tolerant rabbits was confirmed. Subsequently the blood of rabbits treated with antipyretically effective doses of cortisone was shown to contain just as much serum factor activity as that of normal rabbits. In addition, previous incubation of the pyrogen with serum factor failed to influence the antipyretic effect of the drug. It is concluded from these findings that in suppressing pyrogen fever, cortisone acts neither upon the leucopenic reaction nor upon the fever-accelerating factor of the serum. By exclusion it would appear that the drug must influence some later stage of the fever-producing process. The mechanisms involved in the later stages of the response to exogenous pyrogen remain undefined, and the need for determining whether they are related to the prefebrile leucopenia is emphasized. PMID:14354106

Is There an Association Between Cortisol and Hypertension in Overweight or Obese Children?

PubMed

Wirix, Aleid Jg; Finken, Martijn Jj; von Rosenstiel-Jadoul, Ines A; Heijboer, Annemieke C; Nauta, Jeroen; Groothoff, Jaap W; Chinapaw, Mai Jm; Kist-van Holthe, Joana E

2017-12-15

The precise mechanisms behind the development of hypertension in overweight or obese children are not yet completely understood. Alterations in hypothalamic-pituitary-adrenal axis activity may play a role. We aimed to investigate the association between cortisol parameters and hypertension in overweight or obese children. Random urine (n=180) and early-morning saliva samples (n=126) for assessment of cortisol and cortisone were collected from 1) hypertensive overweight children (n=50), 2) normotensive overweight children (n=145), and 3) normotensive non-overweight children (n=75). The age of participants was 10.4±3.3 years and 53% were boys. The urinary cortisol-to-cortisone ratio [β 1.11, 95% confidence interval (CI) 1.05-1.19] as well as urinary cortisol/creatinine (β 1.38, 95% CI 1.09-1.54), and cortisone/creatinine ratios (β 1.26, 95% CI 1.17-1.36) were significantly higher in overweight or obese than in non-overweight children. After adjusting for body mass index-standard deviation score and urinary cortisone/creatinine ratio, but not cortisol/creatinine ratio, was significantly associated with presence of hypertension (β 1.12, 95% CI 1.02-1.23). Salivary cortisol and cortisone levels were significantly lower in overweight or obese than in non-overweight children (β -4.67, 95% CI -8.19- -1.15, and β 0.89, 95% CI 0.80-0.97 respectively). There were no significant differences in cortisol parameters between hypertensive and normotensive overweight or obese children. This study provided further evidence for an increased cortisol production rate with decreased renal 11β-hydroxysteroid dehydrogenase 2 activity and flattening of early-morning peak cortisol and cortisone in overweight or obese children. However, there were no significant differences in cortisol parameters between hypertensive and normotensive overweight and obese children.

Effects of 1,25-dihydroxycholecalciferol on intestinal calcium transport in cortisone-treated rats.

PubMed

Favus, M J; Walling, M W; Kimberg, D V

1973-07-01

The administration of glucocorticoids may decrease intestinal calcium absorption in vivo and the active transport of calcium in rat duodenum in vitro. It has been suggested that this apparent "anti-vitamin D-like" effect of steroid hormones may be related to alterations in vitamin D metabolism. In order to test this hypothesis, vitamin D-deficient control and cortisone-treated rats were given an intraperitoneal injection of 5.5 IU of 1,25-dihydroxycholecalciferol (1,25-DHCC), the probable end-organ active vitamin D metabolite in the intestine, and 16 h later studies of duodenal calcium transport were performed in modified Ussing chambers. In the vitamin D-deficient state, cortisone administration was associated with a diminution in J(MS), J(Net), and the flux ratio (J(MS)/J(SM)). While the magnitude of the increases in J(MS) and J(Net) that resulted from 1,25-DHCC treatment were approximately the same in control and cortisone-treated animals, 1,25-DHCC failed to restore these parameters to "normal levels" in the steroid-treated rats. Furthermore, contrary to the results obtained in the saline-treated controls, 1,25-DHCC failed to reduce J(SM) in the duodenum from cortisone-treated rats. The cortisone-related defect in calcium transport was due to alterations in both unidirectional calcium fluxes (decrease in J(MS) and increase in J(SM)), such that the J(Net) and the flux ratio (J(MS)/J(SM)) were only approximately 50% of the levels achieved in vitamin D-deficient control animals repleted with the same dose of 1,25-DHCC. The administration of 1,25-DHCC was accompanied by a marked increase in the serum calcium levels of control rats, but there was no such response in the cortisone-treated group. The results support the concept that under the conditions of these experiments in the rat the apparent antagonism between glucocorticoids and vitamin D may be due to steroid hormone-related alterations in end organ function that are independent of any direct interaction between the hormone and the vitamin and that cannot be reversed by the vitamin.

Making British cortisone: Glaxo and the development of corticosteroids in Britain in the 1950s-1960s.

PubMed

Quirke, Viviane

2005-12-01

Following the announcement in 1949 in the USA that cortisone offered rheumatoid arthritis sufferers effective treatment for their crippling disease, the Ministry of Health came under considerable pressure from the medical profession and the public to make cortisone available in Britain. The Ministry, therefore, urged British companies to start manufacturing cortisone. Among the several pharmaceutical firms responding to the Ministry's request, Glaxo's expertise in the field of vitamins gave them a head start. This paper describes the varied and flexible strategy that enabled Glaxo to maintain this head start, and the scientific and technical capabilities which the company subsequently built up, enabling them to dominate the market for corticosteroids in Britain. Among the drugs to emerge out of the Glaxo project to manufacture cortisone, which began in 1950 and later became a wider R&D programme on steroids, was the topical steroid Betnovate, launched in 1963, which remains a best-seller today. However, although it led to successful new products, Glaxo's programme had limitations. The paper identifies a missed opportunity, in the shape of the biosynthetic route to steroid drugs, often considered as a milestone in the development of the new biotechnology. Whether or not this missed opportunity proved costly to the company is uncertain. However, it illustrates the role of technological path-dependence, and the importance of the integration between different scientific disciplines, in this case chemistry and biology, in pharmaceutical innovation.

Study on dissolution mechanism of cortisol and cortisone from hair matrix with liquid chromatography-tandem mass spectrometry.

PubMed

Xing, Xue; Chen, Zheng; Li, Jifeng; Zhang, Jing; Deng, Huihua; Lu, Zuhong

2013-06-05

Hair cortisol has been used as a biomarker of chronic stress. The detected contents of hair cortisol might depend on the incubation duration in solvents for no-milled hair samples with 3-layer structure. However, there was no research on the dissolution mechanism of hair analytes. After uniform mixture, no-milled hair samples were incubated in methanol and water for the 12 different durations and milled hair was done as comparison. Hair cortisol and cortisone were determined with high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The measured concentrations of hair cortisol and cortisone showed ≥2 maxima during the entire incubation in methanol and water from 5 min to 72 h for no-milled hair. Hair cortisol concentration measured by LC-MS/MS was increased with the incubation duration. Conversely, it was not held when hair was powdered prior to the incubation in methanol. Hair cortisol and cortisone were dissolved from hair matrix through the 2-stage or multistage mechanism, which might depend on the hair 3-layer structure and its degree of damage. Copyright © 2013 Elsevier B.V. All rights reserved.

Effect of cortisone treatment on the active transport of calcium by the small intestine.

PubMed

Kimberg, D V; Baerg, R D; Gershon, E; Graudusius, R T

1971-06-01

It is generally recognized that glucocorticoid administration may diminish calcium absorption in vivo as well as the active transport of calcium by the intestine in vitro. Recent studies by others have emphasized the possibility of an alteration in the metabolism of vitamin D to 25-hydroxycholecalciferol in accounting for the steroid effects on calcium absorption. The results obtained in the present studies fail to support this hypothesis. The present studies confirm that the administration of cortisone or other glucocorticoids to the rat interferes with the active transport of calcium by duodenal gut sacs in vitro. This abnormality is not due to an alteration in the permeability of the intestine to calcium, and it cannot be corrected by the administration of either massive doses of vitamin D(2) or modest doses of 25-hydroxycholecalciferol. Experiments concerned with the effects of cortisone on the level of the vitamin D-dependent duodenal calcium-binding protein, the amount of bioassayable vitamin D activity in the mucosa, and the distribution and metabolism of (3)H-vitamin D(3), did not provide evidence in favor of a harmone-related defect in either the localization of vitamin D or its metabolism to 25-hydroxycholecalciferol. Alterations in the transport of iron and D-galactose, not dependent on vitamin D, suggest that cortisone treatment may be responsible for more than a simple antagonism to the effects of vitamin D. The results of the present studies indicate that cortisone administration affects the cellular mechanisms mediating calcium transport in a manner that is opposite to the effects of vitamin D, but seems to be independent of any direct interaction with the parent vitamin or its metabolites. If a disorder in vitamin D metabolism is at all involved, it is at a step subsequent to 25-hydroxylation.

Platelet-rich plasma efficacy versus corticosteroid injection treatment for chronic severe plantar fasciitis.

PubMed

Monto, Raymond Rocco

2014-04-01

Chronic plantar fasciitis is a common orthopedic condition that can prove difficult to successfully treat. In this study, autologous platelet-rich plasma (PRP), a concentrated bioactive blood component rich in cytokines and growth factors, was compared to traditional cortisone injection in the treatment of chronic cases of plantar fasciitis resistant to traditional nonoperative management. Forty patients (23 females and 17 males) with unilateral chronic plantar fasciitis that did not respond to a minimum of 4 months of standardized traditional nonoperative treatment modalities were prospectively randomized and treated with either a single ultrasound guided injection of 3 cc PRP or 40 mg DepoMedrol cortisone. American Orthopedic Foot and Ankle Society (AOFAS) hindfoot scoring was completed for all patients immediately prior to PRP or cortisone injection (pretreatment = time 0) and at 3, 6, 12, and 24 months following injection treatment. Baseline pretreatment radiographs and MRI studies were obtained in all cases to confirm the diagnosis of plantar fasciitis. The cortisone group had a pretreatment average AOFAS score of 52, which initially improved to 81 at 3 months posttreatment but decreased to 74 at 6 months, then dropped to near baseline levels of 58 at 12 months, and continued to decline to a final score of 56 at 24 months. In contrast, the PRP group started with an average pretreatment AOFAS score of 37, which increased to 95 at 3 months, remained elevated at 94 at 6 and 12 months, and had a final score of 92 at 24 months. PRP was more effective and durable than cortisone injection for the treatment of chronic recalcitrant cases of plantar fasciitis. Level I, prospective randomized comparative series.

PAROTID FLUID CORTISOL AND CORTISONE.

DTIC Science & Technology

Concentrations of parotid fluid cortisol and cortisone, and of plasma dialyzable cortisol, were measured in normal men before and 2 hours after...of 8.5 to 17.7 micrograms/100 ml. after ACTH treatment, and to 39.4 micrograms/100 ml. after administration of the estrogen. However, parotid fluid...the increase in total plasma cortisol (which was over twice as high after administration of estrogen as of ACTH). Thus parotid fluid corticosteroids

Search for the effect of E-beam irradiation on some steroids

NASA Astrophysics Data System (ADS)

Marciniec, B.; Ogrodowczyk, M.; Dettlaff, K.

2005-03-01

Seven steroid derivatives (hydrocortisone, hydrocortisone acetate, prednisolone, prednisolone acetate, methylprednisolone acetate, dexamethasone and fludrocortisone acetate) irradiated in the solid phase 10 MeV electrons, were studied by chromatographic methods (TLC and HPLC). Before the irradiation the derivatives contained different amounts of the following impurities: cortisone, cortisone acetate, prednisolone, prednisolone acetate and prednisone. After irradiation with a dose of upto 200 kGy radiolytic products were identified: cortisone, cortisone acetate, prednisone, prednisolone and methylprednisone acetate. All the identified radiolytic products were formed as a result of oxidation of the substituent at C 11, and in some cases the oxidation was accompanied by cleavage of the ester bond. The content of impurities before irradiation did not exceed 0.8%, while after the irradiation the content of the products of radiolysis depended on the kind of the derivative and the dose, and varied from 0.6% for a dose of 25 kGy to 4.03% for a dose of 200 kGy. For some derivatives, a linear relationship was found between the loss of a given steroid content and the dose. The studied steroid derivatives are characterised by high radiochemical stability and their sterilisation by irradiation does not lead to loss of the active substance below 97%, i.e. the lower limit admissible by the pharmacopoeias.

Efficacy of Liposomal Amphotericin B and Posaconazole in Intratracheal Models of Murine Mucormycosis

PubMed Central

Luo, Guanpingsheng; Gebremariam, Teclegiorgis; Lee, Hongkyu; French, Samuel W.; Wiederhold, Nathan P.; Patterson, Thomas F.; Filler, Scott G.

2013-01-01

Mucormycosis is a life-threatening fungal infection almost uniformly affecting diabetics in ketoacidosis or other forms of acidosis and/or immunocompromised patients. Inhalation of Mucorales spores provides the most common natural route of entry into the host. In this study, we developed an intratracheal instillation model of pulmonary mucormycosis that hematogenously disseminates into other organs using diabetic ketoacidotic (DKA) or cyclophosphamide-cortisone acetate-treated mice. Various degrees of lethality were achieved for the DKA or cyclophosphamide-cortisone acetate-treated mice when infected with different clinical isolates of Mucorales. In both DKA and cyclophosphamide-cortisone acetate models, liposomal amphotericin B (LAmB) or posaconazole (POS) treatments were effective in improving survival, reducing lungs and brain fungal burdens, and histologically resolving the infection compared with placebo. These models can be used to study mechanisms of infection, develop immunotherapeutic strategies, and evaluate drug efficacies against life-threatening Mucorales infections. PMID:23650163

Lack of regulation of 11β-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism

PubMed Central

Sigurjonsdottir, Helga A; Andrew, Ruth; Stimson, Roland H; Johannsson, Gudmundur; Walker, Brian R

2009-01-01

Objective Evidence from long-term clinical studies measuring urinary steroid ratios, and from in vitro studies, suggests that GH administered for longer than 2 months down-regulates 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), thereby reducing cortisol regeneration in liver and adipose tissue. We aimed to measure acute effects of GH on 11β-HSD1 in liver and adipose tissue in vivo, including using a stable isotope tracer. Design Observational studies of GH withdrawal and reintroduction in patients with hypopituitarism. Methods Twelve men with benign pituitary disease causing GH and ACTH deficiency on stable replacement therapy for >6 months were studied after GH withdrawal for 3 weeks, and after either placebo or GH injections were reintroduced for another 3 weeks. We measured cortisol kinetics during 9,11,12,12-2H4-cortisol (d4-cortisol) infusion, urinary cortisol/cortisone metabolite ratios, liver 11β-HSD1 by appearance of plasma cortisol after oral cortisone, and 11β-HSD1 mRNA levels in subcutaneous adipose biopsies. Results GH withdrawal and reintroduction had no effect on 9,12,12-[2H]3-cortisol (d3-cortisol) appearance, urinary cortisol/cortisone metabolite ratios, initial appearance of cortisol after oral cortisone, or adipose 11β-HSD1 mRNA. GH withdrawal increased plasma cortisol 30–180 min after oral cortisone, increased d4-cortisol clearance, and decreased relative excretion of 5α-reduced cortisol metabolites. Conclusions In this setting, GH did not regulate 11β-HSD1 rapidly in vivo in humans. Altered cortisol metabolism with longer term changes in GH may reflect indirect effects on 11β-HSD1. These data do not suggest that glucocorticoid replacement doses need to be increased immediately after introducing GH therapy to compensate for reduced 11β-HSD1 activity, although dose adjustment may be required in the longer term. PMID:19549748

Intraindividual stability of cortisol and cortisone and the ratio of cortisol to cortisone in saliva, urine and hair.

PubMed

Zhang, Quan; Chen, Zheng; Chen, Shenghuo; Xu, Youyun; Deng, Huihua

2017-02-01

Cortisol, cortisone and the ratio of cortisol to cortisone in saliva, urine and hair are acute, short-term and long-term biomarkers to reliably assess the activity of hypothalamic-pituitary-adrenal (HPA) axis and 11β-hydroxysteroid dehydrogenase (11β-HSD). One key issue is whether these biomarkers have intraindividual relative stability. Salivary, urinary and hair cortisol was proven to show considerable long-term intraindividual relative stability. However, currently unknown is whether cortisone and the ratio in saliva, urine and hair show intraindividual relative stability. The present study utilized a longitudinal design to validate long-term stability within two weeks of three biomarkers in saliva and urine, and long-term stability within twelve months of three hair biomarkers. Salivary, urinary and hair steroids were measured with high performance liquid chromatography tandem mass spectrometry. Three biomarkers in urine and hair showed moderate test-retest correlations with coefficient (r) ranging between 0.22 and 0.56 and good multiple-test consistencies with coefficient of intraclass correlation (ICC) ranging between 0.42 and 0.67. Three single-point salivary biomarkers showed weak to moderate test-retest correlations (r's between 0.01 and 0.38) and poor to fair multiple-test consistencies (ICC's between 0.29 and 0.53) within two weeks. Three single-day salivary biomarkers showed moderate test-retest correlations (r's between 0.23 and 0.53) and good multiple-test consistencies (ICC's between 0.56 and 0.66) within two weeks. Three biomarkers in urine and hair showed moderate long-term intraindividual relative stability. Three single-point salivary biomarkers showed weak to moderate short-term and long-term intraindividual relative stability, but three single-day salivary biomarkers showed moderate short-term and long-term intraindividual relative stability. Copyright © 2016 Elsevier Inc. All rights reserved.

THz spectra of cortisone and the related medicine

NASA Astrophysics Data System (ADS)

Ma, Shihua; Ge, Min; Liu, Guifeng; Song, Xiyu; Zhang, Peng; Wang, Wenfeng

2009-07-01

THz-TDS are used to study four kinds of drug: cortisone, hydrocortisone, prednisone and prednisolone. The THz spectra of them are obtained and analyzed from 0.2 - 1.6 THz. The experimental results shows the four samples have the different THz spectra. Cortisone has a peak at 1.5 THz and a broad absorption peak at 0.96 THz, while hydrocortisone has a weak absorption peak that lies at 1.27 THz. At the same time the prednisone has the stronger absorption peaks than the others, and its two peaks shows at 1.24 THz and 1.5 THz. Prednisolone has a weak broad peak at 1.43 THz. The results of the theoretical calculation were performed using Gaussian 03 software with Density Functional Theory at the basis set of 6-31+G (d, p). The theoretical vibrational frequencies are compared with the experimental results, and the deviations are discussed. The THz spectra of the medicine show THz technique may be help to distinguish some different chemical bond and functional group.

Immunoreactive cortisone in droppings reflect stress levels, diet and growth rate of gull-billed tern chicks.

PubMed

Albano, Noelia; Santiago-Quesada, Francisco; Masero, José A; Sánchez-Guzmán, Juan M; Möstl, Erich

2015-03-01

Blood levels of corticosterone have been traditionally analyzed to assess stress levels in birds; however, measuring steroid hormone metabolites in feces and droppings has gained much interest as a noninvasive technique successfully used for such purposed in vertebrates. Diet may affect these fecal metabolite levels (e.g., due to nutritional stress), however, this variable has not been taken into account in studies with chicks despite the great dietary flexibility of many avian species. In this study, we addressed for the first time this key issue and validated the technique in wild gull-billed tern chicks (Gelochelidon nilotica). Several enzyme immunoassays were used to determine the most appropriate test to measure the stress response. Subsequently, we performed an experiment in captivity to assess adrenocortical activity in gull-billed tern chicks fed with two diets: piscivorous vs. insectivorous. Finally, the relation between the chicks' growth rate and excreted immunoreactive glucocorticoid metabolites (EGMs) was also evaluated. We found the immunoreactive cortisone metabolites to be a good index of stress (as being an index of adrenocortical reactivity) in chicks of this species. Fish-fed chicks had higher levels of cortisone metabolites when comparing both concentration and total daily excreted metabolites. Within each treatment diet, cortisone metabolite levels and growth rates were negatively correlated. These findings suggest that the diet should be considered when using this technique for comparative purposes and highlight the trade-off between stress levels and chicks growth rates. Copyright © 2015 Elsevier Inc. All rights reserved.

Acute effects of 3,4-methylenedioxymethamphetamine and methylphenidate on circulating steroid levels in healthy subjects.

PubMed

Seibert, Julia; Hysek, Cédric M; Penno, Carlos A; Schmid, Yasmin; Kratschmar, Denise V; Liechti, Matthias E; Odermatt, Alex

2014-01-01

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') and methylphenidate are widely used psychoactive substances. MDMA primarily enhances serotonergic neurotransmission, and methylphenidate increases dopamine but has no serotonergic effects. Both drugs also increase norepinephrine, resulting in sympathomimetic properties. Here we studied the effects of MDMA and methylphenidate on 24-hour plasma steroid profiles. 16 healthy subjects (8 men, 8 women) were treated with single doses of MDMA (125 mg), methylphenidate (60 mg), MDMA + methylphenidate, and placebo on 4 separate days using a cross-over study design. Cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, aldosterone, 11-deoxycorticosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone were repeatedly measured up to 24 h using liquid chromatography-tandem mass spectroscopy. MDMA significantly increased the plasma concentrations of cortisol, corticosterone, 11-dehydrocorticosterone, and 11-deoxycorticosterone and also tended to moderately increase aldosterone levels compared with placebo. MDMA also increased the sum of cortisol + cortisone and the cortisol/cortisone ratio, consistent with an increase in glucocorticoid production. MDMA did not alter the levels of cortisone, DHEA, DHEAS, androstenedione, or testosterone. Methylphenidate did not affect any of the steroid concentrations, and it did not change the effects of MDMA on circulating steroids. In summary, the serotonin releaser MDMA has acute effects on circulating steroids. These effects are not observed after stimulation of the dopamine and norepinephrine systems with methylphenidate. The present findings support the view that serotonin rather than dopamine and norepinephrine mediates the acute pharmacologically induced stimulation of the hypothalamic-pituitary-adrenal axis in the absence of other stressors. © 2014 S. Karger AG, Basel.

Genetic influences on hormonal markers of chronic hypothalamic-pituitary-adrenal function in human hair.

PubMed

Tucker-Drob, E M; Grotzinger, A D; Briley, D A; Engelhardt, L E; Mann, F D; Patterson, M; Kirschbaum, C; Adam, E K; Church, J A; Tackett, J L; Harden, K P

2017-01-19

Cortisol is the primary output of the hypothalamic-pituitary-adrenal (HPA) axis and is central to the biological stress response, with wide-ranging effects on psychiatric health. Despite well-studied biological pathways of glucocorticoid function, little attention has been paid to the role of genetic variation. Conventional salivary, urinary and serum measures are strongly influenced by diurnal variation and transient reactivity. Recently developed technology can be used to measure cortisol accumulation over several months in hair, thus indexing chronic HPA function. In a socio-economically diverse sample of 1070 twins/multiples (ages 7.80-19.47 years) from the Texas Twin Project, we estimated effects of sex, age and socio-economic status (SES) on hair concentrations of cortisol and its inactive metabolite, cortisone, along with their interactions with genetic and environmental factors. This is the first genetic study of hair neuroendocrine concentrations and the largest twin study of neuroendocrine concentrations in any tissue type. Glucocorticoid concentrations increased with age for females, but not males. Genetic factors accounted for approximately half of the variation in cortisol and cortisone. Shared environmental effects dissipated over adolescence. Higher SES was related to shallower increases in cortisol with age. SES was unrelated to cortisone, and did not significantly moderate genetic effects on either cortisol or cortisone. Genetic factors account for sizable proportions of glucocorticoid variation across the entire age range examined, whereas shared environmental influences are modest, and only apparent at earlier ages. Chronic glucocorticoid output appears to be more consistently related to biological sex, age and genotype than to experiential factors that cluster within nuclear families.

Furosemide Injection

MedlinePlus

... and cephalexin (Keflex); corticosteroids such as betamethasone (Celestone), budesonide (Entocort), cortisone (Cortone), dexamethasone, fludrocortisone, hydrocortisone (Cortef), methylprednisolone ( ...

Over-the-Counter "Adrenal Support" Supplements Contain Thyroid and Steroid-Based Adrenal Hormones.

PubMed

Akturk, Halis Kaan; Chindris, Ana Maria; Hines, Jolaine M; Singh, Ravinder J; Bernet, Victor J

2018-03-01

To assess whether dietary supplements that are herbal and/or animal-derived products, marketed for enhancing metabolism or promoting energy, "adrenal fatigue," or "adrenal support," contain thyroid or steroid hormones. Twelve dietary adrenal support supplements were purchased. Pregnenolone, androstenedione, 17-hydroxyprogesterone, cortisol, cortisone, dehydroepiandrosterone sulfate, synthetic glucocorticoids (betamethasone, dexamethasone, fludrocortisone, megestrol acetate, methylprednisolone, prednisolone, prednisone, budesonide, and triamcinolone acetonide) levels were measured twice in samples in a blinded fashion. This study was conducted between February 1, 2016, and November 1, 2016. Among steroids, pregnenolone was the most common hormone in the samples. Budesonide, 17-hydroxyprogesterone, androstenedione, cortisol, and cortisone were the others in order of prevalence. All the supplements revealed a detectable amount of triiodothyronine (T3) (63-394.9 ng/tablet), 42% contained pregnenolone (66.12-205.2 ng/tablet), 25% contained budesonide (119.5-610 ng/tablet), 17% contained androstenedione (1.27-7.25 ng/tablet), 8% contained 17-OH progesterone (30.09 ng/tablet), 8% contained cortisone (79.66 ng/tablet), and 8% contained cortisol (138.5 ng/tablet). Per label recommended doses daily exposure was up to 1322 ng for T3, 1231.2 ng for pregnenolone, 1276.4 ng for budesonide, 29 ng for androstenedione, 60.18 ng for 17-OH progesterone, 277 ng for cortisol, and 159.32 ng for cortisone. All the supplements studied contained a small amount of thyroid hormone and most contained at least 1 steroid hormone. This is the first study that measured thyroid and steroid hormones in over-the-counter dietary "adrenal support" supplements in the United States. These results may highlight potential risks of hidden ingredients in unregulated supplements. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

[Glucocorticoid therapy: what is the information sought by patients? Traffic analysis of the website cortisone-info.fr].

PubMed

Poisson, J; Six, M; Morin, C; Fardet, L

2013-05-01

About 1% of the general population are receiving systemic glucocorticoids. The information about this treatment sought by patients is unknown. The website www.cortisone-info.fr aims to provide therapeutic information about glucocorticoids and glucocorticoid therapy. It was posted on January 16, 2012. The information available on the website is documented and based on the recent medical literature. The website is made of 43 pages divided into five main sections (generalities about glucocorticoids, adverse events, measures associated with glucocorticoid therapy, discontinuation of glucocorticoids and, situations requiring attention). The website traffic between February 1st, 2012 and January 4, 2013 was analyzed using Google Analytics. During the study period, the website was visited by 67,496 people (average number of visitors per day: 33 in February 2012, 326 in December 2012). The number of page views was 230,496 or an average of 3.5 pages per visitor. Of these 230,496 page views, 145,431 (63.1%) were related to adverse events and 37,722 (16.4%) were related to generalities about glucocorticoids (e.g., what is cortisone? For which disease? How does it work?). Information particularly sought by visitors was related to the diet to follow during glucocorticoid therapy (page accessed 11,946 times), data about what cortisone is (page accessed 11,829 times) and the effects of glucocorticoids on weight (page accessed 10,442 times). Knowledge of glucocorticoid-treated patients' expectations may help physicians to optimize information they give, thereby helping to reduce patients' concerns about glucocorticoids and to improve adherence to the treatment. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Simultaneous assay of cortisol and dexamethasone improved diagnostic accuracy of the dexamethasone suppression test.

PubMed

Ueland, Grethe Å; Methlie, Paal; Kellmann, Ralf; Bjørgaas, Marit; Åsvold, Bjørn O; Thorstensen, Ketil; Kelp, Oskar; Thordarson, Hrafnkell B; Mellgren, Gunnar; Løvås, Kristian; Husebye, Eystein S

2017-06-01

The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but moderate specificity, for diagnosing hypercortisolism. We have evaluated if simultaneous measurement of S-DXM may correct for variable DXM bioavailability and increase the diagnostic performance of DST, and if saliva (sa) is a feasible adjunct or alternative to serum. Prospective study of DST was carried out in patients with suspected Cushing's syndrome (CS) ( n  = 49), incidentaloma ( n  = 152) and healthy controls ( n  = 101). Cortisol, cortisone and DXM were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Three hundred and two subjects underwent DST; S-cortisol was ≥50 nmol/L in 83 patients, of whom 11 had CS and 27 had autonomous cortisol secretion. The lower 2.5 percentile of S-DXM in subjects with negative DST ( n  = 208) was 3.3 nmol/L, which was selected as the DXM cut-off level. Nine patients had the combination of low S-DXM and positive DST. Of these, three had been misdiagnosed as having autonomous cortisol secretion. DST results were highly reproducible and confirmed in a replication cohort ( n  = 58). Patients with overt CS had significantly elevated post-DST sa-cortisol and sa-cortisone levels compared with controls; 23 of 25 with autonomous cortisol secretion had elevated sa-cortisone and 14 had elevated sa-cortisol. Simultaneous measurement of serum DXM and cortisol reduced false-positive DSTs by 20% and improved the specificity. S-DXM >3.3 nmol/L is sufficient for the suppression of cortisol <50 nmol/L. Measurement of glucocorticoids in saliva is a non-invasive and easy procedure and post-DST sa-cortisone was found particularly useful in the diagnosis of CS. © 2017 European Society of Endocrinology.

The History of Cortisone Discovery and Development.

PubMed

Burns, Christopher M

2016-02-01

Philip Hench, Edward Kendall, and Tadeus Reichstein received the Nobel Prize in medicine and physiology in 1950 for their "investigations of the hormones of the adrenal cortex." Hench and Kendall took compound E from the laboratory to the clinic to the Nobel Prize in a span of 2 years. This article examines the paths that led to the day when the first rheumatoid arthritis patient received cortisone, and from there to the 1950 Nobel Prize ceremony. The aftermath of this achievement is also discussed. Although there have been significant advances in corticosteroid preparations and use since 1950, the side effects remain daunting. Copyright © 2016 Elsevier Inc. All rights reserved.

Recent advances in the study of 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2)Inhibitors.

PubMed

Zhou, Chunchun; Ye, Fan; Wu, He; Ye, Hui; Chen, Quanxu

2017-06-01

11β-Hydroxysteroid dehydrogenase (11β-HSD), which interconverts hormonally active cortisol and inactive cortisone in multiple human tissues, has two distinct isoforms named 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). 11β-HSD2 is an NAD + -dependent oxidase which lowers cortisol by converting it to cortisone while 11β-HSD1 mainly catalyzes the reduction which converts cortisone into cortisol. Selective inhibition of 11β-HSD2 is generally detrimental to health because the accumulation of cortisol can cause metabolic symptoms such as apparent mineralocorticoid excess (AME), fetal developmental defects and lower testosterone levels in males. There has been some advances on the study of 11β-HSD2 inhibitors and we think it necessary to make a summary of the characteristics and inhibiting properties of latest 11β-HSD2 inhibitors. As another review on 11β-HSD2 inhibitors has been issued on 2011 (see review (Ma et al., 2011)), this mini-review concerns advances during the last 5 years. Copyright © 2017 Elsevier B.V. All rights reserved.

Substrate Binding Process and Mechanistic Functioning of Type 1 11β-Hydroxysteroid Dehydrogenase from Enhanced Sampling Methods

PubMed Central

Recanatini, Maurizio; Cavalli, Andrea

2011-01-01

In humans, type 1 11β-hydroxysteroid dehydrogenase (11β-HSD-1) plays a key role in the regulation of the glucocorticoids balance by converting the inactive hormone cortisone into cortisol. Numerous functional aspects of 11β-HSD-1 have been understood thanks to the availability at the Worldwide Protein Data Bank of a number of X-ray structures of the enzyme either alone or in complex with inhibitors, and to several experimental data. However at present, a complete description of the dynamic behaviour of 11β-HSD-1 upon substrate binding is missing. To this aim we firstly docked cortisone into the catalytic site of 11β-HSD-1 (both wild type and Y177A mutant), and then we used steered molecular dynamics and metadynamics to simulate its undocking. This methodology helped shedding light at molecular level on the complex relationship between the enzyme and its natural substrate. In particular, the work highlights a) the reason behind the functional dimerisation of 11β-HSD-1, b) the key role of Y177 in the cortisone binding event, c) the fine tuning of the active site degree of solvation, and d) the role of the S228-P237 loop in ligand recognition. PMID:21966510

Juvenile recurrent parotitis: a retrospective comparison of sialendoscopy versus conservative therapy.

PubMed

Schneider, Helgard; Koch, Michael; Künzel, Julian; Gillespie, M Boyd; Grundtner, Philipp; Iro, Heinrich; Zenk, Johannes

2014-02-01

There are several therapeutic approaches to treat juvenile recurrent parotitis. The aim of this study was to compare sialendoscopy, including prophylactic cortisone irrigation, with observation and a conservative approach of antibiotic therapy alone. Retrospective study, tertiary clinical center. The charts of patients treated for juvenile recurrent parotitis between November 2004 and June 2011 were reviewed. Initial acute flares were always treated with a course of antibiotics. Subsequent treatment consisted of either salivary gland endoscopy including cortisone irrigation or additional pure antibiotic therapy. Patients treated with salivary endoscopy were compared to patients treated with antibiotics alone with regard to the number of inflammatory episodes and pain intensity pre- and posttreatment. Thirty-six patients were treated during the period of study, 15 with salivary endoscopy with cortisone irrigation and 21 with antibiotic therapy alone. A significant reduction in recurrent episodes and pain intensity following therapy was found in both groups. With respect to these two outcomes, the comparison showed two therapeutic options of equal merit. Salivary gland endoscopy is an option in the management of juvenile recurrent parotitis that helps in confirming the diagnosis and that also provides therapeutic intervention. However, although there are further advantages, the definitive value of salivary gland endoscopy requires ongoing evaluation in further prospective studies. 4. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Positive and negative social support and HPA-axis hyperactivity: Evidence from glucocorticoids in human hair.

PubMed

Iob, Eleonora; Kirschbaum, Clemens; Steptoe, Andrew

2018-06-12

While positive social support is associated with lower prevalence of disease and better treatment outcomes, negative social relationships can instead have unfavourable consequences for several physical and mental health conditions. However, the specific mechanisms by which this nexus might operate remain poorly understood. Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity owing to psychosocial stress has been proposed as a potential pathway underlying the link between social support and health. Hair glucocorticoids such as cortisol and cortisone are emerging as promising biomarkers of long-term retrospective HPA activation. Therefore, the aim of this investigation was to examine the effects of positive and negative experiences of social support within key relationships (i.e. spouse/partner, children, other family members, and friends) on cortisol and cortisone. These associations were tested in a sample of 2520 older adults (mean age 68.1) from the English Longitudinal Study of Ageing. Hair samples were collected in wave 6 (2012/13). To understand the impact of cumulative exposure to poor social support, the analysis used self-reported data from waves 4 (2008/09) and 6. Covariates included demographic, socioeconomic, lifestyle, and hair characteristics. In cross sectional analyses, lower positive support from all sources and specifically from children were associated with higher cortisol. Additionally, lower positive support from children was positively associated with cortisone. Similarly, higher overall negative support was related to higher cortisol, and greater negative support from children was also positively associated with cortisone. In longitudinal analyses, there was evidence for positive associations between hair glucocorticoids and cumulative exposure to poorer social support. Experiences of low positive and high negative social support, particularly from children, were both related to higher hair glucocorticoids. Hence, social relationships of poorer quality in later life may have adverse effects on the HPA axis thereby increasing the individual's susceptibility to poor health. Copyright © 2018 Elsevier Ltd. All rights reserved.

The association between perceived emotional support, maternal mood, salivary cortisol, salivary cortisone, and the ratio between the two compounds in response to acute stress in second trimester pregnant women.

PubMed

La Marca-Ghaemmaghami, Pearl; La Marca, Roberto; Dainese, Sara M; Haller, Marina; Zimmermann, Roland; Ehlert, Ulrike

2013-10-01

Little is known about the effect of social support on the reactivity of the hypothalamic-pituitary-adrenal (HPA) axis during pregnancy. Moreover, when investigating the HPA axis most studies do not consider the activity of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), an enzyme within the salivary glands that inactivates cortisol to cortisone. This study explores the association between perceived emotional support and the maternal psychobiological stress response to a standardized naturalistic stressor by assessing maternal mood and the reactivity of salivary cortisol (SalF), salivary cortisone (SalE), and the SalE/(E+F) ratio as a marker of 11β-HSD2 activity. Repeated saliva samples and measures of maternal mood were obtained from 34 healthy second trimester pregnant women undergoing amniocentesis which served as a psychological stressor. The pregnant women additionally responded to a questionnaire of perceived emotional support and provided sociodemographic (e.g., maternal educational degree) and pregnancy-specific data (e.g., planned versus unplanned pregnancy). Perceived emotional support neither showed a significant effect on mood nor on the SalF or SalE response to stress. However, a moderately strong positive association was found between perceived emotional support and SalE/(E+F) (r=.49). Additionally, the final regression analysis revealed a significant negative relationship between educational degree, planned/unplanned pregnancy and SalE/(E+F). Findings suggest a higher metabolization of cortisol to cortisone in pregnant women with higher emotional support. In contrast, higher maternal education and unplanned pregnancy appear to be associated with decreased salivary 11β-HSD2 activity. The current study emphasizes the importance of taking the activity of 11β-HSD2 into account when examining SalF. © 2013.

Determination of free cortisol and free cortisone in human urine by on-line turbulent flow chromatography coupled to fused-core chromatography-tandem mass spectrometry (TFC-HPLC-MS/MS).

PubMed

Sánchez-Guijo, Alberto; Hartmann, Michaela F; Shi, Lijie; Remer, Thomas; Wudy, Stefan A

2014-01-01

Urinary free cortisol and urinary free cortisone are decisive markers for the diagnosis of syndromes related to the dysfunction of the adrenal gland or to evaluate certain enzymatic disorders. Here, we present a new method, designed for routine laboratory use, which enables quick determination of these analytes with minor sample workup. Turbulent flow chromatography shortens sample preparation, and connection to a fused-core particle-packed column (rugged amide-embedded C18 phase) permits a rapid and effective separation of the analytes, as well as additional separation from other related and isobaric compounds present in urine. Urinary isobaric compounds were successfully identified. The method requires only 100 μl of urine supernatant per sample. The total time between injections is 9.5 min. The solvents used for both turbulent and analytical chromatography are water and methanol, and the relatively low flows needed during the method resulted in an extended life of the columns. Linearity showed a R (2) > 0.994. Limit of detection and limit of quantification are 0.5 and 1.0 ng/ml for cortisone and 1.0 and 2.0 ng/ml for cortisol. Recoveries ranged from 99.7 to 109.1 % for cortisone and from 98.7 to 102.9 % for cortisol. Accuracy values (relative errors) for intra- and inter-assay experiments were always below 8 %, whereas precision (percent CV) ranged from 3.7 to 10.7 %. No matrix effects were detected during the validation process. The reproducibility for each analyte's retention time was excellent, with a coefficient of variation always below 0.2 %. The final validation step included the study of urine samples from healthy children and from children previously diagnosed with corticoidal disorders. The high selectivity achieved enables quick data handling.

[Phagocytosis and intracellular proliferation of Nocardia asteroides (strain Weipheld) in cell structures in vitro. 2. Peritoneal macrophages of guinea-pigs (author's transl)].

PubMed

Splino, M; Mĕrka, V; Kyntera, F

1976-08-01

The study deals with the phagocytosis of Nocardia asteroides (strain Weipheld) and the subsequent intracellular proliferation in peritoneal macrophage cells. Normal, two-stage-immunized and long-term cortison-treated guinea-pig (28 mg cortison / kg weight / day during 30 days) macrophages were used. Further, the cytotoxic effect of Nocardia upon the cells in the peritoneal washing liquid in vitro and the influence of the normal, immune and antimacrophage serum upon the phagocytosis and the intracellular proliferation were studied. Among the cells obtained from the peritoneal washing liquid macrophages were most frequently subject to phagocytosis, leukocytes to a lesser degree. The normal macrophages phagocytized in 14.56% (Fig. 1), macrophages of two-stage-immunized guinea-pigs in 18.21% (Fig. 2) and macrophages from cortison treated guinea-pigs in 12.48% of cases. Intracellular observation showed phagocytized germs after 3 min. of exposure. The course of the intracellular proliferation of Nocardia can be seen in Fig. 3. The phagocytosis index increases slowly in all three groups of macrophages; least so in the immunized macrophages (1.30-after 8 hours). The highest values were obtained in the macrophages of cortison treated guinea-pigs (2.02-after 8 hours). Within 8 hours of exposure the filaments of Nocardia grew through the cell membrane of phagocytizing cells (Figs. 4 A, 4 B). Fig. 5 shows the course of the cytopathogenic effect of Nocardia upon the cells. After 1 hr. the number of dead cells increased from 0.30% to 1.9-3.8%; after 4 hrs. it reached 8.15-9.80%; after 8 hrs. 10.1-14.80%. The highest values were observed in cells from cortison treated guinea-pigs (14.80%). After addition of normal serum (time of phagocytosis 60 min.) normal peritoneal macrophages phagocytized in 13.30% of cases; immune serum stimulated phagocytosis (16.21%); antimacrophage serum significantly reduced phagocytosis (4.10%). The phagocytosis index in peritoneal macrophages with normal and immune serum increased, reaching values of 1.20-1.58 with in 8 hours; the differences were statistically not significant (Fig. 6). A significant increase of proliferation was observed in peritoneal macrophages with antimacrophage serum (2.07 in 8 hours). Neither normal nor immune guine-pig serum influenced the cytopathogenic effect of Nocardia on the cells of peritoneal washing liquid (Fig. 7). The antimacrophage serum had a rapid and expressive effect upon the macrophages (78.23% of cells died after 2 hours, 100% after 3 hours of exposure).

Deep Friction Massage Versus Steroid Injection in the Treatment of Lateral Epicondylitis.

PubMed

Yi, Rosemary; Bratchenko, Walter W; Tan, Virak

2018-01-01

The aim of the study was to determine the efficacy of deep friction massage in the treatment of lateral epicondylitis by comparing outcomes with a control group treated with splinting and therapy and with an experimental group receiving a local steroid injection. A randomized clinical trial was conducted to compare outcomes after recruitment of consecutive patients presenting with lateral epicondylitis. Patients were randomized to receive one of 3 treatments: group 1: splinting and stretching, group 2: a cortisone injection, or group 3: a lidocaine injection with deep friction massage. Pretreatment and posttreatment parameters of visual analog scale (VAS) pain ratings, Disabilities of the Arm, Shoulder and Hand (DASH) scores, and grip strength were measured. Outcomes were measured at early follow-up (6-12 weeks) and at 6-month follow-up. There was a significant improvement in VAS pain score in all treatment groups at early follow-up. DASH score and grip strength improved in the cortisone injection group and the deep friction massage group at early follow-up; these parameters did not improve in the splinting and stretching group. At 6-month follow-up, only patients in the deep friction massage group demonstrated a significant improvement in all outcome measures, including VAS pain score, DASH score, and grip strength. Deep friction massage is an effective treatment for lateral epicondylitis and can be used in patients who have failed other nonoperative treatments, including cortisone injection.

Hair cortisol and cortisone are decreased by natural sunlight.

PubMed

Wester, Vincent L; van der Wulp, Nils R P; Koper, Jan W; de Rijke, Yolanda B; van Rossum, Elisabeth F C

2016-10-01

Hair glucocorticoids (cortisol and cortisone) are increasingly used as measures of long-term integrated exposure to glucocorticoid hormones. Glucocorticoids gradually disappear from the hair shaft, which may result from exposure to ultraviolet (UV) radiation in natural sunlight. We aimed to study the influence of sun exposure on hair glucocorticoids. Scalp hair samples were obtained from nine volunteers (median age 33 [range 21-81], 7 females), and part of each hair sample was exposed to three experimental conditions: repeated exposure to natural sunlight for 40h (natural UV), exposure to a high amount of artificial UV radiation, and storage in the dark (control). Hair cortisol (HairF) and cortisone (HairE) were quantified by liquid chromatography-tandem mass spectrometry. When compared to control, HairF was decreased in 9 out of 9 hair samples after natural sunlight exposure (median decrease -3.1pg/mg or -54%, P<0.001) and artificial UV radiation (-4.7pg/mg or -75%, P=0.003). HairE decreased in 8 out of 9 samples, both after natural sunlight (-7.6pg/mg or -32%, P=0.012) and artificial UV (-10.7pg/mg or -52%, P=0.026). Exposure to natural sunlight decreases the glucocorticoid content of scalp hair, apparently through UV radiation, and is therefore an important confounder that should be considered in studies involving the measurement of hair glucocorticoids. Copyright © 2016 Elsevier Ltd. All rights reserved.

Thyroid Reactions in Acute Experimental Conditions, as Investigated with the Help of Radioactive Iodine I$sup 13$$sup 1$; REACTIONS THYROIDIENNES DANS DES ETATS EXPERIMENTAUX AIGUS ETUDIEES A L'AIDE DE L'IODE RADIOACTIF I$sup 13$$sup 1$

DOE Office of Scientific and Technical Information (OSTI.GOV)

Milcou, St.; Sahleanu, V.; Holban, R.

1959-10-31

The thyroid reactions were studied in control rats and guinea pigs and in animals receiving cortisone. The capture of I/sup 131/ by the thyroid was followed under experimenta1 conditions where the harmful agent used represented the microbic toxic component or the antigenic component. An increase in the rate of capture was noted after 24 hr in guinea pigs which had received diphtheria toxin, followed by a drop with finally a second increase. These results showed that there is a definite thyroid functional cycle in response to a toxic aggression. In the case of guinea pigs which were given cortisone atmore » the same time, no such drop was noted. This suggests that thyroid inactivation is connected to the proper functioning of the corticotropic axis and that ACTH release may modify the thyroid reactions. In the rats which were given mixed antithyroid-parathyroid vaccine subcutaneously, a significant drop in the rate of capture was noted. When associated with cortisone, this treatment raised the capture rate somewhat among the controls. This result also suggests that the inactivation of the thyroid in stress is mainly dependent on ACTH release and not on impregnation with the corticoids. (J.S.R.)« less

Extraction of steroidal glucosiduronic acids from aqueous solutions by anionic liquid ion-exchangers

PubMed Central

Mattox, Vernon R.; Litwiller, Robert D.; Goodrich, June E.

1972-01-01

A pilot study on the extraction of three steroidal glucosiduronic acids from water into organic solutions of liquid ion-exchangers is reported. A single extraction of a 0.5mm aqueous solution of either 11-deoxycorticosterone 21-glucosiduronic acid or cortisone 21-glucosiduronic acid with 0.1m-tetraheptylammonium chloride in chloroform took more than 99% of the conjugate into the organic phase; under the same conditions, the very polar conjugate, β-cortol 3-glucosiduronic acid, was extracted to the extent of 43%. The presence of a small amount of chloride, acetate, or sulphate ion in the aqueous phase inhibited extraction, but making the aqueous phase 4.0m with ammonium sulphate promoted extraction strongly. An increase in the concentration of ion-exchanger in the organic phase also promoted extraction. The amount of cortisone 21-glucosiduronic acid extracted by tetraheptylammonium chloride over the pH range of 3.9 to 10.7 was essentially constant. Chloroform solutions of a tertiary, a secondary, or a primary amine hydrochloride also will extract cortisone 21-glucosiduronic acid from water. The various liquid ion exchangers will extract steroidal glucosiduronic acid methyl esters from water into chloroform, although less completely than the corresponding free acids. The extraction of the glucosiduronic acids from water by tetraheptylammonium chloride occurs by an ion-exchange process; extraction of the esters does not involve ion exchange. PMID:5075264

FACTORS INFLUENCING HOST-VIRUS INTERACTIONS

PubMed Central

Boring, William D.; Angevine, D. Murray; Walker, Duard L.

1955-01-01

A study was made of the pathogenesis of infection due to the Conn.-5 strain of Coxsackie virus in 4 to 5 day old infant mice, untreated adult mice, and adult mice treated with cortisone. The quantitative distribution of virus and the evolution of lesions in different tissues were followed for the first 7 days of the infection. Virus dissemination was prompt and widespread via the blood in all groups. In 4 to 5 day old infant mice viral multiplication and cellular injury occurred in many organs and tissues, while in untreated adult mice these processes were largely limited to the pancreas, even though infecting virus appeared to be equally available to other tissues from the blood. Treatment of adult mice with a single injection of 2.5 mg. cortisone resulted in viral multiplication and tissue damage in several sites in addition to the pancreas, the most marked occurring in the liver and heart. In a consideration of possible mechanisms involved, it was thought unlikely that the differences in the course of the disease in the three groups could be attributed solely to differences in the specific immune response. It is suggested that developmental changes in cells and tissues, perhaps related to cellular metabolism and alterable by cortisone administration, are the major factors determining the location and extent of viral multiplication and tissue injury in this infection in mice. PMID:13271687

Addison's Disease

MedlinePlus

... usually involves taking prescription hormones. This can include hydrocortisone, prednisone, or cortisone acetate. If your body is ... treatment typically consists of intravenous (IV) injections of hydrocortisone, saline (salt water), and dextrose (sugar). These injections ...

Validation of an LC-MS/MS salivary assay for glucocorticoid status assessment: Evaluation of the diurnal fluctuation of cortisol and cortisone and of their association within and between serum and saliva.

PubMed

Mezzullo, Marco; Fanelli, Flaminia; Fazzini, Alessia; Gambineri, Alessandra; Vicennati, Valentina; Di Dalmazi, Guido; Pelusi, Carlotta; Mazza, Roberta; Pagotto, Uberto; Pasquali, Renato

2016-10-01

Salivary steroid testing represents a valuable source of biological information; however, the proper measurement of low salivary levels is challenging for direct immunoassays, lacking adequate sensitivity and specificity and causing poor inter-laboratory reproducibility. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has overcome previous analytical limits, often providing results deviating from previous knowledge. Nowadays, LC-MS/MS is being introduced in clinical laboratories for salivary cortisol testing; however, so far only a few studies have reported thorough biological validation based on LC-MS/MS data. In this study, we provide a thorough analytical, pre-analytical and biological validation of an LC-MS/MS method for the measurement of salivary cortisol (F) and of its inactive metabolite cortisone (E). Analytes were extracted from 50μl of saliva, were then separated in 7.5min LC-gradient and detected by negative electrospray ionization-multiple reaction monitoring. The reliability of a widely diffused collection device, Salivette(®), was assessed and the overall procedure was validated. The diurnal cortisol and cortisone fluctuation in saliva and serum was described by a four paired collection protocol (8 am, 12 am, 4 pm and 8 pm) in 19 healthy subjects. The assay allowed the quantitation of F and E down to 39.1 and 78.1pg/ml, with an imprecision range of 5.5-9.5%, 3.9-14.1% and 2.6-14.4%, and an accuracy range of 105.5-113.1%, 88.5-98.7% and 90.7-96.7% for both analytes at low, medium and high levels, respectively. Salivette(®) provided comparable results and better precision (CV<1.0%) as referred to direct spitting (CV<13.0%). A parallel diurnal rhythm in saliva and serum was observed for cortisol and cortisone, with values lowering from the morning to the evening time points (P<0.0001). While salivary E linearly correlated to total serum F (R(2)=0.854, P<0.001), salivary F showed an exponential relationship (R(2)=0.903, P<0.001) with serum F reflecting the free circulating fraction. A non linear association between E and F was observed in saliva (R(2)=0.941, p<0.001) consistent with the type II 11β-HSD activity. We concluded that our LC-MS/MS method allowed a sensitive evaluation of salivary levels of cortisol and cortisone. The simultaneous determination of both hormones in saliva allowed the differential estimation of the active and of the total glucocorticoid exposure over the daytime. The assay could provide further insight into the comprehension of normal and dysfunctional glucocorticoid circadian rhythm. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Measurement of free urinary cortisol and cortisone using liquid chromatography associated with tandem mass spectrometry method].

PubMed

Vieira, José Gilberto H; Nakamura, Odete H; Carvalho, Valdemir M

2005-04-01

Free urinary cortisol (UFF) measurement is one of the most useful screening tests for Cushing's syndrome. Immunoassays employed today by most clinical laboratories present limitations, specially concerning specificity. These limitations restrain a widespread application of the method, as well as the comparison of results obtained by the use of different methods. We present the development and characterization of a UFF and cortisone method based on liquid chromatography and tandem mass spectrometry (LC-MS/MS). A 200 microL aliquot from a 24 h urine sample is mixed with a solution containing a known quantity of deuterated cortisol and on-line extracted in solid phase (C18). The eluate is transferred to a second C18 column (Phenomenex Luna, 3 micro, 50 x 2 mm) and the isocratic mode elution profile is directly applied to a tandem mass spectrometer model Quattro Micro operating in positive mode atmospheric pressure chemical ionization (APCI). All process is automated and the quantification is performed by isotopic dilution, based on the analyte and the deuterated internal standard peak area ratios. The specificity study showed that all the steroids tested presented cross reactivity of <1% for cortisol and cortisone. Functional sensitivity is <1 microg/L for both steroids, and the interassay CV <8%. Recovery and linearity studies were satisfactory and comparison of results obtained using a RIA for UFF and the present method in 98 routine samples showed a correlation of r= 0.838, with the results obtained with LC-MS/MS significantly lower (medians of 22.0 vs. 49.4 microg/24 h for RIA) (P<0.0001). Reference values for cortisol were defined as values between 11 and 43 microg/24 h, compatible to those recently described for similar methods. The concomitant measurement of UF cortisone allows the study of the activity of the enzyme 11beta-HSD2 and the diagnosis of the apparent mineralocorticoid excess syndrome. The method represents the first steroid assay of a new generation, based on automated preparative methods and tandem mass spectrometry, described in our country.

Hemorrhoids

MedlinePlus

... by simply looking at the rectal area. External hemorrhoids can often be detected this way. Tests that may help diagnose the problem include: Rectal exam Sigmoidoscopy Anoscopy Treatment Treatments for hemorrhoids include: Over-the-counter corticosteroid (for example, cortisone) ...

Successful treatment of chronic wound infection in neutropenia and rheumatoid arthritis with filgrastim (rhG-GSF)

PubMed

Fohlman, J; Höglund, M; Bergmann, S

1994-09-01

A 73-year-old woman was diagnosed with seropositive destructive rheumatoid arthritis in 1981. She was treated with cortisone, chloroquine, and cyclophosphamide (Sendoxan) in 1982 and 1984 and contracted severe neutropenia. After that she only received cortisone. During 1991, again low neutrophilic counts were registered, especially granulocytopenia. At first, B-cell lymphoma was suspected, but later Felty's syndrome was established. The patient was treated with high-dose cortisone with some success and had a few minor septic episodes. In May 1992 she contracted a traumatic wound on the back of the lower leg. Conservative treatment resulted in a worsening of the condition and an increased wound area, most likely related to the neutropenic condition. In mid July the patient was hospitalized. Bacterial isolates yielded mixed gram-negative enteric bacteria from the wound. Parenteral antibiotic treatment was started, followed by oral drugs, rhG-CSF (filgrastim) was given subcutaneously once a day, starting 3 days after admission. This resulted in increased numbers of peripheral granulocytes. The ulcer started to heal and by mid August the patient received a transplant with autologous skin grafting. In mid September the wound was completely healed. It is concluded that the combination of antibiotics, skin transplantation, and G-CSF was necessary for the successful result. Actually, the bacterial growth did not call for antibiotics, but it was considered necessary to cover for staphylococci. No worsening of the underlying arthritis was observed.

The Effect of Glycyrrhetinic Acid on Pharmacokinetics of Cortisone and Its Metabolite Cortisol in Rats

PubMed Central

Lin, Dan; Sun, Wei; Wang, Zhe; Chen, Lian-Guo; Chen, Xiao-Le; Wang, Shuang-Hu; Li, Wan-Shu; Ge, Ren-Shan; Hu, Guo-Xin

2012-01-01

The purpose of this paper is to study pharmacokinetics of cortisone (E) and its metabolite cortisol (F) in rats after administration of glycyrrhetinic acid (GA) and cortisone. Healthy male SD rats were randomized to be given 20 mg/kg E or E combined with 10 mg/kg GA. Blood samples were collected at 5, 10, 20, 40, 60, 90, 120, 150, 180, and 240 min after administration. The serum concentrations of E and F were determined by HLPC and pharmacokinetic parameters were calculated using DASver2.0 software. The parameters of AUC(0−t), AUC(0−∞), and Cmax for E in the group of E + GA were significantly higher than those in the group of E (P < 0.01); the half-time (t1/2β) was extended compared to E (P < 0.05) and CL/F was dropped obviously (P < 0.01). The rise in AUC(0−t), AUC(0−∞), and Cmax for cortisol in the group of E + GA was significantly compared to the group of E (P < 0.01). CL/F was lower than E (P < 0.01) and the half-time (t1/2β) was slightly extended. In this study, we find that GA restrains the metabolism of E and F and thus increases AUC, t1/2β, and Cmax of E and F, which may be related to its inhibition effect on 11β-hydroxysteroid dehydrogenase (11β-HSD). PMID:23258958

What is Psoriasis? | NIH MedlinePlus the Magazine

MedlinePlus

... Sometimes psoriasis will appear after a cut, scratch, sunburn, or an infection. How Does Psoriasis Affect Quality ... the skin may be a reaction to severe sunburn or to taking cortisone or other medicines. It ...

Steroids for Treating Cancer (For Parents)

MedlinePlus

... occurring steroid in the body called cortisol. How Cortisol Can Help Cortisol is a hormone (like testosterone or estrogen) that ... body. Synthetic versions of the hormone — including cortisone, hydrocortisone, prednisone, and methylprednisolone and dexamethasone — are prescribed to ...

Menopause and Bone Loss

MedlinePlus

... cortisone) • Eating a diet low in calcium and vitamin D • Getting little or no exercise • Smoking cigarettes • Drinking ... and take a daily calcium supplement if necessary. • Vitamin D. Your body needs vitamin D to absorb calcium ...

Radiolytic degradation scheme for 60Co-irradiated corticosteroids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kane, M.P.; Tsuji, K.

The cobalt 60 radiolytic degradation products have been identified in the following corticosteroids: cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone sodium succinate, isoflupredone acetate, methylprednisolone, methylprednisolone acetate, prednisolone, prednisolone acetate, and prednisone. Two major types of degradation processes have been identified: loss of the corticoid side chain on the D-ring to produce the C-17 ketone and conversion of the C-11 alcohol, if present, to the C-11 ketone. Minor degradation products derived from other changes affecting the side chain are also identified in several corticosteroids. These compounds are frequently associated in corticosteroids as process impurities or degradation compounds. No new radiolyticmore » compounds unique to 60Co-irradiation have been found. The majority of corticosteroids have been shown to be stable to 60Co-irradiation. The rates of radiolytic degradation ranged from 0.2 to 1.4%/Mrad.« less

Clindamycin in a murine model of toxoplasmic encephalitis.

PubMed Central

Hofflin, J M; Remington, J S

1987-01-01

We investigated the efficacy of clindamycin in a murine model of toxoplasmic encephalitis using direct intracerebral inoculation. Clindamycin reduced mortality from 40% in normal mice and 100% in cortisone-treated mice to 0% in both groups. Although we were unable to document appreciable levels of clindamycin in the brains of infected mice, the histological features of cerebral infection were markedly altered. The formation of large numbers of cysts and the intense inflammatory response seen in the brains of normal mice and the unchecked infection and tissue necrosis in the brains of cortisone-treated mice were absent in the brains of clindamycin-treated mice. Enumeration of cysts in the brains of mice 10 weeks after infection revealed a significantly lower number in the clindamycin-treated mice. Spread of infection to other organs was also decreased during clindamycin administration. These observations suggest that clindamycin may have a role in the therapy of toxoplasmic encephalitis. Images PMID:3606059

Apparent mineralocorticoid excess syndrome: report of one family with three affected children.

PubMed

Al-Harbi, Taiba; Al-Shaikh, Adnan

2012-01-01

The syndrome of apparent mineralocorticoid excess (AME) is an autosomal recessive disorder characterized by hypertension, hypokalemia, low renin, and hypoaldosteronism. It is caused by deficiency of 11β-hydroxysteroid dehydrogenase, which results in a defect of the peripheral metabolism of cortisol to cortisone. As a consequence, the serum cortisol half-life (T½) is prolonged, ACTH is suppressed, and serum cortisol concentration is normal. The hormonal diagnosis of the disorder is made by the increased ratio of urine-free cortisol to cortisone. In patients with AME, this ratio is 5-18, while in normal individuals it is <0.5. These studies suggest that an abnormality in cortisol action or metabolism results in cortisol behaving as a potent mineralocorticoid and causing the syndrome of AME. We report three siblings - two female and one male - with the syndrome of apparent mineralocorticoid excess who presented with hypertension, hypokalemia, low renin, and low aldosterone levels. The finding of abnormally high ratios of 24-h urine-free cortisol to cortisone in our three patients (case 1, 8.4; case 2, 25; and case 3, 7.5) confirmed the diagnosis of apparent mineralocorticoid excess syndrome in these children. They were treated with oral potassium supplements. The addition of spironolactone resulted in a decrease in blood pressure, rise in serum potassium and a gradual increase in plasma renin activity in all three. In this study, the genetic testing of those three siblings with the typical clinical features of AME has detected missense mutation c.662C>T (p.Arg208Cys) in exon 3 of the HSD11B2 gene in the homozygous state.

Atraumatic bilateral rupture of the peroneus brevis tendon in recreational sport: A case report

PubMed Central

Scheidegger, Patric; Weisskopf, Lukas; Hirschmüller, Anja

2017-01-01

Issue: Lower extremity tendon injuries often occur in physically active individuals. Most ruptures not involving great force are diagnosed in patients presenting underlying tendon degenerations. This also applies to patients taking medications because of a disease. We have observed several cases of bilateral Achilles tendon ruptures in patients who have been taking cortisone for a long period. We treated a healthy colleague (neurologist) in our clinic who sustained ruptures of the Achilles tendon on the left side (2012) and the peroneus brevis tendon on left side (2015) and right side (2016) after minimal traumata. Aim of this report is to provide a systematic review of this case and a literature review of similar cases, as few such cases have been published. Methods: We reviewed and analysed this patient’s records containing the sport-specific anamnesis, pre-existing condition, anamnesis of medications and therapy. The three injuries were magnetic resonance imaging–proven. Furthermore, the tendon’s condition was examined histologically in the context of the operative treatment through lace technique of the Achilles tendon and transfer of the peroneus brevis to the peroneus longus. We also researched the literature for bilateral ruptures of the peroneal tendons. Results and conclusion: The anamnesis confirmed no underlying disease. The patient took a macrolide antibiotic about half a year prior to the first peroneal injury for an otitis media. He denied having taken any other antibiotics, especially no quinolone antibiotics. However, the patient reported cortisone intake for 2 days some months before the second peroneal injury to treat an allergic reaction. That involved no local cortisone infiltration in the lower extremity. He underwent surgery within the first 2 weeks after each trauma. Each time, postoperative follow-ups revealed a good healing process. Three months after each operation, the patient was free of complaints. Axibal and Anderson described a patient with bilateral peroneus longus and peroneus brevis ruptures, as well as an Achilles tendon rupture on the left side plus tendinopathy of the Achilles tendon on the right side of uncertain aetiology. We detected additional similar cases in patients who had taken medications, especially cortisone and levofloxacine. Further research should be conducted to clarify other risk factors to help prevent such injuries. PMID:29276600

21 CFR 862.1385 - 17-Hydroxycorticosteroids (17-ketogenic steroids) test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1385 17-Hydroxycorticosteroids (17-ketogenic steroids) test system... nucleus in urine. Corticosteroids with this chemical configuration include cortisol, cortisone 11...

21 CFR 862.1385 - 17-Hydroxycorticosteroids (17-ketogenic steroids) test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1385 17-Hydroxycorticosteroids (17-ketogenic steroids) test system... nucleus in urine. Corticosteroids with this chemical configuration include cortisol, cortisone 11...

21 CFR 862.1385 - 17-Hydroxycorticosteroids (17-ketogenic steroids) test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1385 17-Hydroxycorticosteroids (17-ketogenic steroids) test system... nucleus in urine. Corticosteroids with this chemical configuration include cortisol, cortisone 11...

21 CFR 862.1385 - 17-Hydroxycorticosteroids (17-ketogenic steroids) test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1385 17-Hydroxycorticosteroids (17-ketogenic steroids) test system... nucleus in urine. Corticosteroids with this chemical configuration include cortisol, cortisone 11...

Consumption of Green Coffee Reduces Blood Pressure and Body Composition by Influencing 11β-HSD1 Enzyme Activity in Healthy Individuals: A Pilot Crossover Study Using Green and Black Coffee

PubMed Central

Revuelta-Iniesta, R.; Al-Dujaili, E. A. S.

2014-01-01

Dietary polyphenols may have a protective role against the development of CVD. Thus, we aimed to investigate the effects of green coffee (GC), rich in chlorogenic acid, and black coffee (BC) on cardiovascular markers. A randomised pilot crossover study was performed on healthy subjects who consumed both coffees for 2 weeks. We measured anthropometry, blood pressure, and arterial elasticity after each intervention and collected urine samples to monitor antioxidant capacity. Free cortisol and cortisone levels were obtained from urine and analysed by specific ELISA methods. Systolic blood pressure (P = 0.018) and arterial elasticity (P = 0.001) were significantly reduced after GC. BMI (P = 0.04 for BC; P = 0.01 for GC) and abdominal fat (P = 0.01 for BC; P = 0.009 for GC) were also significantly reduced with no changes in energy intake. Urinary free cortisol was significantly reduced from 125.6 ± 85.9 nmol/day to 76.0 ± 54.9 nmol/day following GC and increased to 132.1 ± 89.1 nmol/day after BC. Urinary free cortisone increased by 18% following BC and 9% following GC (nonsignificant). Cortisol/cortisone ratio (indicating 11β-HSD1 activity) was reduced after GC (from 3.5 ± 1.9 to 1.7 ± 1.04, P = 0.002). This suggests that GC can play a role in reducing cardiovascular risk factors. Further research including hypertensive and overweight individuals will now be justified to clarify whether GC could have a therapeutic role in CVD. PMID:25133164

Determination of steroid hormones and their metabolite in several types of meat samples by ultra high performance liquid chromatography-Orbitrap high resolution mass spectrometry.

PubMed

López-García, Marina; Romero-González, Roberto; Garrido Frenich, Antonia

2018-03-09

A new analytical method based on ultra-high performance liquid chromatography (UHPLC) coupled to Orbitrap high resolution mass spectrometry (Orbitrap-HRMS) has been developed for the determination of steroid hormones (hydrocortisone, cortisone, progesterone, prednisone, prednisolone, testosterone, melengesterol acetate, hydrocortisone-21-acetate, cortisone-21-acetate, testosterone propionate, 17α-methyltestosterone, 6α-methylprednisolone and medroxyprogesterone) and their metabolite (17α-hydroxyprogesterone) in three meat samples (chicken, pork and beef). Two different extraction approaches were tested (QuEChERS "quick, easy, cheap, effective, rugged and safe" and "dilute and shoot"), observing that the QuEChERS method provided the best results in terms of recovery. A clean-up step was applied comparing several sorbents, obtaining the best results when florisil and aluminum oxide were used. The optimized method was validated, obtaining suitable results for all validation parameters in the three meat matrices evaluated. Recovery values ranged from 70% to 103% (except for prednisone in beef samples), meanwhile repeatability and reproducibility were obtained at values lower than 18% and 21%, respectively. The limit of quantification (LOQ) was established for most of the compounds at 1.0 μg/kg, except for testosterone in chicken and hydrocortisone-21-acetate and cortisone-21-acetate in pork at 2.0 μg/kg. Decision limit (CCα) and detection capability (CCβ) values ranged from 1.0-2.7 μg/kg and 1.9-5.5 μg/kg, respectively, in the three matrices. Finally, thirty one meat samples were analyzed and two hormones, progesterone and hydrocortisone, were detected in a beef and pork sample at 1.7 and 2.8 μg/kg respectively. Copyright © 2018 Elsevier B.V. All rights reserved.

Depot-specific Regulation of the Conversion of Cortisone to Cortisol in Human Adipose Tissue

PubMed Central

Lee, Mi-Jeong; Fried, Susan K.; Mundt, Steven S.; Wang, Yanxin; Sullivan, Sean; Stefanni, Alice; Daugherty, Bruce L.; Hermanowski-Vosatka, Anne

2015-01-01

Objective Our main objective was to compare the regulation of cortisol production within omental (Om) and abdominal subcutaneous (Abd sc) human adipose tissue. Methods and Procedures Om and Abd sc adipose tissue were obtained at surgery from subjects with a wide range of BMI. Hydroxysteroid dehydrogenase (HSD) activity (3H-cortisone and 3H-cortisol interconversion) and expression were measured before and after organ culture with insulin and/or dexamethasone. Results Type 1 HSD (HSD1) mRNA and reductase activity were mainly expressed within adipocytes and tightly correlated with adipocyte size within both depots. There was no depot difference in HSD1 expression or reductase activity, while cortisol inactivation and HSD2 mRNA expression (expressed in stromal cells) were higher in Om suggesting higher cortisol turnover in this depot. Culture with insulin decreased HSD reductase activity in both depots. Culture with dexamethasone plus insulin compared to insulin alone increased HSD reductase activity only in the Om depot. This depot-specific increase in reductase activity could not be explained by an alteration in HSD1 mRNA or protein, which was paradoxically decreased. However, in Om only, hexose-6-phosphate dehydrogenase (H6PDH) mRNA levels were increased by culture with dexamethasone plus insulin compared to insulin alone, suggesting that higher nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) production within the endoplasmic reticulum (ER) contributed to the higher HSD reductase activity. Discussion We conclude that in the presence of insulin, glucocorticoids cause a depot-specific increase in the activation of cortisone within Om adipose tissue, and that this mechanism may contribute to adipocyte hypertrophy and visceral obesity. PMID:18388900

Treatment of Tuberculosis with Rifamycin-containing Regimens in Immune-deficient Mice

PubMed Central

Zhang, Ming; Li, Si-Yang; Rosenthal, Ian M.; Almeida, Deepak V.; Ahmad, Zahoor; Converse, Paul J.; Peloquin, Charles A.; Nuermberger, Eric L.; Grosset, Jacques H.

2011-01-01

Rationale: Daily rifapentine plus isoniazid-pyrazinamide in mice infected with Mycobacterium tuberculosis produces cure in 3 months. Whether cure corresponds to latent infection contained by host immunity or true tissue sterilization is unknown. Objectives: To determine the length of treatment with rifapentine-isoniazid-pyrazinamide or rifampin-isoniazid-pyrazinamide needed to prevent relapse in immune-deficient mice. Methods: Aerosol-infected BALB/c and nude mice were treated 5 days per week with either 2 months of the rifapentine-based regimen followed by rifapentine-isoniazid up to 12 months or the same regimen with rifampin instead of rifapentine. Cultures of lung homogenates were performed during the first 3 months and then every 3 months. Relapse rates were assessed after 3, 6, 9, and 12 months of treatment in BALB/c (± 1 mo of cortisone) and nude mice. Measurements and Main Results: All rifapentine-treated mice were lung culture–negative at 3 months but 13% of BALB/c that received cortisone and 73% of nude mice relapsed. After 6, 9, and 12 months of treatment no mouse relapsed. Rifampin-treated BALB/c mice remained culture positive at 3 months. All were culture negative at 6, 9, and 12 months. None, including those receiving cortisone, relapsed. Rifampin-treated nude mice harbored more than 4 log10 lung cfu at Month 2 and approximately 6 log10 cfu with isoniazid resistance at Month 3. A supplementary experiment demonstrated that 7 days a week treatment did not prevent isoniazid resistance, whereas addition of ethambutol did. Conclusions: In nude mice, sterilization of tuberculosis is obtained with rifapentine-containing treatment, whereas failure with development of isoniazid resistance is obtained with rifampin-containing treatment. PMID:21330452

SOME PROTECTION METHODS FOR CUTANEOUS IRRADIATION WITH FAST ELECTRONS (in Italian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trucchi, O.

1962-09-01

The influence exerted by some substances, particularly by fatty substances and cortisone derivatives, on the skin reaction to fast electrons is examined. The means employed were applied on the skin immediately before the irradiation; their effectiveness varies in relation with the dose fractionation; this decreases in general the capacity of the various substances tested of modifying the skin reaction. The changes induced by these means are both quantitative and relative to the course (anticipation of the appearance of the erythema); they may occur uniformly in all phases of the reaction or only in one (a change of the first phasemore » of the erythema is usually observed). The quality of the excipient, the action of which is often responsible for the aggravation of the skin reaction, is to be taken into account in the evaluation of the typical effect of the medications. Within the limits of the doses employed (1000 rad in only a sitting, 5000 rad in case of fractionation) the influence of fatty substances on the skin reactions due to irradiation with quick electrons proved not to be marked but only scarcely appreciable. The mineral fats may increase the reaction due to quick electrons in some cases: they do not have, however, either a protective or therapeutic effect during the acute phase of the reaction. The cortisone derivatives are uneffective when they are directly and exclusively applied on the irradiated skin, while they are successfully used by general route, especially in the reactions of the mucous membranes produced by quick electrons; in any way, the topical use of cortisone derivatives with excipients deprived from mineral fats proved to be preferable. Among the physical means employed, the compression gave the best results, in the cases where it could be applied. (auth)« less

Effects of Cortisone Administration on the Metabolism and Localization of 25-Hydroxycholecalciferol in the Rat

PubMed Central

Favus, Murray J.; Kimberg, Daniel V.; Millar, Gail N.; Gershon, Elaine

1973-01-01

Glucocorticoid administration is known to decrease calcium absorption in vivo and the vitamin D-dependent active transport of calcium by rat duodenum in vitro. The basis for this antivitamin D-like effect of glucocorticoids is unclear. Previous studies in the rat failed to demonstrate an effect of glucocorticoid treatment on the hepatic conversion of the parent vitamin to 25-hydroxycholecalciferol (25-HCC). Moreover, pharmacologic doses of 25-HCC did not restore intestinal calcium transport to normal. The results of these experiments suggested that if indeed glucocorticoids interfere with the metabolism of vitamin D, the step involved must be subsequent to 25-hydroxylation. The present studies demonstrate that the administration of cortisone to vitamin D-deficient rats does not affect the rate of conversion of a physiologic dose of [3H]25-HCC to the biologically important metabolite, 1,25-dihydroxycholecalciferol (1,25-DHCC). Furthermore, pretreatment with glucocorticoids affects neither the tissue distribution nor the subcellular localization on or in intestinal mucosal cell nuclei of 1,25-DHCC. Of note is the fact that 1,25-DHCC is currently considered to be the “tissue-active” form of the vitamin in the intestine. Whereas tissues from cortisone-treated animals had increased concentrations of the biologically less active 24,25-DHCC, the physiologic significance of this observation remains unclear. The results of the present studies strongly support the concept that the antivitamin D-like effects of glucocorticoids in the intestine are due to hormonal influences on the biochemical reactions responsible for calcium transport. While the effects of these hormones are opposite in direction to those of vitamin D, they occur by a mechanism that is independent of a direct interaction with either the vitamin or its biologically active metabolites. PMID:4703222

Antistress, Adoptogenic Activity of Sida cordifolia Roots in Mice.

PubMed

Sumanth, Meera; Mustafa, S S

2009-05-01

Ethanol extract of roots of Sida cordifolia was evaluated for antistress, adaptogenic activity using cold restraint stress and swim endurance in mice. Mice pretreated with extract of Sida cordifolia showed significant improvement in the swim duration and reduced the elevated WBC, blood glucose and plasma cortisone.

Antistress, Adoptogenic Activity of Sida cordifolia Roots in Mice

PubMed Central

Sumanth, Meera; Mustafa, S. S.

2009-01-01

Ethanol extract of roots of Sida cordifolia was evaluated for antistress, adaptogenic activity using cold restraint stress and swim endurance in mice. Mice pretreated with extract of Sida cordifolia showed significant improvement in the swim duration and reduced the elevated WBC, blood glucose and plasma cortisone. PMID:20490305

Synthesizing a Life: An Interview with Carl Djerassi

ERIC Educational Resources Information Center

Cardellini, Liberato

2011-01-01

In this interview, Carl Djerassi recalls his first years, from his pleasant childhood, to how he escaped the Nazi persecutions, to his college education in America. He remembers how with his research group he won the race for synthesis of cortisone, and how they then synthesized norethindrone, the active ingredient in oral contraceptives. Djerassi…

Novel 11β-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV.

PubMed

Boudon, Stéphanie M; Vuorinen, Anna; Geotti-Bianchini, Piero; Wandeler, Eliane; Kratschmar, Denise V; Heidl, Marc; Campiche, Remo; Jackson, Eileen; Odermatt, Alex

2017-01-01

Activity and selectivity assessment of new bi-aryl amide 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11β-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11β-HSD1 over 11β-HSD2, 17β-HSD1 and 17β-HSD2. These inhibitors also potently inhibited 11β-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11β-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11β-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.

Prevention effect of rare ginsenosides against stress-hormone induced MTOC amplification

PubMed Central

Lee, Jee-Hyun; Cheong, Kyu Jin; Jung, Youn-Sang; Woo, Tae-Gyun; Yoon, Min-Ho; Oh, Ah-Young; Kang, So-Mi; Lee, Chunghui; Sun, Hokeun; Hwang, Jihwan; Song, Gyu-Yong; Park, Bum-Joon

2016-01-01

Stress has been suggested as one of important cause of human cancer without molecular biological evidence. Thus, we test the effect of stress-related hormones on cell viability and mitotic fidelity. Similarly to estrogen, stress hormone cortisol and its relative cortisone increase microtubule organizing center (MTOC) number through elevated expression of γ-tubulin and provide the Taxol resistance to human cancer cell lines. However, these effects are achieved by glucocorticoid hormone receptor (GR) but not by estrogen receptor (ER). Since ginsenosides possess steroid-like structure, we hypothesized that it would block the stress or estrogen-induced MTOC amplification and Taxol resistance. Among tested chemicals, rare ginsenoside, CSH1 (Rg6) shows obvious effect on inhibition of MTOC amplification, γ-tubulin induction and Taxol resistance. Comparing to Fulvestant (FST), ER-α specific inhibitor, this chemical can block the cortisol/cortisone-induced MTOC deregulation as well as ER-α signaling. Our results suggest that stress hormone induced tumorigenesis would be achieved by MTOC amplification, and CSH1 would be useful for prevention of stress-hormone or steroid hormone-induced chromosomal instability. PMID:27147573

Effects of Carbenoxolone on the Canine Pituitary-Adrenal Axis.

PubMed

Teshima, Takahiro; Matsumoto, Hirotaka; Okusa, Tomoko; Nakamura, Yumi; Koyama, Hidekazu

2015-01-01

Cushing's disease caused by pituitary corticotroph adenoma is a common endocrine disease in dogs. A characteristic biochemical feature of corticotroph adenomas is their relative resistance to suppressive negative feedback by glucocorticoids. The abnormal expression of 11beta-hydroxysteroid dehydrogenase (11HSD), which is a cortisol metabolic enzyme, is found in human and murine corticotroph adenomas. Our recent studies demonstrated that canine corticotroph adenomas also have abnormal expression of 11HSD. 11HSD has two isoforms in dogs, 11HSD type1 (HSD11B1), which converts cortisone into active cortisol, and 11HSD type2 (HSD11B2), which converts cortisol into inactive cortisone. It has been suggested that glucocorticoid resistance in corticotroph tumors is related to the overexpression of HSD11B2. Therefore it was our aim to investigate the effects of carbenoxolone (CBX), an 11HSD inhibitor, on the healthy dog's pituitary-adrenal axis. Dogs were administered 50 mg/kg of CBX twice each day for 15 days. During CBX administration, no adverse effects were observed in any dogs. The plasma adrenocorticotropic hormone (ACTH), and serum cortisol and cortisone concentrations were significantly lower at day 7 and 15 following corticotropin releasing hormone stimulation. After completion of CBX administration, the HSD11B1 mRNA expression was higher, and HSD11B2 mRNA expression was significantly lower in the pituitaries. Moreover, proopiomelanocortin mRNA expression was lower, and the ratio of ACTH-positive cells in the anterior pituitary was also significantly lower after CBX treatment. In adrenal glands treated with CBX, HSD11B1 and HSD11B2 mRNA expression were both lower compared to normal canine adrenal glands. The results of this study suggested that CBX inhibits ACTH secretion from pituitary due to altered 11HSD expressions, and is potentially useful for the treatment of canine Cushing's disease.

Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling.

PubMed

Lavery, G G; Idkowiak, J; Sherlock, M; Bujalska, I; Ride, J P; Saqib, K; Hartmann, M F; Hughes, B; Wudy, S A; De Schepper, J; Arlt, W; Krone, N; Shackleton, C H; Walker, E A; Stewart, P M

2013-02-01

Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH, encoded by H6PD) cause apparent cortisone reductase deficiency (ACRD). H6PDH generates cofactor NADPH for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol. Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD). Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism. To describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases. Clinical, biochemical and genetic assessment of two female patients presenting during childhood. In addition, results of urinary steroid profiling in a total of ten ACRD/CRD patients were compared to identify distinguishing characteristics. Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD. Mutant expression studies confirmed loss of H6PDH activity in both cases. Urinary steroid metabolite profiling by gas chromatography/mass spectrometry suggested ACRD in both cases. In addition, we were able to establish a steroid metabolite signature differentiating ACRD and CRD, providing a basis for genetic diagnosis and future individualised management. Steroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD. This will provide a useful tool in stratifying unresolved adrenal hyperandrogenism in children with premature adrenarche and adult females with polycystic ovary syndrome (PCOS).

Glucocorticoids and 11β-HSD1 are major regulators of intramyocellular protein metabolism

PubMed Central

Hassan-Smith, Zaki K; Doig, Craig L; Sherlock, Mark; Stewart, Paul M; Lavery, Gareth G

2016-01-01

The adverse metabolic effects of prescribed and endogenous glucocorticoid excess, ‘Cushing’s syndrome’, create a significant health burden. While skeletal muscle atrophy and resultant myopathy is a clinical feature, the molecular mechanisms underpinning these changes are not fully defined. We have characterized the impact of glucocorticoids upon key metabolic pathways and processes regulating muscle size and mass including: protein synthesis, protein degradation, and myoblast proliferation in both murine C2C12 and human primary myotube cultures. Furthermore, we have investigated the role of pre-receptor modulation of glucocorticoid availability by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in these processes. Corticosterone (CORT) decreased myotube area, decreased protein synthesis, and increased protein degradation in murine myotubes. This was supported by decreased mRNA expression of insulin-like growth factor (IGF1), decreased activating phosphorylation of mammalian target of rapamycin (mTOR), decreased phosphorylation of 4E binding protein 1 (4E-BP1), and increased mRNA expression of key atrophy markers including: atrogin-1, forkhead box O3a (FOXO3a), myostatin (MSTN), and muscle-ring finger protein-1 (MuRF1). These findings were endorsed in human primary myotubes, where cortisol also decreased protein synthesis and increased protein degradation. The effects of 11-dehydrocorticosterone (11DHC) (in murine myotubes) and cortisone (in human myotubes) on protein metabolism were indistinguishable from that of CORT/cortisol treatments. Selective 11β-HSD1 inhibition blocked the decrease in protein synthesis, increase in protein degradation, and reduction in myotube area induced by 11DHC/cortisone. Furthermore, CORT/cortisol, but not 11DHC/cortisone, decreased murine and human myoblast proliferative capacity. Glucocorticoids are potent regulators of skeletal muscle protein homeostasis and myoblast proliferation. Our data underscores the potential use of selective 11β-HSD1 inhibitors to ameliorate muscle-wasting effects associated with glucocorticoid excess. PMID:27048233

Socioeconomic status in children is associated with hair cortisol levels as a biological measure of chronic stress.

PubMed

Vliegenthart, J; Noppe, G; van Rossum, E F C; Koper, J W; Raat, H; van den Akker, E L T

2016-03-01

Low socioeconomic status (SES) may be associated with a high risk of lifestyle-related diseases such as cardiovascular diseases. There is a strong association between parental SES, stress and indicators of child health and adult health outcome. The exact mechanisms underlying this association have not yet been fully clarified. Low SES may be associated with chronic stress, which may lead to activation of the hypothalamic-pituitary-adrenal (HPA)-axis, resulting in a higher circulating level of the stress hormone cortisol. Therefore, chronic stress may mediate the association between low SES and elevated cortisol levels and its adverse outcomes. We investigated whether SES was associated with a chronic measure of cortisol exposure in a child population. Cortisol and cortisone were measured in scalp hair in 270 children and adolescents, aged 4-18 years, enrolled through school visits. Neighborhood level SES was based on a score developed by the Netherlands Institute for Social Research using postal codes, and this includes neighborhood measures of income education and unemployment. Maternal and paternal education level were used as indicators of family SES. Neighborhood level socioeconomic status score was significantly associated with hair cortisol (β=-0.103, p=0.007, 95%CI [-0.179, -0.028]) and hair cortisone (β=-0.091, p=0.023, 95%CI [-0.167, -0.015]), adjusted for age and sex. Additionally, hair cortisol was significantly correlated with maternal education level and hair cortisone was significantly correlated with paternal education level. The results of our study suggest that the widely shown association between low family SES and adverse child health outcomes may be mediated by chronic stress, given the chronically higher levels of cortisol in children and adolescents in families with low SES. It is especially notable that the association between SES and cortisol was already found in children of young age as this can have major consequences, such as increased risk of cardio metabolic diseases in later life. Copyright © 2015 Elsevier Ltd. All rights reserved.

Changing glucocorticoid action: 11β-Hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation

PubMed Central

Chapman, Karen E.; Coutinho, Agnes E.; Zhang, Zhenguang; Kipari, Tiina; Savill, John S.; Seckl, Jonathan R.

2013-01-01

Since the discovery of cortisone in the 1940s and its early success in treatment of rheumatoid arthritis, glucocorticoids have remained the mainstay of anti-inflammatory therapies. However, cortisone itself is intrinsically inert. To be effective, it requires conversion to cortisol, the active glucocorticoid, by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Despite the identification of 11β-HSD in liver in 1953 (which we now know to be 11β-HSD1), its physiological role has been little explored until recently. Over the past decade, however, it has become apparent that 11β-HSD1 plays an important role in shaping endogenous glucocorticoid action. Acute inflammation is more severe with 11β-HSD1-deficiency or inhibition, yet in some inflammatory settings such as obesity or diabetes, 11β-HSD1-deficiency/inhibition is beneficial, reducing inflammation. Current evidence suggests both beneficial and detrimental effects may result from 11β-HSD1 inhibition in chronic inflammatory disease. Here we review recent evidence pertaining to the role of 11β-HSD1 in inflammation. This article is part of a Special Issue entitled ‘CSR 2013’. PMID:23435016

Betamethasone enemata in ulcerative colitis

PubMed Central

Matts, S. G. Flavell

1962-01-01

In this series a very large therapeutic dose of corticosteroid was administered by retention enemata. For the first week the author gave the equivalent of between 300 and 750 mg. of cortisone daily and for the next three weeks 150 to 375 mg. daily. The results were excellent but systemic effects were noted in all who received more than the smallest dose used. ImagesFIG. 1FIG. 2 PMID:13933911

Steroid Biomarkers and Genetic Studies Reveal Inactivating Mutations in Hexose-6-Phosphate Dehydrogenase in Patients with Cortisone Reductase Deficiency

PubMed Central

Lavery, Gareth G.; Walker, Elizabeth A.; Tiganescu, Ana; Ride, Jon P.; Shackleton, Cedric H. L.; Tomlinson, Jeremy W.; Connell, John M. C.; Ray, David W.; Biason-Lauber, Anna; Malunowicz, Ewa M.; Arlt, Wiebke; Stewart, Paul M.

2008-01-01

Context: Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11β-HSD1 oxoreductase activity requires the reduced nicotinamide adenine dinucleotide phosphate-generating enzyme hexose-6-phosphate dehydrogenase (H6PDH) within the endoplasmic reticulum. CRD manifests with hyperandrogenism resulting in hirsutism, oligo-amenorrhea, and infertility in females and premature pseudopuberty in males. Recent association studies have failed to corroborate findings that polymorphisms in the genes encoding H6PDH (R453Q) and 11β-HSD1 (Intron 3 inserted adenine) interact to cause CRD. Objective: Our objective was to reevaluate the genetics and steroid biochemistry of patients with CRD. Design: We analyzed 24-h urine collection for steroid biomarkers by gas chromatography/mass spectrometry and sequenced the HSD11B1 and H6PD genes in our CRD cohort. Patients: Patients included four cases presenting with hyperandrogenism and biochemical features clearly indicative of CRD. Results: Gas chromatography/mass spectrometry identified steroid biomarkers that correlated with CRD in each case. Three cases were identified as homozygous (R109AfsX3, Y316X, and G359D) and one case identified as compound heterozygous (c.960G→A and D620fsX3) for mutations in H6PD. No mutations affecting enzyme activity were identified in the HSD11B1 gene. Expression and activity assays demonstrate loss of function for all reported H6PDH mutations. Conclusions: CRD is caused by inactivating mutations in the H6PD gene, rendering the 11β-HSD1 enzyme unable to operate as an oxoreductase, preventing local glucocorticoid regeneration. These data highlight the importance of the redox control of cortisol metabolism and the 11β-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity. PMID:18628520

THE PHYSIOLOGICAL SIGNIFICANCE OF THE CORTIOOSTEROIDS IN PAROTID FLUID.

DTIC Science & Technology

A highly sensitive and highly specific technique was devised, utilizing four chromatographic procedures, for the measurement of parotid fluid...cortisol and cortisone on 5 ml of parotid fluid, and plasma cortisol on 1 ml of plasma. In addition techniques are described for measuring plasma...derivative technique is high purified immediately before its use, blank values are too high for the low values found in parotid saliva. Blank values

Septic monoarthritis of the first carpo-metacarpal joint caused by Mycobacterium kansasii.

PubMed

Brutus, J P; Lamraski, G; Zirak, C; Hauzeur, J P; Thys, J P; Schuind, F

2005-02-01

A case of septic carpal monoarthritis due to Mycobacterium kansasii developing 16 months after accidental inoculation in a healthy laboratory technician is reported. No predisposing factor such as immunosuppression, preexisting degenerative, inflammatory arthritis or cortisone injection was present. Treatment with antituberculous oral medication alone resulted in resolution of the disease. Synovectomy was unnecessary. Ten years after the initial causative event, the patient remains free of symptoms.

[Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders].

PubMed

Feldman, Karolina; Likó, István; Nagy, Zsolt; Szappanos, Agnes; Grolmusz, Vince Kornél; Tóth, Miklós; Rácz, Károly; Patócs, Attila

2013-02-24

Glucocorticoids play an important role in the regulation of carbohydrate and amino acid metabolism, they modulate the function of the immune system, and contribute to stress response. Increased and decreased production of glucocorticoids causes specific diseases. In addition to systemic hypo- or hypercortisolism, alteration of local synthesis and metabolism of cortisol may result in tissue-specific hypo- or hypercortisolism. One of the key enzymes participating in the local synthesis and metabolism of cortisol is the 11β-hydroxysteroid dehydrogenase enzyme. Two isoforms, type 1 and type 2 enzymes are located in the endoplasmic reticulum and catalyze the interconversion of hormonally active cortisol and inactive cortisone. The type 1 enzyme mainly works as an activator, and it is responsible for the generation of cortisol from cortisone in liver, adipose tissue, brain and bone. The gene encoding this enzyme is located on chromosome 1. The authors review the physiological and pathophysiological processes related to the function of the type 1 11β-hydroxysteroid dehydrogenase enzyme. They summarize the potential significance of polymorphic variants of the enzyme in clinical diseases as well as knowledge related to inhibitors of enzyme activity. Although further studies are still needed, inhibition of the enzyme activity may prove to be an effective tool for the treatment of several diseases such as obesity, osteoporosis and type 2 diabetes.

Stress hormones predict hyperbolic time-discount rates six months later in adults.

PubMed

Takahashi, Taiki; Shinada, Mizuho; Inukai, Keigo; Tanida, Shigehito; Takahashi, Chisato; Mifune, Nobuhiro; Takagishi, Haruto; Horita, Yutaka; Hashimoto, Hirofumi; Yokota, Kunihiro; Kameda, Tatsuya; Yamagishi, Toshio

2010-01-01

Stress hormones have been associated with temporal discounting. Although time-discount rate is shown to be stable over a long term, no study to date examines whether individual differences in stress hormones could predict individuals' time-discount rates in the relatively distant future (e.g., six month later), which is of interest in neuroeconomics of stress-addiction association. We assessed 87 participants' salivary stress hormone (cortisol, cortisone, and alpha-amylase) levels and hyperbolic discounting of delayed rewards consisting of three magnitudes, at the time-interval of six months. For salivary steroid assays, we employed a liquid chromatography/ mass spectroscopy (LC/MS) method. The correlations between the stress hormone levels and time-discount rates were examined. We observed that salivary alpha-amylase (sAA) levels were negatively associated with time-discount rates in never-smokers. Notably, salivary levels of stress steroids (i.e., cortisol and cortisone) negatively and positively related to time-discount rates in men and women, respectively, in never-smokers. Ever-smokers' discount rates were not predicted from these stress hormone levels. Individual differences in stress hormone levels predict impulsivity in temporal discounting in the future. There are sex differences in the effect of stress steroids on temporal discounting; while there was no sex defference in the relationship between sAA and temporal discounting.

[Sternocostoclavicular hyperostosis--case reports and differential diagnosis].

PubMed

Mick, C; Kirgis, A; Noack, W

1993-01-01

Sternocostoclavicular hyperostosis (SCCH) is a disorder related to collagenoses. SCCH is typically characterised by the triad of swelling of the sternoclavicular and/or sternocostal joints of the first or second rib, palmar and plantar pustulosis (PPP), only limited elevation of inflammation indicating laboratory parameters. Till today the etiology is unclear and no causal therapy is known. Symptomatic treatment consists of administration of NSAID and cortisone, irradiation and even limited resection of the clavicle and rib.

11β-HSD1 Modulates LPS-Induced Innate Immune Responses in Adipocytes by Altering Expression of PTEN

PubMed Central

Lai, Wenfang; Tian, Xue; Xiang, Qing; Chu, Kedan; Wei, Yicong; Deng, Jingti; Zhang, Shaoping; Brown, John

2015-01-01

Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) represents a therapeutic target for treating hyperglycemia in type 2 diabetes. Here, we investigate the effects of 11β-HSD1 on the innate immune response of adipocytes to produce proinflammatory cytokines. The 11β-HSD1 inhibitor emodin, or 11β-HSD1-targeted small interfering RNA, dose dependently suppressed IL-6, IL-1β, and TNF-α expression in lipopolysaccharide-treated 3T3-L1 adipocytes. Inhibiting 11β-HSD1 also reduced phosphatase and tensin homologue (PTEN) expression, a negative regulator of phosphatidylinositol 3-kinase effects, whereas 1pM cortisone or dexamethasone induced IL-6 and PTEN levels. PTEN-targeted small interfering RNA decreased IL-6, IL-1β, and TNF-α without affecting 11β-HSD1 levels. Correspondingly, emodin increased phosphorylated protein kinase B (p-PKB) (Ser473) to PKB ratio but not p-PKB (Thr308) to PKB ratio. Emodin did not increase the p-PKB (Ser473) to PKB ratio when the rapamycin-insensitive companion of mTOR was depleted, further supporting the involvement of mammalian target of rapamycin complex 2 in PKB phosphorylation. Moreover, emodin suppressed phosphorylated inhibitor of κB α (p-IκBα) to IκBα ratio and reduced nuclear factor κ B subunit p50 in the nuclear fraction. In contrast, 1pM cortisone or dexamethasone decreased p-PKB (Ser473) to PKB ratio, increased p-IκBα to IκBα ratio, and increased nuclear NF-κB subunit p50. Additionally, wortmannin had similar effects on IL-6, p-PKB (Ser473) to PKB ratio, and p-IκBα to IκBα ratio as 1pM cortisone or dexamethasone. Finally, emodin treatment of streptozotocin diabetic rats on a high-fat diet reduced levels of IL-6, PTEN, Cluster of Differentiation 68, and the ratio of p-IκBα to IκBα in visceral fat, indicating that our findings in vitro may also apply to visceral fat in vivo. Together, these results suggest that inhibiting 11β-HSD1 reduces lipopolysaccharide-induced proinflammatory innate immune responses in adipocytes by down-regulating PTEN expression, leading to activation of the PI3K/PKB pathway. PMID:25734515

A multicenter, randomized study to test immunosuppressive therapy with oral prednisone for the prevention of restenosis after percutaneous coronary interventions: cortisone plus BMS or DES versus BMS alone to eliminate restenosis (CEREA-DES) - study design and rationale.

PubMed

Ribichini, Flavio; Tomai, Fabrizio; De Luca, Giuseppe; Boccuzzi, Giacomo; Presbitero, Patrizia; Pesarini, Gabriele; Ferrero, Valeria; Ghini, Anna S; Pastori, Francesca; De Luca, Leonardo; Zavalloni, Denis; Soregaroli, Daniela; Garbo, Roberto; Franchi, Elena; Marino, Paolo; Minelli, Massimo; Vassanelli, Corrado

2009-02-01

Several randomized trials and registries have shown a reduction of restenosis after coronary angioplasty with drug-eluting stents (DESs) compared with bare metal stents (BMSs). However, cost-efficacy analysis and long-term outcome of DESs compared to BMSs deserve further assessment. Moreover, concern has been raised regarding adverse clinical events occurring late after DES implantation, in particular, late stent thrombosis related to the suspension of dual antiplatelet therapy. The use of a short-cycle oral treatment with prednisone at immunosuppressive dose after BMS implantation has shown remarkable efficacy in reducing restenosis in nondiabetic patients, with very low additional cost and without the need for long-term dual antiplatelet therapy. Such results are however limited by small sample size. Cortisone plus BMS or DES versus BMS alone to Eliminate Restenosis is an independent, prospective, multicenter, randomized study. It will randomize 375 nondiabetic patients with coronary artery disease in three different arms to BMS (control group), DES (DES group) or BMS followed by a 40-day prednisone treatment (prednisone group). The DES and the prednisone groups will be compared to the control group to investigate the expected clinical advantage. The primary endpoint of the study is the event-free survival of cardiovascular death, myocardial infarction and recurrence of ischemia-needing repeated target vessel revascularization at 1 year. Secondary endpoints are the event-free survival analysis at 2 and 3 years, the restenosis rate at 9 months, and cost-effectiveness at 1, 2 and 3 years. The expected primary endpoint rates are 90% for DESs and for prednisone-treated patients and 77% for BMSs. The study was designed as a superiority trial, to compare DES, and BMS and prednisone, with BMS alone. A sample size of 118 patients per group provides an 80% power, assuming a complete 12-month follow-up information available for each patient. To obviate for cases of drop out, the sample size was increased to 375 patients to be enrolled in five Italian hospitals. This study will provide a magnitude of the net clinical and economic benefits of DES and of the safety and efficacy of BMS and cortisone compared to the standard use of BMS alone in nondiabetic patients with coronary artery disease.

EFFECTS OF BACTERIAL ENDOTOXINS ON METABOLISM

PubMed Central

Berry, L. Joe; Smythe, Dorothy S.

1961-01-01

In vitro secretion of glycocorticoids by adrenal glands pooled from several control mice was compared with that of glands removed from animals following injections of either ACTH or endotoxin. Both substances prevent glycocorticoid synthesis stimulated in vitro with ACTH. Cholesterol content of adrenal glands under these conditions was nearly depleted, indicating maximal response to ACTH or endotoxin prior to their removal for the in vitro tests. In an effort to account physiologically for the manner in which endotoxin suppresses or prevents the rise in urinary nitrogen excreted in response to ACTH, blood non-protein nitrogen levels (NPN) were determined. The following experimental conditions resulted in increased urinary nitrogen excretion but did not alter blood NPN: cortisone given alone or at the same time as endotoxin; ACTH alone; dichloroisoproterenol (DCI) given concurrently with endotoxin; and lactalbumin digest injected intraperitoneally. Increases (2- to 3-fold) in blood NPN were observed when endotoxin was given alone, concurrently with ACTH, or 3 hours prior to cortisone, DCI, or lactalbumin digest. Urinary nitrogen excretion showed no change under these conditions. The elevation in blood NPN in endotoxin-poisoned mice was found to be due almost entirely to urea nitrogen and not to amino acid nitrogen or to other nitrogenous wastes. Blood clearance of mulin, phenol red excretion, and urea elimination were each determined in control and in endotoxin-poisoned mice. The latter mice showed impaired renal function. Treatment with diuretics (diuril and aminophylline) failed to alter oliguria or elevated blood NPN. Hydergine treatment was also without effect. Total carcass NPN and urinary nitrogen excretion data were combined to give a picture of total protein catabolized by mice under different experimental conditions. Cortisone injected at the same time as endotoxin or 3 hours later resulted in the same increase in total NPN. However, in the former case all the extra nitrogen appeared in the urine while in the latter it remained in the carcass. ACTH given alone or concurrently with endotoxin produced large increases in total NPN but less in poisoned mice. This suggests that endotoxin suppresses adrenal response to ACTH. Urea injected into normal mice was recovered quantitatively in urine while in endotoxin-poisoned mice it was partitioned between carcass and urine. Elevation of carcass NPN by means of urea injections failed to alter the lethality of an LD70 dose of endotoxin. PMID:19867206

Affective alterations in patients with Cushing's syndrome in remission are associated with decreased BDNF and cortisone levels.

PubMed

Valassi, E; Crespo, I; Keevil, B G; Aulinas, A; Urgell, E; Santos, A; Trainer, P J; Webb, S M

2017-02-01

Affective alterations and poorer quality of life often persist in patients with Cushing's syndrome (CS) in remission. Brain-derived neurotrophic factor (BDNF) regulates the hypothalamic-pituitary-adrenal axis (HPA) and is highly expressed in brain areas controlling mood and response to stress. Our aims were to assess affective alterations after long-term remission of CS and evaluate whether they are associated with serum BDNF, salivary cortisol (SalF) and/or cortisone (SalE) concentrations. Thirty-six CS patients in remission (32 females/4 males; mean age (±s.d.), 48.8 ± 11.8 years; median duration of remission, 72 months) and 36 gender-, age- and BMI-matched controls were included. Beck Depression Inventory-II (BDI-II), Center for Epidemiological Studies Depression Scale (CES-D), Positive Affect Negative Affect Scale (PANAS), State-Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS) and EuroQoL and CushingQoL questionnaires were completed and measured to evaluate anxiety, depression, stress perception and quality of life (QoL) respectively. Salivary cortisol was measured using liquid chromatography/tandem mass spectrometry (LC/TMS). BDNF was measured in serum using an ELISA. Remitted CS patients showed worse scores in all questionnaires than controls: STAI (P < 0.001), BDI (P < 0.001), CES-D (P < 0.001), PANAS (P < 0.01), PSS (P < 0.01) and EuroQoL (P < 0.01). A decrease in BDNF was observed in CS vs controls (P = 0.038), and low BDNF was associated with more anxiety (r = -0.247, P = 0.037), depression (r = -0.249, P = 0.035), stress (r = -0.277, P = 0.019) and affective balance (r = 0.243, P = 0.04). Morning salivary cortisone was inversely associated with trait anxiety (r = -0.377, P = 0.040) and depressed affect (r = -0.392, P = 0.032) in CS patients. Delay to diagnosis was associated with depressive symptoms (BDI-II: r = 0.398, P = 0.036 and CES-D: r = 0.449, P = 0.017) and CushingQoL scoring (r = -0.460, P < 0.01). Low BDNF levels are associated with affective alterations in 'cured' CS patients, including depression, anxiety and impaired stress perception. Elevated levels of SalE might also be related to poor affective status in these patients. © 2017 European Society of Endocrinology.

Automated saliva processing for LC-MS/MS: Improving laboratory efficiency in cortisol and cortisone testing.

PubMed

Antonelli, Giorgia; Padoan, Andrea; Artusi, Carlo; Marinova, Mariela; Zaninotto, Martina; Plebani, Mario

2016-04-01

The aim of this study was to implement in our routine practice an automated saliva preparation protocol for quantification of cortisol (F) and cortisone (E) by LC-MS/MS using a liquid handling platform, maintaining the previously defined reference intervals with the manual preparation. Addition of internal standard solution to saliva samples and calibrators and SPE on μ-elution 96-well plate were performed by liquid handling platform. After extraction, the eluates were submitted to LC-MS/MS analysis. The manual steps within the entire process were to transfer saliva samples in suitable tubes, to put the cap mat and transfer of the collection plate to the LC auto sampler. Transference of the reference intervals from the manual to the automated procedure was established by Passing Bablok regression on 120 saliva samples analyzed simultaneously with the two procedures. Calibration curves were linear throughout the selected ranges. The imprecision ranged from 2 to 10%, with recoveries from 95 to 116%. Passing Bablok regression demonstrated no significant bias. The liquid handling platform translates the manual steps into automated operations allowing for saving hands-on time, while maintaining assay reproducibility and ensuring reliability of results, making it implementable in our routine with the previous established reference intervals. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Reference intervals for plasma concentrations of adrenal steroids measured by LC-MS/MS: Impact of gender, age, oral contraceptives, body mass index and blood pressure status.

PubMed

Eisenhofer, Graeme; Peitzsch, Mirko; Kaden, Denise; Langton, Katharina; Pamporaki, Christina; Masjkur, Jimmy; Tsatsaronis, George; Mangelis, Anastasios; Williams, Tracy A; Reincke, Martin; Lenders, Jacques W M; Bornstein, Stefan R

2017-07-01

Mass spectrometric-based measurements of the steroid metabolome have been introduced to diagnose disorders featuring abnormal steroidogenesis. Defined reference intervals are important for interpreting such data. Liquid chromatography-tandem mass spectrometry was used to establish reference intervals for 16 steroids (pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, aldosterone, 18-oxocortisol, 18-hydroxycortisol, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, testosterone) measured in plasma from 525 volunteers with (n=227) and without (n=298) hypertension, including 68 women on oral contraceptives. Women showed variable plasma concentrations of several steroids associated with menstrual cycle phase, menopause and oral contraceptive use. Progesterone was higher in females than males, but most other steroids were higher in males than females and almost all declined with advancing age. Using models that corrected for age and gender, body mass index showed weak negative relationships with corticosterone, 21-deoxycortisol, cortisol, cortisone, testosterone, progesterone, 17-hydroxyprogesterone and 11-deoxycorticosterone, but a positive relationship with 18-hydroxycortisol. Hypertensives and normotensives showed negligible differences in plasma concentrations of steroids. Age and gender are the most important variables for plasma steroid reference intervals, which have been established here according to those variables for a panel of 16 steroids primarily useful for diagnosis and subtyping of patients with endocrine hypertension. Copyright © 2017. Published by Elsevier B.V.

Patients Presenting with Miliaria While Wearing Flame Resistant Clothing in High Ambient Temperatures: A Case Series

DTIC Science & Technology

2011-09-22

year-old Caucasian woman with a medical history of eczema developed a miliaria-like rash (small red rash with papules) on her inner thighs, knee fossa... eczema developed itchy miliaria-like rash (small red rash with papules) to his inner thighs, bilateral pos- terior calves, and inner elbow (Figure 2...Our patient sought medical attention from the military dermatologist, who diagnosed the rash as eczema and treated it with a cortisone IM injection

Patients Presenting with Miliaria While Wearing Flame Resistant Clothing in High Ambient Temperatures: A Case Series

DTIC Science & Technology

2011-09-22

Case presentation 1 A 23-year-old Caucasian woman with a medical history of eczema developed a miliaria-like rash (small red rash with papules...perspiration. Case presentation 2 A 31-year-old African-American man with a medical history of eczema developed itchy miliaria-like rash (small...military dermatologist, who diagnosed the rash as eczema and treated it with a cortisone IM injection (name and dose unknown). Our patient deployed to

THE ROLE OF PREDISPOSING FACTORS IN EXPERIMENTAL FUNGUS INFECTIONS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheldon, W.H.; Bauer, H.

Among other factors, the influence of ionizing radiations on susceptibility to fungus diseases is reviewed. X irradiation singly or in combination with cortisone administration has been employed in the study of experimental fungus diseases, and it has been shown that total-body radiation enhaaced infection with Candida albicans, Blastomyces dermatididis, and Cryptococcus neoformans in mice. Enhanced susceptibility to fungus infections following radiation therapy has also been reported, the mechanism resulting in lowered host resistance being presumably the same as in other infections. (BBB)

Immunoassay or LC-MS/MS for the measurement of salivary cortisol in children?

PubMed

Bae, Yoon Ju; Gaudl, Alexander; Jaeger, Sonia; Stadelmann, Stephanie; Hiemisch, Andreas; Kiess, Wieland; Willenberg, Anja; Schaab, Michael; von Klitzing, Kai; Thiery, Joachim; Ceglarek, Uta; Döhnert, Mirko; Kratzsch, Juergen

2016-05-01

Dysregulation of the adrenal cortex has been assessed with measurement of salivary cortisol. So far salivary cortisol is routinely measured with immunoassay (IA). However, liquid chromatography-tandem mass spectrometry (MS) is known to offer better specificity. We compared the concentrations of salivary cortisol measured by MS and IA at basal and stress induced conditions and evaluated reasons for the difference in method-dependent cortisol results. Saliva samples (n=2703) were collected from 169 children (age range: 8-14 years; 81 healthy children; 55 with internalizing and 33 with externalizing disorders) under circadian conditions and during the Trier Social Stress Test for Children (TSST-C). Biochemical analyses were performed with MS for cortisol and cortisone, IA (IBL, RE62011) for cortisol, and enzyme kinetic assay for α-amylase. MS and IA showed mostly comparable results for circadian activity and TSST-C response with similar statistical power. However, IA measured cortisol concentrations about 2.39-fold higher than MS. We found that this difference in measured values between MS and IA was mainly due to different standardization of IA compared to MS. In addition, at cortisol IA concentration below 5 nmol/L, cross-reactivity with cortisone was found to contribute to the lower concordance between MS and IA. Immunoassay and LC-MS/MS were largely comparable in the interpretation of salivary cortisol dynamics in stress research. But the IA method revealed a restricted accuracy in the measuring range below 5 nmol/L.

Interaction of glucocorticoids and progesterone derivatives with human serum albumin.

PubMed

Abboud, Rola; Akil, Mohammad; Charcosset, Catherine; Greige-Gerges, Hélène

2017-10-01

Glucocorticoids (GCs) and progesterone derivatives (PGDs) are steroid hormones with well-known biological activities. Their interaction with human serum albumin (HSA) may control their distribution. Their binding to albumin is poorly studied in literature. This paper deals with the interaction of a series of GCs (cortisol, cortisone, prednisolone, prednisone, 6-methylprednisolone and 9-fluorocortisol acetate) and PGDs (progesterone, hydroxylated PGDs, methylated PGDs and dydrogesterone) with HSA solution (pH 7.4) at molar ratios steroid to HSA varying from 0 to 10. Similar titrations were conducted using Trp aqueous solution. Fluorescence titration method and Fourier transform infrared spectroscopy (FTIR) are used. PGDs (except dydrogesterone), cortisone and 9-fluorocortisol acetate affected weakly the fluorescence of Trp in buffer solution while they decreased in a dose-dependent manner that of HSA. Their binding constants to HSA were then calculated. Moreover, displacement experiment was performed using bilirubin as a site marker. The binding constant of bilirubin to albumin was determined in the absence and presence of a steroid at a molar ratio steroid to HSA of 1. The results indicate that the steroids bind to HSA at site I in a pocket different from that of bilirubin. Furthermore, the peak positions of amide I and amide II bands of HSA were shifted in the presence of progesterone, dydrogesterone and GCs. Also a variation was observed in amide I region indicating the formation of hydrogen bonding between albumin and steroids. Copyright © 2017 Elsevier B.V. All rights reserved.

The effect of cortisol in rat steatotic and non-steatotic liver transplantation from brain-dead donors.

PubMed

Jiménez-Castro, Mónica B; Negrete-Sánchez, Elsa; Casillas-Ramírez, Araní; Gulfo, Jose; Álvarez-Mercado, Ana I; Cornide-Petronio, María Eugenia; Gracia-Sancho, Jordi; Rodés, Juan; Peralta, Carmen

2017-04-25

In the present study, we examined the effects of cortisol on steatotic and non-steatotic liver grafts from brain-dead donors and characterized the underlying mechanisms involved. Non-steatotic liver grafts showed reduced cortisol and increased cortisone levels in association with up-regulation of enzymes that inactivate cortisol. Conversely, steatotic liver grafts exhibited increased cortisol and reduced cortisone levels. The enzymes involved in cortisol generation were overexpressed, and those involved in cortisol inactivation or clearance were down-regulated in steatotic liver grafts. Exogenous administration of cortisol negatively affected hepatic damage and survival rate in non-steatotic liver transplantation (LT); however, cortisol treatment up-regulated the phosphoinositide 3-kinase (PI3K)-protein kinase C (PKC) pathway, resulting in protection against the deleterious effects of brain-dead donors on damage and inflammatory response in steatotic LT as well as in increased survival of recipients. The present study highlights the differences in the role of cortisol and hepatic mechanisms that regulate cortisol levels based on the type of liver. Our findings suggest that cortisol treatment is a feasible and highly protective strategy to reduce the adverse effects of brain-dead donor livers in order to ultimately improve liver graft quality in the presence of steatosis, whereas cortisol treatment would not be recommended for non-steatotic liver grafts. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Comparison of the transplacental pharmacokinetics of cortisol and triamcinolone acetonide in the rhesus monkey

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slikker, W. Jr.; Althaus, Z.R.; Rowland, J.M.

1982-11-01

The late gestational age rhesus monkey was used to study the transplacental pharmacokinetics of radiolabeled triamcinolone acetonide (TAC) and cortisol. Tritiated-TAC and (/sup 14/C)cortisol were administered simultaneously via the maternal radial vein were administered simultaneously via the maternal radial vein and blood samples were serially drawn from catheters implanted in both the maternal femoral artery and fetal umbilical vein and artery. High-performance liquid chromatography of the processed blood samples revealed that from 93 to 100% of the /sup 3/H in the fetal circulation was parent TAC, whereas only 14 to 49% of the /sup 14/C was cortisol during the 40-minmore » period after dose administration. Fetal tissue samples taken at 3 hr after dose administration showed that 75 to 96% of the /sup 3/H present was TAC, whereas no cortisol was observed. TAC demonstrated dose-independent kinetics. Samples collected from the umbilical vein of the in situ placenta after fetectomy revealed that cortisol was extensively converted to cortisone by the placenta, whereas TAC was refractory to placental metabolism. This placental conversion of cortisol to cortisone and the further metabolism and conjugation of cortisol by the fetoplacental unit resulted in a fetal to maternal plasma cortisol ratio of 0.2. In contrast, the lack of placental or fetoplacental metabolism of TAC resulted in a fetal to maternal plasma TAC ratio of 0.6.« less

C/EBPβ Promotes Immunity to Oral Candidiasis through Regulation of β-Defensins

PubMed Central

Simpson-Abelson, Michelle R.; Childs, Erin E.; Ferreira, M. Carolina; Bishu, Shrinivas; Conti, Heather R.; Gaffen, Sarah L.

2015-01-01

Humans or mice subjected to immunosuppression, such as corticosteroids or anti-cytokine biologic therapies, are susceptible to mucosal infections by the commensal fungus Candida albicans. Recently it has become evident that the Th17/IL-17 axis is essential for immunity to candidiasis, but the downstream events that control immunity to this fungus are poorly understood. The CCAAT/Enhancer Binding Protein-β (C/EBPβ) transcription factor is important for signaling by multiple inflammatory stimuli, including IL-17. C/EBPβ is regulated in a variety of ways by IL-17, and controls several downstream IL-17 target genes. However, the role of C/EBPβ in vivo is poorly understood, in part because C/EBPβ-deficient mice are challenging to breed and work with. In this study, we sought to understand the role of C/EBPβ in the context of an IL-17-dependent immune response, using C. albicans infection as a model system. Confirming prior findings, we found that C/EBPβ is required for immunity to systemic candidiasis. In contrast, C/EBPβ-/- mice were resistant to oropharyngeal candidiasis (OPC), in a manner indistinguishable from immunocompetent WT mice. However, C/EBPβ-/- mice experienced more severe OPC than WT mice in the context of cortisone-induced immunosuppression. Expression of the antimicrobial peptide β-defensin (BD)-3 correlated strongly with susceptibility in C/EBPβ-/- mice, but no other IL-17-dependent genes were associated with susceptibility. Therefore, C/EBPβ contributes to immunity to mucosal candidiasis during cortisone immunosuppression in a manner linked to β-defensin 3 expression, but is apparently dispensable for the IL-17-dependent response. PMID:26317211

C/EBPβ Promotes Immunity to Oral Candidiasis through Regulation of β-Defensins.

PubMed

Simpson-Abelson, Michelle R; Childs, Erin E; Ferreira, M Carolina; Bishu, Shrinivas; Conti, Heather R; Gaffen, Sarah L

2015-01-01

Humans or mice subjected to immunosuppression, such as corticosteroids or anti-cytokine biologic therapies, are susceptible to mucosal infections by the commensal fungus Candida albicans. Recently it has become evident that the Th17/IL-17 axis is essential for immunity to candidiasis, but the downstream events that control immunity to this fungus are poorly understood. The CCAAT/Enhancer Binding Protein-β (C/EBPβ) transcription factor is important for signaling by multiple inflammatory stimuli, including IL-17. C/EBPβ is regulated in a variety of ways by IL-17, and controls several downstream IL-17 target genes. However, the role of C/EBPβ in vivo is poorly understood, in part because C/EBPβ-deficient mice are challenging to breed and work with. In this study, we sought to understand the role of C/EBPβ in the context of an IL-17-dependent immune response, using C. albicans infection as a model system. Confirming prior findings, we found that C/EBPβ is required for immunity to systemic candidiasis. In contrast, C/EBPβ(-/-) mice were resistant to oropharyngeal candidiasis (OPC), in a manner indistinguishable from immunocompetent WT mice. However, C/EBPβ(-/-) mice experienced more severe OPC than WT mice in the context of cortisone-induced immunosuppression. Expression of the antimicrobial peptide β-defensin (BD)-3 correlated strongly with susceptibility in C/EBPβ(-/-) mice, but no other IL-17-dependent genes were associated with susceptibility. Therefore, C/EBPβ contributes to immunity to mucosal candidiasis during cortisone immunosuppression in a manner linked to β-defensin 3 expression, but is apparently dispensable for the IL-17-dependent response.

Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake

PubMed Central

McNelis, Joanne C.; Manolopoulos, Konstantinos N.; Gathercole, Laura L.; Bujalska, Iwona J.; Stewart, Paul M.; Tomlinson, Jeremy W.

2013-01-01

Glucocorticoids increase adipocyte proliferation and differentiation, a process underpinned by the local reactivation of inactive cortisone to active cortisol within adipocytes catalyzed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal sex steroid precursor dehydroepiandrosterone (DHEA) has been shown to inhibit 11β-HSD1 in murine adipocytes; however, rodent adrenals do not produce DHEA physiologically. Here, we aimed to determine the effects and underlying mechanisms of the potential antiglucocorticoid action of DHEA and its sulfate ester DHEAS in human preadipocytes. Utilizing a human subcutaneous preadipocyte cell line, Chub-S7, we examined the metabolism and effects of DHEA in human adipocytes, including adipocyte proliferation, differentiation, 11β-HSD1 expression, and activity and glucose uptake. DHEA, but not DHEAS, significantly inhibited preadipocyte proliferation via cell cycle arrest in the G1 phase independent of sex steroid and glucocorticoid receptor activation. 11β-HSD1 oxoreductase activity in differentiated adipocytes was inhibited by DHEA. DHEA coincubated with cortisone significantly inhibited preadipocyte differentiation, which was assessed by the expression of markers of early (LPL) and terminal (G3PDH) adipocyte differentiation. Coincubation with cortisol, negating the requirement for 11β-HSD1 oxoreductase activity, diminished the inhibitory effect of DHEA. Further consistent with glucocorticoid-opposing effects of DHEA, insulin-independent glucose uptake was significantly enhanced by DHEA treatment. DHEA increases basal glucose uptake and inhibits human preadipocyte proliferation and differentiation, thereby exerting an antiglucocorticoid action. DHEA inhibition of the amplification of glucocorticoid action mediated by 11β-HSD1 contributes to the inhibitory effect of DHEA on human preadipocyte differentiation. PMID:24022868

Prednisolone and prednisone neo-formation in bovine urine after sampling.

PubMed

Arioli, F; Casati, A; Fidani, M; Silvestri, M; Pompa, G

2012-06-01

The rise in the frequency of detecting prednisolone in bovine urine from northern Italy has come into focus of attention in recent years. The possibility that neo-formation of prednisolone or that prednisone may occur in urine after collection of samples was therefore investigated. Cow urine collected for official routine controls in Lombardy containing more than 80 ng/ml cortisol, and prednisolone and prednisone below the decision limit (CCα) of the method (0.4 and 0.5 ng/ml, respectively) was used. The C1-2 dehydrogenation of naturally present cortisol and cortisone was checked by incubating urine, both contaminated and uncontaminated with faeces, at 37°C and by collecting samples at 0, 1, 2, 4, 6 and 24 h. The influence of Helix pomatia juice was also investigated in order to determine whether deconjugation could influence the reliability of the results. All samples were analysed by HPLC-MS3 for the presence of cortisol, cortisone, prednisolone and prednisone in negative electrospray ionisation mode, utilising the consecutive reaction monitoring of product ions derived from the formate molecular adduct ([M+HCOO]-). The observed neo-formation of prednisolone shows that inappropriate temperatures in sample storage and processing can result in an incorrect accusation of non-compliance. The faecal contamination of urine, performed with the aim to mimic a collection conducted without the necessary care, moreover, evoked a high increase in prednisolone concentration in two out of seven animals. Moreover, H. pomatia juice had no significant effect on the prednisolone concentration, indicating that this corticosteroid is present in its free form in cow urine.

Tendinopathy in Sport

PubMed Central

Ackermann, Paul W.; Renström, Per

2012-01-01

Context: Tendinopathy is increasing in prevalence and accounts for a substantial part of all sports injuries and occupational disorders. Despite the magnitude of the disorder, high-quality scientific data on etiology and available treatments have been limited. Evidence Acquisition: The authors conducted a MEDLINE search on tendinopathy, or “tendonitis” or “tendinosis” or “epicondylitis” or “jumpers knee” from 1980 to 2011. The emphasis was placed on updates on epidemiology, etiology, and recent patient-oriented Level 1 literature. Results: Repetitive exposure in combination with recently discovered intrinsic factors, such as genetic variants of matrix proteins, and metabolic disorders is a risk factor for the development of tendinopathy. Recent findings demonstrate that tendinosis is characterized by a fibrotic, failed healing response associated with pathological vessel and sensory nerve ingrowth. This aberrant sensory nerve sprouting may partly explain increased pain signaling and partly, by release of neuronal mediators, contribute to the fibrotic alterations observed in tendinopathy. The initial nonoperative treatment should involve eccentric exercise, which should be the cornerstone (basis) of treatment of tendinopathy. Eccentric training combined with extracorporeal shockwave treatment has in some reports shown higher success rates compared to any therapies alone. Injection therapies (cortisone, sclerosing agents, blood products including platelet-rich plasma) may have short-term effects but have no proven long-term treatment effects or meta-analyses to support them. For epicondylitis, cortisone injections have demonstrated poorer long-time results than conservative physiotherapy. Today surgery is less indicated because of successful conservative therapies. New minioperative procedures that, via the endoscope, remove pathologic tissue or abnormal neoinnervation demonstrate promising results but need confirmation by Level 1 studies. Conclusions: Novel targeted therapies are emerging, but multicenter trials are needed to confirm the results of exercise and mini-invasive treatments. PMID:23016086

Factors associated with operative treatment of enthesopathy of the extensor carpi radialis brevis origin.

PubMed

Kachooei, Amir Reza; Talaei-Khoei, Mojtaba; Faghfouri, Aram; Ring, David

2016-04-01

This study investigated the factors associated with variation in the rate of surgery for enthesopathy of the extensor carpi radialis brevis (eECRB). We used a large database from 3 academic hospitals including 5964 patients with the diagnosis of eECRB from 2001 to 2007. Of those, 244 patients (4%) had surgery for eECRB. We used the date of the first encounter as the date of diagnosis. We also recorded the date of the first cortisone injection and surgery for eECRB. We used Cox multivariable regression analysis to find factors associated with surgery. We considered the following explanatory factors: age, sex, race, diabetes, a diagnosis of major depression, a diagnosis of an anxiety disorder, hospital, provider (surgeon vs. nonsurgeon), corticosteroid injection, and the time from diagnosis to the first cortisone injection. The hazard ratio of having surgery was 12-times greater if the initial provider was an orthopedic surgeon rather a nonsurgeon and 1.7-times greater at 1 of the 2 hospitals. The rate of surgery varied substantially, ranging from 0% to 22%. Corticosteroid injection delayed the time to surgery but was ultimately associated with a higher rate of surgery. The majority (86%) of surgeries were done within 1 year of the first documented office visit. It seems likely that an emphasis on the preferences and values of the patient rather than the surgeon would decrease the variation in surgery rates for eECRB observed in this study. Methods for optimizing the influence of patient preferences and values on decision making (eg, decision aids) merit additional study. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Hormone modeling in preterm neonates: establishment of pituitary and steroid hormone reference intervals.

PubMed

Greaves, Ronda F; Pitkin, Janne; Ho, Chung Shun; Baglin, James; Hunt, Rodney W; Zacharin, Margaret R

2015-03-01

Reports suggest significant differences in serum levels of hormones in extremely preterm compared with late preterm and full-term infants. The purpose of this study was to develop reference intervals (RIs) for 3 pituitary hormones and 5 steroid hormones in serum of preterm infants. Blood samples were collected from 248 (128 male and 120 female) preterm neonates born between 24 and 32 weeks' gestation. PARTICIPANTS were recruited from 3 neonatal intensive care wards in Melbourne, Australia. No infant in this cohort had ambiguous genitalia or other endocrine abnormalities. All infants included in the RI determination survived beyond the equivalent of term. Serum was analyzed for prolactin, FSH, and LH by automated electrochemiluminescence immunoassay (Roche Cobas 8000-e601). Liquid chromatography coupled with tandem mass spectrometry was used for analysis of 17-hydroxyprogesterone, androstenedione, cortisol, cortisone, and testosterone. The robust method was applied to define the central 95% RI, after each hormone measure was transformed using a Box-Cox transformation to correct for asymmetry. RIs were established for 8 hormones. Gender-specific intervals were developed for FSH, LH, and testosterone. Cortisone and 17- hydroxyprogesterone required division based on gestational age, with neonates born at <30 weeks' gestation demonstrating higher levels than their older counterparts. Androstenedione, cortisol, and prolactin did not require any division within this cohort for RI assignment. This report provides the first characterization of serum steroids measured by mass spectrometry in preterm neonates, with the additional characterization of 3 pituitary hormones in infants born at ≤32 weeks' gestation. Use of these data allows for correct interpretation of results for very preterm neonates and reduces the risk of incorrect diagnosis due to misinterpretation of data.

Increased production of 11beta-hydroxysteroid dehydrogenase type 2 in the kidney microsomes of squirrel monkeys (Saimiri spp.).

PubMed

Sadosky, Patti W; Scammell, Jonathan G

2008-04-01

In squirrel monkeys (Saimiri spp.), cortisol circulates at levels much higher than those seen in man and other Old World primates, but squirrel monkeys exhibit no physiologic signs of the mineralocorticoid effects of cortisol. These observations suggest that squirrel monkeys have mechanisms for protection of the mineralocorticoid receptor (MR) from these high levels of cortisol. We previously showed that the serum cortisol to cortisone ratio in these animals is low relative to that in human serum, suggesting that production of the MR protective enzyme, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), is increased in squirrel monkeys. Here, we directly evaluate whether increased production of 11beta-HSD2, which inactivates cortisol to cortisone, is a mechanism for protection of MR. In vitro assays showed that 11beta-HSD2 activity in squirrel monkey kidney microsomes was 3 to 7 times higher than that seen in kidney microsomes from pig or rabbit. 11beta-HSD2 protein detected by Western blot analysis was 4 to 9 times greater in squirrel monkey microsomes than in pig or rabbit microsomes. Comparison of the effect of expression of either human or squirrel monkey 11beta-HSD2 on MR transactivation activity showed similar inhibition of MR response to cortisol by both enzymes, indicating that the intrinsic activities of the human and squirrel monkey enzymes are similar. These findings suggest that one mechanism by which squirrel monkeys protect the MR from activation by high cortisol levels in the kidney is by upregulation of 11beta-HSD2 activity through increased production of the enzyme.

Diet-induced weight loss has chronic tissue-specific effects on glucocorticoid metabolism in overweight postmenopausal women.

PubMed

Stomby, A; Simonyte, K; Mellberg, C; Ryberg, M; Stimson, R H; Larsson, C; Lindahl, B; Andrew, R; Walker, B R; Olsson, T

2015-05-01

Tissue-specific glucocorticoid metabolism is altered in obesity, and may increase cardiovascular risk. This dysregulation is normalized by short-term calorie restriction and weight loss, an effect that varies with dietary macronutrient composition. However, tissue-specific glucocorticoid metabolism has not been studied during long-term (>6 months) dietary interventions. Therefore our aim was to test whether long-term dietary interventions, either a paleolithic-type diet (PD) or a diet according to Nordic nutrition recommendations (NNR) could normalize tissue-specific glucocorticoid metabolism in overweight and obese women. Forty-nine overweight/obese postmenopausal women were randomized to a paleolithic diet or a diet according to NNR for 24 months. At baseline, 6 and 24 months anthropometric measurements, insulin sensitivity, excretion of urinary glucocorticoid metabolites in 24-hour collections, conversion of orally administered cortisone to plasma cortisol and transcript levels of 11β hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue were studied. Both diet groups achieved significant and sustained weight loss. Weight loss with the PD was greater than on NNR diet after 6 months (P<0.001) but similar at 24 months. Urinary measurement of 5α-reductase activity was increased after 24 months in both groups compared with baseline (P<0.001). Subcutaneous adipose tissue 11βHSD1 gene expression decreased at 6 and 24 months in both diet groups (P=0.036). Consistent with increased liver 11βHSD1, conversion of oral cortisone to cortisol increased at 6 months (P=0.023) but was unchanged compared with baseline by 24 months. Long-term weight loss in postmenopausal women has tissue-specific and time-dependent effects on glucocorticoid metabolism. This may alter local-tissue cortisol exposure contributing to improved metabolic function during weight loss.

Microstructure of microemulsion modified with ionic liquids in microemulsion electrokinetic chromatography and analysis of seven corticosteroids.

PubMed

Ni, Xinjiong; Yu, Meijuan; Cao, Yuhua; Cao, Guangqun

2013-09-01

In this work, the influences of ionic liquid (IL) as a modifier on microemulsion microstructure and separation performance in MEEKC were investigated. Experimental results showed that synergetic effect between IL 1-butyl-3-methylimidazolium tetrafluoro-borate (BmimBF4 ) and surfactant SDS gave a decreased CMC. With increment of IL in microemulsion, negative ζ potential of the microdroplets reduced gradually. The influence of IL on the dimensions of microdroplet was complicated. At BmimBF4 less than 8 mM, IL made microemulsion droplet smaller in size. While at BmimBF4 more than 10 mM, the size increased and reached to a maximum value at 12 mM, where the microdroplets were larger than that without IL. After that, the micreodroplet size decreased again. Relative fluorescence intensity of the first vibration band of pyrene to the third one (I1 /I3 ) enhanced as IL was added to microemulsion, which indicated that this addition increased environmental polarity in the inner core of microdroplets. Prednisone, hydrocortisone, prednisolone, hydrocortisone acetate, cortisone acetate, prednisolone acetate, and triamcinolone acetonide were analyzed with MEEKC modified with IL to evaluate the separation performance. Cortisone acetate and prednisolone acetate could not be separated at all in typical microemulsion. The seven analytes could be separated by the addition of 10 mM BmimBF4 into the microemulsion system. The method has been used for analysis of corticosteroids in cosmetic samples with simple extraction; the recoveries for seven analytes were between 86 and 114%. This method provides accuracy, reproducibility, pretreatment simplicity, and could be applied to the quality control of cosmetics. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Diagnosis and Management of Combined Central Diabetes Insipidus and Cerebral Salt Wasting Syndrome After Traumatic Brain Injury.

PubMed

Wu, Xuehai; Zhou, Xiaolan; Gao, Liang; Wu, Xing; Fei, Li; Mao, Ying; Hu, Jin; Zhou, Liangfu

2016-04-01

Combined central diabetes insipidus and cerebral salt wasting syndrome after traumatic brain injury (TBI) is rare, is characterized by massive polyuria leading to severe water and electrolyte disturbances, and usually is associated with very high mortality mainly as a result of delayed diagnosis and improper management. We retrospectively reviewed the clinical presentation, management, and outcomes of 11 patients who developed combined central diabetes insipidus and cerebral salt wasting syndrome after traumatic brain injury to define distinctive features for timely diagnosis and proper management. The most typical clinical presentation was massive polyuria (10,000 mL/24 hours or >1000 mL/hour) refractory to vasopressin alone but responsive to vasopressin plus cortisone acetate. Other characteristic presentations included low central venous pressure, high brain natriuretic peptide precursor level without cardiac dysfunction, high 24-hour urine sodium excretion and hypovolemia, and much higher urine than serum osmolarity; normal serum sodium level and urine specific gravity can also be present. Timely and adequate infusion of sodium chloride was key in treatment. Of 11 patients, 5 had a good prognosis 3 months later (Extended Glasgow Outcome Scale score ≥6), 1 had an Extended Glasgow Outcome Scale score of 4, 2 died in the hospital of brain hernia, and 3 developed a vegetative state. For combined diabetes insipidus and cerebral salt wasting syndrome after traumatic brain injury, massive polyuria is a major typical presentation, and intensive monitoring of fluid and sodium status is key for timely diagnosis. To achieve a favorable outcome, proper sodium chloride supplementation and cortisone acetate and vasopressin coadministration are key. Copyright © 2016 Elsevier Inc. All rights reserved.

Development and validation of a GC-C-IRMS method for the confirmation analysis of pseudo-endogenous glucocorticoids in doping control.

PubMed

de la Torre, Xavier; Curcio, Davide; Colamonici, Cristiana; Molaioni, Francesco; Cilia, Marta; Botrè, Francesco

2015-01-01

Glucocorticoids are included in the S9 section of the World Anti-doping Agency (WADA) prohibited list international standard. Some among them are pseudo-endogenous steroids, like cortisol and cortisone, which present the same chemical structure as endogenously produced steroids. We are proposing an analytical method based on gas chromatography coupled to isotope ratio mass spectrometry (GC-C-IRMS) which allows discrimination between endogenous and synthetic origin of the urinary metabolites of the pseudo-endogenous glucocorticoids. A preliminary purification treatment by high-performance liquid chromatography (HPLC) of the target compounds (TC) (i.e., cortisol, tetrahydrocortisone (THE) 5α-tetrahydrocortisone (aTHE), tetrahydrocortisol (THF), and 5α-tetrahydrocortisol (aTHF)) allows collection of extracts with adequate purity for the subsequent analysis by IRMS. A population of 40 urine samples was analyzed for the TC and for the endogenous reference compounds (ERC: i.e., 11-desoxy-tetrahydrocortisol (THS) or pregnanediol). For each sample, the difference between the delta values of the ERCs and TCs (Δδ values) were calculated and based on that, some decision limits for atypical findings are proposed. The limits are below 3% units except for cortisol. The fit to purpose of the method has been confirmed by the analysis of urine samples collected in two patients under treatment with 25 mg of cortisone acetate (p.o). The samples showed Δδ values higher than 3 for at least 24 h following administration depending on the TC considered. The method can easily be integrated into existing procedures already used for the HPLC purification and IRMS analysis of pseudo-endogenous steroids with androgenic/anabolic activity. Copyright © 2015 John Wiley & Sons, Ltd.

Multifactorial monitoring of training load in elite rugby sevens players: cortisol/cortisone ratio as a valid tool of training load monitoring

PubMed Central

Bouaziz, T; Makni, E; Passelergue, P; Tabka, Z; Lac, G; Moalla, W; Chamari, K

2016-01-01

The effectiveness of selected physiological and perceptual measures for monitoring training load and fatigue was studied in 16 male elite rugby sevens players during a 6-week intense training block (IT) and 2-week tapering (TAP). Daily training load (TL) and strain (TS) as well as weekly total score of fatigue (TSF) were quantified respectively by the session-rating of perceived exertion (RPE) method and an 8-item questionnaire. Also, testing was performed and 24 h urinary cortisol (C), cortisone (Cn), adrenaline (A) and noradrenalin (NA) excretion was measured before (T0) and after the IT (T1) and after the TAP (T2). The TL, TS and TSF increased during the IT and decreased during the TAP, in conjunction with a significant drop and improvement, respectively, of performance standards during the two periods. At T1, C and Cn levels increased while A and NA levels decreased, resulting in a higher C/Cn ratio and lower A/NA ratio, respectively. At T2, both C/Cn and A/NA returned to baseline values. The changes in C/Cn ratio, after the 6-week IT, were more closely related to mean TL, TS and TSF (r=0.75-0.76 vs. r=0.48-0.58, p<0.01) and to changes in the majority of performance measures than to A/NA ratio. Only the changes in C/Cn ratio after the 2-week TAP were related to mean TL, TS and TSF (r=0.61-0.68, p<0.01). The changes in hormone levels, training strain and performance standards reflected the physical and mental stressors of training, with complete recovery, as indicated by physiological homeostasis, achieved after an appropriate tapering period. PMID:27601777

Intergenerational gene × environment interaction of FKBP5 and childhood maltreatment on hair steroids.

PubMed

Koenig, Alexandra M; Ramo-Fernández, Laura; Boeck, Christina; Umlauft, Maria; Pauly, Markus; Binder, Elisabeth B; Kirschbaum, Clemens; Gündel, Harald; Karabatsiakis, Alexander; Kolassa, Iris-Tatjana

2018-06-01

The inconsistency in results of cortisol alterations after childhood maltreatment (CM) might arise due to the fact that no study so far considered the effects of environmental factors such as maltreatment load and genetic factors such as the influence of FKBP5 genotype on stress hormone regulation. This study analyzed the interaction between the single nucleotide polymorphism rs1360780 within the FKBP5 gene and the severity of maternal CM experiences (maltreatment load) on hair steroid levels of mother-infant-dyads. Hair samples of N = 474 mothers and N = 331 newborns were collected < 1 week after parturition enabling a retrospective assessment of cortisol, cortisone, and dehydroepiandrosterone (DHEA) using mass spectrometry. The sum score of the Childhood Trauma Questionnaire operationalized the maternal maltreatment load. DNA from whole blood or buccal cells was used for FKBP5 genotyping. The higher the maltreatment load, the higher maternal hair cortisol and cortisone levels in T allele carriers of FKBP5 rs1360780 were observed. Hair cortisol and DHEA levels of newborns with the T allele were reduced with an increasing maternal maltreatment load, while there was an increase of hair cortisol and DHEA in newborns homozygous for the C allele. This study is the very first uncovering a gene (FKBP5) × environment (maltreatment load) interaction on hair steroids in mothers and their offspring, indicating an intergenerational transmission of hypothalamic-pituitary-adrenal axis alterations. These results may help to explain the inconsistency in previous findings on steroid hormone alterations after chronic and traumatic stress and should be considered in future studies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Separations of corticosteroids using electrochemically modulated liquid chromatography: Selectivity enhancements at a porous graphitic carbon stationary phase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ting, E.Y.; Porter, M.D.

Electrochemically modulated liquid chromatography has been applied to the separation of a mixture of structurally similar corticosteroids (i.e., prednisone, prednisolone, cortisone, and hydrocortisone) using a porous graphitic carbon stationary phase. Changes in the voltage applied to the column markedly affected the efficiency as well as the elution order of the separation, with the mixture fully resolved at large negative values of applied potential. Mechanistic aspects in terms of the influence of changes in the applied voltage on the extent of the interactions between these analytes and the stationary phase are briefly discussed. 19 refs., 2 figs.

Addison's disease and pregnancy: case report.

PubMed

Cosimo, Caterina; Franco, Ciro

2009-10-01

Addisonian crises, a rare but life-threatening event in pregnant women, may accompany stressful conditions such as labor, puerperium, infection, hyperemesis gravidarum or surgery. A 36-year-old woman, primigravida, with Addison's disease, diagnosed when she was 10 year-old and treated with cortisone and fludrocortisone. The therapy was regulated to avoid adrenal crisis during pregnancy. The woman underwent to caesarean section at 38th week and gave birth to a normal baby. The successful management of pregnant women with Addison's disease, regarding her state and that of the foetus, reassures those women that nowadays Addison's disease and pregnancy are not incompatible when proper monitoring and management is provided.

Septic Shock

PubMed Central

Lansing, Allan M.

1963-01-01

Septic shock may be defined as hypotension caused by bacteremia and accompanied by decreased peripheral blood flow, evidenced by oliguria. Clinically, a shaking chill is the warning signal. The immediate cause of hypotension is pooling of blood in the periphery, leading to decreased venous return: later, peripheral resistance falls and cardiac failure may occur. Irreversible shock is comparable to massive reactive hyperemia. Reticuloendothelial failure, histamine release, and toxic hypersensitivity may be factors in the pathogenesis of septic shock. Adrenal failure does not usually occur, but large doses of corticosteroid are employed therapeutically to counteract the effect of histamine release or hypersensitivity to endotoxin. The keys to successful therapy are time, antibiotics, vasopressors, cortisone and correction of acidosis. PMID:14063936

LATERAL EPICONDYLITIS OF THE ELBOW

PubMed Central

Cohen, Marcio; da Rocha Motta Filho, Geraldo

2015-01-01

Lateral epicondylitis, also known as tennis elbow, is a common condition that is estimated to affect 1% to 3% of the population. The word epicondylitis suggests inflammation, although histological analysis on the tissue fails to show any inflammatory process. The structure most commonly affected is the origin of the tendon of the extensor carpi radialis brevis and the mechanism of injury is associated with overloading. Nonsurgical treatment is the preferred method, and this includes rest, physiotherapy, cortisone infiltration, platelet-rich plasma injections and use of specific immobilization. Surgical treatment is recommended when functional disability and pain persist. Both the open and the arthroscopic surgical technique with resection of the degenerated tendon tissue present good results in the literature. PMID:27047843

Species differences of 11beta-hydroxysteroid dehydrogenase type 2 function in human and rat term placenta determined via LC-MS/MS.

PubMed

Heussner, Kirsten; Ruebner, Matthias; Huebner, Hanna; Rascher, Wolfgang; Menendez-Castro, Carlos; Hartner, Andrea; Fahlbusch, Fabian B; Rauh, Manfred

2016-01-01

Glucocorticoid-induced fetal programming has been associated with negative metabolic and cardiovascular sequelae in the adult. The placental enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2) shields the fetus from maternal glucocorticoid excess by catalyzing the conversion of these hormones into biologically inactive derivatives. In vivo experiments addressing placental barrier function are mostly conducted in rodents. Therefore we set out to characterize species-specific differences of rat and human placental 11β-HSD2 steroid turnover, introducing Liquid Chromatography Tandem Mass-Spectrometry (LC-MS/MS) as a tool for rat tissue analysis. Using LC-MS/MS we determined corticotropin-releasing hormone (CRH), cortisol (F), cortisone (E), corticosterone (B) and 11-dehydrocorticosterone (A) in human and rat placenta at term and measured the enzymatic 11β-HSD glucocorticoid conversion-rates in placental microsomes of both species. In parallel, further glucocorticoid derivatives and sex steroids were determined in the same placental samples. In contrast to the human placenta, we did not detect CRH in the rat placenta. While cortisol (F) and cortisone (E) were exclusively present in human term placenta (E/F-ratio >1), rat placenta showed significant levels of corticosterone (B) and 11-dehydrocorticosterone (A), with an A/B-ratio <1. In line with these species-specific findings, human placenta showed a prominent 11β-HSD2 activity, while in rat placenta higher 11β-HSD1 glucocorticoid turnover rates were determined. Placental steroid metabolism of human and rat shows relevant species-specific differences, especially regarding the barrier function of 11β-HSD2 at term. The exclusive expression of CRH in the human placenta further points to relevant differences in the regulation of parturition in rats. Consideration of these findings is warranted when transferring results from rodent placental glucocorticoid metabolism into humans. Copyright © 2015 Elsevier Ltd. All rights reserved.

Transuteroplacental metabolism of cortisol and cortisone during mid- and late gestation in the baboon

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pepe, G.J.; Albrecht, E.D.

1984-11-01

We measured uterine extraction (i.e. metabolism) and transuteroplacental interconversion of cortisol (F) and cortisone (E) to determine whether metabolism across the uterus changes during pregnancy and contributes to the MCR of these corticosteroids. On day 100 (n . 4) or 170 (n . 3) of pregnancy (term . day 184), baboons (Papio anubis; 14-18 kg) were sedated with ketamine, and a constant infusion (0.38 ml/min) of 8-12 microCi (/sup 3/H)F and 9-15 microCi (/sup 14/C)E in 80 ml 0.9% NaCl-1% ethanol was initiated (time zero) via a maternal antecubital vein. At 60 min, animals were laparotomized, and at 70, 80,more » and 90 min, blood samples were obtained from right and left uterine veins and from a maternal saphenous vein. At 95 min, a transverse incision was made in the uterus, the fetus was isolated, and blood samples were obtained from the umbilical vein and artery. The cord was then clamped, and the fetus was delivered. Radio-labeled F and E were extracted from serum and purified by sequential paper chromatography, and metabolic parameters were calculated. Endogenous F and E levels were determined by RIA. In the mother, the percent conversions of E to F at midgestation (mean +/- SE; 72 +/- 4) and late gestation (65 +/- 3) were similar and exceeded (P less than 0.01) respective values for oxidation of F to E (51 +/- 7 and 46 +/- 7, respectively), indicating that maternal corticosteroid metabolism favors F formation and is unchanged during the second half of gestation. In contrast, corticosteroid metabolism across the uterus and placenta (transuteroplacental) was altered during pregnancy. At midgestation, transuteroplacental conversion of E to F (37 +/- 9) exceeded (P less than 0.05) the reverse reaction (18 +/- 3), whereas oxidation of F to E at term (28 +/- 4) was 7-fold greater (P less than 0.05) than reduction of E to F (4 +/- 1).« less

Non-Invasive Measurement of Adrenocortical Activity in Blue-Fronted Parrots (Amazona aestiva, Linnaeus, 1758)

PubMed Central

Ferreira, João C. P.; Fujihara, Caroline J.; Fruhvald, Erika; Trevisol, Eduardo; Destro, Flavia C.; Teixeira, Carlos R.; Pantoja, José C. F.; Schmidt, Elizabeth M. S.; Palme, Rupert

2015-01-01

Parrots kept in zoos and private households often develop psychological and behavioural disorders. Despite knowing that such disorders have a multifactorial aetiology and that chronic stress is involved, little is known about their development mainly due to a poor understanding of the parrots’ physiology and the lack of validated methods to measure stress in these species. In birds, blood corticosterone concentrations provide information about adrenocortical activity. However, blood sampling techniques are difficult, highly invasive and inappropriate to investigate stressful situations and welfare conditions. Thus, a non-invasive method to measure steroid hormones is critically needed. Aiming to perform a physiological validation of a cortisone enzyme immunoassay (EIA) to measure glucocorticoid metabolites (GCM) in droppings of 24 Blue-fronted parrots (Amazona aestiva), two experiments were designed. During the experiments all droppings were collected at 3-h intervals. Initially, birds were sampled for 24 h (experiment 1) and one week later assigned to four different treatments (experiment 2): Control (undisturbed), Saline (0.2 mL of 0.9% NaCl IM), Dexamethasone (1 mg/kg IM) and Adrenocorticotropic hormone (ACTH; 25 IU IM). Treatments (always one week apart) were applied to all animals in a cross-over study design. A daily rhythm pattern in GCM excretion was detected but there were no sex differences (first experiment). Saline and dexamethasone treatments had no effect on GCM (not different from control concentrations). Following ACTH injection, GCM concentration increased about 13.1-fold (median) at the peak (after 3–9 h), and then dropped to pre-treatment concentrations. By a successful physiological validation, we demonstrated the suitability of the cortisone EIA to non-invasively monitor increased adrenocortical activity, and thus, stress in the Blue-fronted parrot. This method opens up new perspectives for investigating the connection between behavioural disorders and stress in this bird species, and could also help in their captive management. PMID:26717147

Non-Invasive Measurement of Adrenocortical Activity in Blue-Fronted Parrots (Amazona aestiva, Linnaeus, 1758).

PubMed

Ferreira, João C P; Fujihara, Caroline J; Fruhvald, Erika; Trevisol, Eduardo; Destro, Flavia C; Teixeira, Carlos R; Pantoja, José C F; Schmidt, Elizabeth M S; Palme, Rupert

2015-01-01

Parrots kept in zoos and private households often develop psychological and behavioural disorders. Despite knowing that such disorders have a multifactorial aetiology and that chronic stress is involved, little is known about their development mainly due to a poor understanding of the parrots' physiology and the lack of validated methods to measure stress in these species. In birds, blood corticosterone concentrations provide information about adrenocortical activity. However, blood sampling techniques are difficult, highly invasive and inappropriate to investigate stressful situations and welfare conditions. Thus, a non-invasive method to measure steroid hormones is critically needed. Aiming to perform a physiological validation of a cortisone enzyme immunoassay (EIA) to measure glucocorticoid metabolites (GCM) in droppings of 24 Blue-fronted parrots (Amazona aestiva), two experiments were designed. During the experiments all droppings were collected at 3-h intervals. Initially, birds were sampled for 24 h (experiment 1) and one week later assigned to four different treatments (experiment 2): Control (undisturbed), Saline (0.2 mL of 0.9% NaCl IM), Dexamethasone (1 mg/kg IM) and Adrenocorticotropic hormone (ACTH; 25 IU IM). Treatments (always one week apart) were applied to all animals in a cross-over study design. A daily rhythm pattern in GCM excretion was detected but there were no sex differences (first experiment). Saline and dexamethasone treatments had no effect on GCM (not different from control concentrations). Following ACTH injection, GCM concentration increased about 13.1-fold (median) at the peak (after 3-9 h), and then dropped to pre-treatment concentrations. By a successful physiological validation, we demonstrated the suitability of the cortisone EIA to non-invasively monitor increased adrenocortical activity, and thus, stress in the Blue-fronted parrot. This method opens up new perspectives for investigating the connection between behavioural disorders and stress in this bird species, and could also help in their captive management.

Inverse association of highly chlorinated dioxin congeners in maternal breast milk with dehydroepiandrosterone levels in three-year-old Vietnamese children.

PubMed

Kido, Teruhiko; Honma, Seijiro; Nhu, Dang Duc; Manh, Ho Dung; Van Tung, Dao; Liang, Sun Xian; Anh, Le Thai; Okamoto, Rie; Maruzeni, Shoko; Nakagawa, Hideaki; Hung, Nguyen Ngoc; Son, Le Ke

2016-04-15

This study aims to evaluate the endocrine-disrupting effect of dioxin congeners on adrenal steroid hormones in mother-child pairs. In our previous study, we found that cortisol and cortisone levels were higher in the blood and the saliva of mothers living in a dioxin hotspot area than in mothers from a non-exposed region in Vietnam. In this follow-up study, we determined the salivary steroid hormone levels in 49 and 55 three-year-old children of these mothers in the hotspot and non-exposed region, respectively. Steroid hormones were determined by liquid chromatography-tandem mass spectrometry, and dioxin in the maternal breast milk was determined by gas chromatography-mass spectrometry. Dioxin levels in the breast milk of mothers from the hotspot (median total toxic equivalents polychlorinated dibenzodioxins/polychlorinated dibenzofurans; (TEQ PCDD/Fs) of 11pg/g lipid) were three to four times higher than those of mothers in the non-exposed region (median TEQ PCDD/Fs of 3.07pg/g lipid). Salivary dehydroepiandrosterone (DHEA) levels in children were found to be significantly lower in the hotspot than in the non-exposed region, while cortisol and cortisone levels were not different between the two regions. Highly chlorinated dioxin congeners, such as octacholorodibenzodioxin (OCDD), 1,2,3,4,6,7,8-heptacholorodibenzodioxin (HpCDD) and 1,2,3,4 (or 6), 7,8-hexachlorodibenzodioxin Hx(CDD), showed stronger inverse associations with the children's salivary DHEA than other lowly chlorinated dioxin congeners. Glucocorticoid levels in the mothers exhibited a significantly positive correlation with OCDD and HpCDD/F (polychlorinated dibenzofurans). In conclusion, highly chlorinated dioxin congeners are more strongly correlated with endocrine-disrupting effects on adrenal hormones, resulting in high cortisol levels in the mothers and low DHEA levels in their three-year-old children. Copyright © 2016 Elsevier B.V. All rights reserved.

Glucocorticoid Regulation of Food-Choice Behavior in Humans: Evidence from Cushing's Syndrome

PubMed Central

Moeller, Scott J.; Couto, Lizette; Cohen, Vanessa; Lalazar, Yelena; Makotkine, Iouri; Williams, Nia; Yehuda, Rachel; Goldstein, Rita Z.; Geer, Eliza B.

2016-01-01

The mechanisms by which glucocorticoids regulate food intake and resulting body mass in humans are not well-understood. One potential mechanism could involve modulation of reward processing, but human stress models examining effects of glucocorticoids on behavior contain important confounds. Here, we studied individuals with Cushing's syndrome, a rare endocrine disorder characterized by chronic excess endogenous glucocorticoids. Twenty-three patients with Cushing's syndrome (13 with active disease; 10 with disease in remission) and 15 controls with a comparably high body mass index (BMI) completed two simulated food-choice tasks (one with “explicit” task contingencies and one with “probabilistic” task contingencies), during which they indicated their objective preference for viewing high calorie food images vs. standardized pleasant, unpleasant, and neutral images. All participants also completed measures of food craving, and approximately half of the participants provided 24-h urine samples for assessment of cortisol and cortisone concentrations. Results showed that on the explicit task (but not the probabilistic task), participants with active Cushing's syndrome made fewer food-related choices than participants with Cushing's syndrome in remission, who in turn made fewer food-related choices than overweight controls. Corroborating this group effect, higher urine cortisone was negatively correlated with food-related choice in the subsample of all participants for whom these data were available. On the probabilistic task, despite a lack of group differences, higher food-related choice correlated with higher state and trait food craving in active Cushing's patients. Taken together, relative to overweight controls, Cushing's patients, particularly those with active disease, displayed a reduced vigor of responding for food rewards that was presumably attributable to glucocorticoid abnormalities. Beyond Cushing's, these results may have relevance for elucidating glucocorticoid contributions to food-seeking behavior, enhancing mechanistic understanding of weight fluctuations associated with oral glucocorticoid therapy and/or chronic stress, and informing the neurobiology of neuropsychiatric conditions marked by abnormal cortisol dynamics (e.g., major depression, Alzheimer's disease). PMID:26903790

Higher glucocorticoid secretion in the physiological range is associated with lower bone strength at the proximal radius in healthy children: importance of protein intake adjustment.

PubMed

Shi, Lijie; Sánchez-Guijo, Alberto; Hartmann, Michaela F; Schönau, Eckhard; Esche, Jonas; Wudy, Stefan A; Remer, Thomas

2015-02-01

Whether higher production of glucocorticoids (GCs) within the physiological range may already be affecting bone status in healthy children is unknown. Because dietary protein intake affects both bone and GCs, we examined the association of urinary measures of glucocorticoid status and cortical bone in healthy non-obese children, after particularly controlling for protein intake. Proximal forearm bone parameters were measured by peripheral quantitative computed tomography (pQCT). Subjects studied (n = 175, 87 males, aged 6 to 18 years) had two 24-hour urine samples collected: the first sample at 1 year before bone measurement, and the second sample at the time of bone measurement. Major urinary GC metabolites were measured by mass spectrometry and summed to assess daily adrenal GC secretion (∑C21). Urinary free cortisol (UFF) and cortisone (UFE) were summed to assess potentially bioactive free GCs (UFF + UFE). After controlling for several covariates and especially urinary nitrogen (the biomarker of protein intake) cortisol secretion ∑C21 was inversely associated with all analyzed pQCT measures of bone quality. ∑C21 also predicted a higher endosteal and lower periosteal circumference, explaining both a smaller cortical area and (together with lower BMD) a lower strength-strain-index (SSI). UFF + UFE, UFE itself, and a urinary metabolite-estimate of 11beta-hydroxysteroid dehydrogenase type1 (11beta-HSD1) activity showed corresponding reciprocal associations (p < 0.05) with BMD and bone mineral content, but not with SSI and bone geometry variables. In conclusion, higher GC levels, even within the physiological range, appear to exert negative influences on bone modeling and remodeling already during growth. Our physiological data also suggest a relevant role of cortisone as the direct source for intracrine-generated cortisol by bone cell 11beta-HSD1. © 2014 American Society for Bone and Mineral Research.

Platelet rich plasma versus corticosteroid injection for plantar fasciitis: A comparative study.

PubMed

Jain, Kowshik; Murphy, Philip N; Clough, Timothy M

2015-12-01

Intractable plantar fasciitis can be a difficult condition to treat. Early results of platelet rich plasma (PRP) injection have been promising. We compared PRP to traditional cortisone injection in the treatment of chronic cases of plantar fasciitis resistant to traditional nonoperative management. The aim of the study was to compare the efficacy of PRP to that of Steroid at 3, 6 and 12 months after injection. 60 heels with intractable plantar fasciitis who had failed conservative treatment were randomised to receive either PRP or Steroid injection. All patients were assessed with the Roles-Maudsley (RM) Score, Visual Analogue Score (VAS) for pain and the American Orthopaedic Foot and Ankle Society (AOFAS) score. Data was collected prospectively on the cohort, pre-treatment, at 3, 6 and 12 months post injection and the results were compared. Pre-injection, the two groups were well matched with no statistically significant difference. At 3 months, all three outcome scores had significantly improved from their pretreatment level in both groups. The scores in the Steroid arm were marginally better than in the PRP arm, but this difference was not statistically significant. At 6 months, there was no statistically significant difference between the two groups, though there was a trend for the PRP scores to become better than the Steroid scores. At 12 months, the RM, VAS and AOFAS scores in the PRP arm (1.9, 3.3 and 88.5) were significantly better than the Steroid arm (2.6, 5.3 and 75) with P values of .013, .028 and .033, respectively. PRP is as effective as Steroid injection at achieving symptom relief at 3 and 6 months after injection, for the treatment of plantar fasciitis, but unlike Steroid, its effect does not wear off with time. At 12 months, PRP is significantly more effective than Steroid, making it better and more durable than cortisone injection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fabric phase sorptive extraction-high performance liquid chromatography-photo diode array detection method for simultaneous monitoring of three inflammatory bowel disease treatment drugs in whole blood, plasma and urine.

PubMed

Kabir, Abuzar; Furton, Kenneth G; Tinari, Nicola; Grossi, Laurino; Innosa, Denise; Macerola, Daniela; Tartaglia, Angela; Di Donato, Valentina; D'Ovidio, Cristian; Locatelli, Marcello

2018-05-01

This paper reports a novel fabric phase sorptive extraction-high performance liquid chromatography-photodiode array detection (FPSE-HPLC-PDA) method for the simultaneous extraction and analysis of three drug residues (ciprofloxacin, sulfasalazine, and cortisone) in human whole blood, plasma, and urine samples, generally administered in human patients to treat inflammatory bowel disease (IBD). The drugs of interest were well resolved using a Luna C 18 column (250 mm × 4.6 mm; 5 μm particle size) in gradient elution mode within 20 min. The analytical method was optimized and validated in the range 0.05-10 μg/mL for whole blood, 0.25-10 μg/mL for human plasma, and 0.10-10 μg/mL for human urine. Blank human whole blood, plasma, and urine were used as the sample matrix for the method development and validation; while methyl-p-hydroxybenzoate was used as the internal standard (IS). Weighted-matrix matched standard calibration curves showed a good linearity up to a concentration of 10 μg/mL. The intra- and inter-day accuracy values (precision and trueness) were found in the range from -10.9% to 12.3%, and the performances of the validated FPSE-HPLC-PDA were further tested on real IBD patient samples. This is the first FPSE procedure applied simultaneously to whole blood, plasma, and urine samples for the determination of residual IBD drugs, which possess a wide range of polarity (logP values ranging from 2.30 for Ciprofloxacin, to 1.66 for Cortisone, and 2.92 for Sulfasalazine). The new approach exhibits high potential for immediate adoptation as a rapid, robust and green analytical tool for future clinical and pharmaceutical applications. Copyright © 2018 Elsevier B.V. All rights reserved.

Glucocorticoid Regulation of Food-Choice Behavior in Humans: Evidence from Cushing's Syndrome.

PubMed

Moeller, Scott J; Couto, Lizette; Cohen, Vanessa; Lalazar, Yelena; Makotkine, Iouri; Williams, Nia; Yehuda, Rachel; Goldstein, Rita Z; Geer, Eliza B

2016-01-01

The mechanisms by which glucocorticoids regulate food intake and resulting body mass in humans are not well-understood. One potential mechanism could involve modulation of reward processing, but human stress models examining effects of glucocorticoids on behavior contain important confounds. Here, we studied individuals with Cushing's syndrome, a rare endocrine disorder characterized by chronic excess endogenous glucocorticoids. Twenty-three patients with Cushing's syndrome (13 with active disease; 10 with disease in remission) and 15 controls with a comparably high body mass index (BMI) completed two simulated food-choice tasks (one with "explicit" task contingencies and one with "probabilistic" task contingencies), during which they indicated their objective preference for viewing high calorie food images vs. standardized pleasant, unpleasant, and neutral images. All participants also completed measures of food craving, and approximately half of the participants provided 24-h urine samples for assessment of cortisol and cortisone concentrations. Results showed that on the explicit task (but not the probabilistic task), participants with active Cushing's syndrome made fewer food-related choices than participants with Cushing's syndrome in remission, who in turn made fewer food-related choices than overweight controls. Corroborating this group effect, higher urine cortisone was negatively correlated with food-related choice in the subsample of all participants for whom these data were available. On the probabilistic task, despite a lack of group differences, higher food-related choice correlated with higher state and trait food craving in active Cushing's patients. Taken together, relative to overweight controls, Cushing's patients, particularly those with active disease, displayed a reduced vigor of responding for food rewards that was presumably attributable to glucocorticoid abnormalities. Beyond Cushing's, these results may have relevance for elucidating glucocorticoid contributions to food-seeking behavior, enhancing mechanistic understanding of weight fluctuations associated with oral glucocorticoid therapy and/or chronic stress, and informing the neurobiology of neuropsychiatric conditions marked by abnormal cortisol dynamics (e.g., major depression, Alzheimer's disease).

Crystal Structure of Human Liver [delta][superscript 4]-3-Ketosteroid 5[beta]-Reductase (AKR1D1) and Implications for Substrate Binding and Catalysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Di Costanzo, Luigi; Drury, Jason E.; Penning, Trevor M.

2008-07-15

AKR1D1 (steroid 5{beta}-reductase) reduces all {Delta}{sup 4}-3-ketosteroids to form 5{beta}-dihydrosteroids, a first step in the clearance of steroid hormones and an essential step in the synthesis of all bile acids. The reduction of the carbon-carbon double bond in an {alpha}{beta}-unsaturated ketone by 5{beta}-reductase is a unique reaction in steroid enzymology because hydride transfer from NADPH to the {beta}-face of a {Delta}{sup 4}-3-ketosteroid yields a cis-A/B-ring configuration with an {approx}90{sup o} bend in steroid structure. Here, we report the first x-ray crystal structure of a mammalian steroid hormone carbon-carbon double bond reductase, human {Delta}{sup 4}-3-ketosteroid 5{beta}-reductase (AKR1D1), and its complexes withmore » intact substrates. We have determined the structures of AKR1D1 complexes with NADP{sup +} at 1.79- and 1.35-{angstrom} resolution (HEPES bound in the active site), NADP{sup +} and cortisone at 1.90-{angstrom} resolution, NADP{sup +} and progesterone at 2.03-{angstrom} resolution, and NADP{sup +} and testosterone at 1.62-{angstrom} resolution. Complexes with cortisone and progesterone reveal productive substrate binding orientations based on the proximity of each steroid carbon-carbon double bond to the re-face of the nicotinamide ring of NADP{sup +}. This orientation would permit 4-pro-(R)-hydride transfer from NADPH. Each steroid carbonyl accepts hydrogen bonds from catalytic residues Tyr{sup 58} and Glu{sup 120}. The Y58F and E120A mutants are devoid of activity, supporting a role for this dyad in the catalytic mechanism. Intriguingly, testosterone binds nonproductively, thereby rationalizing the substrate inhibition observed with this particular steroid. The locations of disease-linked mutations thought to be responsible for bile acid deficiency are also revealed.« less

Crystal Structure of Human Liver delta {4}-3-Ketosteroid 5 beta-Reductase (AKR1D1) and Implications for Substrate Binding and Catalysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Di Costanzo,L.; Drury, J.; Penning, T.

2008-01-01

AKR1D1 (steroid 5{beta}-reductase) reduces all 4-3-ketosteroids to form 5{beta}-dihydrosteroids, a first step in the clearance of steroid hormones and an essential step in the synthesis of all bile acids. The reduction of the carbon-carbon double bond in an a,{beta}-unsaturated ketone by 5{beta}-reductase is a unique reaction in steroid enzymology because hydride transfer from NADPH to the {beta}-face of a 4-3-ketosteroid yields a cis-A/B-ring configuration with an {approx}90 bend in steroid structure. Here, we report the first x-ray crystal structure of a mammalian steroid hormone carbon-carbon double bond reductase, human 4-3-ketosteroid 5{beta}-reductase (AKR1D1), and its complexes with intact substrates. We havemore » determined the structures of AKR1D1 complexes with NADP+ at 1.79- and 1.35- Angstroms resolution (HEPES bound in the active site), NADP+ and cortisone at 1.90- Angstroms resolution, NADP+ and progesterone at 2.03- Angstroms resolution, and NADP+ and testosterone at 1.62- Angstroms resolution. Complexes with cortisone and progesterone reveal productive substrate binding orientations based on the proximity of each steroid carbon-carbon double bond to the re-face of the nicotinamide ring of NADP+. This orientation would permit 4-pro-(R)-hydride transfer from NADPH. Each steroid carbonyl accepts hydrogen bonds from catalytic residues Tyr58 and Glu120. The Y58F and E120A mutants are devoid of activity, supporting a role for this dyad in the catalytic mechanism. Intriguingly, testosterone binds nonproductively, thereby rationalizing the substrate inhibition observed with this particular steroid. The locations of disease-linked mutations thought to be responsible for bile acid deficiency are also revealed.« less

Determination of a steroid profile in heel prick blood using LC-MS/MS.

PubMed

Boelen, Anita; Ruiter, An F C; Claahsen-van der Grinten, Hedi L; Endert, Erik; Ackermans, Mariette T

2016-01-01

The aim of this study was to improve the sensitivity of the congenital adrenal hyperplasia (CAH) neonatal screening by including second-tier steroid profiling on a DBS using LC-MS. We developed a method to measure the steroid profile in DBS and established gestational age-specific reference ranges of cortisol, cortisone, 11-deoxycortisol, 21-deoxycortisol, 17-hydroxyprogesterone, testosterone, Δ4-androstenedione, corticosterone and 11-deoxycorticosterone using 450 heel prick samples of neonates, participating in the Dutch Screening Program. Analyzing 92 cards with a positive CAH screening showed that only 21-deoxycortisol was 100% specific for diagnosed CAH patients. Steroid precursors can be measured in DBS and we suggest to implement the method as a second tier testing for CAH in The Netherlands.

Unicameral and aneurysmal bone cysts.

PubMed

Campanacci, M; Capanna, R; Picci, P

1986-03-01

One hundred and seventy-eight cases of unicameral bone cysts (UBC) treated with curettage and bone grafting were compared to 141 cases treated with cortisone injections. The end results were comparable in the two groups. Local recurrence risk factors in the surgical group were active cyst and previous operations. In the other group they were multilocation of the cyst, active cyst, and size of cyst. A new radiographic classification of aneurysmal bone cyst (ABC) is proposed in a report of 198 cases of ABC. The treatment of choice in ABC is surgical and the type (curettage, curettage plus phenole or cryosurgery, resection or hemiresection) is selected on the basis of the radiographic aspect and the rate of growth of the cyst. Radiotherapy is only indicated in inoperable ABC cases.

How to learn from patients: Fuller Albright's exploration of adrenal function.

PubMed

Schwartz, T B

1995-08-01

Fuller Albright (1900-1969) was acknowledged as the preeminent clinical and investigative endocrinologist of his day by many of his contemporaries, but his many achievements are all but unknown to the present generation of physicians. This article describes how he used his clinical knowledge and a few tools--the measurement of urinary 17-ketosteroid excretion and the administration of methyltestosterone--to elucidate the major hormonal functions of the adrenal cortex and to clarify the pathophysiology of the Cushing syndrome. In addition, in a tour de force of clinical reasoning, he predicted, 5 years before the event, the discovery of a hormone that would reverse the endocrinologic abnormalities of congenital adrenal hyperplasia. Fittingly, he and pioneer pediatric endocrinologist Lawson Wilkins were the first to treat this disease successfully with cortisone.

[Chronic Inflammatory Demyelinating Polyneuropathy].

PubMed

Balke, M; Wunderlich, G; Brunn, A; Fink, G R; Lehmann, H C

2016-12-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic progressive or relapsing autoimmune neuropathy with heterogeneous clinical presentation. Symptoms typically include symmetrical, proximal and/or distal paresis and sensory loss. Atypical CIDP variants are increasingly recognized, including subtypes with rapid onset as well as variants with pure sensory, focal or marked asymmetrical deficits. Diagnosis is established by compatible symptoms, characteristic electrophysiological features and cerebrospinal fluid analysis. In unequivocal cases, inflammatory infiltrates in sural nerve biopsy support the diagnosis. Recent studies suggest that diagnostic imaging techniques such as MRI and nerve ultrasound may become useful tools for establishing the diagnosis. First-line therapies include immunoglobulines, steroids, and plasmapheresis. Immunosuppressant agents and monoclonal antibodies are used in therapy-refractory cases or as cortison-saving agents. © Georg Thieme Verlag KG Stuttgart · New York.

Pharmacological characterization of the selective 11β-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes.

PubMed

Hamilton, Bradford S; Himmelsbach, Frank; Nar, Herbert; Schuler-Metz, Annette; Krosky, Paula; Guo, Joan; Guo, Rong; Meng, Shi; Zhao, Yi; Lala, Deepak S; Zhuang, Linghang; Claremon, David A; McGeehan, Gerard M

2015-01-05

To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11β-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11β-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585. Copyright © 2014 Elsevier B.V. All rights reserved.

STUDIES ON THE ORIGIN OF CIRCULATING 18-HYDROXYCORTISOL AND 18-OXOCORTISOL IN NORMAL HUMAN SUBJECTS.

PubMed Central

Freel, E Marie; Shakerdi, Loai A; Friel, Elaine C; Wallace, A Michael; Davies, Eleanor; Fraser, Robert; Connell, John MC

2005-01-01

18-hydroxycortisol (18-OHF) and 18-oxocortisol (18oxo-F) are derivatives of cortisol found in Primary Aldosteronism but whose origin and regulation in normal subjects is uncertain. 18-OHF can be synthesised by zona fasciculata 11-β hydroxylase; 18-oxoF can only be produced by zona glomerulosa aldosterone synthase (AS). Stably transfected cell lines expressing either CYP11B1 (11β-hydroxylase) or CYP11B2 (AS) were incubated with cortisol and other substrates over a range of concentrations. Both enzymes could synthesise 18-OHF from cortisol but only AS could synthesise 18-oxoF. AS was more efficient than 11β-hydroxylase at 18-hydroxylation. The apparent Km of AS for cortisol was estimated to be 2.6μM. In 5 patients with adrenal insufficiency maintained on hydrocortisone, urinary free cortisol and cortisone levels were high; 18-oxoF was detectable in all patients and 18-hydroxycortisol in 3. It is likely that the 18-oxygenated steroids were synthesised from circulating cortisol, either in the zona glomerulosa or at extra-adrenal sites. In 8 male volunteers, dexamethasone treatment decreased urinary excretion rates of free cortisol, cortisone, 18-OHF and 18-oxoFl, confirming dependence of 18-oxygenated steroid levels on cortisol availability. In both groups, hydrocortisone administration resulted in detectable levels of 18-OHF and raised levels of 18-oxoF. There was close correlation between 18-oxoF and cortisol excretion during hydrocortisone administration in normal subjects (r=0.86, p<0.001). These data show, for the first time, that 18-OHF and 18oxoF can be synthesised from circulating cortisol. The close correlation between 18-oxoF and cortisol suggests that 18-oxoF is normally produced by the action of aldosterone synthase utilising circulating cortisol as a substrate. Although 18OHF can be synthesized using circulating cortisol as substrate, our data suggest this is normally produced in the zona fasciculata by 11β-hydroxylase from locally available cortisol. PMID:15356073

Anti-diabetic and anti-inflammatory effect of a novel selective 11β-HSD1 inhibitor in the diet-induced obese mice.

PubMed

Park, Sung Bum; Jung, Won Hoon; Kang, Nam Sook; Park, Ji Seon; Bae, Gyu Hwan; Kim, Hee Youn; Rhee, Sang Dal; Kang, Seung Kyu; Ahn, Jin Hee; Jeong, Hye Gwang; Kim, Ki Young

2013-12-05

It has been reported that the selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus, metabolic syndrome and inflammation. In the present study, we investigated the anti-diabetic and anti-inflammatory effects of N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl) sulfonyl)thiazolidine-2-carboxamide (KR-67105), a novel 11β-HSD1 inhibitor, in diabetic mice model and preadipocyte model. KR-67105 concentration dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 overexpressing cells and mouse 3T3-L1 adipocytes. Furthermore, KR-67105 concentration-dependently inhibited 11β-HSD1 activity in the ex vivo assay of C57BL/6 mice. In the study with diet-induced obese (DIO) mice, the administration of KR-67105 (100mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity as determined by the oral glucose tolerance test and the insulin tolerance test. Anti-diabetic effect by KR-67105 was associated with the suppression of diabetic related genes expression in liver and fat. Furthermore, KR-67105 suppressed 11β-HSD1 activity in liver and fat of diabetic mice, but showed no effect on adrenal grand weight/body weight ratio and plasma corticosterone concentration in diabetic mice. In 3T3-L1 preadipocytes, cortisone induced the mRNA of inflammatory cytokines and 11β-HSD1 and reactive oxygen species formation. This effect was abolished by co-incubation with KR-67105 in a concentration-dependent manner. Moreover, KR-67105 attenuated cortisone induced iNOS expression and phosphorylation of NF-κB p65, p38 MAPK, and ERK1/2 in preadipocytes. Taken together, it is concluded that a selective 11β-HSD1 inhibitor, KR-67105, may provide a new therapeutic window in the prevention and treatment of type 2 diabetes with chronic inflammation without toxicity. © 2013 Elsevier B.V. All rights reserved.

[Residual states in 30 percent of adult patients with Bell's palsy. Early treatment with cortisone improves the healing process].

PubMed

Berg, Thomas; Stjernquist-Desatnik, Anna; Kanerva, Mervi; Hultcrantz, Malou; Engström, Mats; Jonsson, Lars

2015-01-06

Bell's palsy is an acute unilateral weakness or paralysis of the face of unknown cause. The incidence of the disease is 30 individuals per 100,000 per year. It is a diagnosis of exclusion and other known causes for acute peripheral facial palsy must be ruled out. The prognosis is overall favorable and about 70% of the patients recover completely within 6 months without treatment. Recent randomized controlled Bell's palsy trials have shown that treatment with corticosteroids shortens time to recovery and improves recovery rates while antiviral treatment alone is not more effective than placebo. The combination of corticosteroids and antivirals has not been proven more effective than corticosteroids alone. We present an update of Bell's palsy in adults with focus on diagnosis, treatment and follow-up of these patients.

Relationship of 24-hour urinary free cortisol to 4-hour salivary morning and afternoon cortisol and cortisone as measured by a time-integrated oral diffusion sink.

PubMed

Kathol, R G; Poland, R E; Stokes, P E; Wade, S

1995-05-01

The relationship between salivary corticosteroids integrated over 4-hour periods and urinary free cortisol collected over 24 hours was investigated in normal controls. Twenty-one normal volunteers wore "oral diffusion sink" sampling devices in their mouths for two 4-hour periods (08:00-12:00 hours and 13:00-17:00 hours) and on the same day collected a 24-hour urine specimen. Time-integrated salivary corticosteroid concentrations were determined from the sample devices and urinary free cortisol was measured. Salivary corticosteroids were not consistently higher in the morning than in the afternoon period and did not differ between men and women. Urinary free cortisol levels were higher in women. No salivary corticosteroids measure was significantly correlated with urinary free cortisol. We conclude that time-integrated salivary corticosteroids do not reflect urinary free cortisol levels in normal controls.

He-Ne Laser Acupuncture: Treatment Of Rhinopharyngeal Infection.

NASA Astrophysics Data System (ADS)

Dussert, Dr.

1984-03-01

Ladies and gentlemen, 23 months ago I treated the following emergency cases in my surgery : 1) A man of 53 suffering from dyspnoea (clinically speaking he was a case of exniratory bradypnoea). He had just been hospitalised for a month and had been undergoing cortisone treatment. I made him sit, and b/ irradiating each of the stellar ganglions for six minutes by laser at an impulse wave length of 6 in low frequency I freed up this patient, who started to breathe normally. 2) Some time after this : A child of 7 came to see me. He was suffering from an attack of asthma. I passed each of the stellar ganglions under the laser at impulse wave length 6 in low frequency for 4 minutes. The child witnes ed his attack calming down. In view of these two cases I decided to organise a research project.

Controlled release of cortisone drugs from block copolymers synthetized by ATRP

NASA Astrophysics Data System (ADS)

Valenti, G.; La Carta, S.; Mazzotti, G.; Rapisarda, M.; Perna, S.; Di Gesù, R.; Giorgini, L.; Carbone, D.; Recca, G.; Rizzarelli, P.

2016-05-01

Diseases affecting posterior eye segment, like macular edema, infection and neovascularization, may cause visual impairment. Traditional treatments, such as steroidal-drugs intravitreal injections, involve chronic course of therapy usually over a period of years. Moreover, they can require frequent administrations of drug in order to have an adequately disease control. This dramatically reduce patient's compliance. Efforts have been made to develop implantable devices that offer an alternative therapeutic approach to bypass many challenges of conventional type of therapy. Implantable drug delivery systems (DDS) have been developed to optimize therapeutic properties of drugs and ensure their slow release in the specific site. Polymeric materials can play an essential role in modulating drug delivery and their use in such field has become indispensable. During last decades, acrylic polymers have obtained growing interest. Biocompatibility and chemical properties make them extremely versatile, allowing their use in many field such as biomedical. In particular, block methacrylate copolymer with a balance of hydrophilic and hydrophobic properties can be suitable for prolonged DDS in biomedical devices. In this work, we focused on the realization of a system for controlled and long term release of betamethasone 17,21-dipropionate (BDP), a cortisone drug, from methacrylic block copolymers, to be tested in the treatment of the posterior eye's diseases. Different series of methyl methacrylate/hydroxyethyl methacrylate (MMA/HEMA) block and random copolymers, with different monomer compositions (10-60% HEMA), were synthetized by Atom Transfer Radical Polymerization (ATRP) to find the best hydrophilic/hydrophobic ratio, able to ensure optimal kinetic release. Copolymer samples were characterized by NMR spectroscopy (1H-NMR, 13C-NMR, CosY), SEC, TGA and DSC. Monitoring of drug release from films loaded with BDP was carried out by HPLC analysis. Evaluation of different kinetic models allowed to deduce that release of BDP is controlled over time from PMMA-b-PHEMA 53/47. In particular, PMMA-b-PHEMA 53/47 showed the best release profile to achieve the therapeutic reference dose of 3 µg/die, employed in treatment of posterior eye disease, up to four months. Accordingly, PMMA-b-PHEMA 53/47 has been tested to prepare ocular inserts. Ocular inserts with different shape and the same area of polymer films have been obtained using silicon moulds made by a 3D printer.

Controlled release of cortisone drugs from block copolymers synthetized by ATRP

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valenti, G.; La Carta, S.; Rapisarda, M.

Diseases affecting posterior eye segment, like macular edema, infection and neovascularization, may cause visual impairment. Traditional treatments, such as steroidal-drugs intravitreal injections, involve chronic course of therapy usually over a period of years. Moreover, they can require frequent administrations of drug in order to have an adequately disease control. This dramatically reduce patient’s compliance. Efforts have been made to develop implantable devices that offer an alternative therapeutic approach to bypass many challenges of conventional type of therapy. Implantable drug delivery systems (DDS) have been developed to optimize therapeutic properties of drugs and ensure their slow release in the specific site.more » Polymeric materials can play an essential role in modulating drug delivery and their use in such field has become indispensable. During last decades, acrylic polymers have obtained growing interest. Biocompatibility and chemical properties make them extremely versatile, allowing their use in many field such as biomedical. In particular, block methacrylate copolymer with a balance of hydrophilic and hydrophobic properties can be suitable for prolonged DDS in biomedical devices. In this work, we focused on the realization of a system for controlled and long term release of betamethasone 17,21-dipropionate (BDP), a cortisone drug, from methacrylic block copolymers, to be tested in the treatment of the posterior eye’s diseases. Different series of methyl methacrylate/hydroxyethyl methacrylate (MMA/HEMA) block and random copolymers, with different monomer compositions (10–60% HEMA), were synthetized by Atom Transfer Radical Polymerization (ATRP) to find the best hydrophilic/hydrophobic ratio, able to ensure optimal kinetic release. Copolymer samples were characterized by NMR spectroscopy ({sup 1}H-NMR, {sup 13}C-NMR, CosY), SEC, TGA and DSC. Monitoring of drug release from films loaded with BDP was carried out by HPLC analysis. Evaluation of different kinetic models allowed to deduce that release of BDP is controlled over time from PMMA-b-PHEMA 53/47. In particular, PMMA-b-PHEMA 53/47 showed the best release profile to achieve the therapeutic reference dose of 3 µg/die, employed in treatment of posterior eye disease, up to four months. Accordingly, PMMA-b-PHEMA 53/47 has been tested to prepare ocular inserts. Ocular inserts with different shape and the same area of polymer films have been obtained using silicon moulds made by a 3D printer.« less

HPLC-ESI-MS/MS assessment of the tetrahydro-metabolites of cortisol and cortisone in bovine urine: promising markers of dexamethasone and prednisolone treatment.

PubMed

Chiesa, Luca; Panseri, Sara; Pavlovic, Radmila; Cannizzo, Francesca Tiziana; Biolatti, Bartolomeo; Divari, Sara; Villa, Roberto; Arioli, Francesco

2016-07-01

The effects of long-term administration of low doses of dexamethasone (DX) and prednisolone (PL) on the metabolism of endogenous corticosteroids were investigated in veal calves. In addition to cortisol (F) and cortisone (E), whose interconversion is regulated by 11β-hydroxysteroid dehydrogenases (11βHSDs), special attention was paid to tetrahydrocortisol (THF), allo-tetrahydrocortisol (aTHF), tetrahydrocortisone (THE) and allo-tetrahydrocortisone (aTHE), which are produced from F and E by catalytic activity of 5α and 5β-reductases. A specifically developed HPLC-ESI-MS/MS method achieved the complete chromatographic separation of two pairs of diastereoisomers (THF/aTHF and THE/aTHE), which, with appropriate mass fragmentation patterns, provided an unambiguous conformation. The method was linear (r(2) > 0.9905; 0.5-25 ng ml(-1)), with LOQQ of 0.5 ng ml(-1). Recoveries were in range 75-114%, while matrix effects were minimal. The experimental study was carried out on three groups of male Friesian veal calves: group PL (n = 6, PL acetate 15 mg day(-1) p.o. for 31 days); group DX (n = 5, 5 mg of estradiol (E2) i.m., weekly, and 0.4 mg day(-1) of DX p.o. for 31 days) and a control group (n = 8). Urine was collected before, during (twice) and at the end of treatment. During PL administration, the tetrahydro-metabolite levels decreased gradually and remained low after the suspension of treatment. DX reduced urinary THF that persisted after the treatment, while THE levels decreased during the experiment, but rebounded substantially after the DX was withdrawn. Both DX and PL significantly interfered with the production of F and E, leading to their complete depletion. Taken together, the results demonstrate the influence of DX and PL administration on 11βHSD activity and their impact on dysfunction of the 5-reductase pathway. In conclusion, profiling tetrahydro-metabolites of F and E might serve as an alternative, indirect but reliable, non-invasive procedure for assessing the impact of synthetic glucocorticosteroids administration.

[Updates on the earlier treatments for atopic dermatitis].

PubMed

Jelen, G

1998-01-01

The GERDA classes have the function of updating our knowledge of dermato-allergology. One of the themes tackled this year was the treatment of atopic dermatitis. Apart from consideration of treatment or exception with cortisone, it seemed to be of interest to find the relevance of "old treatments" for atopic dermatitis, either preventive or symptomatic. Preventive treatment made reference to correction of food factors (diet in infants, removal of maternal allergens, supplementation on fatty acids) and of environmental factors especially the fight against house dust mites by use of anti-mite mattress covers. Miracle treatments of atopy do not always exist. Thus there is often need for, besides local corticosteroid therapy, an external symptomatic treatment where the emphasis is on the struggle against skin microbiology, the fight against pruritic inflammatory conditions and above all the battle against xerosis. Knowledge of the physiology of the stratum corneum gives better understanding of the effect of emollients and moisturizers in restoration of the cutaneous barrier, of which dysfunction is one of the elements of atopic dermatitis.

Hair cortisol as a biological marker for burnout symptomatology.

PubMed

Penz, Marlene; Stalder, Tobias; Miller, Robert; Ludwig, Vera M; Kanthak, Magdalena K; Kirschbaum, Clemens

2018-01-01

Burnout is a syndrome with negative impact on cognitive performance and mood as a consequence of long-term stress at work. It is further associated with increased risk for mental and physical diseases. One potential pathway to mediate chronic work-stress and adverse health conditions in burnout is through alterations in long-term glucocorticoid secretion. Here, we present cross-sectional data on hair cortisol/cortisone (hairF/hairE) concentrations and burnout from a population-based sample of the Dresden Burnout Study (DBS; N=314 hair samples). Burnout symptoms (emotional exhaustion, cynical attitudes toward work, and reduced efficacy) were assessed with the Maslach Burnout Inventory-General Survey (MBI-GS). To control for potential confounds, depressivity was as well assessed using the Patient Health Questionnaire (PHQ-9) screening instrument for major depression. The present findings indicate specific hypercortisolism in participants who suffer from burnout. No significant associations were found between depressivity and hairF/hairE. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prophylaxis of radiation dermatitis with a topical cortisone cream

DOE Office of Scientific and Technical Information (OSTI.GOV)

Potera, M.E.; Lookingbill, D.P.; Stryker, J.A.

Nineteen cancer patients receiving radiation therapy to the head, neck, chest wall, or abdomen were evaluated in a double-blind study to determine the effectiveness of 0.2% hydrocortisone valerate vs. placebo in reducing acute radiation dermatitis. Patients applied hydrocortisone valerate to one-half of the irradiated area and the placebo to the other half beginning two weeks after the initiation of radiotherapy and continuing until three weeks after completion. Left and right sides were scored each week with respect to erythema, dry desquamation, moist desquamation, ulceration, and the duration and intensity of symptoms such as soreness, burning, and itching. No statistically significantmore » difference was found between the 0.2% hydrocortisone valerate and the placebo in the acute skin response or the symptoms of radiation dermatitis. The patients were evaluated three months following radiotherapy for evidence of skin atrophy. There were no differences found between hydrocortisone valerate and the placebo with respect to the late effects of radiation therapy.« less

Prophylaxis of radiation dermatitis with a topical cortisone cream

DOE Office of Scientific and Technical Information (OSTI.GOV)

Potera, M.E.; Lookingbill, D.P.; Stryker, J.A.

Nineteen cancer patients receiving radiation therapy to the head, neck, chest wall, or abdomen were evaluated in a double-blind study to determine the effectiveness of 0.2% hydrocortisone valerate vs placebo in reducing acute radiation dermatitis. Patients applied hydrocortisone valerate to one-half of the irradiated area and the placebo to the other half beginning two weeks after the initiation of radiotherapy and continuing until three weeks after completion. Left and right sides were scored each week with respect to erythema, dry desquamation, moist desquamation, ulceraton, and the duration and intensity of symptoms such as soreness, burning, and itching. No statistically significantmore » difference was found between the 0.2% hydrocortisone valerate and the placebo in the acute skin response or the symptoms of radiation dermatitis. The patients were evaluated three months following radiotherapy for evidence of skin atrophy. There was no difference found between hydrocortisone valerate and the placebo with respect to the late effects of radiation therapy.« less

CORTICOTROPIN (ACTH) AND CORTISONE—Newer Concepts of Their Use in Clinical Practice

PubMed Central

Kinsell, Laurance W.; Boling, Lenore; Partridge, John W.; Foreman, Nadine

1953-01-01

On the basis of three years' experience with corticotropin and cortisone, it seems probable that the place of these hormones in clinical medicine will be one of increasing importance. At present they may be used to attain certain specific objectives: 1. To return a large number of chronic invalids to a place of full activity in the community. This applies particularly to patients with rheumatoid arthritis and bronchial asthma. Many years of continuous therapy will be required in the majority of such patients. 2. As life-saving agents in patients with certain diseases of unknown etiologic delineation that almost always cause death. In some patients treated for some of those diseases, therapy may eventually be discontinued. 3. As life-saving agents (in conjunction with intensive antibiotic therapy) in patients with severe infections inadequately responsive to chemotherapy alone. Many of the untoward effects of hormonal therapy may be minimized or prevented by appropriate adjuvant measures. PMID:13059621

Expression of 11β-hydroxysteroid dehydrogenase isoforms in canine adrenal glands treated with trilostane.

PubMed

Teshima, Takahiro; Matsumoto, Hirotaka; Kumagai, Takayuki; Kurano, Mai; Koyama, Hidekazu

2014-06-01

Trilostane, a competitive inhibitor of 3β-hydroxysteroid dehydrogenase, is often used to treat canine hyperadrenocorticism. In some species, trilostane has been shown to have additional effects on steroid biosynthesis, and it has been postulated that trilostane might have effects on 11β-hydroxysteroid dehydrogenase (11β-HSD) in dogs. To investigate the effect of trilostane on 11β-HSD in canine adrenal glands, healthy Beagle dogs were treated with trilostane for 8 weeks. Trilostane treatment resulted in a significant decrease of the cortisol/cortisone ratio in the serum. The adrenal gland mRNA and protein expression levels of 11β-HSD type 1 and 11β-HSD type 2 were significantly higher and significantly lower respectively in dogs treated with trilostane compared to those in control healthy Beagle dogs. These findings suggest that trilostane may have an effect on 11β-HSD activity in canine adrenal glands. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Hormones and hair growth].

PubMed

Trüeb, R M

2010-06-01

With respect to the relationship between hormones and hair growth, the role of androgens for androgenetic alopecia (AGA) and hirsutism is best acknowledged. Accordingly, therapeutic strategies that intervene in androgen metabolism have been successfully developed for treatment of these conditions. Clinical observations of hair conditions involving hormones beyond the androgen horizon have determined their role in regulation of hair growth: estrogens, prolactin, thyroid hormone, cortisone, growth hormone (GH), and melatonin. Primary GH resistance is characterized by thin hair, while acromegaly may cause hypertrichosis. Hyperprolactinemia may cause hair loss and hirsutism. Partial synchronization of the hair cycle in anagen during late pregnancy points to an estrogen effect, while aromatase inhibitors cause hair loss. Hair loss in a causal relationship to thyroid disorders is well documented. In contrast to AGA, senescent alopecia affects the hair in a diffuse manner. The question arises, whether the hypothesis that a causal relationship exists between the age-related reduction of circulating hormones and organ function also applies to hair and the aging of hair.

[Chronic recurrent parotitis].

PubMed

Zenk, J; Koch, M; Klintworth, N; Iro, H

2010-03-01

Chronic recurrent parotitis is a non-obstructive disease with episodes of mostly painful swelling of the gland. It is categorized into a juvenile and an adult form, even without clear information on its actual origin. As to the etiology of the juvenile form, genetic factors and duct malformations as well as bacterial infections are discussed. Very rarely a complete lymphatic transformation of the gland might take place. Juvenile chronic recurrent parotitis is self-limiting in about 90% of all cases, as patients grow up. The diagnosis is based on patient history and clinical findings. Sonography is the imaging method of choice. Sialendoscopy shows a typical whitish pattern of the ducts in juvenile disease. Strictures or stenoses are typical for the adult form. The therapy of choice is gland massage and sialagogues, in addition to the administration of antibiotics. In more severe cases sialendoscopy together with rinsing of the ducts and instillation of cortisone are indicated. Total parotidectomy remains the last choice and is rarely necessary.

Bee sting therapy-induced hepatotoxicity: A case report.

PubMed

Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

2011-10-27

The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo.

Immunological markers as predictors of developing steroid-induced diabetes mellitus in pemphigus vulgaris patients: An observational study.

PubMed

Dănescu, Ana Sorina; Bâldea, Ioana; Leucuţa, Daniel Corneliu; Lupan, Iulia; Samaşca, Gabriel; Sitaru, Cassian; Chiorean, Roxana; Baican, Adrian

2018-04-01

The aim of this study was to evaluate the clinical importance of autoantibodies in pemphigus vulgaris patients who developed steroid-induced diabetes mellitus (SID) because of the glucocorticoid therapy of pemphigus.A total of 137 patients with pemphigus vulgaris were studied. Patients with SID and pemphigus were compared with those that had only pemphigus. The variables recorded were: age at diagnosis, sex, body mass index, presence of diabetes mellitus (DM), cumulative cortisone dose, treatment duration, value of anti-desmoglein 1 and 3, and anti-glutamic acid decarboxylase autoantibodies.A total of 31 patients (22.62%) that developed steroid-induced DM were identified. Anti-glutamic acid decarboxylase autoantibodies were positive in 20.75% of patients with pemphigus vulgaris and in 25.75% of patients with pemphigus vulgaris and SID.The overall anti-glutamic acid decarboxylase autoantibodies prevalence in pemphigus patients was high, and the risk of developing DM in patients with pemphigus remains a serious problem, being associated with increased risk of mortality.

Bee sting therapy-induced hepatotoxicity: A case report

PubMed Central

Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

2011-01-01

The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo. PMID:22059110

The effect of high level tennis matches on urine steroid profiles in professional tennis players.

PubMed

Muñoz, D; Toribio, F; Timón, R; Olcina, G; Maynar, J I; Maynar, M

2010-12-01

Modern day, tennis matches are characterized by shorter and more intense efforts with players enduring great physical and psychological stress. The aim of this study was to evaluate acute changes in the urinary steroid profile of elite tennis players following professional tournament matches. Eight professional male tennis players participated in this study. Urine samples were collected before and after tennis matches corresponding to the quarter finals of the Spanish Tennis Masters. After the match, there was a significant fall (P<0.05) in testosterone, androsterone, etiocholanolone, and dehydroepiandrosterone (DHEA). Cortisone increased whereas tetrahydrocortisone (THE) decreased. The anabolic/catabolic hormone ratio also decreased, although only the fall in total suprarenal androgen (TSA)/total corticosteroid (TC) and DHEA/(THE+THF) ratios had a significant decrease (P<0.05). These results indicate that a professional tennis match modifies the urine steroid profiles of players, increasing corticosteroid and decreasing androgen excretion in urine, suggesting an important adrenal activation.

Differential expression of 11β-hydroxysteroid dehydrogenase type 1 and 2 in mild and moderate/severe persistent allergic nasal mucosa and regulation of their expression by Th2 cytokines: asthma and rhinitis.

PubMed

Jun, Y J; Park, S J; Hwang, J W; Kim, T H; Jung, K J; Jung, J Y; Hwang, G H; Lee, S H; Lee, S H

2014-02-01

Glucocorticoids are used to treat allergic rhinitis, but the mechanisms by which they induce disease remission are unclear. 11β-hydroxysteroid dehydrogenase (11β-HSD) is a tissue-specific regulator of glucocorticoid responses, inducing the interconversion of inactive and active glucocorticoids. We analysed the expression and distribution patterns of 11β-HSD1, 11β-HSD2, and steroidogenic enzymes in normal and allergic nasal mucosa, and cytokine-driven regulation of their expression. The production levels of cortisol in normal, allergic nasal mucosa and in cultured epithelial cells stimulated with cytokines were also determined. The expression levels of 11β-HSD1, 11β-HSD2, steroidogenic enzymes (CYP11B1, CYP11A1), and cortisol in normal, mild, and moderate/severe persistent allergic nasal mucosa were assessed by real-time PCR, Western blot, immunohistochemistry, and ELISA. The expression levels of 11β-HSD1, 11β-HSD2, CYP11B1, CYP11A1, and cortisol were also determined in cultured nasal epithelial cell treated with IL-4, IL-5, IL-13, IL-17A, and IFN-γ. Conversion ratio of cortisone to cortisol was evaluated using siRNA technique, 11β-HSD1 inhibitor, and the measurement of 11β-HSD1 activity. The expression levels of 11β-HSD1, CYP11B1, and cortisol were up-regulated in mild and moderate/severe persistent allergic nasal mucosa. By contrast, 11β-HSD2 expression was decreased in allergic nasal mucosa. In cultured epithelial cells treated with IL-4, IL-5, IL-13, and IL-17A, 11β-HSD1 expression and activity increased in parallel with the expression levels of CYP11B1 and cortisol, but the production of 11β-HSD2 decreased. CYP11A1 expression level was not changed in allergic nasal mucosa or in response to stimulation with cytokines. SiRNA technique or the measurement of 11β-HSD1 activity showed that nasal epithelium activates cortisone to cortisol in a 11β-HSD-dependent manner. These results indicate that the localized anti-inflammatory effects of glucocorticoids are regulated by inflammatory cytokines, which can modulate the expression of 11β-HSD1, 11β-HSD2, and CYP11B1, and by the intracellular concentrations of bioactive glucocorticoids. © 2013 John Wiley & Sons Ltd.

Expression of 11β-hydroxysteroid dehydrogenase 1 and 2 in patients with chronic rhinosinusitis and their possible contribution to local glucocorticoid activation in sinus mucosa.

PubMed

Jun, Young Joon; Park, Se Jin; Kim, Tae Hoon; Lee, Seung Hoon; Lee, Ki Jeong; Hwang, Soo Min; Lee, Sang Hag

2014-10-01

It has been suggested that glucocorticoids might act in target tissues to increase their own intracellular availability in response to inflammatory stimuli. These mechanisms depend on the local metabolism of glucocorticoids catalyzed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). This study is to investigate the effect of chronic rhinosinusitis (CRS) on expression of 11β-HSD1, 11β-HSD2, steroidogenic enzymes (cytochrome P450, family 11, subfamily B, polypeptide 1 [CYP11B1] and cytochrome P450, family 11, subfamily A, polypeptide 1 [CYP11A1]), and endogenous cortisol levels in human sinus mucosa. Expression levels were compared with those of healthy control subjects. The expression levels of 11β-HSD1, 11β-HSD2, CYP11B1, CYP11A1, and cortisol were measured in healthy control subjects, patients with CRS with nasal polyps, and patients with CRS without nasal polyps by using real-time PCR, Western blotting, immunohistochemistry, and ELISA. Expression levels of 11β-HSD1, 11β-HSD2, CYP11B1, CYP11A1, and cortisol were determined in cultured epithelial cells treated with CRS-relevant cytokines. The conversion ratio of cortisone to cortisol was evaluated by using the small interfering RNA technique, 11β-HSD1 inhibitor, and measurement of 11β-HSD1 activity. 11β-HSD1, CYP11B1, and cortisol levels increased in patients with CRS with nasal polyps and those with CRS without nasal polyps, but 11β-HSD2 expression decreased. In cultured epithelial cells treated with IL-4, IL-5, IL-13, IL-1β, TNF-α, and TGF-β1, 11β-HSD1 expression and activity increased in parallel with expression levels of CYP11B1 and cortisol, but the production of 11β-HSD2 decreased. The small interfering RNA technique or the measurement of 11β-HSD1 activity showed that the sinus epithelium activates cortisone to cortisol in an 11β-HSD-dependent manner. These results indicate that CRS-relevant cytokines can modulate the expression of 11β-HSD1, 11β-HSD2, and CYP11B1 in the sinus mucosa, resulting in increasing intracellular concentrations of bioactive glucocorticoids. Copyright © 2014. Published by Elsevier Inc.

Placental 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression very early during human pregnancy.

PubMed

Salvante, K G; Milano, K; Kliman, H J; Nepomnaschy, P A

2017-04-01

Maternal physiologic stress during gestation has been reported to be associated with negative developmental outcomes, including intra-uterine growth restriction and reduced birth weight, which can impact postnatal development, behavior and health. The human fetus is partially protected from elevated cortisol exposure by placental 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which oxidizes bioactive cortisol into bio-inactive cortisone. Importantly, despite the critical protective role hypothesized for 11β-HSD2, the onset of its placental expression has yet to be clearly established. To this aim, we present immunocytochemical analysis of placentas collected 3-6 weeks post-conception. 11β-HSD2 was present as early as 3 weeks post-conception in syncytiotrophoblasts, where most maternal-fetal exchange occurs, and in columnar epithelial cells encircling uterine endometrial glands, which provide early histiopathic nutrition to the embryo. 11β-HSD2 expression in these critical maternal-fetal exchange areas is consistent with its hypothesized protective role. Future studies should investigate the mechanisms that may modulate embryonic glucocorticoid exposure earlier, immediately post-conception.

Inhibition of placental 11beta-hydroxysteroid dehydrogenase type 2 by lead.

PubMed

St-Pierre, Joey; Fraser, Marc; Vaillancourt, Cathy

2016-10-01

Lead interferes with cortisol blood concentration, increases the risk of obstetrical complications, and could alter fetal development. The placenta controls maternal cortisol transfer to the fetus by the activity of the type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2), which converts cortisol into inactive cortisone. This study determines the effect of lead on the expression and activity of the placental 11β-HSD2 in human trophoblast-like BeWo cells. Cells were treated with increasing concentration (0-1000nM) of PbCl2 for 24h. 11β-HSD2 protein expression was reduced by 45% at 1000nM of PbCl 2 compared to untreated cells, while the activity was significantly reduced by PbCl 2 at 10, 100 and 1000nM. This study shows the direct inhibitory action of lead on placental 11β-HSD2 activity and suggests that this heavy metal reduces the efficiency of the placental protection against the adverse effects of high cortisol level during fetal development. Copyright © 2016 Elsevier Inc. All rights reserved.

[Investigation of metabolites of Triptergium wilfordii on liver toxicity by LC-MS].

PubMed

Zhao, Xiao-mei; Liu, Xin-ying; Xu, Chang; Ye, Tao; Jin, Cheng; Zhao, Kui-jun; Ma, Zhi-jie; Xiao, Xiao-he

2015-10-01

In this paper, biomarkers of liver toxicity of Triptergium wilfordii based on metabolomics was screened, and mechanism of liver toxicity was explored to provide a reference for the clinical diagnosis for liver toxicity of Triptergium wilfordii. MS method was carried on the analysis to metabolic fingerprint spectrum between treatment group and control group. The potential biomarkers were compared and screened using the multivariate statistical methods. As well, metabolic pathway would be detailed description. Combined with PCA and OPLS-DA pattern recognition analysis, 20 metabolites were selected which showed large differences between model group and blank group (VIP > 1.0). Seven possible endogenous biomarkers were analyzed and identified. They were 6-phosphate glucosamine, lysophospholipid, tryptophan, guanidine acetic acid, 3-indole propionic acid, cortisone, and ubiquinone. The level changes of above metabolites indicated that the metabolism pathways of amino acid, glucose, phospholipid and hormone were disordered. It is speculated that liver damage of T. wilfordii may be associated with the abnormal energy metabolism in citric acid cycle, amino acid metabolism in urea cycle, and glucose metabolism. It will be helpful to further research liver toxicity ingredients of Triptergium wilfordii.

Suitability of bovine bile compared to urine for detection of free, sulfate and glucuronate boldenone, androstadienedione, cortisol, cortisone, prednisolone, prednisone and dexamethasone by LC-MS/MS.

PubMed

Chiesa, Luca; Nobile, Maria; Panseri, Sara; Vigo, Daniele; Pavlovic, Radmila; Arioli, Francesco

2015-12-01

The administration of boldenone and androstadienedione to cattle is forbidden in the European Union, while prednisolone is permitted for therapeutic purposes. They are pseudoendogenous substances (endogenously produced under certain circumstances). The commonly used matrices in control analyses are urine or liver. With the aim of improving the residue controls, we previously validated a method for steroid analysis in bile. We now compare urine (a 'classic' matrix) to bile, both collected at the slaughterhouse, to understand whether the detection of steroids in the latter is easier. With the aim of having clearer results, we tested the presence of the synthetic corticosteroid dexamethasone. The results show that bile does not substantially improve the detection of boldenone, or its conjugates, prednisolone and prednisone. Dexamethasone, instead, was found in 10 out of 53 bovine bile samples, but only in one urine sample from the same animals. Bile could constitute a novel matrix for the analysis of residues in food-producing animals, and possibly not only of synthetic corticosteroids. Copyright © 2015 Elsevier Ltd. All rights reserved.

Endocrine regulation of carbohydrate metabolism in hypometabolic animals

NASA Technical Reports Server (NTRS)

Musacchia, X. J.

1988-01-01

Experimental hypothermia and natural hibernation are two forms of hypometabolism with recognized physiological changes, including depression of endocrine and metabolic functions. To better understand functional changes, helox (i.e., helium and oxygen (80:20) mixtures) and low ambient temperatures have been used to induce hypothermia in hamsters and rats. Both clinical and biological survival, i.e., survival without recovery and survival with recovery from hypothermia, respectively, are related to depth and length of hypothermia. In the rat, body temperatures of 15 degrees C for periods greater than 6-10 h greatly restrict biological survival. The role of glucocorticoids in enhancing thermogenic capacity of rats was assessed using triamcinolone [correction of triamcinalone] acetonide. In the hamster, treatment with cortisone acetate prolonged both clinical and biological survival. Hypothermic hamsters continue utilizing circulating glucose until they become hypoglycemic and die. Hypothermic rats do not utilize glucose and respond with a significant hypoinsulinema. The role of endocrines in the regulation of carbohydrate homeostasis and metabolism differs in hibernation and hypothermia. Glucocorticoids influence the hypothermic response in both species, specifically by prolonging induction of hypothermia in rats and by prolonging survival in hypothermic hamsters.

A new technique for promoting cyclic utilization of cyclodextrins in biotransformation.

PubMed

Shen, Yanbing; Yu, Ziqi; Yang, Xu; Wang, Fang; Luo, Jianmei; Wang, Min

2017-01-01

Cyclodextrins (CDs) can improve the productivity of steroid biotransformation by enhancing substrate solubility. CDs can be recycled by grafting them with appropriate carriers. Loofah fiber is an excellent grafting material for CDs, and can be applied to the biotransformation and recycling of β-cyclodextrin (β-CD). In this work, a technique for recycling β-CD in cortisone acetate (CA) biotransformation by Arthrobacter simplex CPCC 140451 was studied. Loofah fiber-grafted β-CD (LF-β-CD) was prepared using epichlorohydrin, which is a cross-linking agent. The grafting yield of β-CD was 74.8 mg g -1 dried fibers. LF-β-CD could increase the solubility of CA and enhance biotransformation. The initial conversion rate of CA was 1.5-fold higher than that of the blank group. LF-β-CD was also used in biocatalytic reactions for eight cycles, and it maintained the conversion ratio of CA at approximately 90%. Given the above positive results, LF-β-CD can be utilized in biotechnological recycling applications. This method can also be applied to CD derivatives and hydrophobic compounds.

Intraarticular cortisone injection for osteoarthritis of the hip. Is it effective? Is it safe?

PubMed

Kruse, David W

2008-12-01

Osteoarthritis of the hip is a significant source of morbidity in the elderly. Treatment guidelines are available for the management of hip osteoarthritis, but these do not address the application of intraarticular corticosteroid injection. The intraarticular injection of corticosteroid is used in the management of other large joint osteoarthritic diseases and is well studied in the knee, however, this data cannot be used to make sound clinical decisions regarding its use for hip osteoarthritis. There are also concerns regarding the safety of this modality. Review of the published literature reveals that there are eight trials examining the efficacy of intraarticular corticosteroid injection for hip osteoarthritis and of these only four are randomized controlled trials. In general, the available literature demonstrates a short-term reduction of pain with corticosteroid injection and is indicated for patients refractory to non-pharmacologic or analgesic and NSAID therapy. The use of radiologic-guidance is recommended and, with proper sterile technique, the risk of adverse outcomes is very low. Future randomized controlled trials are needed to further examine the efficacy and safety of intraarticular corticosteroid injection for hip osteoarthritis.

Sodium alginate-grafted β-cyclodextrins as a matrix for immobilized Arthrobacter simplex for cortisone acetate biotransfromation

NASA Astrophysics Data System (ADS)

Shen, Yanbing; Niu, Lulu; Yu, Ziqi; Wang, Min; Shang, Zhihua; Yang, Yan

2018-06-01

Cyclodextrins (CDs) are used to resolve the low aqueous solubility of steroids, but the high cost of CDs is still a limiting factor in biotransformation process. This study, which is based on grafting and immobilization techniques, focused on synthesizing for the first time sodium alginate (SA)-grafted β-CD (SA-β-CD) and alginate-grafted β-CD for the immobilization of Arthrobacter simplex (ASP) cells (SA-β-CD-cells) and subsequent recycling of CDs and cells. FTIR spectium and X-ray diffraction proved that β-CD was successfully grafted with SA, whereas the grafting yield of β-CD was 10.3 μmol g-1. SA-β-CD could increase the solubility of CA by 3.5-fold, whereas the transformation rate was enhanced by 10%. The conversion ratio of CA was over 92% after the SA-β-CD recycling for nine cycles. In addition, after SA-β-CD-cells were applied in biocatalytic reactions for eight cycles, the conversion ratio of CA was over 90%. These advantages suggest great potential for using both grafting and immobilized techniques in steroid transformation.

The relationship of choline acetyltransferase activity at the neuromuscular junction to changes in muscle mass and function

PubMed Central

Diamond, Ivan; Franklin, Gary M.; Milfay, Dale

1974-01-01

1. The role of muscle mass and function in the regulation of choline acetyltransferase activity at the neuromuscular junction has been investigated in the rat. 2. Choline acetyltransferase (ChAc) is located in presynaptic nerve terminals and is a specific enzymatic marker of cholinergic innervation in muscle. 3. ChAc activity increased co-ordinately with developmental growth of the soleus muscle. However, another form of muscle growth, work hypertrophy, did not produce an increase in ChAc. 4. Growth arrest of muscle by hypophysectomy did not alter the normal development of ChAc activity, and cortisone-induced muscle atrophy did not reduce ChAc activity in the soleus or plantaris. 5. Tenotomy-induced muscle atrophy provoked a significant fall in ChAc in the soleus and plantaris. 6. The tonic soleus had significantly greater ChAc activity than the phasic plantaris. 7. These observations suggest that muscle mass per se does not influence the development and regulation of ChAc in muscle but that the quality of muscle contraction may modulate enzyme activity. PMID:4818500

Imidacloprid insecticide exposure induces stress and disrupts glucose homeostasis in male rats.

PubMed

Khalil, Samah R; Awad, Ashraf; Mohammed, Hesham H; Nassan, Mohamed Abdo

2017-10-01

In the present study, we evaluated the stress response in adult rats who were administered imidacloprid (IMI) orally in two doses (0.5 and 1.0mg/kg bw for 60days). It led to an alteration in the levels of cortisone and catecholamines and induced behavioral deficits, particularly in the animals exposed to the dose of 1.0mg/kg. IMI was further analyzed for the effect on glucose homeostasis in developing and adult rats at a dose of 1.0mg/kg bw where it elicited a hyperglycemic effect. Moreover, we observed an alteration in the mRNA levels of glucose transporters. Histopathological and immunohistochemical data displayed structural perturbations in pancreatic tissue with a decline in the expression of insulin and GLUT4, particularly in the developing rats. Collectively, IMI treatment resulted in stress represented by behavioral and biochemical changes, particularly at a dose of 1.0mg/kg bw. Moreover, IMI perturbed the glucose regulation through hyperglycemic activity in both developing and adult rats, an observation clearly evident in the developing rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Attenuation of the cortisol response to stress in female rainbow trout chronically exposed to dietary selenomethionine.

PubMed

Wiseman, Steve; Thomas, Jith K; McPhee, Landon; Hursky, Olesya; Raine, Jason C; Pietrock, Michael; Giesy, John P; Hecker, Markus; Janz, David M

2011-10-01

Selenomethionine (Se-Met) is the major dietary form of selenium (Se). While Se is a required nutrient, it can also influence the physiological stress response because it stimulates greater concentrations of cortisol in blood plasma of exposed fish. However, little is known about the effects of exposure to Se on the ability to cope with a secondary stressor. In the current study, female rainbow trout were exposed to an environmentally relevant dietary concentration (8.47 mg Se/kg dry mass (dm)) of Se-Met for 126 d, after which time fish were subjected to a 3-min handling stressor and sampled at 2h and 24h post-stressor exposure. Concentrations of cortisol, cortisone, glucose, and lactate in blood plasma and concentrations of glycogen and triglycerides in liver and muscle were determined. Abundances of transcripts of proteins involved in corticosteroidogenesis were determined using quantitative RT-PCR. Concentrations of cortisol were significantly greater in blood plasma of trout exposed to Se-Met, relative to control trout sampled prior to the handling stressor. A typical response of cortisol to the handling stressor was observed in the control trout. However, trout exposed to Se-Met were unable to mount a cortisol response to the handling stressor. Concentrations of cortisone, the inactive metabolite of cortisol, were significantly greater following the handling stressor in trout exposed to Se-Met. In trout exposed to Se-Met, transcript abundance of melanocortin 2 receptor (mc2r) and peripheral benzodiazepine receptor (pbr) were greater, which is consistent with the conclusion that synthesis of cortisol was greater. However, abundances of transcripts of cytochrome P450 side-chain cleavage (p450scc) and cytochrome P450 11B1 (cyp11b1) were not significantly different between controls and Se-Met exposed trout. Exposure to Se-Met affected accumulation and tissue partitioning of glycogen and triglycerides in liver and muscle as concentrations of these energy reserves were greater in muscle, but not liver. Concentrations of glycogen and triglycerides in muscle, but not in liver, were lesser following the handling stressor suggesting that the muscle energy reserves are an important source of energy required for recovery from the handling stressor. The results of the study demonstrate that chronic exposure to dietary Se-Met elicits a stress response, but prevents a cortisol response to a secondary handling stressor, most likely due to cortisol inactivation. Moreover, exposure to Se-Met has effects on concentrations of energy reserves that are important for providing the energy necessary to cope with a secondary stressor. Copyright © 2011 Elsevier B.V. All rights reserved.

Combination of Estrogen and Immunosuppressive Agents to Establish a Mouse Model of Candidiasis with Concurrent Oral and Vaginal Mucosal Infection.

PubMed

Wang, Le; Wang, Chong; Mei, Huan; Shen, Yongnian; Lv, Guixia; Zeng, Rong; Zhan, Ping; Li, Dongmei; Liu, Weida

2016-02-01

Mouse model is an appropriate tool for pathogenic determination and study of host defenses during the fungal infection. Here, we established a mouse model of candidiasis with concurrent oral and vaginal mucosal infection. Two C. albicans strains sourced from clinical candidemia (SC5314) and mucosal infection (ATCC62342) were tested in ICR mice. The different combinational panels covering estrogen and immunosuppressive agents, cortisone, prednisolone and cyclophosphamide were used for concurrent oral and vaginal candidiasis establishment. Prednisolone in combination with estrogen proved an optimal mode for concurrent mucosal infection establishment. The model maintained for 1 week with fungal burden reached at least 10(5) cfu/g of tissue. This mouse model was evaluated by in vivo pharmacodynamics of fluconazole and host mucosal immunity of IL-17 and IL-23. Mice infected by SC5314 were cured by fluconazole. An increase in IL-23 in both oral and vaginal homogenates was observed after infection, while IL-17 only had a prominent elevation in oral tissue. This model could properly mimic complicated clinical conditions and provides a valuable means for antifungal assay in vivo and may also provide a useful method for the evaluation of host-fungal interactions.

Mast cells express 11β-hydroxysteroid dehydrogenase type 1: a role in restraining mast cell degranulation.

PubMed

Coutinho, Agnes E; Brown, Jeremy K; Yang, Fu; Brownstein, David G; Gray, Mohini; Seckl, Jonathan R; Savill, John S; Chapman, Karen E

2013-01-01

Mast cells are key initiators of allergic, anaphylactic and inflammatory reactions, producing mediators that affect vascular permeability, angiogenesis and fibrosis. Glucocorticoid pharmacotherapy reduces mast cell number, maturation and activation but effects at physiological levels are unknown. Within cells, glucocorticoid concentration is modulated by the 11β-hydroxysteroid dehydrogenases (11β-HSDs). Here we show expression and activity of 11β-HSD1, but not 11β-HSD2, in mouse mast cells with 11β-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11β-HSD1-deficient mice show ultrastructural evidence of increased activation, including piecemeal degranulation and have a reduced threshold for IgG immune complex-induced mast cell degranulation. Consistent with reduced intracellular glucocorticoid action in mast cells, levels of carboxypeptidase A3 mRNA, a glucocorticoid-inducible mast cell-specific transcript, are lower in peritoneal cells from 11β-HSD1-deficient than control mice. These findings suggest that 11β-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses.

Effect of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog

PubMed Central

Basu, Rita; Ramnanan, Christopher J.; Farmer, Tiffany D.; Neal, Doss; Scott, Melanie; Jacobson, Peer; Rizza, Robert A.; Cherrington, Alan D.

2010-01-01

Inactive cortisone is converted to active cortisol within the liver by 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), and impaired regulation of this process may be related to increased hepatic glucose production (HGP) in individuals with type 2 diabetes. The primary aim of this study was to investigate the effect of acute 11β-HSD1 inhibition on HGP and fat metabolism during insulin deficiency. Sixteen conscious, 42-h-fasted, lean, healthy dogs were studied. Somatostatin was infused to create insulin deficiency, and the animals were treated with a specific 11β-HSD1 inhibitor (compound 531) or placebo for 5 h. 11β-HSD1 inhibition completely suppressed hepatic cortisol production, and this attenuated the increase in HGP that occurred during insulin deficiency. PEPCK and glucose-6-phosphatase expression were decreased when 11β-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11β-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes. PMID:20159854

Investigations of the microbial transformation of cortisol to prednisolone in urine samples.

PubMed

Bredehöft, Michael; Baginski, Rainer; Parr, Maria-Kristina; Thevis, Mario; Schänzer, Wilhelm

2012-03-01

Doping control samples are normally collected under non-sterile conditions and sometimes, storage and transportation are influenced by parameters such as the temperature. Therefore, microbial contamination and subsequent alteration of a sample's composition are possible. Studies regarding sample collection in cattle breeding have already shown enzymatic transformation of endogenous testosterone to boldenone causing false-positive findings. The aim of the present study was to investigate whether positive doping cases with the synthetic corticosteroids prednisolone and prednisone may result from microbial transformation of the endogenous corticosteroids cortisol and cortisone, respectively. A method comprising parameters such as pH values and screening results for synthetic glucocorticosteroids as well as incubation experiments followed by liquid chromatographic and mass spectrometric analysis was employed to test for contaminating germs with Δ(1)-dehydrogenase activity. Over 700 urine samples comprising inpatient and doping control specimens were investigated. In none of them, 1,2-dehydrogenating activity was confirmed. These findings are in accordance with other studies. However, the problem of microbial alteration of doping control specimens with special respect to 1,2-dehydrogenation must not be underestimated. Article from a special issue on steroids and microorganisms. Copyright © 2010 Elsevier Ltd. All rights reserved.

Impact of maternal steroids during pregnancy.

PubMed

Reynolds, Rebecca M

2016-12-01

Increased fetal exposure to glucocorticoids is a key mechanism thought to underlie the early life programming of later life disease. There is substantial experimental data in animal models in support of this hypothesis. Emerging evidence suggests glucocorticoid programming may also occur in humans with some studies now linking maternal endogenous cortisol levels with size at birth and gestation at delivery. The dramatic changes to the maternal hypothalamic-pituitary-adrenal axis during pregnancy mean that large-scale studies in humans are challenging to conduct. One of the key regulators of fetal glucocorticoid exposure is the activity of placental "barrier" enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD2) which converts active cortisol to inactive cortisone. In animal models, this enzyme is down-regulated by various influences including maternal malnutrition, inflammation or stress but it is not known whether this is a major factor in regulation of human fetal glucocorticoid exposure. More studies are needed to understand the mechanisms whereby altered fetal glucocorticoid exposure may alter fetal growth trajectories and whether changes in the maternal hypothalamic-pituitary-adrenal axis in pregnancy could be suitable as a biomarker to identify those pregnancies most at risk. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Optimization of dispersive liquid-phase microextraction based on solidified floating organic drop combined with high-performance liquid chromatography for the analysis of glucocorticoid residues in food.

PubMed

Huang, Yuan; Zheng, Zhiqun; Huang, Liying; Yao, Hong; Wu, Xiao Shan; Li, Shaoguang; Lin, Dandan

2017-05-10

A rapid, simple, cost-effective dispersive liquid-phase microextraction based on solidified floating organic drop (SFOD-LPME) was developed in this study. Along with high-performance liquid chromatography, we used the developed approach to determine and enrich trace amounts of four glucocorticoids, namely, prednisone, betamethasone, dexamethasone, and cortisone acetate, in animal-derived food. We also investigated and optimized several important parameters that influenced the extraction efficiency of SFOD-LPME. These parameters include the extractant species, volumes of extraction and dispersant solvents, sodium chloride addition, sample pH, extraction time and temperature, and stirring rate. Under optimum experimental conditions, the calibration graph exhibited linearity over the range of 1.2-200.0ng/ml for the four analytes, with a reasonable linearity(r 2 : 0.9990-0.9999). The enrichment factor was 142-276, and the detection limits was 0.39-0.46ng/ml (0.078-0.23μg/kg). This method was successfully applied to analyze actual food samples, and good spiked recoveries of over 81.5%-114.3% were obtained. Copyright © 2017. Published by Elsevier B.V.

Identification of UGT2B9*2 and UGT2B33 isolated from female rhesus monkey liver.

PubMed

Dean, Brian; Arison, Byron; Chang, Steve; Thomas, Paul E; King, Christopher

2004-06-01

Two UDP-glucuronosyltransferases (UGT2B9(*)2 and UGT2B33) have been isolated from female rhesus monkey liver. Microsomal preparations of the cell lines expressing the UGTs catalyzed the glucuronidation of the general substrate 7-hydroxy-4-(trifluoromethyl)coumarin in addition to selected estrogens (beta-estradiol and estriol) and opioids (morphine, naloxone, and naltrexone). UGT2B9(*)2 displayed highest efficiency for beta-estradiol-17-glucuronide production and did not catalyze the glucuronidation of naltrexone. UGT2B33 displayed highest efficiency for estriol and did not catalyze the glucuronidation of beta-estradiol. UGT2B9(*)2 was found also to catalyze the glucuronidation of 4-hydroxyestrone, 16-epiestriol, and hyodeoxycholic acid, while UGT2B33 was capable of conjugating 4-hydroxyestrone, androsterone, diclofenac, and hyodeoxycholic acid. Three glucocorticoids (cortisone, cortisol, and corticosterone) were not substrates for glucuronidation by liver or kidney microsomes or any expressed UGTs. Our current data suggest the use of beta-estradiol-3-glucuronidation, beta-estradiol-17-glucuronidation, and estriol-17-glucuronidation to assay UGT1A01, UGT2B9(*)2, and UGT2B33 activity in rhesus liver microsomes, respectively.

Electrochemical and surface plasmon resonance characterization of β-cyclodextrin-based self-assembled monolayers and evaluation of their inclusion complexes with glucocorticoids

NASA Astrophysics Data System (ADS)

Frasconi, Marco; Mazzei, Franco

2009-07-01

This paper describes the characterization of a self-assembled β-cyclodextrin (β-CD)-derivative monolayer (β-CD-SAM) on a gold surface and the study of their inclusion complexes with glucocorticoids. To this aim the arrangement of a self-assembled β-cyclodextrin-derivative monolayer on a gold surface was monitored in situ by means of surface plasmon resonance (SPR) spectroscopy and double-layer capacitance measurements. Film thickness and dielectric constant were evaluated for a monolayer of β-CD using one-color-approach SPR. The selectivity of the β-CD host surface was verified by using electroactive species permeable and impermeable in the β-CD cavity. The redox probe was selected according to its capacity to permeate the β-CD monolayer and its electrochemical behavior. In order to evaluate the feasibility of an inclusion complex between β-CD-SAM with some steroids such as cortisol and cortisone, voltammetric experiments in the presence of the redox probes as molecules competitive with the steroids have been performed. The formation constant of the surface host-guest by β-CD-SAM and the steroids under study was calculated.

[Correlations between the hypothalamo-pituitary-adrenal axis and the metabolic syndrome].

PubMed

Góth, Miklós; Hubina, Erika; Korbonits, Márta

2005-01-09

The metabolic syndrome has several similarities with Cushing's syndrome (impaired glucose tolerance, hypertension, dyslipidemia, central obesity) suggesting that abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis may have a link with the metabolic syndrome. Several studies suggested an association between the clinical signs of the metabolic syndrome and the increased hypothalamic-pituitary-adrenal axis activity based on increased cortisol concentration at 09.00 a.m. and increased cortisol response to corticotropin. According to the Barker hypothesis the fetal malnutrition could determine adult cardiovascular diseases (coronary heart disease, hypertension), some endocrine and metabolic disorders (obesity, type 2 diabetes and hyperlipidemia). The suggested mechanism of the phenomenon is that the suboptimal fetal nutrition results in glucocorticoid overproduction. The 11beta-hydroxysteroid dehydrogenase (converts biological inactive cortisone to cortisol and vice versa) is an important enzyme in cortisol metabolism. The increased expression of 11beta-hydroxysteroid dehydrogenase type 1 in fat tissue could lead to central obesity and impaired glucose tolerance. The hypothesis that increased corticotropin-releasing hormone production drives the overactive hypothalamo-pituitary-adrenal axis was not proven. Further investigations are needed to identify additional pathogenetic factors and to find new therapeutic possibilities.

A Rare and Severe Complication Following Thyroid Fine Needle Aspiration: Retropharyngeal Cellulitis

PubMed Central

Cesareo, Roberto; Naciu, Anda; Barberi, Antonio; Pasqualini, Valerio; Pelle, Giuseppe; Manfrini, Silvia; Tabacco, Gaia; Pantano, Angelo Lauria; Campagna, Giuseppe; Cianni, Roberto; Palermo, Andrea

2016-01-01

Introduction Fine needle aspiration (FNA) is the most accurate and cost-effective method for evaluating thyroid nodules. We have reported a rare complication related to the procedure: severe retropharyngeal cellulitis. Case Presentation A thirty-five-year-old female was admitted to hospital with hoarseness, laryngeal stridor and dyspnea without fever that emerged about 3 days after a first diagnostic FNA. After the procedure, the patient felt her voice became hoarse and 1 day before presentation began to have dyspnea, without fever. It had become difficult for her to swallow solids, and she felt as if food was sticking in her throat. In the emergency room, hematochemical tests and CT scan of the neck/mediastinum had been performed. This showed leukocytosis with neutrophilia and a severe cellulitis framework with involvement of the laterocervical neck area and in particular, the invasion of the retropharynx and the upper part of the mediastinum. The patient was admitted in hospital for an anti-inflammatory therapy with cortisone and antibiotic therapy. Conclusions For the first time to our knowledge, we have reported a severe retropharyngeal and upper mediastinum cellulitis, probably due to the FNA procedure in an immunocompetent young woman. PMID:28123438

11β-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice

PubMed Central

Hermanowski-Vosatka, Anne; Balkovec, James M.; Cheng, Kang; Chen, Howard Y.; Hernandez, Melba; Koo, Gloria C.; Le Grand, Cheryl B.; Li, Zhihua; Metzger, Joseph M.; Mundt, Steven S.; Noonan, Heather; Nunes, Christian N.; Olson, Steven H.; Pikounis, Bill; Ren, Ning; Robertson, Nancy; Schaeffer, James M.; Shah, Kashmira; Springer, Martin S.; Strack, Alison M.; Strowski, Matthias; Wu, Kenneth; Wu, TsueiJu; Xiao, Jianying; Zhang, Bei B.; Wright, Samuel D.; Thieringer, Rolf

2005-01-01

The enzyme 11β–hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11β-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11β-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11β-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11β-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself. PMID:16103409

The pentose phosphate pathway of glucose metabolism. Hormonal and dietary control of the oxidative and non-oxidative reactions of the cycle in liver

PubMed Central

Novello, F.; Gumaa, J. A.; McLean, Patricia

1969-01-01

1. Measurements were made of the non-oxidative reactions of the pentose phosphate cycle in liver (transketolase, transaldolase, ribulose 5-phosphate epimerase and ribose 5-phosphate isomerase activities) in a variety of hormonal and nutritional conditions. In addition, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities were measured for comparison with the oxidative reactions of the cycle; hexokinase, glucokinase and phosphoglucose isomerase activities were also included. Starvation for 2 days caused significant lowering of activity of all the enzymes of the pentose phosphate cycle based on activity in the whole liver. Re-feeding with a high-carbohydrate diet restored all the enzyme activities to the range of the control values with the exception of that of glucose 6-phosphate dehydrogenase, which showed the well-known `overshoot' effect. Re-feeding with a high-fat diet also restored the activities of all the enzymes of the pentose phosphate cycle and of hexokinase; glucokinase activity alone remained unchanged. Expressed as units/g. of liver or units/mg. of protein hexokinase, glucose 6-phosphate dehydrogenase, transketolase and pentose phosphate isomerase activities were unchanged by starvation; both 6-phosphogluconate dehydrogenase and ribulose 5-phosphate epimerase activities decreased faster than the liver weight or protein content. 2. Alloxan-diabetes resulted in a decrease of approx. 30–40% in the activities of 6-phosphogluconate dehydrogenase, ribose 5-phosphate isomerase, ribulose 5-phosphate epimerase and transketolase; in contrast with this glucose 6-phosphate dehydrogenase, transaldolase and phosphoglucose isomerase activities were unchanged. Treatment of alloxan-diabetic rats with protamine–zinc–insulin for 3 days caused a very marked increase to above normal levels of activity in all the enzymes of the pentose phosphate pathway except ribulose 5-phosphate epimerase, which was restored to the control value. Hexokinase activity was also raised by this treatment. After 7 days treatment of alloxan-diabetic rats with protamine–zinc–insulin the enzyme activities returned towards the control values. 3. In adrenalectomized rats the two most important changes were the rise in hexokinase activity and the fall in transketolase activity; in addition, ribulose 5-phosphate epimerase activity was also decreased. These effects were reversed by cortisone treatment. In addition, in cortisone-treated adrenalectomized rats glucokinase activity was significantly lower than the control value. 4. In thyroidectomized rats both ribose 5-phosphate isomerase and transketolase activities were decreased; in contrast with this transaldolase activity did not change significantly. Hypophysectomy caused a 50% fall in transketolase activity that was partially reversed by treatment with thyroxine and almost fully reversed by treatment with growth hormone for 8 days. 5. The results are discussed in relation to the hormonal control of the non-oxidative reactions of the pentose phosphate cycle, the marked changes in transketolase activity being particularly outstanding. PMID:5791534

Cluster headache: clinical features and therapeutic options.

PubMed

Gaul, Charly; Diener, Hans-Christoph; Müller, Oliver M

2011-08-01

Cluster headache is the most common type of trigemino-autonomic headache, affecting ca. 120 000 persons in Germany alone. The attacks of pain are in the periorbital area on one side, last 90 minutes on average, and are accompanied by trigemino-autonomic manifestations and restlessness. Most patients have episodic cluster headache; about 15% have chronic cluster headache, with greater impairment of their quality of life. The attacks often possess a circadian and seasonal rhythm. Selective literature review Oxygen inhalation and triptans are effective acute treatment for cluster attacks. First-line drugs for attack prophylaxis include verapamil and cortisone; alternatively, lithium and topiramate can be given. Short-term relief can be obtained by the subcutaneous infiltration of local anesthetics and steroids along the course of the greater occipital nerve, although most of the evidence in favor of this is not derived from randomized clinical trials. Patients whose pain is inadequately relieved by drug treatment can be offered newer, invasive treatments, such as deep brain stimulation in the hypothalamus (DBS) and bilateral occipital nerve stimulation (ONS). Pharmacotherapy for the treatment of acute attacks and for attack prophylaxis is effective in most patients. For the minority who do not gain adequate relief, newer invasive techniques are available in some referral centers. Definitive conclusions as to their value cannot yet be drawn from the available data.

Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens

PubMed Central

Kalleda, Natarajaswamy; Amich, Jorge; Arslan, Berkan; Poreddy, Spoorthi; Mattenheimer, Katharina; Mokhtari, Zeinab; Einsele, Hermann; Brock, Matthias; Heinze, Katrin Gertrud; Beilhack, Andreas

2016-01-01

Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4+ or CD8+ T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b+ myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b+ myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. PMID:27468286

Allergic contact dermatitis from medical adhesive bandages in patients who report having a reaction to medical bandages.

PubMed

Widman, Travis J; Oostman, Holly; Storrs, Frances J

2008-01-01

Medical adhesive bandages are extensively used in both inpatient and outpatient medicine. However, few reports describing proven allergic contact dermatitis (ACD) from medical adhesive bandages exist in the literature. These reports do not adequately correspond to the frequency that patients report having an "allergy" to medical adhesive bandages. To determine if there is a chemical present in medical adhesive bandages that causes ACD in people who identify themselves as having an "allergy" to medical adhesive bandages. Twenty-six patients were enrolled and underwent patch testing with our standard trays (104 chemicals) and a customized adhesive tray (54 chemicals and 10 tapes and bandages in their whole form). We were able to identify an allergen in four patients that was related to their presumed adhesive allergy (Mastisol, neomycin/bacitracin [two different patients], and cortisone-10 cream, respectively). However, there were no positive allergic reactions to the tapes or bandages or any relevant allergic reactions to our customized adhesive tray. Eight (73%) of the 11 patients who had the bandage or tape left on for 7 days had an irritant reaction. We feel that the perceived reactions are not secondary to ACD but instead are due to an irritant contact dermatitis.

[Pharmacogenic osteoporosis beyond cortisone. Proton pump inhibitors, glitazones and diuretics].

PubMed

Kann, P H; Hadji, P; Bergmann, R S

2014-05-01

[corrected] There are many drugs which can cause osteoporosis or at least favor its initiation. The effect of hormones and drugs with antihormonal activity, such as glucocorticoids and aromatase inhibitors, on initiation of osteoporosis is well known. In addition, proton pump inhibitors, glitazones and diuretics also influence the formation of osteoporosis. The results of currently available studies on the correlation between proton pump inhibitors, glitazones and diuretics on formation of osteoporosis were evaluated and summarized. Proton pump inhibitors and glitazones increase the risk for osteoporotic fractures. Loop diuretics may slightly increase fracture risk, whereas thiazides were shown to be osteoprotective by reducing fracture probability on a relevant scale. Proton pump inhibitors should not be prescribed without serious consideration and then only as long as necessary. Alternatively, the administration of the less effective H2 antagonists should be considered when possible due to the reduction of acid secretion. Because the long-term intake of thiazides is associated with a clinically relevant reduction in the risk of fractures and they are economic and well-tolerated, prescription can be thoroughly recommended within the framework of differential diagnostic considerations in an appropriate clinical context. The briefly increased risk of falling immediately after starting diuretic therapy is the only point which needs to be considered.

Pseudohyperaldosteronism due to mumijo consumption during pregnancy: a licorice-like syndrome.

PubMed

Stavropoulos, Konstantinos; Sotiriadis, Alexandros; Patoulias, Dimitrios; Imprialos, Konstantinos; Dampali, Roxani; Athyros, Vasileios; Dinas, Konstantinos

2018-06-22

Herbal supplements are widely used during pregnancy, although there are insufficient data regarding their efficacy and safety. Some of them have been associated with hypertension, including licorice, which induces the so called mineralocorticoid-excess syndrome, a clinical picture resembling to pseudohyperaldosteronism. This action is mediated via inhibition of 11-hydroxysteroid dehydrogenase type 2 (11-HSD2), leading to impaired inactivation of cortisol to cortisone, accumulation of cortisol, and finally to excessive mineralocorticoid activity, especially in the distal and cumulative tubule of kidneys. This syndrome is characterized by hypertension and hypokalemia. Herein, we report a case of a 37-year-old pregnant woman, who was referred from obstetrics department to our department due to persistent hypertension and hypokalemia. She consumed a herbal supplement called "mumijo" during the last 6 months. After a thorough diagnostic work-up, the diagnosis of a "licorice-like syndrome" due to mumijo consumption was made. Potassium supplementation at the acute phase and discontinuation of mumijo were the treatment of choice. This is the first report of pseudohyperaldosteronism due to mumijo consumption in literature. Clinicians should be aware of this side effect and this agent should be included in those causing pseudohyperaldosteronism. Besides all, our case highlights the undeniable value of a detailed medical history.

Myasthenia gravis imitating pituitary apoplexy in macroprolactinoma.

PubMed

Zoli, Matteo; Guaraldi, Federica; Faustini, Marco; Mazzatenta, Diego

2018-06-02

Myasthenia gravis (MG) is an autoimmune disease affecting neuromuscular transmission that manifests with muscle weakness and typically involves the eye muscles, often producing diplopia and ptosis. Recent studies suggest that hyperprolactinaemia may have a role in the development of MG, although its association with prolactinoma is extremely rare. We report the unusual case of a 71-year-old male affected with macroprolactinoma, who presented at our Center 2 weeks after starting cabergoline treatment because of acute onset of headache, diplopia, and ptosis. On admission, he presented with drowsiness, dropped head, swallowing impairment and bilateral ptosis, which rapidly worsened. Based on clinical manifestation and history, emergency surgery was performed on suspicion of pituitary apoplexy (PA), the typical complication occurring in patients with macroadenomas who present these symptoms. No pituitary haemorrhage was found. The symptoms initially resolved after surgery, but soon returned and worsened day by day, especially in the evening, despite the increase of cortisone replacement doses. MG was thus suspected and confirmed by the detection of antibodies to the acetylcholine receptor. Pyridostigmine was started with prompt improvement of neurological symptoms. In conclusion, although very rare, MG should be considered in the differential diagnosis of patients with macroprolactinomas and suggestive neurological symptoms in order to provide early and appropriate treatment. The role of hyperprolactinaemia in MG onset and evolution is also discussed.

Premature adrenarche: novel lessons from early onset androgen excess.

PubMed

Idkowiak, Jan; Lavery, Gareth G; Dhir, Vivek; Barrett, Timothy G; Stewart, Paul M; Krone, Nils; Arlt, Wiebke

2011-08-01

Adrenarche reflects the maturation of the adrenal zona reticularis resulting in increased secretion of the adrenal androgen precursor DHEA and its sulphate ester DHEAS. Premature adrenarche (PA) is defined by increased levels of DHEA and DHEAS before the age of 8 years in girls and 9 years in boys and the concurrent presence of signs of androgen action including adult-type body odour, oily skin and hair and pubic hair growth. PA is distinct from precocious puberty, which manifests with the development of secondary sexual characteristics including testicular growth and breast development. Idiopathic PA (IPA) has long been considered an extreme of normal variation, but emerging evidence links IPA to an increased risk of developing the metabolic syndrome (MS) and thus ultimately cardiovascular morbidity. Areas of controversy include the question whether IPA in girls is associated with a higher rate of progression to the polycystic ovary syndrome (PCOS) and whether low birth weight increases the risk of developing IPA. The recent discoveries of two novel monogenic causes of early onset androgen excess, apparent cortisone reductase deficiency and apparent DHEA sulphotransferase deficiency, support the notion that PA may represent a forerunner condition for PCOS. Future research including carefully designed longitudinal studies is required to address the apparent link between early onset androgen excess and the development of insulin resistance and the MS.

[Clinical aspects and therapy of the posner-schlossmann-syndrom (author's transl)].

PubMed

Hollwich, F

1978-05-01

Difficulties in the early diagnosis of the Posner-Schlossmann syndrome can be avoided by looking for the following typical clinical signs: Very fine, unpigmented precipitates, which are often only signly present, and which are scattered over the entire cornea: bright white in incident light, translucent in reflected light, and in transmitted light dark in spots. Posterior synechiae are not present. Obvious differences in color or heterochromia are present in only 30-40% of the cases. In the remaining cases, there ist only a slight color difference or unilateral, diffusely trophic hypochromia of the iris, often only after several attacks. The chamber angle is and remains open during the attacks. There are similarities between glaucomatocyclitic crisis and heterochromic cyclitis: Unilaterality, the same specific precipitates, no synechiae, and practically the same percentage of color differences of the iris. Hypochromic dystrophy of the iris dependent on the magnitude and duration of the cyclitic process. In both cases, there is the same rate of physical changes, pointing to a congenital damage of the sympathetic nervous system (status dysraphicus Passow). Hence, the Posner-Schlossmann syndrome can be regarded as a special case of heterochromic cyclitis. Neither miotics nor mydriatics, nor operation during the crisis. Acetazolamide (Diamox) combined with local cortisone will stop the crisis.

Palate morphogenesis in mouse embryos after x-irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Callas, Gerald; Walker, Bruce E.

1963-01-01

The development of cleft palate was investigated by irradiating pregnant female C57BL and A/Jax mice on the 11 1/3 day of gestation with 300-r, whole-body doses and examining the fetuses at subsequent intervals. When palate stage was compared with chronological age, morphological rating, or embryonic weight, it was obvious that intermediate stages of palate closure persisted in x-irradiated embryos long after such stages had been passed in normal embryos. Thus, movement of the palatine shelves from the sagittal to the horizontal plane was retarded by x irradiation. Measurements of head and palate did not show any consistent disproportionality of palatemore » growth in the xirradiated embryos except that which resulted from retardation of shelf movement. X irradiation affected A/Jax strain litters more severely than C57BL strain litters according to cleft palate frequency and average palate stage at 18 1/3 days postconception. Cleft palate was seen in 73.1% of strain C57BL fetuses and in 99.5% of A/Jax fetuses. A variety of malformations other than cleft palate were also observed in the offspring of treated mice. Morphologic analysis of cleft palate development after xray treatment gave essentially the same results as comparable analyses of cleft palates produced by cortisone, hypervitaminosis A, and riboflavin deficiency. (TCO)« less

Virtual reality jogging as a novel exposure paradigm for the acute urge to be physically active in patients with eating disorders: Implications for treatment.

PubMed

Paslakis, Georgios; Fauck, Vanessa; Röder, Kathrin; Rauh, Elisabeth; Rauh, Manfred; Erim, Yesim

2017-11-01

The acute urge to be physically active is a relevant clinical phenomenon in patients suffering from eating disorders. In this study with n = 20 female patients with anorexia nervosa and n = 10 female patients with bulimia nervosa, a virtual reality (VR) jogging paradigm was applied as a novel highly immersive 3D exposure paradigm. Patients were asked to rate their acute urge to be physically active during the exposure procedure. A 10-item self-report questionnaire (smQ) was developed to capture the cognitive, emotional, and behavioral aspects of the acute urge to move. We hypothesized that exposure would lead to habituation of the urge to be physically active. We also hypothesized that leptin levels would be associated with the degree of the subjective urge to be physically active, while habituation would be associated with a decrease in stress hormones (α-amylase, cortisol, and cortisone in saliva). A statistically significant change in subjective scores in the smQ from baseline to postexposure was seen. Our novel VR paradigm may serve as a therapeutic tool for exposure and habituation of the urge of acutely engaging in physical activity in patients with eating disorders. © 2017 Wiley Periodicals, Inc.

Safe adalimumab therapy for rheumatoid arthritis in a patient with pre-existing multiple myeloma.

PubMed

Mielke, Frank; Schweigert, Marcus

2008-04-01

We report on a patient with rheumatoid arthritis (RA) who was treated with adalimumab and retrospectively diagnosed as having a multiple myeloma. In addition to the determination of clinical symptoms, investigations included radiography of the thorax, spine, hands and feet, arthrosonography, determination of laboratory parameters (including C-reactive protein levels and presence of antibodies against cyclic citrullinated peptide), cytogenetics and electrocardiography. RA was initially diagnosed in 1988. Stage II and stage III RA were diagnosed for the left and right foot, respectively, in 1996. Joints of both hands were diagnosed with stage I RA; both wrists and some finger joints showed signs of synovitis. Plasmocytoma was diagnosed in 2004; however, investigation of medical records revealed evidence of multiple myeloma 8 years earlier, in 1996. RA was originally treated with gold, sulfasalazine, azathioprin and glucocorticoid. Methotrexate was later used in addition to cortisone and then in combination with a selective cyclo-oxygenase-2 inhibitor. A combination therapy consisting of adalimumab (40 mg every 2 weeks), methotrexate (15 mg weekly) and a cyclo-oxygenase-2 inhibitor (rofecoxib 25 mg daily until July 2004, etoricoxib 90 mg daily from October 2004) was started in November 2003. Adalimumab therapy was interrupted for 6 months owing to safety concerns, but was resumed after a careful risk-benefit assessment.

ON THE PROPHYLAXIS OF RADIATION-CONDITIONED HYDRONEPHROSIS (CLINICAL AND ANIMAL EXPERIMENTAL STUDIES)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muth, H.; Legerlotz, C.

1962-10-01

Means of preventirg hydronephrosis, developing from injury to the ureter during radiotherapy of gynecologic carcinoma, were investigated. These studies were based on previous observations that cortisone tended to reduce the incidence of ureteral strictures following irradiation of cervical carcinoma. Female rats were irradiated with 300 r, delivered to a 2 x 4.5 cm abdominal area, in repeated doses to give a total of 4500 r. The animals were injected intramuscularly with 0.5 mg of a crystalline suspension of prednisolone every week during and after irradiation, and control animals were treated with folliclestimulating hormone (FSH). Pyelonephritis developed in 44% of FSH-treatedmore » animals compared with only 18% in prednisolone-treated rats; severe ureteral sclerosis was found in 36 and 20%; and histological detectable hydronephrosis was seen in 80 and 0%, respectively. It was concluded that this anti-inflammatory steroid inhibits development of the 2 factors which appear most responsible for radiation-induced hydronephrosis, namely, ascending pyelonephritis and ureteral sclerosis. This was confirmed in human subjects. In 50 women undergoing radiation treatment of uterine carcinoma, administration of a total dose of 500 mg prednisolone over a 3- month period completely prevented hydronephrosis, whereas this complication arose in 10% of women who did not receive this steroid. (H.H.D.)« less

Hormones in infant rhesus monkeys' (Macaca mulatta) hair at birth provide a window into the fetal environment.

PubMed

Kapoor, Amita; Lubach, Gabriele; Hedman, Curtis; Ziegler, Toni E; Coe, Christopher L

2014-04-01

It is established that maternal parity can affect infant growth and risk for several disorders, but the prenatal endocrine milieu that contributes to these outcomes is still largely unknown. Recently, it has been shown that hormones deposited in hair can provide a retrospective reflection of hormone levels while the hair was growing. Taking advantage of this finding, our study utilized hair at birth to investigate if maternal parity affected fetal hormone exposure during late gestation. Hair was collected from primiparous and multiparous mother and infant monkeys at birth and used to determine steroid hormones embedded in hair while the infant was in utero. A high-pressure liquid chromatography-triple quadrupole mass spectrometry technique was refined, which enabled the simultaneous measurement of eight hormones. Hormone concentrations were dramatically higher in neonatal compared to maternal hair, reflecting extended fetal exposure as the first hair was growing. Further, hair cortisone was higher in primiparous mothers and infants when compared to the multiparous dyads. This research demonstrates that infant hair can be used to track fetal hormone exposure and a panel of steroid hormones can be quantified from hair specimens. Given the utility in nonhuman primates, this approach can be translated to a clinical setting with human infants.

Changes in the expression of potassium channels during mouse T cell development

PubMed Central

1986-01-01

In this report we have combined the whole-cell electrophysiological recording technique with flow microfluorometry to isolate phenotypically defined thymocytes and T lymphocytes. Results obtained showed that J11d-/Lyt-2-/L3T4- cells express none or very few delayed rectifier K+ channels, whereas most other Lyt-2-/L3T4- cells, as well as typical cortical thymocytes (Lyt-2+/L3T4+), do express K+ channels. Mature (Lyt-2+/L3T4- or Lyt-2-/L3T4+) thymocytes, which are heterogeneous for J11d expression, were also found to be heterogeneous for K+ channel expression. Consistent with this finding was the observation that the cortisone-resistant subpopulation of thymocytes, which express low levels of J11d, were enriched for cells expressing low levels of K+ channels. Mature phenotype peripheral T lymphocytes expressed very low levels of K+ channels, but upon activation with Con A were found to express high levels of K+ channels. The results suggest that K+ channel expression in T cells is developmentally regulated. Increased expression of the channel is induced in response to mitogenic signals throughout the T cell lineage. Expression of the channel, therefore, serves as a useful marker in defining steps in the T cell differentiation pathway. PMID:2431091

Aplastic anemia as a feature of systemic lupus erythematosus: a case report and literature review.

PubMed

Chalayer, Émilie; Ffrench, Martine; Cathébras, Pascal

2015-06-01

Peripheral cytopenias are common in systemic lupus erythematosus, but bone marrow involvement is rarely reported. Aplastic anemia is the result of immune-mediated destruction of hematopoietic stem cells causing pancytopenia and characterized by an empty bone marrow. This rare but serious disease has been described as an unusual manifestation of systemic lupus erythematosus. We reviewed the 25 cases published in the English language literature and discuss the clinical presentation, outcome, treatment, and pathophysiology of aplastic anemia as a complication of systemic lupus erythematosus. We report here the first case of aplastic anemia associated with systemic lupus erythematosus treated with an allogeneic hematopoietic stem cell transplant. Over one half of patients received concomitantly the diagnoses of systemic lupus erythematosus and aplastic anemia. No clinical or histological features can distinguish primary aplastic anemia from aplastic anemia occurring in systemic lupus erythematosus patients. The overall mortality is about 15% and corticosteroid-based therapy alone or in combination with other immunomodulatory drugs can restore bone marrow function. Systemic lupus erythematosus may be complicated by bone marrow involvement. The diagnosis of peripheral cytopenias should be confirmed by bone marrow aspiration. All these patients should receive cortisone as a first treatment. Plasma exchanges seem to have some efficacy. Other different immunomodulatory therapies were used with variable results.

Hormones in Infant Hair at Birth Provide a Window into the Fetal Environment

PubMed Central

Kapoor, Amita; Lubach, Gabriele; Hedman, Curtis; Ziegler, Toni E.; Coe, Christopher L.

2014-01-01

Background It is established that maternal parity can affect infant growth and risk for several disorders, but the prenatal endocrine milieu that contributes to these outcomes is still largely unknown. Recently, it has been shown that hormones deposited in hair can provide a retrospective reflection of hormone levels while the hair was growing. Taking advantage of this finding, our study utilized hair at birth to investigate if maternal parity affected fetal hormone exposure during late gestation. Methods Hair was collected from primiparous and multiparous mother and infant monkeys at birth and used to determine steroid hormones embedded in hair while the infant was in utero. An LC/MS/MS technique was refined, which enabled the simultaneous measurement of 8 hormones. Results Hormone concentrations were dramatically higher in neonatal compared to maternal hair, reflecting extended fetal exposure as the first hair was growing. Further, hair cortisone was higher in primiparous mothers and infants when compared to the multiparous dyads. Conclusion This research demonstrates that infant hair can be used to track fetal hormone exposure and a panel of steroid hormones can be quantified from hair specimens. Given the utility in nonhuman primates, this approach can be translated to a clinical setting with human infants. PMID:24418932

[Regenerative medicine: orthopaedical applications and medico legal questions].

PubMed

Ricci, S; Ricci, O; Tucci, C E; Massoni, F; Sarra, M V; Ricci, S

2012-01-01

Over the last decades, the increase in the global population's mean age has implied a corresponding increase in degenerative disease affecting various anatomical areas and tissues, including bones and cartilages, thus provoking a rising number of disabilities and a wider usage of drugs, mostly anti-inflammatory and cortisone. New developments in technologic and biomedical fields gave birth to new subjects, such as tissue engineering, cell therapy, gene therapy that, by and large, create a knowledge network falling under the concept of Regenerative Medicine. This science is essentially based on the usage of stem cells that can replicate and renovate themselves originating, if adequately stimulated, a number of cell types. Inter alia, in orthopaedic field a particular type of adult stem cells is used, the mesenchymal stem cells (MSCs). If combined with synthetic material produced in laboratories, the usage of these cells has provided inspiration for new study interests; today, it can be applied in various degenerative and post-traumatic pathologies, with great therapeutic benefits for the patient. Actually, many studies write about an improvement in patients' life quality. In this sense appear significant reflections on legal medicine, both in accidents and insurance, of this innovative therapeutic alternative and is hopefully an equally valid process of improvement of regulatory and case law.

The Role and Regulation of the 11 Beta-Hydroxysteroid Dehydrogenase Enzyme System in Patients with Inflammatory Bowel Disease.

PubMed

Hussey, M; Holleran, G; Smith, S; Sherlock, Mark; McNamara, D

2017-12-01

Glucocorticoids are known to modulate a number of immunological responses including counteracting inflammation. Within tissues expressing the glucocorticoid and mineralocorticoid receptors including the colon, glucocorticoid metabolism is regulated by the isoenzymes of 11ß-hydroxysteroid dehydrogenase (11β-HSD). 11β-HSD1 acts as an oxidoreductase converting inactive cortisone into active cortisol, while 11β-HSD2 acts as a dehydrogenase converting active cortisol to inactive cortisone. Hexose-6 phosphate dehydrogenase (H6PDH) is a key regulator of 11β-HSD1 activity via its generation of NADPH. Variations in the 11β-HSD enzyme system in relation to levels of expression and regulation may have a role in IBD. The aim of this study was to investigate possible abnormalities of 11β-HSD enzyme system in the colon of patients with IBD. By using quantitative real-time PCR, we investigated the transcription levels of 11β-HSD1 and 2 in colonic tissue from IBD patients and healthy controls undergoing a colonoscopy for disease assessment. Disease activity was recorded using clinical (Mayo Score/Harvey-Bradshaw Index), Biochemical (C-reactive protein), histological, and endoscopic parameters. In addition, transcription levels of H6PDH and the glucocorticoid receptor alpha (GR-α) as well as key pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, Rela (subunit for NF Kappa B)) were later examined among this group, and results were correlated with 11β-HSD2 gene expression. Results and patient demographics were expressed as a mean (and SD), and differences between IBD patients and control groups were analyzed using a Student's t test or Mann-Whitney U test as appropriate, with a p value of ≤0.05 considered significant. Results were controlled for disease activity as outlined above. Results have demonstrated a significant downregulation in 11β-HSD2 expression in IBD patients compared with controls (13.8 ± 17.1 au vs. 318.4 ± 521.1 au, p = 0.01), whereas levels of 11β-HSD1 did not appear to vary across the two groups. Among IBD patients, there was a trend toward higher 11β-HSD1 expression in inflamed tissue compared with matched non-inflamed tissue (422.1 ± 944 au vs. 102.2 ± 103.9, P = 0.09). Levels of H6PDH and the GR-α expression did not appear to vary among active inflamed IBD tissue and controls. As a result, we examined the association between pro-inflammatory cytokines and levels of 11β-HSD2 expression. Results showed an upregulation of key pro-inflammatory cytokine mRNA expression (TNF-α, IL-1β, IL-6) during inflammation with an associated downregulation of 11β-HSD2 mRNA expression when compared to controls. Dysregulation in this pathway could have a potential role in IBD pathogenesis and may account for exogenous glucocorticoid resistance in IBD. Further work assessing the role of the 11β-HSD enzyme system in steroid-resistant subjects is warranted.

Salivary cortisol and cortisone responses to short-term psychological stress challenge in late adolescent and young women with different hyperandrogenic states.

PubMed

Mezzullo, Marco; Fanelli, Flaminia; Di Dalmazi, Guido; Fazzini, Alessia; Ibarra-Gasparini, Daniela; Mastroroberto, Marianna; Guidi, Jenny; Morselli-Labate, Antonio Maria; Pasquali, Renato; Pagotto, Uberto; Gambineri, Alessandra

2018-05-01

Hyperandrogenic disorders have been associated with psychological distress, reduced quality of life, anxiety and depression. The hypothalamic-pituitary-adrenal (HPA) axis plays a pivotal role in the adaptive response to stressor events. Salivary cortisol (SalF) and cortisone (SalE) testing have been proven to be useful in the evaluation of HPA-axis activity. This study investigated whether SalF and SalE responses to two putative stressor levels differed between the hyperandrogenic states in late adolescent and young women, thus measuring the HPA-axis adaptive response to acute stress events. We selected 161 drug-free females aged 16-19 years from a large population previously enrolled in a cross-sectional epidemiological study. Saliva was collected in the morning before and after two putative stressor events consisting in a self-filled questionnaire (weaker stressor) and in a structured interview plus physical examination by an endocrinologist (stronger stressor). SalF and SalE, as well as blood steroids, were assessed by liquid chromatography-tandem mass spectrometry. Subjects were subdivided into different groups according to the presence of: isolated menstrual irregularities (MI, oligo-amenorrhea; n = 22), isolated hirsutism (HIR, modified Ferriman-Gallwey score ≥ 8; n = 26), isolated hyperandrogenaemia (HT, testosterone >0.438 ng/mL; n = 14), and polycystic ovary syndrome (PCOS, MI with HIR and/or HT, n = 16). The remaining 83 apparently healthy subjects were used as controls. SalF and SalE significantly decreased after the weaker stressor, following the physiologic diurnal loss, in all the groups except for isolated HIR, where they remained unchanged (P = 0.091 and P = 0.118, respectively). In contrast, SalF and SalE remained unchanged after the stronger stressor in isolated MI, isolated HT and controls, whereas SalF increased significantly in isolated HIR (P = 0.011), and SalE increased significantly both in isolated HIR (P = 0.005) and in PCOS (P = 0.011) groups. SalF percentage variation in response to the stronger stressor was positively associated with systolic blood pressure in PCOS (P = 0.018), and both SalF and SalE percentage variations were positively associated with diastolic blood pressure in the isolated HIR group (P = 0.010 and P = 0.006, respectively). In addition, in the isolated HIR group, the SalF percentage variation was negatively associated with HDL cholesterol levels (P = 0.005). Finally, SalF and SalE percentage variations were positively associated with circulating androstenedione (P = 0.031 and P = 0.011, respectively) and DHEA (P = 0.020 and P = 0.003, respectively) in the isolated HIR group. In conclusion, this study demonstrates that hirsute and PCOS adolescent and young women are characterized by HPA-axis overactivity in response to stressful stimuli, as detectable by salivary glucocorticoid measurements. These data also indicate that the higher the HPA-axis activity, the higher the adrenal androgen output and the worse the metabolic profile. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Influence of Age, Sex, Pregnancy, Starvation, and Other Factors on the Cytoplasmic Ribonucleoproteins of Rat Liver

PubMed Central

Petermann, Mary L.; Hamilton, Mary G.

1958-01-01

Rat liver was homogenized in 0.88 M sucrose. The DNA and total RNA were determined, and the homogenate was fractionated by differential centrifugation. The pellets obtained between 30 minutes at 20,000 g and 180 minutes at 105,000 g were analyzed for RNA and nitrogen. The ribonucleoproteins were determined in the analytical ultracentrifuge. The non-pellet RNA was calculated by difference. The results are reported as amounts per 6.7 x 10-9 mg. of DNA. In young, growing male rats the amounts of microsomal protein and ribonucleoprotein B (83S) increased with age. Non-pregnant adult females showed less non-pellet RNA and much more ribonucleoprotein C (63S) than did adult males. During pregnancy both of these cell constituents reverted to levels characteristic for male animals. Starvation for 5 days resulted in a reduction in the mass of liver tissue, the non-pellet RNA, the microsomal protein, and ribonucleoproteins B and C. During recovery from starvation the return of the liver to normal paralleled the rate at which body weight was restored. Treatment with cortisone, 25 mg. per rat per day for 5 days, caused an increase in microsomal protein and a decrease in ribonucleoprotein B. Treatment with 6-mercapto-purine, 50 mg. per kilo per day for 5 days, caused little change in liver composition in either males or females. PMID:13610943

Experimental Modification of Rat Pituitary Growth Hormone Cell Function During and After Spaceflight

NASA Technical Reports Server (NTRS)

Hymer, W. C.; Salada, T.; Nye, P.; Grossman, E. J.; Lane, P. K.; Grindeland, R. E.

1996-01-01

Space-flown rats show a number of flight-induced changes in the structure and function of pituitary Growth Hormone (GH) cells after in vitro postflight testing. To evaluate the possible effects of microgravity on GH cells themselves, freshly dispersed rat anterior pituitary gland cells were seeded into vials containing serum +/- 1 micron HydroCortisone (HC) before flight. Five different cell preparations were used: the entire mixed-cell population of various hormone-producing cell types, cells of density less than 1.071 g/sq cm (band 1), cells of density greater than 1.071 g/sq cm (band 2), and cells prepared from either the dorsal or ventral part of the gland. Relative to ground control samples, bioactive GH released from dense cells during flight was reduced in HC-free medium but was increased in HC-containing medium. Band I and mixed cells usually showed opposite HC-dependent responses. Release of bioactive GH from ventral flight cells was lower; postflight responses to GH-releasing hormone challenge were reduced, and the cytoplasmic area occupied by GH in the dense cells was greater. Collectively, the data show that the chemistry and cellular makeup of the culture system modifies the response of GH cells to microgravity. As such, these cells offer a system to identify gravisensing mechanisms in secretory cells in future microgravity research.

Recent Advances in Hydrocortisone Replacement Treatment.

PubMed

Mallappa, Ashwini; Debono, Miguel

2016-01-01

Since the first use of cortisone in patients around 65 years ago, the use of synthetic glucocorticoids has made a crucial impact on the treatment of several diseases in medicine. Although significant reductions in morbidity and mortality have occurred in patients suffering from cortisol deficiency, conventional hydrocortisone replacement treatment is still inadequate. A major limitation is that it fails to replace cortisol in a physiological manner. Cortisol has a distinct circadian rhythm and acts as a secondary messenger synchronizing the central to peripheral clocks, hence playing a key role in biological processes and the circadian timing system. Circadian misalignment has been associated with ill-health and so nonphysiological glucocorticoid treatment could explain the increased mortality rate, poor quality of life and metabolic complications in patients suffering from adrenal insufficiency. Attempts at replacing cortisol in a physiological manner have shown significant progress in the past decade with the development of modified-release formulations of hydrocortisone (Chronocort® and Plenadren®) and continuous subcutaneous hydrocortisone infusions. Initial studies investigating the use of these replacement regimens are promising, demonstrating both clinical and biochemical improvement. Larger studies are needed to determine whether this novel approach enhances long-term outcomes in both children and adults with cortisol deficiency. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. Published by S. Karger AG, Basel.

Prostaglandins, steroids and reception (an attempt to model the structure of the active centers of adrenoreception).

PubMed

Podymov, V K; Piruzyan, L A; Gladkikh, S P; Kats, M M; Nizhnii, S V

1980-01-01

On the basis of numerous results of investigations on adrenergic systems, an orientational model of the adrenoreceptor (AR) is postulated. Its active center includes low-molecular-weight components--prostaglandins (PGE, PGF), steroids (cortisone, hydrocortisone), S+-adenosylmethionine, Ca, Mg, and Mn ions. Appraisal of the stereospecific characteristics of such a functional unit of AR explains the difference in the nature and magnitude of the effects of interaction of the catecholamines, their agonists and antagonists will the so-called alpha- and beta-AR. Depending on the organ or tissue in which the AR is located, its protein subunits comprise adenylcyclase (beta-AR) or Na,K-ATPase (alpha-AR). An obligatory component of the AR is catechol-O-methyltransferase. The model elaborated describes satisfactorily the molecular mechanisms of action of many pharmacological agents, explains why attempts to isolate and reconstruct the AR have proved fruitless, and gives grounds for rejecting the hypothesis that there exist steroid, prostaglandin, and purinergic receptors, linking the exceptionally high and diverse activity of these biologically active substances with their participation in adrenoreception among other reasons. A conception of the active centers of the AR as low-molecular-weight entities permits the explanation of such phenomena as the desensitization of the AR, the "interconversion" of beta-AR into alpha-AR with a change in the parameters of the medium, and certain components of the pathogenesis of bronchial asthma, etc.

Drug prescription patterns in patients with Addison's disease: a Swedish population-based cohort study.

PubMed

Björnsdottir, Sigridur; Sundström, Anders; Ludvigsson, Jonas F; Blomqvist, Paul; Kämpe, Olle; Bensing, Sophie

2013-05-01

There are no published data on drug prescription in patients with Addison's disease (AD). Our objective was to describe the drug prescription patterns in Swedish AD patients before and after diagnosis compared with population controls. We conducted a population-based cohort study in Sweden. Through the Swedish National Patient Register and the Swedish Prescribed Drug Register, we identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. Direct evidence of the AD diagnosis from patient charts was not available. We identified 11 996 matched controls by the Register of Population. We determined the ratio of observed to expected number of patients treated with prescribed drugs. Overall, Swedish AD patients received more prescribed drugs than controls, and 59.3% of the AD patients had medications indicating concomitant autoimmune disease. Interestingly, both before and after the diagnosis of AD, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives, and drugs for obstructive airway disease (all P values < .05). Notably, an increased prescription of several antihypertensive drugs and high-ceiling diuretics was observed after the diagnosis of AD. Gastrointestinal symptoms and anemia, especially in conjunction with autoimmune disorders, should alert the physician about the possibility of AD. The higher use of drugs for cardiovascular disorders after diagnosis in patients with AD raises concerns about the replacement therapy.

Altered cerebral glucose metabolism normalized in a patient with a pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS)-like condition following treatment with plasmapheresis: a case report.

PubMed

Nave, A H; Harmel, P; Buchert, R; Harms, L

2018-05-02

Pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS) is a specific autoimmune response to group-A streptococcal infections in children and adolescents with a sudden onset of obsessive-compulsive disorders or tic-like symptoms. Cerebral metabolic changes of patients have not yet been observed. We present a case of an 18-year old male with a PANDAS-like condition after developing tic-like symptoms and involuntary movements three weeks after cardiac surgery. The patient had suffered from pharyngotonsillitis before the symptoms started. The anti-streptolysin O (ASO) titer was elevated (805 kU/l). Antibiotic therapy did not improve his condition. Intravenous immunoglobulins and high-dose cortisone therapy had minor beneficial effects on his involuntary movements. 18F-Fluorodeoxyglucose positron emission tomography/ computer tomography (18F-FDG PET/CT) demonstrated pronounced hypermetabolism of the basal ganglia and cortical hypometabolism. The patient was treated with five cycles of plasmapheresis. A marked clinical improvement was observed after four months. Cerebral metabolic alterations had completely normalized. This is the first report of cerebral metabolic changes observed on FDG-PET/CT in a patient with a PANDAS-like condition with a normalization following immunomodulatory treatment. Cerebral FDG-PET/CT might be a promising tool in the diagnosis of PANDAS.

Pancreatitis, panniculitis and polyarthritis (PPP-) syndrome caused by post-pancreatitis pseudocyst with mesenteric fistula. Diagnosis and successful surgical treatment. Case report and review of literature.

PubMed

Dieker, Wulf; Derer, Johannes; Henzler, Thomas; Schneider, Alexander; Rückert, Felix; Wilhelm, Torsten J; Krüger, Bernd

2017-01-01

Pancreatitis, panniculitis and polyarthritis syndrome is a very rare extra-pancreatic complication of pancreatic diseases. While in most cases this syndrome is caused by acute or chronic pancreatitis, we report a case of a 62-year-old man presenting with extensive intraosseous fat necrosis, polyarthritis and panniculitis caused by a post-pancreatitis pseudocyst with a fistula to the superior mesenteric vein and extremely high blood levels of lipase. This became symptomatic 2.5 years after an episode of acute pancreatitis and as in most cases abdominal symptoms were absent. Treatment by surgical resection of the pancreatic head with the pseudocyst and mesenteric fistula led to complete remission of all symptoms. A review of the literature revealed that all publications are limited to case reports. Most authors hypothesize that an unspecific damage can cause a secretion of pancreatic enzymes to the bloodstream leading to a systemic lipolysis and fat tissue necrosis, especially of subcutaneous tissue, bone marrow, inducing panniculitis, polyarthritis and osteonecrosis. Even if caused by an acute pancreatitis abdominal symptoms are often mild or absent in most cases leading to misdiagnosis and poor prognosis. While symptomatic treatment with NSAR and cortisone showed poor to moderate response, causal treatment can be successful depending on the underlying pancreatic disease. Copyright © 2017. Published by Elsevier Ltd.

Metabolomics Reveals Target and Off-Target Toxicities of a Model Organophosphate Pesticide to Roach (Rutilus rutilus): Implications for Biomonitoring

PubMed Central

2011-01-01

The ability of targeted and nontargeted metabolomics to discover chronic ecotoxicological effects is largely unexplored. Fenitrothion, an organophosphate pesticide, is categorized as a “red list” pollutant, being particularly hazardous to aquatic life. It acts primarily as a cholinesterase inhibitor, but evidence suggests it can also act as an androgen receptor antagonist. Whole-organism fenitrothion-induced toxicity is well-established, but information regarding target and off-target molecular toxicities is limited. Here we study the molecular responses of male roach (Rutilus rutilus) exposed to fenitrothion, including environmentally realistic concentrations, for 28 days. Acetylcholine was assessed in brain; steroid metabolism was measured in testes and plasma; and NMR and mass spectrometry-based metabolomics were conducted on testes and liver to discover off-target toxicity. O-demethylation was confirmed as a major route of pesticide degradation. Fenitrothion significantly depleted acetylcholine, confirming its primary mode of action, and 11-ketotestosterone in plasma and cortisone in testes, showing disruption of steroid metabolism. Metabolomics revealed significant perturbations to the hepatic phosphagen system and previously undocumented effects on phenylalanine metabolism in liver and testes. On the basis of several unexpected molecular responses that were opposite to the anticipated acute toxicity, we propose that chronic pesticide exposure induces an adapting phenotype in roach, which may have considerable implications for interpreting molecular biomarker responses in field-sampled fish. PMID:21410251

TREATMENT OF RADIOGENIC RECTITIS BY PREDNISOLONE (in Portuguese)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Catita, A.C.

1961-09-01

Observations are reported in 10 patients irradiated for carcinoma oE the uterine corpus or cervix. Radiogenic rectitis is a frequent sequel of radiation- treated carcinoma of the uterus, due to the extreme radiosensitivity of the rectal mucosa. It is known that vaginal mucosa is able to sustain 30,000 r without alteration, but rectal mucosa can tolerate only 6000 r. The 10 uterine cervix carcinoma patients were pretreated with a total of l90 mg each of prednisolone over a period of 11 days, and 5 also received and rectoscopic observations were made on the 1st, 7th, 14th, and 30th day aftermore » termination of irradiation. Results showed that cortisone derivatives are the best therapeutic aids for this pathologic condition, both as curative and prophylactic agents. As compared with an equal number of controls, in the treated cases prednisolone reduced the frequency of rectitis by 75% as recorded in the initial observation periods and in the later observation periods to 50%. Due to the increase in rectitis, it was concluded that prednisolone administration should have taken place over a longer period than the 11 days used here. The use of prednisolone as a prophylactic rather than a curative agent is recommended to prevent the occurrence of infectious processes developing due to reduced resistance of the damaged tissues to the bacteria indigenous to the rectum. (TCO)« less

Preliminary data on Pemphigus vulgaris treatment by a proteomics-defined peptide: a case report

PubMed Central

Angelini, Giovanni; Bonamonte, Domenico; Lucchese, Alberta; Favia, Gianfranco; Serpico, Rosario; Mittelman, Abraham; Simone, Simone; Sinha, Animesh A; Kanduc, Darja

2006-01-01

Background Although described by Hippocrates in 400 B.C., pemphigus disease still needs a safe therapeutical approach, given that the currently used therapies (i.e. corticosteroids and immunosuppressive drugs) often provoke collateral effects. Here we present preliminary data on the possible use of a proteomics derived desmoglein peptide which appears promising in halting disease progression without adverse effects. Methods The low-similarity Dsg349–60REWVKFAKPCRE peptide was topically applied for 1 wk onto a lesion in a patient with a late-stage Pemphigus vulgaris (PV) complicated by diabetes and cataract disease. The peptide was applied as an adjuvant in combination with the standard corticosteroid-based immunosuppressive treatment. Results After 1 wk, the treated PV eroded lesion appeared dimensionally reduced and with an increased rate of re-epithelization when compared to adjacent non-treated lesions. Short-term benefits were: decrease of anti-Dsg antibody titer and reduction of the corticosteroid dosage. Long-term benefits: after two years following the unique 1-wk topical treatment, the decrease of anti-Dsg antibody titer persists. The patient is still at the low cortisone dosage. Adverse effects: no adverse effect could be monitored. Conclusion With the limits inherent to any preliminary study, this case report indicates that topical treatment with Dsg349–60REWVKFAKPCRE peptide may represent a feasible first step in the search for a simple, effective and safe treatment of PV. PMID:17062151

Symmetry adapted cluster-configuration interaction calculation of the photoelectron spectra of famous biological active steroids

NASA Astrophysics Data System (ADS)

Abyar, Fatemeh; Farrokhpour, Hossein

2014-11-01

The photoelectron spectra of some famous steroids, important in biology, were calculated in the gas phase. The selected steroids were 5α-androstane-3,11,17-trione, 4-androstane-3,11,17-trione, cortisol, cortisone, corticosterone, dexamethasone, estradiol and cholesterol. The calculations were performed employing symmetry-adapted cluster/configuration interaction (SAC-CI) method using the 6-311++G(2df,pd) basis set. The population ratios of conformers of each steroid were calculated and used for simulating the photoelectron spectrum of steroid. It was found that more than one conformer contribute to the photoelectron spectra of some steroids. To confirm the calculated photoelectron spectra, they compared with their corresponding experimental spectra. There were no experimental gas phase Hesbnd I photoelectron spectra for some of the steroids of this work in the literature and their calculated spectra can show a part of intrinsic characteristics of this molecules in the gas phase. The canonical molecular orbitals involved in the ionization of each steroid were calculated at the HF/6-311++g(d,p) level of theory. The spectral bands of each steroid were assigned by natural bonding orbital (NBO) calculations. Knowing the electronic structures of steroids helps us to understand their biological activities and find which sites of steroid become active when a modification is performing under a biological pathway.

In vitro and in vivo antimicrobial activities of seeds of Caesalpinia bonduc (Lin.) Roxb.

PubMed

Arif, Tasleem; Mandal, T K; Kumar, Naresh; Bhosale, J D; Hole, Archana; Sharma, G L; Padhi, M M; Lavekar, G S; Dabur, Rajesh

2009-05-04

Caesalpinia bonduc (Lin.) Roxb. is a known drug in Ayurveda to treat various diseases specifically tumors, cysts and cystic fibrosis (CF). The aim of this study was to assess in vitro as well as in vivo antimicrobial activity of Caesalpinia bonduc seeds. The in vitro antimicrobial activities of seed coat and seed kernel extracts were investigated by microbroth dilution assay. In vivo activities of hydro-alcoholic extracts were investigated in rat models of chronic Pseudomonas aeruginosa pneumonia mimicking that in patients with cystic fibrosis. Various extracts of plant seeds exhibited in vitro antimicrobial activities in a range of 22-350 microg/ml. The extracts also showed activity against methicillin resistant (MR) Staphylococcus aureus and ampicillin resistant (AR) Pseudomonas aeruginosa as in the sensitive strains. In rat model of chronic Pseudomonas aeruginosa pneumonia, hydro-alcoholic extracts of Caesalpinia bonduc seed kernel (CBSK) and Caesalpinia bonduc seed coat (CBSC) were injected subcutaneously in the test groups of animals. The control groups were treated with cortisone and saline. Two weeks after challenge with Pseudomonas aeruginosa, the CBSK treated animals showed a significant bacterial clearance from the lungs (P<0.04) and less severe incidence of lung abscess (P<0.05). Results showed that Caesalpinia bonduc may have the potential to be promising natural medicine, with other forms of treatments, for CF patients with chronic Pseudomonas aeruginosa lung infections.

Diagnosis and Management of Distal Clavicle Osteolysis.

PubMed

DeFroda, Steven F; Nacca, Christopher; Waryasz, Gregory R; Owens, Brett D

2017-03-01

Distal clavicle osteolysis is an uncommon condition that most commonly affects weight lifters and other athletes who perform repetitive overhead activity. Although this condition most commonly presents in young active men, it is becoming increasing more common in women with the rise in popularity of body building and extreme athletics. Distal clavicle osteolysis can be debilitating, especially in those with rigorous training regimens, preventing exercise because of pain with activities such as bench presses and chest flies. Aside from a careful history and physical examination, radiographic evaluation is essential in distinguishing isolated distal clavicle osteolysis from acromioclavicular joint pathology, despite a potentially similar presentation of the 2 conditions. Nonoperative therapy that includes activity modification, nonsteroidal anti-inflammatory drugs, and cortisone injections is the first-line management for this condition. Patients whose conditions are refractory to nonoperative modalities may benefit from distal clavicle resection via either open or arthroscopic techniques. Arthroscopic techniques typically are favored because of improved cosmesis and the added benefit of the ability to assess the glenohumeral joint during surgery to rule out concomitant pathology. There are varying operative techniques even within arthroscopic management, with pros and cons of a direct and an indirect surgical approach. Patients often do well after such procedures and are able to return to their preinjury level of participation in a relatively short period. [Orthopedics. 2017; 40(2):119-124.]. Copyright 2016, SLACK Incorporated.

Disseminated hyperkeratotic and granulomatous nodules in a child with fatal Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis.

PubMed

Brinkmeier, Thomas; Reuter, Thomas; Metze, Dieter; Frosch, Peter J; Herbst, Rudolf A

2006-01-01

Hemophagocytic lymphohistiocytosis is a rare and potentially fatal syndrome associated with a variety of genetic, malignant, autoimmune, or infectious conditions. The importance of cutaneous presentations of this syndrome has only recently been brought forward. We report the first case of Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis presenting with papulonodular and granulomatous skin lesions. A girl of African origin developed several umbilicated papules on her extremities and face at the age of 18 months. She was born in Germany, had never visited Africa, and was otherwise healthy. Over the next 5 months the lesions progressed in size and number and became hyperkeratotic. Histopathologic analysis of early lesions revealed a superficial lympho- and plasmacellular dermatitis with some features of panniculitis. Later biopsy specimens from nodular lesions showed the formation of tuberculoid granulomas in the deep dermis. At the age of 23 months she became severely ill, rapidly developing high fever, hepatosplenomegaly, icterus, pancytopenia, and ascites. On the basis of bone marrow and lymph node biopsies, the diagnosis of hemophagocytic lymphohistiocytosis was established. However, this phenomenon could not be detected in any of the skin specimens. An active Epstein-Barr virus infection was diagnosed by polymerase chain reaction in blood, lymphoid tissue, and skin. Despite chemotherapy with etoposide and cortisone, the girl expired 14 days after clinical onset of her systemic disease.

The early history of giant cell arteritis and polymyalgia rheumatica: first descriptions to 1970.

PubMed

Hunder, Gene G

2006-08-01

Giant cell arteritis and polymyalgia rheumatica were described separately more than 100 years ago. However, the original reports of both conditions were neglected for many years. After the article by Horton et al on giant cell arteritis in the 1930s and studies published by others in the 1940s, giant cell arteritis began to be recognized as a specific disease. In the 1950s and 1960s, many of the numerous presentations and complications of giant cell arteritis were recorded. In a somewhat similar fashion, physicians became cognizant of polymyalgia rheumatica only after several independent descriptions in the 1940s and 1950s. The rapid response of both syndromes to glucocorticoid therapy was discovered shortly after cortisone's effect on rheumatoid arthritis was described. The origin of the proximal aching and stiffness in polymyalgia rheumatica was more difficult to understand. The relatively minor findings in the joints on physical examination seemed insufficient to account for the severe discomfort. As the link between polymyalgia rheumatica and giant cell arteritis became apparent, some thought the aching in polymyalgia rheumatica was related to vasculitis. The debate about whether proximal synovitis or vasculitis was the cause of the symptoms continued after 1970. Although the reason these 2 conditions were associated was not considered by 1970, the establishment of the syndromes as clinically linked entities provided the groundwork for further progress in the next decades.

Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates.

PubMed

Tsilchorozidou, Tasoula; Honour, John W; Conway, Gerard S

2003-12-01

Androgen excess in women with polycystic ovary syndrome (PCOS) may be ovarian and/or adrenal in origin, and one proposed contributing mechanism is altered cortisol metabolism. Increased peripheral metabolism of cortisol may occur by enhanced inactivation of cortisol by 5alpha-reductase (5alpha-R) or impaired reactivation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) resulting in decreased negative feedback suppression of ACTH secretion maintaining normal plasma cortisol concentrations at the expense of androgen excess. We have tested whether any enzyme dysregulation was related to circulating insulin or androgen concentrations in women with PCOS and have sought to clarify their relationship with obesity. First, to avoid obesity-related effects on cortisol metabolism, 18 lean women with PCOS were compared with 19 lean controls who were closely matched for body mass index (BMI). Second, the impact of obesity was studied in a cross-section of 42 PCOS women of a broad range of BMI. We measured 24-h urinary excretion of steroid metabolites by gas chromatography/mass spectrometry and fasting metabolic and hormone profiles. Urinary excretion of androgens [androsterone (P = 0.003), etiocholanolone (P = 0.02), and C19 steroid sulfates (P = 0.009)], cortisone metabolites [tetrahydrocortisone (THE) (P = 0.02), alpha-cortolone (P < 0.001), beta-cortol + beta-cortolone (P < 0.001), cortolones (P < 0.001), and E metabolites (P < 0.001)], and TCM (P = 0.002) were raised in lean PCOS subjects when compared with controls. A significantly higher 5alpha-tetrahydrocortisol (5alpha-THF)/5beta-THF ratio (P = 0.04) and a significantly lower alpha-THF + THF + alpha-cortol/THE + cortolones ratio (P = 0.01) were found in lean PCOS women compared with lean controls, indicating both enhanced 5alpha-R and reduced 11beta-HSD1 activities. A decreased THE/cortolones ratio (P = 0.03) was also found in lean PCOS women compared with lean controls, indicating increased 20 alpha/beta-HSD activity. In the group of 42 PCOS subjects, measures of 5alpha/5beta reduction were positively correlated with the homeostasis model insulin resistance index (HOMA-R): alpha-THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5alpha /total 5beta and HOMA-R (r = 0.37; P = 0.02). A positive correlation was also found between measures of 5alpha-R and BMI (r = 0.37; P = 0.02). No correlation was found between measures of 11beta-HSD1 activity and indices of insulin sensitivity or BMI. We have demonstrated that there is an increased production rate of cortisol and androgens as measured in vivo in lean PCOS women. Insulin seems to enhance 5alpha reduction of steroids in PCOS but was not associated with the elevated cortisol production rate. The changes in 5alpha-R, 11beta-HSD1, and 20alpha/beta-HSD enzyme activities observed in PCOS may contribute to the increased production rates of cortisol and androgens, supporting the concept of a widespread dysregulation of steroid metabolism. This dysregulation does not seem to be the primary cause of PCOS because no correlation was found between serum androgen levels or urinary excretion of androgens with measurements of either 5alpha-R or 11beta-HSD1 activities.

Stability of an Alcohol-free, Dye-free Hydrocortisone (2 mg/mL) Compounded Oral Suspension.

PubMed

Manchanda, Arushi; Laracy, Melissa; Savji, Taslim; Bogner, Robin H

2018-01-01

The stability of hydrocortisone in a commercially available dye-free oral vehicle was monitored to establish a beyond-use date for hydrocortisone oral suspension 2 mg/mL. Hydrocortisone oral suspension (2 mg/mL) was prepared from 10-mg tablets in a dye-free oral vehicle (Oral Mix, Medisca) and stored at 4°C and 25°C for 90 days in amber, plastic prescription bottles and oral syringes. The suspendability and dose repeatability of the oral suspension were evaluated. The solubility of hydrocortisone in the dye-free vehicle was determined. Over 90 days, pH and concentration of hydrocortisone in the oral suspension were measured. The stability-indicating nature of a high-pressure liquid chromatographic assay was evaluated in detail. The solubility of hydrocortisone in the dye-free vehicle was 230 mcg/mL at 25°C. This means that about 90% of the drug remains in the solid state where it is less susceptible to degradation. The preparation suspended well to support dose repeatability. The chromatographic assay resolved hydrocortisone from cortisone, excipients in the vehicle, and all degradation products. The assay passed United States Pharmacopeia system suitability tests. Hydrocortisone oral suspension (2 mg/mL) compounded using a dye-free, alcohol-free oral vehicle, Oral Mix, was stable in amber plastic bottles and syringes stored at 4°C and 25°C for 90 days within a 95% confidence interval. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Pregnane Glycosides Interfere With Steroidogenic Enzymes to Down-Regulate Corticosteroid Production in Human Adrenocortical H295R Cells

PubMed Central

KOMARNYTSKY, SLAVKO; ESPOSITO, DEBORA; POULEV, ALEXANDER; RASKIN, ILYA

2013-01-01

A group of bioactive steroidal glycosides (pregnanes) with anorectic activity in animals was isolated from several genera of milkweeds including Hoodia and Asclepias. In this study, we investigated the effects, structure-activity relationships, and mechanism of action of pregnane glycosides on steroidogenesis in human adrenocortical H295R cells. Administration of pregnane glycosides for 24 h suppressed the basal and forskolin-stimulated release of androstenedione, corticosterone, and cortisone from H295R cells. The conversion of progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone to either androstenedione or 11-deoxycortisol was most strongly affected, with 12-cinnamoyl-, benzoyl-, and tigloyl-containing pregnanes showing the highest activity. Incubation of pregnane glycosides for 24 h had no effect on mRNA transcripts of CYP11A1, CYP21A1, CYP11B1 cytochrome enzymes and steroidogenic acute regulatory protein (StaR) protein, yet resulted in twofold decrease in HSD3B1 mRNA levels. At the same time, pregnane glycosides had no effect on the CYP1, 2, or 3 drug and steroid metabolism enzymes and showed weak Na+/K+ ATPase and glucocorticoid receptor binding. Taken together, these data suggest that pregnane glycosides specifically suppress steroidogenesis through strong inhibition of 11β-hydroxylase and steroid 17-alpha-monooxygenase, and weak inhibition of cytochrome P450 side chain cleavage enzyme and 21β-hydroxylase, but not 3β-hydroxysteroid dehydrogenase/isomerase. PMID:23065845

Assessment of glucocorticoid therapy with salivary cortisol in secondary adrenal insufficiency.

PubMed

Ceccato, Filippo; Albiger, Nora; Reimondo, Giuseppe; Frigo, Anna Chiara; Ferasin, Sergio; Occhi, Gianluca; Mantero, Franco; Terzolo, Massimo; Scaroni, Carla

2012-12-01

Appropriate glucocorticoid replacement therapy in adrenal insufficiency (AI) is crucial, given the risks of chronic under- or overtreatment, particularly in patients on multiple medications. Salivary sampling allows for non-invasive, stress-free cortisol measurement. To determine whether salivary cortisol measurement is helpful in assessing the adequacy of glucocorticoid therapy with cortisone acetate (CA) in patients with secondary AI. A prospective cohort study at the Endocrinology Unit of Padua University Hospital. Six samples of salivary cortisol were collected from 28 patients with secondary AI on CA treatment and from 36 healthy volunteers at fixed times of the day, and used to calculate salivary cortisol levels at each time point and the area under the curve (AUC) across the different sampling times. Salivary cortisol levels were lower in patients than in controls in the morning but no differences were found in the afternoon or at night before resting. Salivary cortisol levels were higher in patients immediately following CA administration. Ten patients showed an AUC above the 97.5th percentile of controls, without clinical signs of hypercortisolism, and salivary cortisol levels 90 min after each dose of CA predict the AUC. All patients had severe GH deficiency and there were no differences in salivary cortisol levels or AUC between patients treated or not with GH. Two salivary cortisol determinations, able to predict the daily AUC, may allow for assessing the adequacy of glucocorticoid replacement therapy in secondary AI and for identifying cases of over- or undertreatment.

Decreased physical activity, reduced QoL and presence of debilitating fatigue in patients with Addison's disease.

PubMed

van der Valk, Eline S; Smans, Lisanne C C J; Hofstetter, Hedwig; Stubbe, Janine H; de Vries, Marieke; Backx, Frank J G; Hermus, Ad R M M; Zelissen, Pierre M J

2016-09-01

Health-related quality of life in patients with Addison's disease has been assessed in various European countries, indicating a reduced quality of life. However, no studies have addressed the impact of Addison's disease on physical activity. The aim of this study was to investigate the quality of life in Dutch patients with Addison's disease particularly regarding the presence of fatigue and the ability to be physically active. In this cross-sectional study, a postal survey was performed among Dutch patients with Addison's disease on stable glucocorticoid replacement therapy with hydrocortisone or cortisone acetate. For quality of life and physical activity assessment, patients completed general and health-related quality of life and physical activity questionnaires, and scores were compared to Dutch controls. A total of 328 patients with Addison's disease were studied. In patients with Addison's disease, only 45·7% met the standard of physical activity (Combinorm) compared to 67·8% of Dutch controls (P < 0·01). Forty-eight per cent of patients showed abnormal fatigue, while 61% had severe fatigue. The CIS fatigue scores were significantly higher compared to controls (P < 0·01). We found reduced general subjective health-related QoL scores in both male and female patients, especially in younger patients <65 years of age. Physical activity is decreased in patients with Addison's disease, combined with a reduced subjective health-related QoL and increased fatigue. © 2016 John Wiley & Sons Ltd.

Symposium: evidence for the use of intra-articular cortisone or hyaluronic acid injection in the hip

PubMed Central

Chandrasekaran, Sivashankar; Lodhia, Parth; Suarez-Ahedo, Carlos; Vemula, S. Pavan; Martin, Timothy J.; Domb, Benjamin G.

2016-01-01

The primary purpose of this review article is to discuss the role of diagnostic, corticosteroid, hyaluronic acid (HA) and platelet rich plasma (PRP) in the treatment of osteoarthritis (OA) and femoroacetabular impingement (FIA). These treatments play an important biological role in the non-operative management of these conditions. Two independent reviewers performed an search of PubMed for articles that contained at least one of the following search terms pertaining to intra-articular hip injection—local anaesthetic, diagnostic, ultrasound, fluoroscopic, image guided, corticosteroid, HA, PRP, OA, labral tears and FAI. Seventy-two full text articles were suitable for inclusion. There were 18 articles addressing the efficacy of diagnostic intra-articular hip injections. With respect to efficacy in OA there were 25 articles pertaining to efficacy of corticosteroid, 22 of HA and 4 of PRP. There were three articles addressing the efficacy of biologics in FAI. Diagnostic intra-articular hip injections are sensitive and specific for differentiating between intra-articular, extra-articular and spinal causes of hip symptoms. Ultrasound and fluoroscopy improves the precision of intra-articular positioning of diagnostic injections. Corticosteroids are more effective than HA and PRP in alleviating pain from hip OA. A higher dose of corticosteroids produces a longer benefit but volume of injection has no significant effect. Intra-articular corticosteroids do not increase infection rates of subsequent arthroplasty. There is currently limited evidence to warrant the routine use of therapeutic injections in the management of labral tears and FIA. PMID:27026814

Pistacia lentiscus Oleoresin: Virtual Screening and Identification of Masticadienonic and Isomasticadienonic Acids as Inhibitors of 11β-Hydroxysteroid Dehydrogenase 1.

PubMed

Vuorinen, Anna; Seibert, Julia; Papageorgiou, Vassilios P; Rollinger, Judith M; Odermatt, Alex; Schuster, Daniela; Assimopoulou, Andreana N

2015-04-01

In traditional medicine, the oleoresinous gum of Pistacia lentiscus var. chia, so-called mastic gum, has been used to treat multiple conditions such as coughs, sore throats, eczema, dyslipidemia, and diabetes. Mastic gum is rich in triterpenes, which have been postulated to exert antidiabetic effects and improve lipid metabolism. In fact, there is evidence of oleanonic acid, a constituent of mastic gum, acting as a peroxisome proliferator-activated receptor γ agonist, and mastic gum being antidiabetic in mice in vivo. Despite these findings, the exact antidiabetic mechanism of mastic gum remains unknown. Glucocorticoids play a key role in regulating glucose and fatty acid metabolism, and inhibition of 11β-hydroxysteroid dehydrogenase 1 that converts inactive cortisone to active cortisol has been proposed as a promising approach to combat metabolic disturbances including diabetes. In this study, a pharmacophore-based virtual screening was applied to filter a natural product database for possible 11β-hydroxysteroid dehydrogenase 1 inhibitors. The hit list analysis was especially focused on the triterpenoids present in Pistacia species. Multiple triterpenoids, such as masticadienonic acid and isomasticadienonic acid, main constituents of mastic gum, were identified. Indeed, masticadienonic acid and isomasticadienonic acid selectively inhibited 11β-hydroxysteroid dehydrogenase 1 over 11β-hydroxysteroid dehydrogenase 2 at low micromolar concentrations. These findings suggest that inhibition of 11β-hydroxysteroid dehydrogenase 1 contributes to the antidiabetic activity of mastic gum. Georg Thieme Verlag KG Stuttgart · New York.

11β-hydroxysteroid dehydrogenase type 1 and pregnancy: Role in the timing of labour onset and in myometrial contraction.

PubMed

Damiani, Francesco; Makieva, Sofia; Rinaldi, Sara F; Hua, Lei; Marcolongo, Paola; Petraglia, Felice; Norman, Jane E

2017-05-15

Glucocorticoids play a primary role in the maturation of fetal organs and may contribute to the onset of labour. Glucocorticoid activity depends on the 11β-hydroxysteroid dehydrogenase family (11β-HSDs), catalysing the interconversion between "active" cortisol into inactive cortisone. No definitive study exists on 11β-HSD expression profile in human decidua and myometrium during pregnancy. We investigated the implications of 11β-HSD1 in the regulation of uterine activity in pregnancy, examining its role on contraction of a myocyte cell line and murine 11β-hsd1 levels in utero. Murine 11β-hsd1 mRNA and protein levels in utero progressively increased until the last day of gestation and significantly decreased at the onset of labour (P < 0.0001) (n = 3 to 5 in the various gestational days analysed). Experiments on human myometrial samples confirm the significant fall in 11β-hsd1 mRNA levels at labour, compared to end pregnancy samples (n = 5 to 8). In vitro experiments showed that human myometrial contraction is inhibited by using a non-selective inhibitor of 11β-HSD1. The present study shows the temporal localisation of 11β-HSD1 in uterus, highlighting its importance in the timing of gestation and suggesting its contribution in the myometrium contraction. Copyright © 2017 Elsevier B.V. All rights reserved.

Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing.

PubMed

Correa, Fernanda A; França, Marcela M; Fang, Qing; Ma, Qianyi; Bachega, Tania A; Rodrigues, Andresa; Ozel, Bilge A; Li, Jun Z; Mendonca, Berenice B; Jorge, Alexander A L; Carvalho, Luciani R; Camper, Sally A; Arnhold, Ivo J P

2017-12-01

Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS -3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene.

Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis

PubMed Central

Alcina, Antonio; Ramagopalan, Sreeram V; Fernández, Óscar; Catalá-Rabasa, Antonio; Fedetz, María; Ndagire, Dorothy; Leyva, Laura; Arnal, Carmen; Delgado, Concepción; Lucas, Miguel; Izquierdo, Guillermo; Ebers, George C; Matesanz, Fuencisla

2010-01-01

A recent genome-wide association study (GWAS) performed by the The Wellcome Trust Case–Control Consortium based on 12 374 nonsynonymous single-nucleotide polymorphisms (SNPs) provided evidence for several genes involved in multiple sclerosis (MS) susceptibility. In this study, we aimed at verifying the association of 19 SNPs with MS, with P-values ≤0.005, in an independent cohort of 732 patients and 974 controls, all Caucasian from the South of Spain. We observed an association of the rs17368528 polymorphism with MS (P=0.04, odds ratio (OR)=0.801, 95% confidence interval (CI)=0.648–0.990). The association of this polymorphism with MS was further validated in an independent set of 1318 patients from the Canadian Collaborative Project (P=0.04, OR=0.838, 95% CI=0.716–0.964). This marker is located on chromosome 1p36.22, which is 1 Mb away from the MS-associated kinesin motor protein KIF1B, although linkage disequilibrium was not observed between these two markers. The rs17368528 SNP results in an amino-acid substitution (proline to leucine) in the fifth exon of the hexose-6-phosphate dehydrogenase (H6PD) gene, in which some variants have been reported to attenuate or abolish H6PD activity, in individuals with cortisone reductase deficiency. This study corroborates the association of one locus determined by GWAS and points to H6PD as a new candidate gene for MS. PMID:19935835

THE INFLUENCE OF HYDROCORTISONE ON THE ACTION OF EXCESS VITAMIN A ON LIMB BONE RUDIMENTS IN CULTURE

PubMed Central

Fell, Honor B.; Thomas, Lewis

1961-01-01

The effect of hydrocortisone has been studied in organ cultures of the cartilaginous long bone rudiments from 7-day chick embryos and of the well ossified limb bones from late fetal mice. In the chick rudiments, which grow rapidly in culture, the growth rate was much reduced by hydrocortisone, less intercellular material was formed, and the hypertrophic cells of the shaft were much smaller than in the controls in normal medium. In the late fetal mouse bones, which grow very little in culture, hydrocortisone had no obvious effect on growth but arrested resorption of the cartilage. These effects resemble those described by others in the skeleton of animals treated with cortisone or hydrocortisone. The influence of hydrocortisone on the response of the chick and mouse explants to excess vitamin A was investigated. In the presence of excess vitamin A, cartilage (chick, mouse) and bone (mouse) rapidly disintegrated, but when hydrocortisone also was added to the medium, this dissolution of the intercellular material was much retarded, though not suppressed. The retardative action of hydrocortisone on the changes produced by excess vitamin A in skeletal tissue in culture, contrasts sharply with the strongly additive effect of the two agents on the skeleton in the intact animal (Selye, 1958). It is suggested that this discrepancy between the results obtained in vitro and in vivo is probably due to systemic factors that operate in the body but are eliminated in organ cultures. PMID:13698768

Differential protective effects of immune lymphoid cells against transplanted line Ib leukemia and immune polioencephalomyelitis. [X radiation, mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duffey, P.S.; Lukasewycz, O.A.; Olson, D.S.

1978-12-01

The capacity of immune cells obtained from the major lymphoid compartments to protect C58 mice from transplanted line Ib leukemia, and from an age-dependent autoimmune CNS disease (immune polioencephalomyelitis = IPE) elicited by immunizing old C58 mice with inactivated Ib cells was quantified. Cells used for comparative adoptive protection tests were harvested from the major lymphoid compartments 14 to 15 days after young C58 mice were immunized with inactivated Ib cell preparations. Regression curves were plotted from survival data and the log/sub 10/PD/sub 50/ values were determined. Immune spleen (ISC) and peritoneal cells (IPEC) were significantly more protective against transplantedmore » Ib cells than immune lymph node (ILNC), thymic (ITC), and marrow cells (IMC). In contrast, IPEC and IMC were not protective against IPE and ITC were only marginally protective. ILNC afforded significant protection to transplantable leukemia but were only marginally protective to IPE. When ISC were treated with anti-thy 1.2 serum and complement, protection against transplanted leukemia and IPE was reduced > 99%. When donors of immune lymphoid cells were treated with 12.5 mg of cortisone acetate daily for 2 days before lymphoid cells were harvested, protection against transplanted Ib cells by ISC was reduced by approximately 90% whereas protection against IPE was totally eliminated. Considered together, these results indicate that the protective mechanisms to transplantable leukemia and IPE differ significantly in the same indicator mouse strain.« less

Simultaneous Determination of Seven Neuroactive Steroids Associated with Depression in Rat Plasma and Brain by High Performance Liquid Chromatography-Tandem Mass Spectrometry.

PubMed

Wang, Youqiong; Tang, Lipeng; Yin, Wei; Chen, Jiesi; Leng, Tiandong; Zheng, Xiaoke; Zhu, Wenbo; Zhang, Haipeng; Qiu, Pengxin; Yang, Xiaoxiao; Yan, Guangmei; Hu, Haiyan

2016-01-01

Sensitive and specific biomarkers are required for the diagnosis and treatment of depression because the existing diagnostic criteria are subjective and could produce false positives or negatives. Some endogenous neuroactive steroids that have shown either antidepressant effects or concentration changes in individuals with depression could provide potential biomarkers. In this study, a simple and specific method was developed to simultaneously determine seven endogenous neuroactive steroids in biological samples: cortisone, cortisol, dehydroepiandrosterone, estradiol, progesterone, pregnenolone, and testosterone. After liquid-liquid extraction, chromatographic separation was achieved on a C18 column with gradient elution using water-methanol at a flow rate of 300 μL min(-1). Detection and quantitation were performed by tandem mass spectrometry with atmospheric pressure chemical ionization and selected reaction monitoring. Plasma and brain neuroactive steroid levels were then determined in control rats and rats exposed to forced swimming, a classical rodent model of depression. The results showed that the plasma concentrations of testosterone, pregnenolone, and progesterone significantly increased in rats exposed to the forced swimming test. In contrast, brain homogenate levels of cortisol, estradiol, and progesterone decreased, while pregnenolone levels were elevated in this model of depression. In conclusion, a new method to quantify neuroactive steroids was successfully developed and applied to their investigation in rat plasma and brain. The findings of this study indicated that plasma testosterone, pregnenolone, and progesterone levels could provide potential biomarkers for the diagnosis and treatment of depression.

Comparison of a homology model and the crystallographic structure of human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in a structure-based identification of inhibitors

NASA Astrophysics Data System (ADS)

Miguet, Laurence; Zhang, Ziding; Barbier, Maryse; Grigorov, Martin G.

2006-02-01

Human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes the interconversion of cortisone into active cortisol. 11βHSD1 inhibition is a tempting target for the treatment of a host of human disorders that might benefit from blockade of glucocorticoid action, such as obesity, metabolic syndrome, and diabetes type 2. Here, we report an in silico screening study aimed at identifying new selective inhibitors of human 11βHSD1 enzyme. In the first step, homology modeling was employed to build the 3D structure of 11βHSD1. Further, molecular docking was used to validate the predicted model by showing that it was able to discriminate between known 11βHSD1 inhibitors or substrates and non-inhibitors. The homology model was found to reproduce closely the crystal structure that became publicly available in the final stages of this work. Finally, we carried out structure-based virtual screening experiments on both the homology model and the crystallographic structure with a database of 114'000 natural molecules. Among these, 15 molecules were consistently selected as inhibitors based on both the model and crystal structures of the enzyme, implying a good quality for the homology model. Among these putative 11βHSD1 inhibitors, two were flavonone derivatives that have already been shown to be potent inhibitors of the enzyme.

Cortisol intermediates and hydrocortisone responsiveness in critical neonatal disease.

PubMed

Khashana, Abdelmoneim; Saarela, Timo; Ramet, Mika; Hallman, Mikko

2017-07-01

Therapy-resistant hypotension complicates diseases in neonates. Our objective was to investigate whether lack of therapeutic response to plasma expanders and inotropes associates with serum levels of cortisol and its precursors. We investigated 96 infants with hypotension and critical neonatal disease for cortisol metabolism and are divided into responders and non-responders to plasma expanders and inotropes. Serum concentrations of steroids were analysed soon after the onset of volume expansion and inotrope treatment for shock. The 48 non-responders were treated with intravenous hydrocortisone (HC) and serum cortisol concentrations were monitored a week later. The mean cortisol concentrations did not differ between the responders and non-responders: 13.6 ± 2.5 and 12.5 ± 4.5 μg/dL, respectively. Dehydroepiandrosterone (37.3 ± 19.5 versus 324.0 ± 106.3; p < 0.0001) and 17-hydroxy-pregnenolone concentrations were lower in responders than in non-responders. Dehydroepiandrosterone levels in non-responders were inversely associated with postnatal age (r = 0.50, p < 0.0001). There were no differences in 17-hydroxy-progesterone, 11-deoxy-cortisol and cortisone between the responders and non-responders. Hydrocortisone administration acutely increased blood pressure. Six non-responders who died despite HC administration had low levels of cortisol. The responders had normal serum cortisol after HC treatment. Precursors of cortisol, proximal to the 3β-hydroxysteroid dehydrogenase activity, accumulated in neonates with hypotension, responding to HC treatment.

Tracheomalacia associated with Mounier-Kuhn syndrome in the Intensive Care Unit: treatment with Freitag stent. A case report.

PubMed

Giannoni, S; Benassai, C; Allori, O; Valeri, E; Ferri, L; Dragotto, A

2004-09-01

Tracheomalacia is a process characterized by softness of the supporting tracheal cartilages, by the extension of the posterior membranous wall and by reduction of the tracheal antero-posterior diameter. Exceptionally, tracheomalacia can be associated with tracheobronchomegaly or Mounier-Kuhn syndrome. Fibro-bronchoscopy represents the ''gold standard'' for diagnosis. The case of a 79-year-old male observed after hospitalization in a medical ward for chronic pulmonary obstructive disease (COPD) decompensation, and with basal left bronchopulmonary focus, is described. During this period, a progressive worsening of clinical conditions occurred, despite cortisone and antibiotic therapy, and the patient was transferred to the ICU for dyspnea, hypoxia, hypocapnia and with a diagnosis of pulmonary fibrosis. Bronchoscopy, performed during spontaneous breathing, revealed tracheomalacia which was responsible for tracheal dynamic complete stenosis during expiration and dynamic subtotal stenosis of the left primary bronchus in the first tract, together with sputum retention. Moreover, this investigation confirmed the diagnosis of tracheobronchomegaly already seen on CT. It was suggested to place a Freitag stent, since the insertion of another model would not have had enough chance of stability, due to the enormous extension of the tracheal lumen and could not have guaranteed good clearance of the secretions. Seven days after this intervention, performed in an outpatients' setting, the patient was dismissed from the ICU, without the help of O2, with good ventilation, saturation in line with his age and good expectoration.

Apparent mineralocorticoid excess and the long term treatment of genetic hypertension.

PubMed

Razzaghy-Azar, Maryam; Yau, Mabel; Khattab, Ahmed; New, Maria I

2017-01-01

Apparent mineralocorticoid excess (AME) is a genetic disorder causing severe hypertension, hypokalemia, and hyporeninemic hypoaldosteronism owing to deficient 11 beta-hydroxysteroid dehydrogenase type-2 (11βHSD2) enzyme activity. The 11βHSD2 enzyme confers mineralocorticoid receptor specificity for aldosterone by converting cortisol to its inactive metabolite, cortisone and inactivating the cortisol-mineralocorticoid receptor complex. The 20year follow-up of a consanguineous Iranian family with three sibs affected with AME shows the successes and pitfalls of medical therapy with spironolactone. The three sibs, (female, male, female) were diagnosed at the ages of 14, 11, and 4 years, respectively. At diagnosis, hypertensive retinopathy and left ventricular hypertrophy were present in the eldest female and retinopathy was noted in the male sib. Spironolactone treatment resulted in decreased blood pressure and rise in serum potassium levels. The older female, age 36, developed reduced left ventricular function with mitral and tricuspid regurgitation and renal failure after her second pregnancy. She was treated with renal transplantation resulting in cure of AME with decreased blood pressure and weaning from antihypertensives. Her younger sibs, age 34 and 26, do not have end organ damage. Early and vigilant treatment improves morbidity in patients with AME. Mineralocorticoid receptor antagonists normalize blood pressure, correct hypokalemia and reduce hypertensive end-organ damage in patients with AME. Low dose dexamethasone can be considered, though the response may be variable. Future directions of therapy include selective mineralocorticoid antagonists. Copyright © 2016 Elsevier Ltd. All rights reserved.

Quantification of steroid hormones in human serum by liquid chromatography-high resolution tandem mass spectrometry.

PubMed

Matysik, Silke; Liebisch, Gerhard

2017-12-01

A limited specificity is inherent to immunoassays for steroid hormone analysis. To improve selectivity mass spectrometric analysis of steroid hormones by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been introduced in the clinical laboratory over the past years usually with low mass resolution triple-quadrupole instruments or more recently by high resolution mass spectrometry (HR-MS). Here we introduce liquid chromatography-high resolution tandem mass spectrometry (LC-MS/HR-MS) to further increase selectivity of steroid hormone quantification. Application of HR-MS demonstrates an enhanced selectivity compared to low mass resolution. Separation of isobaric interferences reduces background noise and avoids overestimation. Samples were prepared by automated liquid-liquid extraction with MTBE. The LC-MS/HR-MS method using a quadrupole-Orbitrap analyzer includes eight steroid hormones i.e. androstenedione, corticosterone, cortisol, cortisone, 11-deoxycortisol, 17-hydroxyprogesterone, progesterone, and testosterone. It has a run-time of 5.3min and was validated according to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidelines. For most of the analytes coefficient of variation were 10% or lower and LOQs were determined significantly below 1ng/ml. Full product ion spectra including accurate masses substantiate compound identification by matching their masses and ratios with authentic standards. In summary, quantification of steroid hormones by LC-MS/HR-MS is applicable for clinical diagnostics and holds also promise for highly selective quantification of other small molecules. Copyright © 2017 Elsevier B.V. All rights reserved.

Glucocorticoids reduce phobic fear in humans

PubMed Central

Soravia, Leila M.; Heinrichs, Markus; Aerni, Amanda; Maroni, Caroline; Schelling, Gustav; Ehlert, Ulrike; Roozendaal, Benno; de Quervain, Dominique J.-F.

2006-01-01

Phobias are characterized by excessive fear, cued by the presence or anticipation of a fearful situation. Whereas it is well established that glucocorticoids are released in fearful situations, it is not known whether these hormones, in turn, modulate perceived fear. As extensive evidence indicates that elevated glucocorticoid levels impair the retrieval of emotionally arousing information, they might also inhibit retrieval of fear memory associated with phobia and, thereby, reduce phobic fear. Here, we investigated whether acutely administrated glucocorticoids reduced phobic fear in two double-blind, placebo-controlled studies in 40 subjects with social phobia and 20 subjects with spider phobia. In the social phobia study, cortisone (25 mg) administered orally 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation, exposure, and recovery phase of the stressor. Moreover, the stress-induced release of cortisol in placebo-treated subjects correlated negatively with fear ratings, suggesting that endogenously released cortisol in the context of a phobic situation buffers fear symptoms. In the spider phobia study, repeated oral administration of cortisol (10 mg), but not placebo, 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again 2 days after the last cortisol administration, suggesting that cortisol may also have facilitated the extinction of phobic fear. Cortisol treatment did not reduce general, phobia-unrelated anxiety. In conclusion, the present findings in two distinct types of phobias indicate that glucocorticoid administration reduces phobic fear. PMID:16567641

Longitudinal analyses of the steroid metabolome in obese PCOS girls with weight loss.

PubMed

Reinehr, Thomas; Kulle, Alexandra; Rothermel, Juliane; Knop-Schmenn, Caroline; Lass, Nina; Bosse, Christina; Holterhus, Paul-Martin

2017-05-01

The underlying mechanisms of polycystic ovarian syndrome (PCOS) are not fully understood yet. The aim of the study was to get functional insights into the regulation of steroid hormones in PCOS by steroid metabolomics. This is a longitudinal study of changes of steroid hormones in 40 obese girls aged 13-16 years (50% with PCOS) participating in a 1-year lifestyle intervention. Girls with and without PCOS were matched to age, BMI and change of weight status. We measured progesterone, 17-hydroxyprogesterone, 17-hydroxyprogenolon, 11-deoxycorticosterone, 21-deoxycorticosterone, deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol, cortisone, androstenedione, testosterone, dehydroepiandrostendione-sulfate (DHEA-S), estrone and estradiol by LC-MS/MS steroid profiling at baseline and one year later. At baseline, obese PCOS girls demonstrated significantly higher androstenedione and testosterone concentrations compared to obese girls without PCOS, whereas the other steroid hormones including glucocorticoids, mineralocorticoids, estrogens and precursors of androgens did not differ significantly. Weight loss in obese PCOS girls was associated with a significant decrease of testosterone, androstenedione, DHEA-S, cortisol and corticosterone concentrations. Weight loss in obese non-PCOS girls was associated with a significant decrease of DHEA-S, cortisol and corticosterone concentrations, whereas no significant changes of testosterone and androstenedione concentrations could be observed. Without weight loss, no significant changes of steroid hormones were measured except an increase of estradiol in obese PCOS girls without weight loss. The key steroid hormones in obese adolescents with PCOS are androstenedione and testosterone, whereas glucocorticoids, mineralocorticoids, estrogens and precursors of androgens did not differ between obese girls with and without PCOS. © 2017 The authors.

Plasma Nervonic Acid Is a Potential Biomarker for Major Depressive Disorder: A Pilot Study.

PubMed

Kageyama, Yuki; Kasahara, Takaoki; Nakamura, Takemichi; Hattori, Kotaro; Deguchi, Yasuhiko; Tani, Munehide; Kuroda, Kenji; Yoshida, Sumiko; Goto, Yu-Ichi; Inoue, Koki; Kato, Tadafumi

2018-03-01

Diagnostic biomarkers of major depressive disorder, bipolar disorder, and schizophrenia are urgently needed, because none are currently available. We performed a comprehensive metabolome analysis of plasma samples from drug-free patients with major depressive disorder (n=9), bipolar disorder (n=6), schizophrenia (n=17), and matched healthy controls (n=19) (cohort 1) using liquid chromatography time-of-flight mass spectrometry. A significant effect of diagnosis was found for 2 metabolites: nervonic acid and cortisone, with nervonic acid being the most significantly altered. The reproducibility of the results and effects of psychotropic medication on nervonic acid were verified in cohort 2, an independent sample set of medicated patients [major depressive disorder (n=45), bipolar disorder (n=71), schizophrenia (n=115)], and controls (n=90) using gas chromatography time-of-flight mass spectrometry. The increased levels of nervonic acid in patients with major depressive disorder compared with controls and patients with bipolar disorder in cohort 1 were replicated in the independent sample set (cohort 2). In cohort 2, plasma nervonic acid levels were also increased in the patients with major depressive disorder compared with the patients with schizophrenia. In cohort 2, nervonic acid levels were increased in the depressive state in patients with major depressive disorder compared with the levels in the remission state in patients with major depressive disorder and the depressive state in patients with bipolar disorder. These results suggested that plasma nervonic acid is a good candidate biomarker for the depressive state of major depressive disorder. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Topical 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Corrects Cutaneous Features of Systemic Glucocorticoid Excess in Female Mice.

PubMed

Tiganescu, Ana; Hupe, Melanie; Uchida, Yoshikazu; Mauro, Theadora; Elias, Peter M; Holleran, Walter M

2018-01-01

Glucocorticoid (GC) excess drives multiple cutaneous adverse effects, including skin thinning and poor wound healing. The ubiquitously expressed enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates mouse corticosterone from 11-dehydrocorticosterone (and human cortisol from cortisone). We previously demonstrated elevated 11β-HSD1 activity during mouse wound healing, but the interplay between cutaneous 11β-HSD1 and systemic GC excess is unexplored. Here, we examined effects of 11β-HSD1 inhibition by carbenoxolone (CBX) in mice treated with corticosterone (CORT) or vehicle for 6 weeks. Mice were treated bidaily with topical CBX or vehicle (VEH) 7 days before wounding and during wound healing. CORT mice displayed skin thinning and impaired wound healing but also increased epidermal integrity. 11β-HSD1 activity was elevated in unwounded CORT skin and was inhibited by CBX. CORT mice treated with CBX displayed 51%, 59%, and 100% normalization of wound healing, epidermal thickness, and epidermal integrity, respectively. Gene expression studies revealed normalization of interleukin 6, keratinocyte growth factor, collagen 1, collagen 3, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 4 by CBX during wound healing. Importantly, proinflammatory cytokine expression and resolution of inflammation were unaffected by 11β-HSD1 inhibition. CBX did not regulate skin function or wound healing in the absence of CORT. Our findings demonstrate that 11β-HSD1 inhibition can limit the cutaneous effects of GC excess, which may improve the safety profile of systemic steroids and the prognosis of chronic wounds. Copyright © 2018 Endocrine Society.

Expression of 11β-hydroxysteroid dehydrogenase type 2 is deregulated in colon carcinoma.

PubMed

Moravec, Martin; Svec, Jirí; Ergang, Peter; Mandys, Václav; Reháková, Lenka; Zádorová, Zdena; Hajer, Jan; Kment, Milan; Pácha, Jirí

2014-04-01

Although the effects of glucocorticoids on proliferation, differentiation and apoptosis are well known, and steroid hormones have been identified to play a role in pathogenesis and the development of various cancers, limited data are available regarding the relationship between the local metabolism of glucocorticoids and colorectal adenocarcinoma (CRC) formation. Glucocorticoid metabolism is determined by 11β-hydroxysteroid dehydrogenases type 1 and 2 (11HSD1, 11HSD2), which increase the local concentration of cortisol due to the reduction of cortisone, or decrease this concentration due to the oxidation of cortisol. The objective of this study was to evaluate the extent of 11HSD1 and 11HSD2 mRNA in pre-malignant colorectal polyps and in CRC. The specimens were retrieved from patients by endoscopic or surgical resection and the expression of 11HSD1 and 11HSD2 was measured by real-time PCR. The polyps were of the following histological types: hyperplastic polyps and adenomas with low- or high-grade dysplasia. The neoplastic tissue of CRC obtained during tumor surgery was also studied. It was found that 11HSD2 was not only downregulated in CRC but already in the early stages of neoplastic transformation (adenoma with low-grade dysplasia). In contrast, the level of 11HSD1 was significantly increased in CRC but not in pre-malignant polyps. The results demonstrate that the downregulation of 11HSD2 gene expression is a typical feature of the development of colorectal polypous lesions and their transformation into CRC.

Longitudinal analyses of the steroid metabolome in obese PCOS girls with weight loss

PubMed Central

Kulle, Alexandra; Rothermel, Juliane; Knop-Schmenn, Caroline; Lass, Nina; Bosse, Christina; Holterhus, Paul-Martin

2017-01-01

Objective The underlying mechanisms of polycystic ovarian syndrome (PCOS) are not fully understood yet. The aim of the study was to get functional insights into the regulation of steroid hormones in PCOS by steroid metabolomics. Design This is a longitudinal study of changes of steroid hormones in 40 obese girls aged 13–16 years (50% with PCOS) participating in a 1-year lifestyle intervention. Girls with and without PCOS were matched to age, BMI and change of weight status. Methods We measured progesterone, 17-hydroxyprogesterone, 17-hydroxyprogenolon, 11-deoxycorticosterone, 21-deoxycorticosterone, deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol, cortisone, androstenedione, testosterone, dehydroepiandrostendione-sulfate (DHEA-S), estrone and estradiol by LC–MS/MS steroid profiling at baseline and one year later. Results At baseline, obese PCOS girls demonstrated significantly higher androstenedione and testosterone concentrations compared to obese girls without PCOS, whereas the other steroid hormones including glucocorticoids, mineralocorticoids, estrogens and precursors of androgens did not differ significantly. Weight loss in obese PCOS girls was associated with a significant decrease of testosterone, androstenedione, DHEA-S, cortisol and corticosterone concentrations. Weight loss in obese non-PCOS girls was associated with a significant decrease of DHEA-S, cortisol and corticosterone concentrations, whereas no significant changes of testosterone and androstenedione concentrations could be observed. Without weight loss, no significant changes of steroid hormones were measured except an increase of estradiol in obese PCOS girls without weight loss. Conclusions The key steroid hormones in obese adolescents with PCOS are androstenedione and testosterone, whereas glucocorticoids, mineralocorticoids, estrogens and precursors of androgens did not differ between obese girls with and without PCOS. PMID:28373267

Core body temperature, skin temperature, and interface pressure. Relationship to skin integrity in nursing home residents.

PubMed

Knox, D M

1999-06-01

To ascertain the effects of 1-, 1 1/2-, and 2-hour turning intervals on nursing home residents' skin over the sacrum and trochanters. (1) the higher the core body temperature, the higher the skin surface temperature; (2) the 2-hour turning interval would have significantly higher skin surface temperature; (3) there would be no relationship between skin surface temperature and interface pressure; and (4) the sacrum would have the lowest skin surface temperature. Modified Latin-square. For-profit nursing home. Convenience sample of 26 residents who scored < 3 on the Short Portable Mini-Mental Status Questionnaire and did not have (1) open wounds; (2) albumin levels < 3.3 mg/dL; (3) severe arthritis; (4) cortisone, anticoagulation, insulin therapy or 3 medications for hypertension; and/or (5) were totally bedridden. First Temp measured core temperature; a disposable thermistor temperature probe, skin temperature; and a digital interface pressure evaluator, the interface pressure. Negative correlation (r = -.33, P = .003) occurred between core body temperature and skin surface temperature. Skin surface temperature rose at the end of the 2-hour turning interval but was not significant (F = (2.68) = .73, P = .49). Weak negative relationship (r = -12, P = .29) occurred between skin surface temperature and interface pressure, and sacral skin surface temperature was significantly lower for the left trochanter only (F = (8.68) = 7.05, P = .002). Although hypotheses were not supported, more research is needed to understand how time in position and multiple chronic illnesses interact to affect skin pressure tolerance.

Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor

PubMed Central

Voisin, Maud; de Medina, Philippe; Mallinger, Arnaud; Dalenc, Florence; Huc-Claustre, Emilie; Leignadier, Julie; Serhan, Nizar; Soules, Régis; Ségala, Grégory; Mougel, Aurélie; Noguer, Emmanuel; Mhamdi, Loubna; Bacquié, Elodie; Iuliano, Luigi; Zerbinati, Chiara; Lacroix-Triki, Magali; Chaltiel, Léonor; Filleron, Thomas; Cavaillès, Vincent; Al Saati, Talal; Rochaix, Philippe; Duprez-Paumier, Raphaelle; Franchet, Camille; Ligat, Laetitia; Lopez, Fréderic; Record, Michel; Poirot, Marc; Silvente-Poirot, Sandrine

2017-01-01

Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC. PMID:29078321

Stress-induced changes of neurosteroid profiles in rat brain and plasma under immobilized condition.

PubMed

Park, Myeong Hyeon; Rehman, Shaheed Ur; Kim, In Sook; Choi, Min Sun; Yoo, Hye Hyun

2017-05-10

In this study, various neurosteroids in brain and plasma were simultaneously determined using liquid chromatography-tandem mass spectrometry and their profile changes in a stress-induced rats were investigated. The investigated neurosteroids are as follows: progesterone (P4), 5α-dihydroprogesterone (5α-DHP), 5β-dihydroprogesterone, estrone, androstenedione (AE), cortisol, cortisone, corticosterone (CORT), dehydroepiandrosterone (DHEA), pregnanolone (3α,5β-THP), allopregnanolone (ALLO), 11-deoxycorticosterone (DOC), 11-deoxycortisol, pregnenolone (PREG), and 5α/5β-tetrahydrodeoxycorticosterone (5α/5β-THDOC). Brain and plasma samples were processed using solid-phase extraction with methanol and acetic acid (99:1), and derivatized with a hydroxylamine reagent. Separation was achieved within 13min at a flow rate of 0.4mL/min with a C18 column (3.0×50mm, 2.7μm). The triple quadrupole mass spectrometer was operated in the positive electrospray ionization mode. Using this method, the neurosteroid level variation was quantitated and investigated in the brain and plasma upon immobilization stress in rats. As a result, AE, CORT, DOC, P4, 5α-DHP, 5α/5β-THDOC, DHEA, 3α,5β-THP, ALLO, and PREG levels were significantly altered in both the brain and plasma samples when stress was induced. These findings demonstrated that stress leads to the alteration of the GABAergic neurosteroid profile. The present results will be helpful for furthering an understanding of the role of neurosteroids in stressed conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

Efficacy of SCH27899 in an Animal Model of Legionnaires' Disease Using Immunocompromised A/J Mice

PubMed Central

Brieland, Joan K.; Loebenberg, David; Menzel, Fred; Hare, Roberta S.

2000-01-01

The efficacy of SCH27899, a new everninomicin antibiotic, against replicative Legionella pneumophila lung infections in an immunocompromised host was evaluated using a murine model of Legionnaires' disease. A/J mice were immunocompromised with cortisone acetate and inoculated intratracheally with L. pneumophila serogroup 1 (105 CFU per mouse). At 24 h postinoculation, mice were administered either SCH27899 (6 to 60 mg/kg [MPK] intravenously) or a placebo once daily for 5 days, and mortality and intrapulmonary growth of L. pneumophila were assessed. In the absence of SCH27899, there was 100% mortality in L. pneumophila-infected mice, with exponential intrapulmonary growth of the bacteria. In contrast, administration of SCH27899 at a dose of ≥30 MPK resulted in ≥90% survival of infected mice, which was associated with inhibition of intrapulmonary growth of L. pneumophila. In subsequent studies, the efficacy of SCH27899 was compared to ofloxacin (OFX) and azithromycin (AZI). Administration of SCH27899, OFX, or AZI at a dose of ≥30 MPK once daily for 5 days resulted in ≥85% survival of infected mice and inhibition of intrapulmonary growth of the bacteria. However, L. pneumophila CFU were recovered in lung homogenates following cessation of therapy with all three antibiotics. These studies demonstrate that SCH27899 effectively prevents fatal replicative L. pneumophila lung infection in immunocompromised A/J mice by inhibition of intrapulmonary growth of the bacteria. However, in this murine model of pulmonary legionellosis, SCH27899, like OFX and AZI, was bacteriostatic. PMID:10770771

Reactions of Microsolvated Organic Compounds at Ambient Surfaces: Droplet Velocity, Charge State, and Solvent Effects

NASA Astrophysics Data System (ADS)

Badu-Tawiah, Abraham K.; Campbell, Dahlia I.; Cooks, R. Graham

2012-06-01

The exposure of charged microdroplets containing organic ions to solid-phase reagents at ambient surfaces results in heterogeneous ion/surface reactions. The electrosprayed droplets were driven pneumatically in ambient air and then electrically directed onto a surface coated with reagent. Using this reactive soft landing approach, acid-catalyzed Girard condensation was achieved at an ambient surface by directing droplets containing Girard T ions onto a dry keto-steroid. The charged droplet/surface reaction was much more efficient than the corresponding bulk solution-phase reaction performed on the same scale. The increase in product yield is ascribed to solvent evaporation, which causes moderate pH values in the starting droplet to reach extreme values and increases reagent concentrations. Comparisons are made with an experiment in which the droplets were pneumatically accelerated onto the ambient surface (reactive desorption electrospray ionization, DESI). The same reaction products were observed but differences in spatial distribution were seen associated with the "splash" of the high velocity DESI droplets. In a third type of experiment, the reactions of charged droplets with vapor phase reagents were examined by allowing electrosprayed droplets containing a reagent to intercept the headspace vapor of an analyte. Deposition onto a collector surface and mass analysis showed that samples in the vapor phase were captured by the electrospray droplets, and that instantaneous derivatization of the captured sample is possible in the open air. The systems examined under this condition included the derivatization of cortisone vapor with Girard T and that of 4-phenylpyridine N-oxide and 2-phenylacetophenone vapors with ethanolamine.

Does systemic steroid deficiency affect inner ear functions?

PubMed

Dogan, Remzi; Merıc, Ayşenur; Gedık, Ozge; Tugrul, Selahattin; Eren, Sabri Baki; Ozturan, Orhan

2015-01-01

Today corticosteroids are employed for the treatment of various inner ear disorders. In this study we have investigated probable changes in hearing functions resulting from a deficiency of systemic steroid secretions. Twenty four healthy female rats were used in our study, allocated into three groups (medical adrenalectomy, medical adrenalectomy+dexamethasone, no treatment). Audiological evaluations were conducted at the beginning of the study and on days 7, 14 and 21. Blood samples were taken at the beginning and at the end of the study and blood corticosterone levels were determined. While there were no significant differences between the basal, 7th, 14th and 21st day DPOAE values of group 1, their ABR threshold values showed significant increases. In group 2, there were no significant differences between the basal, 7th, 14th and 21st day DPOAE values. ABR thresholds of group 2 showed significant increases on days 7 and 14 as compared to their basal values, but there were no significant differences between the 21st day and basal ABR threshold values. There were no significant differences between the basal cortisol levels of the three groups. The mean cortisol level of group 1 on day 21 was found to be significantly lower than those of groups 2 and 3. The results of the study demonstrated that there were no significant changes in DPOAE values with the cessation of cortisol secretion, while there was a progressive increase in ABR thresholds, which could be overcome with cortisone replacement. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor.

PubMed

Voisin, Maud; de Medina, Philippe; Mallinger, Arnaud; Dalenc, Florence; Huc-Claustre, Emilie; Leignadier, Julie; Serhan, Nizar; Soules, Régis; Ségala, Grégory; Mougel, Aurélie; Noguer, Emmanuel; Mhamdi, Loubna; Bacquié, Elodie; Iuliano, Luigi; Zerbinati, Chiara; Lacroix-Triki, Magali; Chaltiel, Léonor; Filleron, Thomas; Cavaillès, Vincent; Al Saati, Talal; Rochaix, Philippe; Duprez-Paumier, Raphaelle; Franchet, Camille; Ligat, Laetitia; Lopez, Fréderic; Record, Michel; Poirot, Marc; Silvente-Poirot, Sandrine

2017-10-31

Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC. Published under the PNAS license.

Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience.

PubMed

Olsson, Richard F; Hagelberg, Stefan; Schiller, Bodil; Ringdén, Olle; Truedsson, Lennart; Åhlin, Anders

2016-06-01

Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m) and fludarabine (30 mg/m) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.

Long-term (6-wk) hindlimb suspension inhibits spermatogenesis in adult male rats

NASA Technical Reports Server (NTRS)

Tash, Joseph S.; Johnson, Donald C.; Enders, George C.

2002-01-01

The International Space Station will allow extended habitation in space and long-term exposure to microgravity (microG). A concern is the impact of long-term microG exposure on the ability of species to reproduce. The model often used to simulate microG is rat hindlimb suspension (HLS), where the hindlimbs are elevated above the cage floor with a tail harness. Experiments described here are the first to examine the effect of long-term HLS on testicular function in adult male rats. Free-roaming (controls), animals with only the tail harnessed but hindlimbs in contact with the cage floor (TO), and HLS animals were tested for 6 wk. Cryptorchidism was prevented in TO and HLS animals by partial constriction of the inguinal canal with sutures. All parameters were compared at the end of the 6-wk experiment. Testicular weights and spermatogenesis were significantly reduced by HLS, such that no spermatogenic cells beyond round spermatids were present and epididymides were devoid of mature sperm. In many tubules, loss of all germ cells, except a few spermatogonia, resulting in histopathology similar to the Sertoli cell, was observed. Spermatogenesis appeared unaffected in control and TO animals. Sertoli and Leydig cell appearance, testosterone, luteinizing hormone, and follicle-stimulating hormone levels, and epididymal and seminal vesicle weight were unchanged by HLS. Cortisone was not elevated by HLS; thus stress may not be a factor. These results demonstrate that spermatogenesis is severely inhibited by long-term HLS, whereas testicular androgen production is not. These results have significant implications regarding serious effects of long-term exposure to microG on the reproductive capability of scrotal mammals, including humans.

Acute Hydrocortisone Treatment Increases Anxiety but Not Fear in Healthy Volunteers: A Fear-Potentiated Startle Study

PubMed Central

Grillon, Christian; Heller, Randi; Hirschhorn, Elizabeth; Kling, Mitchel A.; Pine, Daniel S.; Schulkin, Jay; Vythilingam, Meena

2011-01-01

Background The debilitating effects of chronic glucocorticoids excess are well-known, but comparatively little is understood about the role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration aversive states, such as “anxiety,” but not relatively similar, briefer aversive states, such as “fear.” However, no prior experimental studies in humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but dissociable aversive states. The current study examines these effects, as instantiated with short- and long-duration threats. Methods Healthy volunteers (n = 18) received placebo or a low (20 mg) or a high (60 mg) dose of hydrocortisone in a double-blind crossover design. Subjects were exposed repeatedly to three 150-sec duration conditions: no shock; predictable shocks, in which shocks were signaled by a short-duration threat cue; and unpredictable shocks. Aversive states were indexed by acoustic startle. Fear was operationally defined as the increase in startle reactivity during the threat cue in the predictable condition (fear-potentiated startle). Anxiety was operationally defined as the increase in baseline startle from the no shock to the two threat conditions (anxiety-potentiated startle). Results Hydrocortisone affected neither baseline nor short-duration, fear-potentiated startle but increased long-duration anxiety-potentiated startle. Conclusions These results suggest that hydrocortisone administration in humans selectively increases anxiety but not fear. Possible mechanisms implicated are discussed in light of prior data in rodents. Specifically, hydrocortisone might increase anxiety via sensitization of corticotrophin-releasing hormones in the bed nucleus of the stria terminalis. PMID:21277566

Effects of Hydrocortisone on the Regulation of Blood Pressure: Results From a Randomized Controlled Trial.

PubMed

Werumeus Buning, Jorien; van Faassen, Martijn; Brummelman, Pauline; Dullaart, Robin P F; van den Berg, Gerrit; van der Klauw, Melanie M; Kerstens, Michiel N; Stegeman, Coen A; Muller Kobold, Anneke C; Kema, Ido P; Wolffenbuttel, Bruce H R; van Beek, André P

2016-10-01

Cardiovascular risk is increased in patients with secondary adrenal insufficiency, which may be ascribed to an unfavorable metabolic profile consequent to a relatively high hydrocortisone replacement dose. We determined the effects of a higher versus a lower glucocorticoid replacement dose on blood pressure (BP), the renin-angiotensin-aldosterone system, 11β-hydroxysteroid dehydrogenase enzyme activity and circulating (nor)metanephrines. Forty-seven patients with secondary adrenal insufficiency from the University Medical Center Groningen participated in this randomized double-blind crossover study. Patients randomly received 0.2-0.3 mg hydrocortisone/kg body weight followed by 0.4-0.6 mg hydrocortisone/kg body weight, or vice versa, each during 10 weeks. BP and regulating hormones were measured. The higher hydrocortisone dose resulted in an increase in systolic BP of 5 (12) mm Hg (P = .011), diastolic BP of 2 (9) mm Hg (P = .050), and a median [interquartile range] drop in plasma potassium of -0.1 [-0.3; 0.1] nmol/liter (P = .048). The higher hydrocortisone dose led to decreases in serum aldosterone of -28 [-101; 9] pmol/liter (P = .020) and plasma renin of -1.3 [-4.5; 1.2 ] pg/mL (P = .051), and increased the ratio of plasma and urinary cortisol to cortisone (including their metabolites) (P < .001 for all). Furthermore, on the higher dose, plasma and urinary normetanephrine decreased by -0.101 [-0.242; 0.029] nmol/liter (P < .001) and -1.48 [-4.06; 0.29] μmol/mol creatinine (P < .001) respectively. A higher dose of hydrocortisone increased systolic and diastolic BP and was accompanied by changes in the renin-angiotensin-aldosterone system, 11β-hydroxysteroid dehydrogenase enzyme activity, and circulating normetanephrine. This demonstrates that hydrocortisone dose even within the physiological range affects several pathways involved in BP regulation.

Amphiphilic polymeric micelle as pseudostationary phase in electrokinetic chromatography for analysis of eight corticosteroids in cosmetics.

PubMed

Xu, Xiaojin; Ni, Xinjiong; Cao, Yuhua; Zhuo, Xiaolu; Yang, Xiaoxiao; Cao, Guangqun

2014-03-01

Amphiphilic polymeric micelle, as a novel pseudostationary phase in EKC was used to determine eight kinds of corticosteroids namely hydrocortisone, prednisolone, hydrocortisone acetate, prednisone, cortisone acetate, prednisolone acetate, dexamethasone, and triamcinolone acetonide in cosmetics. Amphiphilic random copolymer poly(methyl methacrylate-co-methacrylic acid) (P(MMA-co-MAA)) was micellizated via neutralization in alkaline aqueous solution. The influences of the molar ratio of monomer MMA to MAA, the concentration of polymer and pH on the polymeric micelle microstructure and EKC performances were investigated. As molar ratio of MMA to MAA in P(MMA-co-MAA) increased, both CMC and environmental polarity of the inner core in polymeric micelle decreased dramatically. With increasing monomer ratio, the size of polymeric micelles increased firstly, and then decreased, finally increased again. ζ potential of the micelle had a slight decline trend. As increment of polymer concentration, the size of the polymeric micelle increased steadily. By optimizing the monomer ratio, the polymer concentration, and pH of the running buffer, as well as operation conditions such as separation voltage and temperature, the eight analytes could be separated within 16.5 min using 7.5 mg/mL polymer with the monomer ratio of 7:3 dissolved in pH 9.2 borax buffer as the running buffer. The method has been used for analysis of corticosteroids in cosmetic samples with simple extraction; the recoveries for eight analytes were between 85.9 and 106%. This method was of accuracy, repeatability, pretreatment simplicity, and could be applied to the quality control of cosmetics. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Higher proportion of fast-twitch (type II) muscle fibres in idiopathic inflammatory myopathies - evident in chronic but not in untreated newly diagnosed patients.

PubMed

Loell, I; Helmers, S B; Dastmalchi, M; Alexanderson, H; Munters, L A; Nennesmo, I; Lindroos, E; Borg, K; Lundberg, I E; Esbjörnsson, M

2011-01-01

Polymyositis and dermatomyositis are idiopathic, inflammatory myopathies characterized by proximal muscle fatigue. Conventional immunosuppressive treatment gives a variable response. Biopsies from chronic patients display a low proportion type I and a high proportion of type II muscle fibres. This raised a suspicion that the low proportion of type I fibres might play a role in the muscle fatigue. To investigate whether the muscle fibre attributes evident in chronic myositis are characteristic for the polymyositis and dermatomyosistis diseases themselves. Muscle biopsies were obtained from thigh muscle from untreated patients (n = 18), treated responders (n = 14) and non-responders (n = 6) and from healthy controls (n = 11), respectively. For clinical evaluations, creatine kinase, functional index of myositis and cumulative dose of cortisone were established.   Chronic patients had a lower proportion of type I fibres and a higher proportion of type II fibres compared to untreated myositis patients and healthy controls. Fibre cross-sectional area (CSA) did not differ between patients and healthy individuals but all women had a 20% smaller type II fibre CSA compared to men. Untreated polymyositis and dermatomyositis patients and healthy controls have a different fibre type composition than chronic polymyositis and dermatomyositis patients. Fibre CSA did not differ between healthy controls or any of the patient groups. A low proportion of oxidative muscle fibres can therefore be excluded as a contributing factor causing muscle fatigue at disease onset and the gender difference should be taken into consideration when evaluating fibre CSA in myositis. © 2010 The Authors. Clinical Physiology and Functional Imaging © 2010 Scandinavian Society of Clinical Physiology and Nuclear Medicine.

Platelet-rich plasma for chronic lateral epicondylitis: is one injection sufficient?

PubMed

Glanzmann, Michael C; Audigé, Laurent

2015-12-01

Chronic lateral epicondylitis is generally treated using nonsurgical methods including physiotherapy and infiltrations of cortisone or platelet-rich plasma (PRP). The latter is known for its simple application as well as associated low risk of adverse events, which lend to its widespread use in treating various musculoskeletal conditions. There is limited evidence on the effectiveness of PRP injections to optimally treat chronic lateral epicondylitis. This study explored the effectiveness of single or repeated injections for patients with symptoms that spanned 6 months or more and were unresponsive to alternate conservative measures. Patients with chronic lateral epicondylitis received PRP injections in 4-week intervals that were complemented with standardized physical therapy. Patient-reported outcomes based on the patient-rated elbow evaluation (PREE), quick disabilities of the arm, shoulder and hand (qDASH), and EuroQol (five dimensions) 3-level version (EQ5D3L) questionnaires were documented at each visit including 6 months after the first injection. These outcomes were compared between patients receiving 1 vs. 2 or 3 PRP injections. Sixty-two patients received one (n = 36) or more (n = 26) PRP injections. The mean baseline to 6-month follow-up scores of the PREE and qDASH questionnaires improved significantly from 54.0 to 23.0 and 50.3 to 20.7, respectively. The mean baseline EQ5D3L-visual analogue scale score improved from 62.5 to 82.9 by 6 months post-injection. These outcomes did not significantly differ between the patients who received varying numbers of injections. Patients with chronic lateral epicondylitis reported significant pain relief and gain in function as well as quality of life 6 months after localized PRP treatment. A single PRP injection may be sufficient.

Shock wave therapy for chronic proximal plantar fasciitis.

PubMed

Ogden, J A; Alvarez, R; Levitt, R; Cross, G L; Marlow, M

2001-06-01

Three hundred two patients with chronic heel pain caused by proximal plantar fasciitis were enrolled in a study to assess the treatment effects consequent to administration of electrohydraulicall-generated extracorporeal shock waves. Symptoms had been present from 6 months to 18 years. Each treated patient satisfied numerous inclusion and exclusion criteria before he or she was accepted into this study, which was approved by the Food and Drug Administration as a randomized, double-blind evaluation of the efficacy of shock wave therapy for this disorder. Overall, at the predetermined evaluation period 3 months after one treatment, 56% more of the treated patients had a successful result by all four of the evaluation criteria when compared with the patients treated with a placebo. This difference was significant and corroborated the fact that this difference in the results was specifically attributable to the shock wave treatment, rather than any natural improvement caused by the natural history of the condition. The current study showed that the directed application of electrohydraulic-generated shock waves to the insertion of the plantar fascia onto the calcaneus is a safe and effective nonsurgical method for treating chronic, recalcitrant heel pain syndrome that has been present for at least 6 months and has been refractory to other commonly used nonoperative therapies. This technology, when delivered using the OssaTron (High Medical Technology, Kreuz-lingen, Switzerland), has been approved by the Food and Drug Administration specifically for the treatment of chronic proximal plantar fasciitis. The results suggest that this therapeutic modality should be considered before any surgical options, and even may be preferable to cortisone injection, which has a recognized risk of rupture of the plantar fascia and recurrence of symptoms.

Disseminated intravascular coagulation induced by progesterone in the pregnant rat. Prevention by estogens.

PubMed

Stamler, F W

1977-03-01

Fatal disseminated intravascular coagulation (DIC) was induced in female rats by administration of progesterone in late pregnacy. This prevented parturition, with intrauterine fetal death 2 to 4 days past term and subsequent retention of dead fetuses. Concomitantly with or closely following the intrauterine death of their litters, a large proportion of pregnant rats died with histologically evident DIC. Administration of cortisone, heparin, or disoumarin did not prevent DIC, and xi-aminocaproic acid, acetylsalicylic acid, or an onion-rich diet tended to increase its incidence. Antibiotic regimens gave variable results, with significant decrease in DIC only with a combination of two wide-spectrum penicillins. Neomycin and polymyxin had little effect on susceptible Sprague-dawley derived rats, but polymxin caused a significant increase in DIC in a resistant strain of hooded rats. Fatal maternal DIC was completely prevented only by use of natural or synthetic estrogens concurrently with progesterone, although this did not alter the sequence of abnormally prolonged pregnacy with intrauterine fetal death and retention of dead fetuses. Potencies of estrogens varied greatly, but all compounds tested prevented DIC at adequate dosage levels. Diethylstilbestrol, the most potent drug tested, was completely protective at 1 mug daily given subcutaneously. beta-Estradiol was the most effective natural estrogen, giving complete protection with a 10-mug daily subcutaneous injection. Estrogens were much more potent by subcutaneous injection than by oral ingestion, and toxic side effects were sometimes noted with higher levels of the latter. For estrogen therapy to be effective, it was necessary to begin its use before the expected onset of DIC, and in no instance was there evidence of reversal of this process after signs of illness were observed.

Disseminated intravascular coagulation induced by progesterone in the pregnant rat. Prevention by estogens.

PubMed Central

Stamler, F. W.

1977-01-01

Fatal disseminated intravascular coagulation (DIC) was induced in female rats by administration of progesterone in late pregnacy. This prevented parturition, with intrauterine fetal death 2 to 4 days past term and subsequent retention of dead fetuses. Concomitantly with or closely following the intrauterine death of their litters, a large proportion of pregnant rats died with histologically evident DIC. Administration of cortisone, heparin, or disoumarin did not prevent DIC, and xi-aminocaproic acid, acetylsalicylic acid, or an onion-rich diet tended to increase its incidence. Antibiotic regimens gave variable results, with significant decrease in DIC only with a combination of two wide-spectrum penicillins. Neomycin and polymyxin had little effect on susceptible Sprague-dawley derived rats, but polymxin caused a significant increase in DIC in a resistant strain of hooded rats. Fatal maternal DIC was completely prevented only by use of natural or synthetic estrogens concurrently with progesterone, although this did not alter the sequence of abnormally prolonged pregnacy with intrauterine fetal death and retention of dead fetuses. Potencies of estrogens varied greatly, but all compounds tested prevented DIC at adequate dosage levels. Diethylstilbestrol, the most potent drug tested, was completely protective at 1 mug daily given subcutaneously. beta-Estradiol was the most effective natural estrogen, giving complete protection with a 10-mug daily subcutaneous injection. Estrogens were much more potent by subcutaneous injection than by oral ingestion, and toxic side effects were sometimes noted with higher levels of the latter. For estrogen therapy to be effective, it was necessary to begin its use before the expected onset of DIC, and in no instance was there evidence of reversal of this process after signs of illness were observed. Images Figure 3 Figure 4 Figure 1 Figure 2 PMID:65916

11β-Hydroxysteroid dehydrogenase type-2 and type-1 (11β-HSD2 and 11β-HSD1) and 5β-reductase activities in the pathogenia of essential hypertension.

PubMed

Campino, Carmen; Carvajal, Cristian A; Cornejo, Javiera; San Martín, Betty; Olivieri, Oliviero; Guidi, Giancesare; Faccini, Giovanni; Pasini, Francesco; Sateler, Javiera; Baudrand, Rene; Mosso, Lorena; Owen, Gareth I; Kalergis, Alexis M; Padilla, Oslando; Fardella, Carlos E

2010-02-01

Cortisol availability is modulated by several enzymes: 11β-HSD2, which transforms cortisol (F) to cortisone (E) and 11β-HSD1 which predominantly converts inactive E to active F. Additionally, the A-ring reductases (5α- and 5β-reductase) inactivate cortisol (together with 3α-HSD) to tetrahydrometabolites: 5αTHF, 5βTHF, and THE. The aim was to assess 11β-HSD2, 11β-HSD1, and 5β-reductase activity in hypertensive patients. Free urinary F, E, THF, and THE were measured by HPLC-MS/MS in 102 essential hypertensive patients and 18 normotensive controls. 11β-HSD2 enzyme activity was estimated by the F/E ratio, the activity of 11β-HSD1 in compare to 11β-HSD2 was inferred by the (5αTHF + 5βTHF)/THE ratio and 5β-reductase activity assessed using the E/THE ratio. Activity was considered altered when respective ratios exceeded the maximum value observed in the normotensive controls. A 15.7% of patients presented high F/E ratio suggesting a deficit of 11β-HSD2 activity. Of the remaining 86 hypertensive patients, two possessed high (5αTHF + 5βTHF)/THE ratios and 12.8% had high E/THE ratios. We observed a high percentage of alterations in cortisol metabolism at pre-receptor level in hypertensive patients, previously misclassified as essential. 11β-HSD2 and 5β-reductase decreased activity and imbalance of 11β-HSDs should be considered in the future management of hypertensive patients.

11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes.

PubMed

Itoi, Saori; Terao, Mika; Murota, Hiroyuki; Katayama, Ichiro

2013-10-18

The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10(-13) M cortisol, whereas 1 × 10(-5) M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11β-HSD1 appears to modulate expression of inflammatory cytokines in NHEKs. Copyright © 2013 Elsevier Inc. All rights reserved.

Human pediculosis: a critical health problem and what about nursing policy?

PubMed

El-Bahnasawy, Mamdouh M; Abdel, Fadil Eman Ebrahim; Morsy, Tosson A

2012-12-01

Lice infestation on the human body (also known as pediculosis) is very common. Cases number in the hundreds of millions worldwide. Three distinct presentations of lice infection exist and each is caused by a unique parasite. Head lice (Pediculus humanus capitis) is by far and away the most common infestation and favors no particular socioeconomic group. A genetically close "cousin," Pediculus humanus corporis, is responsible for body lice and is more commonly associated with poverty, overcrowding, and poor hygiene. Pubic lice (crabs) are caused by Pthirus pubis and is transmitted by intimate and/or sexual contact. No doubt, human lice infestation is an increasing problem worldwide, Apart from being an irritating and a shaming human ecto-parasite, they transmit serious infectious diseases; epidemic or classical typhus, epidemic relapsing fever as well as Trench fever. Eradication of lice infestation prevents transmission of infectious diseases. People who live and work in close proximity to louse-infested individuals may secondarily acquire lice even if they regularly wash their clothes and have good hygiene. Thus, all louse-infested persons and workers in close contact with such persons should periodically inspected and use long-acting safe insecticides. Human lice can be treated with agents such as DDT, malathion, and lindane, but reports of resistance to one or more of them have recently appeared. Pyrethroid permethrin when applied as a dust or spray to clothing or bedding is highly effective against lice and is the delousing agent of choice. Fabric treated with permethrin retains toxicity to lice even after 20 washings, thereby offering significant long-term passive protection against epidemic typhus. Itching may continue even after all lice are destroyed. This happens because of a lingering allergic reactionto their bites. Over-the-counter cortisone (corticosteroid) creams or calamine lotion may help.

A Network Pharmacology Approach to Determine the Active Components and Potential Targets of Curculigo Orchioides in the Treatment of Osteoporosis.

PubMed

Wang, Nani; Zhao, Guizhi; Zhang, Yang; Wang, Xuping; Zhao, Lisha; Xu, Pingcui; Shou, Dan

2017-10-27

BACKGROUND Osteoporosis is a complex bone disorder with a genetic predisposition, and is a cause of health problems worldwide. In China, Curculigo orchioides (CO) has been widely used as a herbal medicine in the prevention and treatment of osteoporosis. However, research on the mechanism of action of CO is still lacking. The aim of this study was to identify the absorbable components, potential targets, and associated treatment pathways of CO using a network pharmacology approach. MATERIAL AND METHODS We explored the chemical components of CO and used the five main principles of drug absorption to identify absorbable components. Targets for the therapeutic actions of CO were obtained from the PharmMapper server database. Pathway enrichment analysis was performed using the Comparative Toxicogenomics Database (CTD). Cytoscape was used to visualize the multiple components-multiple target-multiple pathways-multiple disease network for CO. RESULTS We identified 77 chemical components of CO, of which 32 components could be absorbed in the blood. These potential active components of CO regulated 83 targets and affected 58 pathways. Data analysis showed that the genes for estrogen receptor alpha (ESR1) and beta (ESR2), and the gene for 11 beta-hydroxysteroid dehydrogenase type 1, or cortisone reductase (HSD11B1) were the main targets of CO. Endocrine regulatory factors and factors regulating calcium reabsorption, steroid hormone biosynthesis, and metabolic pathways were related to these main targets and to ten corresponding compounds. CONCLUSIONS The network pharmacology approach used in our study has attempted to explain the mechanisms for the effects of CO in the prevention and treatment of osteoporosis, and provides an alternative approach to the investigation of the effects of this complex compound.

Acute Effects of Lysergic Acid Diethylamide on Circulating Steroid Levels in Healthy Subjects.

PubMed

Strajhar, P; Schmid, Y; Liakoni, E; Dolder, P C; Rentsch, K M; Kratschmar, D V; Odermatt, A; Liechti, M E

2016-03-01

Lysergic acid diethylamide (LSD) is a serotonin 5-hydroxytryptamine-2A (5-HT2A ) receptor agonist that is used recreationally worldwide. Interest in LSD research in humans waned after the 1970s, although the use of LSD in psychiatric research and practice has recently gained increasing attention. LSD produces pronounced acute psychedelic effects, although its influence on plasma steroid levels over time has not yet been characterised in humans. The effects of LSD (200 μg) or placebo on plasma steroid levels were investigated in 16 healthy subjects using a randomised, double-blind, placebo-controlled, cross-over study design. Plasma concentration-time profiles were determined for 15 steroids using liquid-chromatography tandem mass-spectrometry. LSD increased plasma concentrations of the glucocorticoids cortisol, cortisone, corticosterone and 11-dehydrocorticosterone compared to placebo. The mean maximum concentration of LSD was reached at 1.7 h. Mean peak psychedelic effects were reached at 2.4 h, with significant alterations in mental state from 0.5 h to > 10 h. Mean maximal concentrations of cortisol and corticosterone were reached at 2.5 h and 1.9 h, and significant elevations were observed 1.5-6 h and 1-3 h after drug administration, respectively. LSD also significantly increased plasma concentrations of the androgen dehydroepiandrosterone but not other androgens, progestogens or mineralocorticoids compared to placebo. A close relationship was found between plasma LSD concentrations and changes in plasma cortisol and corticosterone and the psychotropic response to LSD, and no clockwise hysteresis was observed. In conclusion, LSD produces significant acute effects on circulating steroids, especially glucocorticoids. LSD-induced changes in circulating glucocorticoids were associated with plasma LSD concentrations over time and showed no acute pharmacological tolerance. © 2016 British Society for Neuroendocrinology.

Comparative Analysis of Amphotericin B Lipid Complex and Liposomal Amphotericin B Kinetics of Lung Accumulation and Fungal Clearance in a Murine Model of Acute Invasive Pulmonary Aspergillosis▿

PubMed Central

Lewis, Russell E.; Liao, Guangling; Hou, Jinggou; Chamilos, Georgios; Prince, Randall A.; Kontoyiannis, Dimitrios P.

2007-01-01

The reformulation of amphotericin B (AMB) into a lipid complex (AMB lipid complex [ABLC]) or liposomal carrier (liposomal AMB [L-AMB]) changes the rate and extent of drug distribution to the lung. The importance of pharmacokinetic differences among the various lipid AMB formulations in the treatment of invasive pulmonary aspergillosis (IPA) remains unknown. We compared the kinetics of AMB lung accumulation and fungal clearance of ABLC- and L-AMB-treated mice with acute IPA. BALB/c mice were immunosuppressed with cyclophosphamide and cortisone before intranasal inoculation with 1.5 × 106 Aspergillus fumigatus 293 conidia. ABLC or L-AMB was administered in daily intravenous doses (1, 5, or 10 mg/kg of body weight), starting 12 h after infection and continuing until day 5. At predetermined times (0, 24, 72, and 120 h), mice were euthanized, and lungs were harvested for determinations of lung fungal burdens (quantitative PCR) and total AMB lung tissue concentrations. Both ABLC and L-AMB were effective at reducing lung fungal burdens at doses of ≥5 mg/kg/day. Clearance of A. fumigatus during the first 24 h was associated with AMB tissue concentrations of >4 μg/g. At 5 mg/kg/day, ABLC produced a more rapid fungal clearance than did L-AMB, but at the end of therapy, fungal burden reductions were similar for both formulations and were not improved with higher dosages. These data suggest that ABLC delivers active AMB to the lung more rapidly than does L-AMB, resulting in faster Aspergillus clearance in an experimental model of IPA. However, pharmacodynamic differences between the two formulations were less apparent when mice were dosed at 10 mg/kg/day. PMID:17261624

[From the plant to chemistry--the early history of "rheumatic medication"].

PubMed

Kaiser, H

2008-05-01

The empirical administration of medication of plant, animal and even mineral origin goes back thousands of years. It was only in the 19th century that such therapy gained a scientific basis by means of the possibility to extract the active substances and analyze them chemically, and ultimately create them synthetically and modify them chemically.Meadow saffron was used from the 2nd century BC for the treatment of joint disease and gout; the active ingredient colchicine was discovered in 1819. For 4000 years willow bark has also been considered a remedy against fever, pain and gout. The active ingredient salicin was isolated in 1829, followed by salicyl acid in 1838, while the better tolerated acetylsalicylic acid was synthesized in 1897. Although the antipyretic agent cinchona was never a rheumatic remedy, it was initially considered an important antiinflammatory medication. In 1844, during the search for an alternative to quinin, antipyrin was developed, from which many antiphlogistic, antipyretic and analgetic active substances were later derived. Following the Second World War, the strongest antiinflammatory drug, cortisone, was discovered, derivates of which are still indispensable today for the treatment of inflammatory rheumatic diseases. At about the same time, there was a new wave of research which lead to the development of a large number of so-called non-steroidal antiinflammatory drugs. Following the discovery of proinflammatory cytokines in the 1970s, it became possible in the 1990s to produce antibodies against these substances, which gave rheumatic therapy new perspectives in the form of "biologicals". The sap from poppy seed capsules was already considered to have analgesic properties in the time of Hippocrates. The active ingredient morphine was isolated at the beginning of the 19th century. Today, only synthetically produced"opioids" are used, if at all, for the treatment of rheumatic disease.

Hair analysis reveals subtle HPA axis suppression associated with use of local corticosteroids: The Lifelines cohort study.

PubMed

Wester, Vincent L; Noppe, Gerard; Savas, Mesut; van den Akker, Erica L T; de Rijke, Yolanda B; van Rossum, Elisabeth F C

2017-06-01

Scalp hair is increasingly used to measure the long-term exposure to endogenous glucocorticoids hormones. Long-term cortisone (HairE) and cortisol (HairF) have been associated with obesity, metabolic syndrome, cardiovascular disease and psychopathology. However, little is known about the influence of the use of local corticosteroids and major stressful life events on hair glucocorticoids. We determined HairE and HairF using liquid chromatography - tandem mass spectrometry in 295 adult participants of the population-based Lifelines cohort study (75% females, median age 42). We collected anthropometry and fasting metabolic laboratory values, questionnaires on hair characteristics, recent use of corticosteroids, and recent major stressful life events. After adjustment for covariates, hair glucocorticoids increased with age, male sex, black or brown hair color, and frequency of sweating on the scalp, and decreased with higher hair washing frequency (P<0.05). HairE was decreased in participants who used systemic corticosteroids (5.4 vs. 8.5pg/mg hair, P=0.041), and in participants who only used local agents such as inhaled, topical and nasal corticosteroids (6.8 vs. 8.5pg/mg, P=0.005). Recent life events were positively associated with HairF after adjustment for age and sex (P=0.026), but this association lost significance after adjustment for hair related characteristics (P>0.05). HairE can be a useful marker to detect mild adrenal suppression due to corticosteroid use in the general population, even when only inhaled, nasal or topical corticosteroids are used, which suggests that these commonly used agents induce systemic effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

Characterisation of 11β-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat

PubMed Central

Bujalska, Iwona J; Durrani, Omar M; Abbott, Joseph; Onyimba, Claire U; Khosla, Pamela; Moosavi, Areeb H; Reuser, Tristan T Q; Stewart, Paul M; Tomlinson, Jeremy W; Walker, Elizabeth A; Rauz, Saaeha

2007-01-01

Glucocorticoids (GCs) have a profound effect on adipose biology increasing tissue mass causing central obesity. The pre-receptor regulation of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that activates cortisol from cortisone has been postulated as a fundamental mechanism underlying the metabolic syndrome mediating adipocyte hyperplasia and hypertrophy in the omental (OM) depot. Orbital adipose tissue (OF) is the site of intense inflammation and tissue remodelling in several orbital inflammatory disease states. In this study, we describe features of the GC metabolic pathways in normal human OF depot and compare it with subcutaneous (SC) and OM depots. Using an automated histological characterisation technique, OF adipocytes were found to be significantly smaller (parameters: area, maximum diameter and perimeter) than OM and SC adipocytes (P<0·001). Although immunohistochemical analyses demonstrated resident CD68+ cells in all three whole tissue adipose depots, OF CD68 mRNA and protein expression exceeded that of OM and SC (mRNA, P<0·05; protein, P<0·001). In addition, there was higher expression of glucocorticoid receptor (GR)α mRNA in the OF whole tissue depot (P<0·05). Conversely, 11β-HSD1 mRNA together with the markers of late adipocyte differentiation (FABP4 and G3PDH) were significantly lower in OF. Primary cultures of OF preadipocytes demonstrated predominant 11β-HSD1 oxo-reductase activity with minimal dehydrogenase activity. Orbital adipocytes are smaller, less differentiated, and express low levels of 11β-HSD1 but abundant GRα compared with SC and OM. OF harbours a large CD68+ population. These characteristics define an orbital microenvironment that has the potential to respond to sight-threatening orbital inflammatory disease. PMID:17283228

Effect of genetic polymorphism on the inhibition of dopamine formation from p-tyramine catalyzed by brain cytochrome P450 2D6.

PubMed

Niwa, Toshiro; Shizuku, Marina; Yamano, Kaori

2017-04-15

The inhibitory effects of steroid hormones, including glucocorticoids such as cortisol, and related compounds on dopamine formation from p-tyramine, catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. Inhibition constants (K i ) or 50% inhibitory concentrations of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, progesterone, and pregnenolone) and quinidine and quinine-typical potent inhibitors of the human CYP2D6 and rat CYP2D subfamily, respectively-toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were compared. Although most steroid hormones had no or minor inhibitory effects on the dopamine formation by all CYP2D6 variants, progesterone inhibited the metabolism and K i value against CYP2D6.10 was approximately twice that for CYP2D6.1 and CYP2D6.2. Quinidine exhibited stronger inhibition than quinine; however, these two compounds inhibited the CYP2D6.10-mediated reaction more weakly than the CYP2D6.1 and CYP2D6.2 reactions. These results suggest that CYP2D6 polymorphism would affect drug interaction through dopamine formation in the brain. Copyright © 2017 Elsevier Inc. All rights reserved.

Contrasting influence of NADPH and a NADPH-regenerating system on the metabolism of carbonyl-containing compounds in hepatic microsomes.

PubMed

Mazur, Christopher S; Kenneke, John F; Goldsmith, Michael-Rock; Brown, Cather

2009-09-01

Carbonyl containing xenobiotics may be susceptible to NADPH-dependent cytochrome P450 (P450) and carbonyl-reduction reactions. In vitro hepatic microsome assays are routinely supplied NADPH either by direct addition of NADPH or via an NADPH-regenerating system (NRS). In contrast to oxidative P450 transformations, which occur on the periphery of a microsome vesicle, intraluminal carbonyl reduction depends on transport of cofactors across the endoplasmic reticulum (ER) membrane into the lumen. Glucose 6-phosphate, a natural cofactor and component of the NRS matrix, is readily transported across the ER membrane and facilitates intraluminal NADPH production, whereas direct addition of NADPH has limited access to the lumen. In this study, we compared the effects of direct addition of NADPH and use of an NRS on the P450-mediated transformation of propiconazole and 11 beta-hydroxysteroid dehydrogenase type 1 (HSD1) carbonyl reduction of cortisone and the xenobiotic triadimefon in hepatic microsomes. Our results demonstrate that the use of NADPH rather than NRS can underestimate the kinetic rates of intraluminal carbonyl reduction, whereas P450-mediated transformations were unaffected. Therefore, in vitro depletion rates measured for a carbonyl-containing xenobiotic susceptible to both intraluminal carbonyl reduction and P450 processes may not be properly assessed with direct addition of NADPH. In addition, we used in silico predictions as follows: 1) to show that 11 beta-HSD1 carbonyl reduction was energetically more favorable than oxidative P450 transformation; and 2) to calculate chemical binding score and the distance between the carbonyl group and the hydride to be transferred by NADPH to identify other 11 beta-HSD1 substrates for which reaction kinetics may be underestimated by direct addition of NADPH.

Protective effects of carbenoxolone, an 11β-HSD1 inhibitor, against chemical induced dry eye syndrome.

PubMed

Na, Yoon-Ju; Choi, Kyoung-Jin; Park, Sung Bum; Sung, Hye-Rim; Jung, Won Hoon; Kim, Hee Youn; Rhee, Sang Dal; Kim, Ki Young

2017-11-01

Dry eye syndrome (DES) is a disorder of the eye due to tear deficiency or excessive evaporation that causes damage to the eye and is associated with discomfort and dryness. 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) is an enzyme that converts inactive cortisone to active cortisol. Recently, 11β-HSD1 has been expressed in human and rodent eyes and has been recognized as a target of glaucoma. In this study, the therapeutic effects and underlying mechanisms of topical carbenoxolone, an 11β-HSD1 inhibitor, were investigated in benzalkonium chloride (BAC)-treated human conjunctival epithelial cells and a rat DES model. In the in vitro study, carbenoxolone dose-dependently inhibited cell death and 11β-HSD1 activity in BAC-treated human conjunctival epithelial cells. For the in vivo study, carbenoxolone or a solvent was administered to the BAC-induced DES model twice daily. BAC-treated rat eyes showed significant increases in ocular surface damage, a reduction of tears, decrease corneal thickness, corneal basement membrane destruction, apoptosis in the conjunctival epithelium, and expression of pro-inflammatory cytokines (TNF-α and IL-6) and 11β-HSD1. These effects of BAC were reversed by topical carbenoxolone treatment. These results demonstrate that carbenoxolone can prevent DES by inhibiting pro-inflammatory cytokine expression and cell death of the corneal and conjunctival epithelium via inhibition of both 11β-HSD1 activity and expression in the eyes of BAC-treated rats. It is suggested that topical 11β-HSD1 inhibitors may provide a new therapeutic window in the prevention and/or treatment of DES.

Schizophrenia or Atypical Lupus Erythematosus with Predominant Psychiatric Manifestations over 25 Years: Case Analysis and Review

PubMed Central

Mack, Axel; Pfeiffer, Christiane; Schneider, E. Marion; Bechter, Karl

2017-01-01

We observed a case over 25 years of relapsing–remitting schizophrenic spectrum disorder, varying regarding the main symptomatology between more depressive or more schizoaffective or rather typical schizophrenic syndrome. Diseased phases were repeatedly accompanied by minor skin lesions, which were initially classified as mixed tissue disorder. Psychotic phases were waxing–waning over years. During one later relapse, skin involvement was severe, classified to likely represent an allergic reaction to psychopharmaca; this generalized exanthema remitted rapidly with cortisone treatment and azathioprine. Under continued azathioprine and low dose neuroleptics, the patient remitted completely, appearing psychiatrically healthy for 16 years. When azathioprine was set off due to pregnancy, an extraordinary severe relapse of schizophrenia like psychosis accompanied by most severe skin lesions developed within a few weeks, then requiring 2 years of psychiatric inpatient treatment. Finally, a diagnosis of systemic lupus erythematodes plus neuropsychiatric lupus was made. A single CSF sample in 2013 showed suspicious biomarkers, matching with CSF cytokine profiling in schizophrenic and affective spectrum disorder patients and indicated mild neuroinflammation. Complex immune suppressive treatment was reinitiated short after relapse, but was only partially successful. However, surprisingly the psychosis and skin lesions remitted (in parallel) when belimumab was given (add-on). The very details of this complicated, long-term disease course are discussed also with regard to general ideas, in particular with respect to the question if this case of seemingly comorbid schizophrenia with minor autoimmunity signs represented a case of one emerging autoimmune disorder with variant manifestations systemically and within the CNS, though atypically with predominant appearance as a schizophrenia spectrum disorder. PMID:28798699

Discovery of safety biomarkers for atorvastatin in rat urine using mass spectrometry based metabolomics combined with global and targeted approach.

PubMed

Kumar, Bhowmik Salil; Lee, Young-Joo; Yi, Hong Jae; Chung, Bong Chul; Jung, Byung Hwa

2010-02-19

In order to develop a safety biomarker for atorvastatin, this drug was orally administrated to hyperlipidemic rats, and a metabolomic study was performed. Atorvastatin was given in doses of either 70 mg kg(-1) day(-1) or 250 mg kg(-1) day(-1) for a period of 7 days (n=4 for each group). To evaluate any abnormal effects of the drug, physiological and plasma biochemical parameters were measured and histopathological tests were carried out. Safety biomarkers were derived by comparing these parameters and using both global and targeted metabolic profiling. Global metabolic profiling was performed using liquid chromatography/time of flight/mass spectrometry (LC/TOF/MS) with multivariate data analysis. Several safety biomarker candidates that included various steroids and amino acids were discovered as a result of global metabolic profiling, and they were also confirmed by targeted metabolic profiling using gas chromatography/mass spectrometry (GC/MS) and capillary electrophoresis/mass spectrometry (CE/MS). Serum biochemical and histopathological tests were used to detect abnormal drug reactions in the liver after repeating oral administration of atorvastatin. The metabolic differences between control and the drug-treated groups were compared using PLS-DA score plots. These results were compared with the physiological and plasma biochemical parameters and the results of a histopathological test. Estrone, cortisone, proline, cystine, 3-ureidopropionic acid and histidine were proposed as potential safety biomarkers related with the liver toxicity of atorvastatin. These results indicate that the combined application of global and targeted metabolic profiling could be a useful tool for the discovery of drug safety biomarkers. Copyright 2009 Elsevier B.V. All rights reserved.

Biological Variability in Serum Cortisol Concentration Post-adrenocorticotropic Hormone Stimulation in Healthy Dogs.

PubMed

Gal, A; Weidgraaf, K; Bowden, J P; Lopez-Villalobos, N; Cave, N J; Chambers, J P; Castillo-Alcala, F

2017-05-01

The ACTH stimulation has low sensitivity for the diagnosis of hypercortisolism possibly as a result of biological and analytical variability. To report the components of biological and analytical variability in serum cortisol concentration post-ACTH stimulation ([cortisol]) in healthy dogs. Fourteen healthy harrier hound dogs. The data were extracted from a separate, prospective, randomized, double-blinded, controlled discovery study in which dogs treated with vehicle control and 4 different doses of cortisone acetate (CA) for 7 days had an ACTH stimulation test performed to confirm the dose-dependent effect of CA. The index of individuality (IoI), the critical difference between sequential measurements (C D ), and the number of measurements required to assess the homeostatic set point (HSP) of [cortisol] with confidence intervals (CI) of 90 and 95% were estimated. The IoI was equal to 1.1 and the C D was 3.3 μg/dL (92 nmol/L). The number of measurements required to assess the HSP of [cortisol] with CI of 90 and 95% were 3 and 15, respectively. Additionally, mean [cortisol] was higher in males than in females (13.3 ± 4 μg/dL [366 ± 114 nmol/L] vs. 11.5 ± 2.5 μg/dL [318 ± 65 nmol/L], respectively; P = .046). As expected, treatment with CA resulted in a dose-dependent suppression of [cortisol]. False-negative test results in hypercortisolism could occur when [cortisol] is outside of the individual's HSP and within the reference interval. The large C D emphasizes the importance of assessing clinically relevant parameters in the diagnosis and monitoring of HC. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Development of an animal-borne blood sample collection device and its deployment for the determination of cardiovascular and stress hormones in phocid seals.

PubMed

Takei, Yoshio; Suzuki, Ippei; Wong, Marty K S; Milne, Ryan; Moss, Simon; Sato, Katsufumi; Hall, Ailsa

2016-10-01

An animal-borne blood sampler with data-logging functions was developed for phocid seals, which collected two blood samples for the comparison of endocrinological/biochemical parameters under two different conditions. The sampler can be triggered by preset hydrostatic pressure, acceleration (descending or ascending), temperature, and time, and also manually by light. The sampling was reliable with 39/50 (78%) successful attempts to collect blood samples. Contamination of fluids in the tubing to the next blood sample was <1%, following the prior clearance of the tubing to a waste syringe. In captive harbor seals ( Phoca vitulina ), the automated blood-sampling method was less stressful than direct blood withdrawal, as evidenced by lower levels of stress hormones ( P < 0.05 for ACTH and P = 0.078 for cortisol). HPLC analyses showed that both cortisol and cortisone were circulating in seal blood. Using the sampler, plasma levels of cardiovascular hormones, atrial natriuretic peptide (ANP), AVP, and ANG II were compared in grey seals ( Halichoerus grypus ), between samples collected when the animals were on land and in the water. HPLC analyses determined that [Met 12 ] ANP (1-28) and various forms of angiotensins (ANG II, III, and IV) were circulating in seal blood. Although water immersion profoundly changes the plasma levels of cardiovascular hormones in terrestrial mammals, there were only tendencies toward an increase in ANP ( P = 0.069) and a decrease in AVP ( P = 0.074) in the seals. These results suggest that cardiovascular regulation in phocid seals may have undergone adaptation during evolution of the carnivore to a semiaquatic lifestyle. Copyright © 2016 the American Physiological Society.

Accuracy of immunoassay and mass spectrometry urinary free cortisol in the diagnosis of Cushing's syndrome.

PubMed

Aranda, G; Careaga, M; Hanzu, F A; Patrascioiu, I; Ríos, P; Mora, M; Morales-Romero, B; Jiménez, W; Halperin, I; Casals, G

2016-10-01

Urinary free cortisol (UFC) determination by highly specific methods as mass spectrometry instead of commercially available antibody-based immunoassays is increasingly recommended. However, clinical comparisons of both analytical approaches in the screening of Cushing's syndrome (CS) are not available. The aim of this study was to evaluate the diagnostic value of mass spectrometry versus immunoassay measurements of 24 h-UFC in the screening of CS. Cross-sectional study of 33 histologically confirmed CS patients: 25 Cushing's disease, 5 adrenal CS and 3 ectopic CS; 92 non-CS patients; and 35 healthy controls. UFC by immunoassay (UFCxIA) and mass spectrometry (UFCxMS), urinary free cortisone (UFCo) and UFC:UFCo ratio were measured, together with creatinine-corrected values. Sensitivity, specificity, AUC and Landis and Koch concordance index were determined. AUC for UFCxIA and UFCxMS were 0.77 (CI 0.68-0.87) and 0.77 (CI 0.67-0.87) respectively, with a kappa coefficient 0.60 and strong Landis and Koch concordance index. The best calculated cutoff values were 359 nmol/24 h for UFCxIA (78 % sensitivity, 62 % specificity) and 258.1 nmol/24 h for UCFxMS (53 % sensitivity, 86 % specificity). The upper limit of UFCxIA and UCFxMS reference ranges were 344.7 and 169.5 nmol/24 h respectively. Sensitivity and specificity for CS diagnosis at these cutpoints were 84 and 56 % for UFCxIA and 81 and 54 % for UFCxMS. According to our data, both methods present a very similar diagnostic value. However, results suggest that lower cutoff points for mass spectrometry may be necessary in order to improve clinical sensitivity.

A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1.

PubMed

Li, Wei; Li, Jianhua; Ashok, Mala; Wu, Rongqian; Chen, Dazhi; Yang, Lihong; Yang, Huan; Tracey, Kevin J; Wang, Ping; Sama, Andrew E; Wang, Haichao

2007-03-15

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10-25 microM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis.

A Cardiovascular Drug Rescues Mice from Lethal Sepsis by Selectively Attenuating a Late-Acting Proinflammatory Mediator, High Mobility Group Box 11

PubMed Central

Li, Wei; Li, Jianhua; Ashok, Mala; Wu, Rongqian; Chen, Dazhi; Yang, Lihong; Yang, Huan; Tracey, Kevin J.; Wang, Ping; Sama, Andrew E.; Wang, Haichao

2007-01-01

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-γ) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10–25 μM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis. PMID:17339485

Different glucocorticoids vary in their genomic and non-genomic mechanism of action in A549 cells

PubMed Central

Croxtall, Jamie D; van Hal, Peter Th W; Choudhury, Qam; Gilroy, Derek W; Flower, Rod J

2002-01-01

We have examined the effects of 12 glucocorticoids as inhibitors of A549 cell growth. Other than cortisone and prednisone, all the glucocorticoids inhibited cell growth and this was strongly correlated (r=0.91) with inhibition of prostaglandin (PG)E2 formation. The molecular mechanism by which the active steroids prevented PGE2 synthesis was examined and three groups were identified. Group A drugs did not inhibit arachidonic acid release but inhibited the induction of COX2. Group B drugs were not able to inhibit the induction of COX2 but inhibited arachidonic acid release through suppression of cPLA2 activation. Group C drugs were apparently able to bring about both effects. The inhibitory actions of all steroids was dependent upon glucocorticoid receptor occupation since RU486 reversed their effects. However, group A acted through the NF-κB pathway to inhibit COX2 as the response was blocked by the inhibitor geldanamycin which prevents dissociation of GR and the effect was blocked by APDC, the NF-κB inhibitor. On the other hand, the group B drugs were not inhibited by NF-κB inhibitors or geldanamycin but their effect was abolished by the src inhibitor PP2. Group C drugs depended on both pathways. In terms of PGE2 generation, there is clear evidence of two entirely separate mechanisms of glucocorticoid action, one of which correlates with NF-κB mediated genomic actions whilst the other, depends upon rapid effects on a cell signalling system which does not require dissociation of GR. The implications for these findings are discussed. PMID:11815387

Ultraviolet- and infrared-induced 11 beta-hydroxysteroid dehydrogenase type 1 activating skin photoaging is inhibited by red ginseng extract containing high concentration of ginsenoside Rg3(S).

PubMed

Nam, Jin-Ju; Min, Ji-Eun; Son, Min-Ho; Oh, Jin-Hwan; Kang, Seunghyun

2017-11-01

Sun irradiation is one of major extrinsic stressors responsible for premature skin aging through activation and expression of 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone to active cortisol. The aim of this study was to evaluate the inhibitory effects of red ginseng extract containing high concentrations of ginsenoside Rg3 (S) (GERg3) on 11β-HSD1-induced skin photoaging. To evaluate the inhibitory effects of GERg3 on ultraviolet- (UV) or infrared (IR)-induced skin photoaging, human dermal fibroblasts or a normal human 3D skin model was exposed to UV or an IR. RT-PCR, ELISA, Western blot, and H&E staining were used for evaluations. GERg3 was isolated from crude red ginseng. GERg3 inhibited the increased expressions of 11β-HSD1, interleukin (IL)-6, and matrix metalloproteinase-1 (MMP-1) in UVB- or IR-exposed Hs68 cells. Additionally, the increased cortisol, IL-6, and MMP-1 expressions were effectively reduced by GERg3 in UVA-exposed 3D skin models. The photoinduced decrease in type 1 procollagen also recovered as a result of GERg3 treatment in Hs68 cells and the 3D skin model. In addition, the UVA-exposed dermal thickness was decreased in comparison with the UVA-protected 3D skin model, recovered with GERg3 treatment. GERg3 had antiphotoaging effects in UV- or IR-exposed human dermal fibroblasts and normal human 3D skin model. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The secretion, synthesis, and metabolism of cortisol and its downstream genes in the H-P-I axis of rare minnows (Gobiocypris rarus) are disrupted by acute waterborne cadmium exposure.

PubMed

Liu, Xiao-Hong; Xie, Bi-Wen; Wang, Zhi-Jian; Jin, Li; Zhang, Yao-Guang

2016-01-01

The H (hypothalamic)-P (pituitary)-I (interrenal) axis plays a critical role in the fish stress response and is regulated by several factors. Cadmium (Cd) is one of the most toxic heavy metals in the world, but its effects on the H-P-I axis of teleosts are largely unknown. Using rare minnow (Gobiocypris rarus) as an experimental animal, we found that Cd only disrupted the secretion and synthesis of cortisol. Neither hormones at the H or P level nor the expressions of their receptor genes (corticotropin-releasing hormone receptor (CRHR) and melanocortin receptor 2 (MC2R)) were affected. Steroidogenic acute regulator (StAR), CYP11A1 and CYP11B1, which encode the key enzymes in the cortisol synthesis pathway, were significantly up-regulated in the kidney (including the head kidney). The level of 11β-HSD2, which is required for the conversion of cortisol to cortisone, was increased in the kidney, intestine, brain, and hepatopancreas, whereas the expression of 11β-HSD1, which encodes the reverse conversion enzyme, was increased in the gill, kidney and almost unchanged in other tissues. The enzyme activity concentration of 11β-HSD2 was increased in the kidney as well. The level of glucocorticoid receptor (GR) decreased in the intestine, gill and muscle, and the key GR regulator FK506 binding protein5 (FKBP5) was up-regulated in the GR-decreased tissues, whereas the level of nuclear receptor co-repressor 1 (NCoR1), another GR regulator remained almost unchanged. Thus, GR, FKBP5 and 11β-HSD2 may be involved in Cd-induced cortisol disruption. Copyright © 2016 Elsevier Inc. All rights reserved.

Severe metabolic alkalosis, hypokalemia, and respiratory acidosis induced by the Chinese herbal medicine yokukansan in an elderly patient with muscle weakness and drowsiness.

PubMed

Yamada, Shunsuke; Tokumoto, Masanori; Kansui, Yasuo; Wakisaka, Yoshinobu; Uchizono, Yuji; Tsuruya, Kazuhiko; Ooboshi, Hiroaki

2013-05-01

Yokukansan is a Chinese herbal medicine containing licorice that has been shown to alleviate the behavioral and psychological symptoms of Alzheimer's disease, with few adverse effects. Increasing numbers of patients with Alzheimer's disease in Japan are now being treated with this drug. However, yokukansan should be used with caution because of its potential to induce pseudoaldosteronism through the inhibition of 11-beta-hydroxysteroid dehydrogenase type 2, which metabolizes cortisol into cortisone. We present the case of an 88-year-old woman with a history of Alzheimer's disease who was transferred to our emergency department because of drowsiness, anorexia, and muscle weakness. Her blood pressure was 168/90 mmHg. Laboratory data showed serum potassium of 1.9 mmol/l, metabolic alkalosis (pH 7.54; HCO 3 - , 50.5 mmol/l; chloride, 81 mmol/l; sodium, 140 mmol/l), and respiratory disorders (pCO 2 , 60.5 mmHg; pO 2 , 63.8 mmHg). Plasma renin activity and aldosterone concentration were suppressed, and urinary potassium excretion was 22 mmol/l (calculated transtubular potassium gradient 12.9). An electrocardiogram showed flat T-waves and U-waves with ventricular premature contractions. Echocardiography denied volume depletion. Medical interview disclosed that she had been treated with a Chinese herbal medicine (yokukansan) containing licorice. The final diagnosis was pseudoaldosteronism and respiratory acidosis induced by licorice. Hypokalemia, metabolic alkalosis, and respiratory acidosis all subsided shortly after the discontinuation of yokukansan and initiation of intravenous potassium replacement. This case highlights the need for nephrologists to consider the possible involvement of Chinese herbal medicines, including yokukansan, when they encounter hypokalemia in elderly patients.

Virtual Screening as a Strategy for the Identification of Xenobiotics Disrupting Corticosteroid Action

PubMed Central

Praxmarer, Lukas; Chantong, Boonrat; Cereghetti, Diego; Winiger, Rahel; Schuster, Daniela; Odermatt, Alex

2012-01-01

Background Impaired corticosteroid action caused by genetic and environmental influence, including exposure to hazardous xenobiotics, contributes to the development and progression of metabolic diseases, cardiovascular complications and immune disorders. Novel strategies are thus needed for identifying xenobiotics that interfere with corticosteroid homeostasis. 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) and mineralocorticoid receptors (MR) are major regulators of corticosteroid action. 11β-HSD2 converts the active glucocorticoid cortisol to the inactive cortisone and protects MR from activation by glucocorticoids. 11β-HSD2 has also an essential role in the placenta to protect the fetus from high maternal cortisol concentrations. Methods and Principal Findings We employed a previously constructed 3D-structural library of chemicals with proven and suspected endocrine disrupting effects for virtual screening using a chemical feature-based 11β-HSD pharmacophore. We tested several in silico predicted chemicals in a 11β-HSD2 bioassay. The identified antibiotic lasalocid and the silane-coupling agent AB110873 were found to concentration-dependently inhibit 11β-HSD2. Moreover, the silane AB110873 was shown to activate MR and stimulate mitochondrial ROS generation and the production of the proinflammatory cytokine interleukin-6 (IL-6). Finally, we constructed a MR pharmacophore, which successfully identified the silane AB110873. Conclusions Screening of virtual chemical structure libraries can facilitate the identification of xenobiotics inhibiting 11β-HSD2 and/or activating MR. Lasalocid and AB110873 belong to new classes of 11β-HSD2 inhibitors. The silane AB110873 represents to the best of our knowledge the first industrial chemical shown to activate MR. Furthermore, the MR pharmacophore can now be used for future screening purposes. PMID:23056542

Glucocorticoid activity and metabolism with NaCl-induced low-grade metabolic acidosis and oral alkalization: results of two randomized controlled trials.

PubMed

Buehlmeier, Judith; Remer, Thomas; Frings-Meuthen, Petra; Maser-Gluth, Christiane; Heer, Martina

2016-04-01

Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid-base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases.

The acute autonomic stress response and amniotic fluid glucocorticoids in second-trimester pregnant women.

PubMed

La Marca-Ghaemmaghami, Pearl; Dainese, Sara M; La Marca, Roberto; Zimmermann, Roland; Ehlert, Ulrike

2015-01-01

The maternal autonomic nervous system (ANS) has received little attention in the investigation of biological mechanisms linking prenatal stress to fetal cortisol (F) excess. In vitro, norepinephrine and epinephrine inhibit placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which protects the fetus from F overexposure by inactivating it to cortisone (E). Here, we investigated the acute ANS stress response to an amniocentesis and its association with amniotic fluid F, E, and E/(E + F) as a marker of fetoplacental 11β-HSD2 activity. An aliquot of amniotic fluid was obtained from 34 healthy, second-trimester pregnant women undergoing amniocentesis. Repeated assessment of mood states served to examine the psychological stress response to amniocentesis. Saliva samples were collected to measure stress-induced changes in salivary α-amylase concentrations in response to amniocentesis. Cardiac parameters were measured continuously. Undergoing amniocentesis induced significant psychological and autonomic alterations. Low-frequency (LF)/high-frequency (HF) baseline, suggested to reflect sympathovagal balance, was negatively correlated with amniotic E/(E + F) (r=-0.53, p = .002) and positively with F (r = 0.62, p < .001). In contrast, a stronger acute LF/HF response was positively associated with E/(E + F) (r = 0.44, p = .012) and negatively with F (r=-0.40, p = .025). These findings suggest that the maternal ANS is involved in the regulation of the fetoplacental barrier to stress. Allostatic processes may have been initiated to counterbalance acute stress effects. In contrast, higher LF/HF baseline values, possibly indicative of chronic stress exposure, may have inhibited 11β-HSD2 activity in the fetoplacental unit. These results parallel animal findings of up-regulated placental 11β-HSD2 in response to acute stress but impairment under chronic stress.

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

PubMed Central

Chapman, Karen; Holmes, Megan

2013-01-01

Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues. PMID:23899562

The 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor INCB13739 Improves Hyperglycemia in Patients With Type 2 Diabetes Inadequately Controlled by Metformin Monotherapy

PubMed Central

Rosenstock, Julio; Banarer, Salomon; Fonseca, Vivian A.; Inzucchi, Silvio E.; Sun, William; Yao, Wenqing; Hollis, Gregory; Flores, Robert; Levy, Richard; Williams, William V.; Seckl, Jonathan R.; Huber, Reid

2010-01-01

OBJECTIVE 11-β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the 11βHSD1 inhibitor INCB13739 were assessed when added to ongoing metformin monotherapy in patients with type 2 diabetes exhibiting inadequate glycemic control (A1C 7–11%). RESEARCH DESIGN AND METHODS This double-blind placebo-controlled paralleled study randomized 302 patients with type 2 diabetes (mean A1C 8.3%) on metformin monotherapy (mean 1.5 g/day) to receive one of five INCB13739 doses or placebo once daily for 12 weeks. The primary end point was the change in A1C at study end. Other end points included changes in fasting glucose, lipids, weight, adverse events, and safety. RESULTS After 12 weeks, 200 mg of INCB13739 resulted in significant reductions in A1C (−0.6%), fasting plasma glucose (−24 mg/dl), and homeostasis model assessment–insulin resistance (HOMA-IR) (−24%) compared with placebo. Total cholesterol, LDL cholesterol, and triglycerides were all significantly decreased in hyperlipidemic patients. Body weight decreased relative to placebo after INCB13739 therapy. A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was observed. Basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged by INCB13739. Adverse events were similar across all treatment groups. CONCLUSIONS INCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11βHSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes. PMID:20413513

Immunodetection of 11 beta-hydroxysteroid dehydrogenase type 2 in human mineralocorticoid target tissues: evidence for nuclear localization.

PubMed

Shimojo, M; Ricketts, M L; Petrelli, M D; Moradi, P; Johnson, G D; Bradwell, A R; Hewison, M; Howie, A J; Stewart, P M

1997-03-01

11 beta-Hydroxysteroid dehydrogenase (11 beta HSI) is an enzyme complex responsible for the conversion of hormonally active cortisol to inactive cortisone; two isoforms of the enzyme have been cloned and characterized. Clinical observations from patients with the hypertensive syndrome apparent mineralocorticoid excess, recently explained on the basis of mutations in the human 11 beta HSD2 gene, suggest that it is the 11 beta HSD2 isoform that serves a vital role in dictating specificity upon the mineralocorticoid receptor (MR). We have raised a novel antibody in sheep against human 11 beta HSD2 using synthetic multiantigenic peptides and have examined the localization and subcellular distribution of 11 beta HSD2 in mineralocorticoid target tissues. The immunopurified antibody recognized a single band of approximately 44 kDa in placenta, trophoblast, and distal colon. In kidney tissue, two bands of approximately 44 and 48 kDa were consistently observed. No signal was seen in decidua, adrenal, or liver. Immunoperoxidase studies on the mineralocorticoid target tissues, kidney, colon, and parotid gland indicated positive staining in epithelial cells known to express the MR: respectively, renal collecting ducts, surface and crypt colonic epithelial cells, and parotid duct epithelial cells. No staining was seen in these tissues in other sites. The intracellular localization of 11 beta HSD2 in kidney and colon epithelial cells was addressed using confocal laser microscopy. Parallel measurements of 11 beta HSD2 and nuclear propidium iodide fluorescence on sections scanned through an optical section of approximately 0.1 micron indicated significant 11 beta HSD2 immunofluorescence in the nucleus. In human kidney, colon, and salivary gland, 11 beta HSD2 protects the MR from glucocorticoid excess in an autocrine fashion. Furthermore, within these tissues, 11 beta HSD2, which had been considered to be a microsomal enzyme, is also found in the nucleus, suggesting that the interaction between the MR and aldosterone or cortisol is in part a nuclear event.

Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer’s Disease Using Metabolomics

PubMed Central

Trushina, Eugenia; Dutta, Tumpa; Persson, Xuan-Mai T.; Mielke, Michelle M.; Petersen, Ronald C.

2013-01-01

Alzheimer’s Disease (AD) currently affects more than 5 million Americans, with numbers expected to grow dramatically as the population ages. The pathophysiological changes in AD patients begin decades before the onset of dementia, highlighting the urgent need for the development of early diagnostic methods. Compelling data demonstrate that increased levels of amyloid-beta compromise multiple cellular pathways; thus, the investigation of changes in various cellular networks is essential to advance our understanding of early disease mechanisms and to identify novel therapeutic targets. We applied a liquid chromatography/mass spectrometry-based non-targeted metabolomics approach to determine global metabolic changes in plasma and cerebrospinal fluid (CSF) from the same individuals with different AD severity. Metabolic profiling detected a total of significantly altered 342 plasma and 351 CSF metabolites, of which 22% were identified. Based on the changes of >150 metabolites, we found 23 altered canonical pathways in plasma and 20 in CSF in mild cognitive impairment (MCI) vs. cognitively normal (CN) individuals with a false discovery rate <0.05. The number of affected pathways increased with disease severity in both fluids. Lysine metabolism in plasma and the Krebs cycle in CSF were significantly affected in MCI vs. CN. Cholesterol and sphingolipids transport was altered in both CSF and plasma of AD vs. CN. Other 30 canonical pathways significantly disturbed in MCI and AD patients included energy metabolism, Krebs cycle, mitochondrial function, neurotransmitter and amino acid metabolism, and lipid biosynthesis. Pathways in plasma that discriminated between all groups included polyamine, lysine, tryptophan metabolism, and aminoacyl-tRNA biosynthesis; and in CSF involved cortisone and prostaglandin 2 biosynthesis and metabolism. Our data suggest metabolomics could advance our understanding of the early disease mechanisms shared in progression from CN to MCI and to AD. PMID:23700429

Anti-inflammatory effect of a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor via the stimulation of heme oxygenase-1 in LPS-activated mice and J774.1 murine macrophages.

PubMed

Park, Sung Bum; Park, Ji Seon; Jung, Won Hoon; Kim, Hee Youn; Kwak, Hyun Jung; Ahn, Jin Hee; Choi, Kyoung-Jin; Na, Yoon-Ju; Choi, Sunhwa; Dal Rhee, Sang; Kim, Ki Young

2016-08-01

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive cortisone to the active cortisol. 11β-HSD1 may be involved in the resolution of inflammation. In the present study, we investigate the anti-inflammatory effects of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), a selective 11β-HSD1 inhibitor, in lipopolysaccharide (LPS)-activated C57BL/6J mice and macrophages. LPS increased 11β-HSD1 activity and expression in macrophages, which was inhibited by KR-66344. In addition, KR-66344 increased survival rate in LPS treated C57BL/6J mice. HO-1 mRNA expression level was increased by KR-66344, and this effect was reversed by the HO competitive inhibitor, ZnPP, in macrophages. Moreover, ZnPP reversed the suppression of ROS formation and cell death induced by KR-66344. ZnPP also suppressed animal survival rate in LPS plus KR-66344 treated C57BL/6J mice. In the spleen of LPS-treated mice, KR-66344 prevented cell death via suppression of inflammation, followed by inhibition of ROS, iNOS and COX-2 expression. Furthermore, LPS increased NFκB-p65 and MAPK phosphorylation, and these effects were abolished by pretreatment with KR-66344. Taken together, KR-66344 protects against LPS-induced animal death and spleen injury by inhibition of inflammation via induction of HO-1 and inhibition of 11β-HSD1 activity. Thus, we concluded that the selective 11β-HSD1 inhibitor may provide a novel strategy in the prevention/treatment of inflammatory disorders in patients. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

UVB induces epidermal 11β-hydroxysteroid dehydrogenase type 1 activity in vivo.

PubMed

Tiganescu, Ana; Hupe, Melanie; Jiang, Yan J; Celli, Anna; Uchida, Yoshikazu; Mauro, Theodora M; Bikle, Daniel D; Elias, Peter M; Holleran, Walter M

2015-05-01

Detrimental consequences of ultraviolet radiation (UVR) in skin include photoageing, immunosuppression and photocarcinogenesis, processes also significantly regulated by local glucocorticoid (GC) availability. In man, the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) generates the active GC cortisol from cortisone (or corticosterone from 11-dehydrocorticosterone in rodents). 11β-HSD1 oxo-reductase activity requires the cofactor NADPH, generated by hexose-6-phosphate dehydrogenase. We previously demonstrated increased 11β-HSD1 levels in skin obtained from photoexposed versus photoprotected anatomical regions. However, the direct effect of UVR on 11β-HSD1 expression remains to be elucidated. To investigate the cutaneous regulation of 11β-HSD1 following UVR in vivo, the dorsal skin of female SKH1 mice was irradiated with 50, 100, 200 and 400 mJ/cm(2) UVB. Measurement of transepidermal water loss, 11β-HSD1 activity, mRNA/protein expression and histological studies was taken at 1, 3 and 7 days postexposure. 11β-HSD1 and hexose-6-phosphate dehydrogenase mRNA expression peaked 1 day postexposure to 400 mJ/cm(2) UVB before subsequently declining (days 3 and 7). Corresponding increases in 11β-HSD1 protein and enzyme activity were observed 3 days postexposure coinciding with reduced GC receptor mRNA expression. Immunofluorescence studies revealed 11β-HSD1 localization to hyperproliferative epidermal keratinocytes in UVB-exposed skin. 11β-HSD1 expression and activity were also induced by 200 and 100 (but not 50) mJ/cm(2) UVB and correlated with increased transepidermal water loss (indicative of barrier disruption). UVB-induced 11β-HSD1 activation represents a novel mechanism that may contribute to the regulation of cutaneous responses to UVR exposure. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Recovery of HPA Axis Function After Successful Gonadotropin-Induced Pregnancy and Delivery in a Woman With Panhypopituitarism: Case Report and Review.

PubMed

Wang, Yi; Zhang, Qiongyue; Yang, Jianzhi; Zhao, Xiaolong; He, Min; Shou, Xuefei; Li, Shiqi; Li, Yiming; Wang, Yongfei; Ye, Hongying

2015-09-01

Hypopituitarism is defined as the partial or complete defect of anterior pituitary hormone secretion. Patients with hypopituitarism usually need life-long hormone replacement therapy. However, in this case, we report a patient with panhypopituitarism whose hypothalamus-pituitary-adrenal (HPA) axis function was completely recovered after pregnancy and delivery. In this case study, we reported the case management and conducted a review of literature to identify the possible mechanism of pituitary function recovery. The patient who suffered from secondary amenorrhea was found a nonfunctioning pituitary macroadenoma, and the hormone test showed serum cortisol, FT3, FT4, thyrotropic hormone, and prolactin were at normal range. After surgical removal of the tumor which invasion in the sellar region, the patient had panhypopituitarism confirmed by the routine hormone test. Though spontaneous pregnancy is impossible in female patients with panhypopituitarism, the patient was restored fertility by the help of artificial reproductive techniques. After the confirmation of the pregnancy, levothyroixine was increased to 75 μg daily and readjusted to 150 μg daily before delivery according to the monthly measurement thyroid function. Hydrocortisone 10 mg daily replaced cortisone acetate; the dose was increased according to the symptoms of morning sickness. A single stress dose of hydrocortisone (200 mg) was used before elective cesarean delivery and was tapered to the dose of 10 mg per day in 1 week. Levothyroixine was reduced to 75 μg daily after delivery. During follow-up, her hypothalamus-pituitary-adrenal (HPA) axis function was completely recovered. The peak serum cortisol level could increase to 19.08 μg/dL by insulin-induced hypoglycemia. However, growth hormone remained unresponsive to the insulin-tolerance test, and thyroid hormone still needed exogenous supplementation. Hormone replacement therapy needed closely followed by endocrinologist and multidisciplinary cooperation during the pregnancy of patients with hypopituitarism. This case indicates that the pituitary function may partially recover after pregnancy in panhypopituitarism patients.

Detection of boldenone, its conjugates and androstadienedione, as well as five corticosteroids in bovine bile through a unique immunoaffinity column clean-up and two validated liquid chromatography-tandem mass spectrometry analyses.

PubMed

Chiesa, L; Nobile, M; Panseri, S; Sgoifo Rossi, C A; Pavlovic, R; Arioli, F

2014-12-10

The presence of β-boldenone II phase metabolites and prednisolone in urine samples, owing to endogenous or natural origin or illicit treatment, is under debate within the European Union. The detection of β-boldenone conjugates, α-boldenone conjugates at concentrations higher than 2 ng mL(-1) and prednisolone above the cut-off level of 5 ng mL(-1) in urine have been, until now, critical in deciding if illegal drug use has occurred. The use of urine sometimes is not entirely satisfactory, especially when the drug is administrated at low doses or when its metabolic conversion is very fast. This subsequently would hamper its detection in urine. The introduction of a new, advantageous matrix where the illicit treatment can be investigated would be highly appreciated. In this study, we have developed and validated a simple and unique immunoaffinity clean-up procedure, which was applied to bovine bile samples, followed by two different analytical liquid chromatography-electrospray-tandem mass spectrometry methods. The first method tests androstadienedione, α- and β-boldenone sulphate, glucuronate and related free forms, while the other method assays prednisolone, prednisone, dexamethasone, cortisone, and cortisol. The methods were validated according to European Commission Decision 2002/657/EC. The evaluated parameters were linearity, specificity, precision (repeatability and intra-laboratory reproducibility), recovery, decision limit and detection capability. The decision limits (CCα) were between 0.38 and 0.45 ng mL(-1) for anabolic steroids, and 0.13 and 0.15 ng mL(-1) as far as corticosteroids were concerned. Intra- and inter-day repeatability was below 15.8 and 19.9% for all analytes, respectively. The methods were applied to the analysis of some bile samples collected from untreated young bulls in order to investigate the presence of the studied steroids in this matrix. Copyright © 2014 Elsevier B.V. All rights reserved.

Glucocorticoid Signaling Enhances Expression of Glucose-Sensing Molecules in Immature Pancreatic Beta-Like Cells Derived from Murine Embryonic Stem Cells In Vitro.

PubMed

Ghazalli, Nadiah; Wu, Xiaoxing; Walker, Stephanie; Trieu, Nancy; Hsin, Li-Yu; Choe, Justin; Chen, Chialin; Hsu, Jasper; LeBon, Jeanne; Kozlowski, Mark T; Rawson, Jeffrey; Tirrell, David A; Yip, M L Richard; Ku, Hsun Teresa

2018-06-06

Pluripotent stem cells may serve as an alternative source of beta-like cells for replacement therapy of type 1 diabetes; however, the beta-like cells generated in many differentiation protocols are immature. The maturation of endogenous beta cells involves an increase in insulin expression starting in late gestation and a gradual acquisition of the abilities to sense glucose and secrete insulin by week 2 after birth in mice; however, what molecules regulate these maturation processes are incompletely known. In this study, we aim to identify small molecules that affect immature beta cells. A cell-based assay, using pancreatic beta-like cells derived from murine embryonic stem (ES) cells harboring a transgene containing an insulin 1-promoter driven enhanced green fluorescent protein reporter, was used to screen a compound library (NIH Clinical Collection-003). Cortisone, a glucocorticoid, was among five positive hit compounds. Quantitative reverse transcription-polymerase chain reaction analysis revealed that glucocorticoids enhance the gene expression of not only insulin 1 but also glucose transporter-2 (Glut2; Slc2a2) and glucokinase (Gck), two molecules important for glucose sensing. Mifepristone, a pharmacological inhibitor of glucocorticoid receptor (GR) signaling, reduced the effects of glucocorticoids on Glut2 and Gck expression. The effects of glucocorticoids on ES-derived cells were further validated in immature primary islets. Isolated islets from 1-week-old mice had an increased Glut2 and Gck expression in response to a 4-day treatment of exogenous hydrocortisone in vitro. Gene deletion of GR in beta cells using rat insulin 2 promoter-driven Cre crossed with GR flox/flox mice resulted in a reduced gene expression of Glut2, but not Gck, and an abrogation of insulin secretion when islets were incubated in 0.5 mM d-glucose and stimulated by 17 mM d-glucose in vitro. These results demonstrate that glucocorticoids positively regulate glucose sensors in immature murine beta-like cells.

Elevation of 11β-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: evidence for an intergenerational effect of maternal trauma exposure.

PubMed

Bierer, Linda M; Bader, Heather N; Daskalakis, Nikolaos P; Lehrner, Amy L; Makotkine, Iouri; Seckl, Jonathan R; Yehuda, Rachel

2014-10-01

Adult offspring of Holocaust survivors comprise an informative cohort in which to study intergenerational transmission of the effects of trauma exposure. Lower cortisol and enhanced glucocorticoid sensitivity have been previously demonstrated in Holocaust survivors with PTSD, and in offspring of Holocaust survivors in association with maternal PTSD. In other work, reduction in the activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), which inactivates cortisol, was identified in Holocaust survivors in comparison to age-matched, unexposed Jewish controls. Therefore, we investigated glucocorticoid metabolism in offspring of Holocaust survivors to evaluate if similar enzymatic decrements would be observed that might help to explain glucocorticoid alterations previously shown for Holocaust offspring. Holocaust offspring (n=85) and comparison subjects (n=27) were evaluated with clinical diagnostic interview and self-rating scales, and asked to collect a 24-h urine sample from which concentrations of cortisol and glucocorticoid metabolites were assayed by GCMS. 11β-HSD-2 activity was determined as the ratio of urinary cortisone to cortisol. Significantly reduced cortisol excretion was observed in Holocaust offspring compared to controls (p=.046), as had been shown for Holocaust survivors. However, 11β-HSD-2 activity was elevated for offspring compared to controls (p=.008), particularly among those whose mothers had been children, rather than adolescents or adults, during World War II (p=.032). The effect of paternal Holocaust exposure could not be reliably investigated in the current sample. The inverse association of offspring 11β-HSD-2 activity with maternal age at Holocaust exposure is consistent with the influence of glucocorticoid programming. Whereas a long standing reduction in 11β-HSD-2 activity among survivors is readily interpreted in the context of Holocaust related deprivation, understanding the directional effect on offspring will require replication and further exploration. Published by Elsevier Ltd.

A validated analytical method to study the long-term stability of natural and synthetic glucocorticoids in livestock urine using ultra-high performance liquid chromatography coupled to Orbitrap-high resolution mass spectrometry.

PubMed

De Clercq, Nathalie; Julie, Vanden Bussche; Croubels, Siska; Delahaut, Philippe; Vanhaecke, Lynn

2013-08-02

Due to their growth-promoting effects, the use of synthetic glucocorticoids is strictly regulated in the European Union (Council Directive 2003/74/EC). In the frame of the national control plans, which should ensure the absence of residues in food products of animal origin, in recent years, a higher frequency of prednisolone positive bovine urines has been observed. This has raised questions with respect to the stability of natural corticoids in the respective urine samples and their potential to be transformed into synthetic analogs. In this study, a ultra high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) methodology was developed to examine the stability of glucocorticoids in bovine urine under various storage conditions (up to 20 weeks) and to define suitable conditions for sample handling and storage, using an Orbitrap Exactive™. To this end, an extraction procedure was optimized using a Plackett-Burman experimental design to determine the key conditions for optimal extraction of glucocorticoids from urine. Next, the analytical method was successfully validated according to the guidelines of CD 2002/657/EC. Decision limits and detection capabilities for prednisolone, prednisone and methylprednisolone ranged, respectively, from 0.1 to 0.5μgL(-1) and from 0.3 to 0.8μgL(-1). For the natural glucocorticoids limits of detection and limits of quantification for dihydrocortisone, cortisol and cortisone ranged, respectively, from 0.1 to 0.2μgL(-1) and from 0.3 to 0.8μgL(-1). The stability study demonstrated that filter-sterilization of urine, storage at -80°C, and acidic conditions (pH 3) were optimal for preservation of glucocorticoids in urine and able to significantly limit degradation up to 20 weeks. Copyright © 2013 Elsevier B.V. All rights reserved.

11β Hydroxysteroid dehydrogenase type 2 and dietary acid load are independently associated with blood pressure in healthy children and adolescents.

PubMed

Krupp, Danika; Shi, Lijie; Maser-Gluth, Christiane; Pietzarka, Marion; Remer, Thomas

2013-03-01

The reduced activity of 11β hydroxysteroid dehydrogenase type 2 (11βHSD2) contributes to elevated blood pressure (BP) in clinical syndromes, but its effect on BP in the physiologic range is unclear. We examined the association of 11βHSD2 activity with BP in healthy children independent of known BP-related dietary and other factors and determined whether the diet-dependent acid load may constitute a dietary factor related to BP. We conducted a cross-sectional analysis in 267 healthy children (age range: 4-14 y) who provided a 24-h urine sample, a parallel 3-d weighed dietary record, and 1-3 BP measurements ±1.5 y around the urine collection. The ratio of urinary free cortisone to cortisol measured by using a radioimmunoassay was used as an index for 11βHSD2. Urinary net acid excretion and the urinary and dietary potential renal acid load (PRAL) were used to predict the diet-dependent acid load. The PRAL was calculated as the sum of major mineral nonbicarbonate anions minus the sum of mineral cations. Sex-, age- and height-independent SD scores (SDSs) of systolic and diastolic BP were used as outcomes in linear regression analyses. 11βHSD2 was inversely associated with systolic BP SDSs in basic models and in analyses adjusted for body size, maternal BP, breastfeeding, and dietary intakes of total energy, salt, and fruit and vegetables (P = 0.03). In models that included indexes of dietary acid load instead of fruit and vegetables, all 3 acid-load biomarkers were significantly (P = 0.006-0.02) directly related to systolic BP. A lower 11βHSD2 activity and higher dietary acid load may independently contribute to higher systolic BP in healthy children.

Upregulation of adipose 11-beta-hydroxysteroid dehydrogenase type 1 expression in ovariectomized rats is due to obesity rather than lack of estrogen.

PubMed

Paulsen, Søren K; Nielsen, Maria P; Richelsen, Bjørn; Bruun, Jens M; Flyvbjerg, Allan; Pedersen, Steen B

2008-04-01

Increased tissue activity of cortisol induced by the activation of inert cortisone to active cortisol through 11-beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) may play a role in the metabolic syndrome. We recently found that 11beta-HSD1 in subcutaneous adipose tissue (AT) was lower in lean women compared with lean men. Estrogen suppresses hepatic and renal 11beta-HSD1 in rats; hence we investigated the in vitro effect of estrogen on human and rat AT, and the in vivo effects on rat AT 11beta-HSD1 expression. Wistar rats were divided into four groups of eight animals. One group was sham-operated (controls) and others were ovariectomized (OVX). One OVX group was left untreated (OVX-E), another (OVX+E) received estrogen treatment, and one received a hypo-caloric diet (OVX-E+D), matching the weight gain of the control group. AT from women undergoing liposuction or surgery and from killed male and female rats were incubated with estrogen alone or in the presence of IL-1beta. Gene expressions were determined by real-time reverse transcriptase PCR. Ovariectomy resulted in a 280% increase in adipose 11beta-HSD1 expression P < 0.05). 11beta-HSD1 expression in the (OVX+E)-group was significantly reduced compared with the nonsubstituted group (P < 0.05). 11beta-HSD1 expression in the (OVX-E+D)-group was reduced significantly (P < 0.05) when compared with the level of the estrogen-substituted group. No significant differences between the control group, the (OVX+E)-group, and the (OVX-E+D)-group were found. In the in vitro studies, no direct effect of estrogen on adipose 11beta-HSD1 was found. The upregulation of 11beta-HSD1 in ovariectomized rats was most likely due to changes in body composition rather than lack of estrogen.

Best Practices During Hip Arthroscopy: Aggregate Recommendations of High-Volume Surgeons.

PubMed

Gupta, Asheesh; Suarez-Ahedo, Carlos; Redmond, John M; Gerhardt, Michael B; Hanypsiak, Bryan; Stake, Christine E; Finch, Nathan A; Domb, Benjamin G

2015-09-01

To survey surgeons who perform a high volume of hip arthroscopy procedures regarding their operative technique, type of procedure, and postoperative management. We conducted a cross-sectional survey of 27 high-volume orthopaedic surgeons specializing in hip arthroscopy to report their preferences and practices related to their operative practice and postoperative rehabilitation protocol. All participants completed the survey in person in an anonymous fashion during a meeting of the American Hip Institute. All surgeons perform hip arthroscopy with the patient in the supine position, accessing the central compartment of the hip initially, using intraoperative fluoroscopy. All surgeons perform labral repair (100%), with the majority performing labral reconstructions (77.8%) and gluteus medius repairs (81.5%). There is variability in the type of anchors used during labral repair. Most surgeons perform capsular closure in most cases (88.9%), inject either intra-articular cortisone or platelet-rich plasma at the conclusion of the procedure (59%), and prescribe a postoperative hip brace for some or all patients (59%). There is considerable variability in rehabilitation protocols. All surgeons routinely prescribe postoperative heterotopic ossification prophylaxis to their patients, with most surgeons (88.9%) prescribing a nonsteroidal anti-inflammatory medication for 3 weeks. Forty percent of the respondents use the modified Harris Hip Score as the most important outcome measure. Consistent practices such as use of intraoperative fluoroscopy, heterotopic ossification prophylaxis, and labral repair skills were identified by surveying 27 hip arthroscopy surgeons at high-volume centers. Most of the surgeons performed routine capsular closure unless underlying conditions precluded capsular release or plication. The survey identified higher variability between surgeons regarding postoperative rehabilitation protocols and use of intra-articular pharmacologic injections at the end of the procedure. These data may provide surgeons with a set of aggregate trends that may help guide training, clinical practice, and research in the evolving field of hip arthroscopy. Copyright © 2015 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Inflammatory mechanisms and oxidative stress in Peyronie's disease: therapeutic "rationale" and related emerging treatment strategies.

PubMed

Paulis, Gianni; Brancato, Tommaso

2012-02-01

Peyronie's disease (PD) is a connective tissue disorder characterized by a fibrous plaque involving the tunica albuginea of the penis. The inelastic fibrous plaque leads to a penile curvature. Several Authors have suggested an immunological genesis of this disease, others have linked PD with Dupuytren's contracture. Signs of this disease are curvature, penile pain, penile deformity, difficulty with coitus, shortening, hinging, narrowing and erectile dysfunction. The natural history of PD and the clinical course can develop from spontaneous resolution of symptoms to progressive penile deformity and impotence. Surgical treatment is indicated when patients fail the conservative medical treatment and however, only in case of disease stabilization with a condition of impossibility of penetration. The medical treatment is indicated in the development stage of PD for at least one year after diagnosis and whenever in case of penile pain. Current non-surgical therapy includes vitamin-E, verapamil, para-aminobenzoate, propoleum, colchicine, carnitine, tamoxifen, interferons, collagenase, hyaluronidase, cortisone, pentoxifylline, superoxide dismutase, iontophoresis, radiation, extracorporeal shock wave therapy (ESWT) and the penile extender. The etiology of this fibrotic disease is not widely known, although in recent years pathophysiological knowledge has evolved and new studies propose the penile trauma as cause of the disease. The penile trauma results in a delamination of the tunica albuginea with a consequent small hematoma, then the process evolves as an inflammation with accumulation of inflammatory cells and production of reactive oxygen species (ROS). In the course of the inflammation, Peyronie's disease occurs due to the activation of nuclear factor kappa-B, that induces the production of inducible nitric oxide synthase (iNOS), with an increase of nitric oxide, leading to increased production of peroxynitrite anion. All these processes result in the proliferation of fibroblasts and myo-fibroblasts and excessive production of collagen between the layers of the tunica albuginea (penile plaque). Referring to the current knowledge of inflammatory and oxidative mechanisms of PD, a possible therapeutic strategy is then analyzed. © 2012 Bentham Science Publishers

Gas chromatography-mass spectrometry profiling of steroids in urine of patients with acute intermittent porphyria.

PubMed

Casals, Gregori; Marcos, Josep; Pozo, Óscar J; Aguilera, Paula; Herrero, Carmen; To-Figueras, Jordi

2013-06-01

Acute intermittent porphyria (AIP) is an autosomal dominant disease that results from a deficiency of hydroxymethylbilane synthase, the third enzyme of the heme biosynthetic pathway. AIP carriers may present acute neurovisceral attacks with hepatic overproduction of heme-precursors. In some patients, remission of the acute symptoms leads to long-term hepatic metabolic abnormalities. In this study, gas chromatography-mass spectrometry (GC/MS) was used to investigate urinary steroid metabolome of AIP patients. Steroid profiling in urine was performed in a group of AIP patients with biochemically active disease (n=22) and healthy controls (n = 20). Five asymptomatic AIP family carriers were also studied. Commonly used ratios for the evaluation of disturbances in the steroid metabolism were calculated. We found that etiocholanolone/androsterone and tetrahydrocortisol/5α-tetrahydrocortisol (THF/5α-THF) metabolic ratios were significantly increased in the urine of AIP patients compared to controls (2.3 ± 0.3 vs 0.8 ± 0.1; p < 0.001 and 2.9 ± 0.7 vs 0.9 ± 0.1; p < 0.01). The (THF+5α-THF)/tetrahydrocortisone ratio was reduced among the AIP patients (p < 0.01). Quantification of the steroid absolute concentrations showed that these variations were due to a decrease of the 5α metabolites. Other ratios, like cortisol/cortisone and 6β-hydroxycortisol/cortisol in the free steroid fraction did not show differences between patients and controls. All ratios were normal among the family carriers. A significant number of AIP patients present a basal decrease of steroid 5α-reductase activity in the liver. The deficiency may be related to malnutrition and hepatic energy misbalance associated with active AIP. Urinary steroid profiling by GC/MS may be a valuable tool to assess hepatic metabolome in AIP. Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Clinical Improvement of Subacute and Chronic Otitis Media With Effusion Treated With Hyaluronic Acid Plus Hypertonic Solution via Nasal Lavage: A Randomized Controlled Trial.

PubMed

Cioffi, Luigi; Gallo, Patrizia; D'Avino, Antonio; Carlomagno, Francesco; Aloi, Giuseppe; D'Onofrio, Antonietta; Del Gaizo, Donatella; Giuliano, Maria; De Franchis, Raffaella; Sandomenico, Maria L; Pecoraro, Anna

2017-01-01

Background . This study, a randomized controlled trial, aims to demonstrate a clinically significant improvement in subacute and chronic otitis media with effusion through the administration of hyaluronic acid associated with hypertonic solution compared with the administration of hypertonic solution alone. The setting was an outpatient clinic of 20 primary care pediatrician offices affiliated with the 3 Local Health Units (Azienda Sanitaria Locale) of Naples. Materials and Methods . The study was conducted for 6 months, from October 2014 to the end of March 2015. The study saw the participation of 20 pediatricians who were experts in pneumatic otoscopy, each of whom enrolled 15 children. Each investigator was randomized to carry out the treatment with 3% hypertonic solution or high-molecular-weight hyaluronic acid + 3% hypertonic solution. Results . A total of 275 children were enrolled, of whom 11(equal to 4% ) were lost to follow-up. A total of 264 children completed the trial according to the protocol, 120 in the hyaluronic acid + hypertonic solution group and 144 in the hypertonic solution group. Hyaluronic acid associated with hypertonic solution and hypertonic solution alone administered by nasal lavage have proven to be safe and effective in the treatment of prolonged otitis media with effusion (initial score of -0.5, final score of 0.9, P < 001, for the hypertonic + hyaluronic acid group; initial score of -0.3, final score of 0.2, P < .001, for the hypertonic solution group). Though starting from a less favorable initial clinical score (-0.5 vs -0.3, P < .016), hyaluronic acid associated with hypertonic solution resulted in a significant increase in clinical healing (0.9 vs 0.2, P < .001). One interesting outcome was the significant reduction in the consumption of drugs (cortisone and antibiotics) during the follow-up.

Long-term clinical follow-up of the multicentre, randomized study to test immunosuppressive therapy with oral prednisone for the prevention of restenosis after percutaneous coronary interventions: Cortisone plus BMS or DES veRsus BMS alone to EliminAte Restenosis (CEREA-DES).

PubMed

Ribichini, Flavio; Tomai, Fabrizio; Pesarini, Gabriele; Zivelonghi, Carlo; Rognoni, Andrea; De Luca, Giuseppe; Boccuzzi, Giacomo; Presbitero, Patrizia; Ferrero, Valeria; Ghini, Anna S; Marino, Paolo; Vassanelli, Corrado

2013-06-01

To analyse the clinical outcome at 4 years in patients with coronary artery disease treated with bare metal stents (BMS) vs. BMS and oral prednisone, or drug-eluting stents (DES), all assuming similar adjunctive medical treatment. Five Italian hospitals enrolled 375 non-diabetic, ischaemic patients without contraindications to dual anti-platelet treatment or corticosteroid therapy in a randomized controlled study. The primary endpoint was the event-free survival of cardiovascular death, myocardial infarction, and recurrence of ischaemia needing repeated target vessel revascularization at 1 year, and this was significantly lower in the BMS group (80.8%) compared with the prednisone (88.0%) and DES group (88.8%, P = 0.04 and 0.006, respectively). The long-term analysis of the primary endpoint was a pre-specified aim of the trial, and was performed at 1447 days (median, IQ range = 1210-1641). Patients receiving BMS alone had significantly lower event-free survival (75.3%) compared with 84.1% in the prednisone group (HR: 0.447; 95% CI: 0.25-0.80, P = 0.007) and 80.6% in DES patients (HR: 0.519; 95% CI: 0.29-0.93, P = 0.03). Prednisone-treated patients did not develop new treatment-related clinical problems. Drug-eluting stents patients suffered more very late stent thrombosis as a cause of spontaneous myocardial infarction. The need for target vessel revascularization remained lower in the prednisone and DES groups (13.6 and 15.2%, respectively), compared with BMS (23.2%). The clinical benefits of prednisone compared with BMS only persisted almost unchanged at 4 years. Drug-eluting stents performed better than BMS at long-term, although the advantages observed at 1 year were in part attenuated because of the occurrence of very late stent thrombosis and late revascularizations. Clinical Trial NCT 00369356.

11β-Hydroxysteroid Dehydrogenase Type 1 Regulates Glucocorticoid-Induced Insulin Resistance in Skeletal Muscle

PubMed Central

Morgan, Stuart A.; Sherlock, Mark; Gathercole, Laura L.; Lavery, Gareth G.; Lenaghan, Carol; Bujalska, Iwona J.; Laber, David; Yu, Alice; Convey, Gemma; Mayers, Rachel; Hegyi, Krisztina; Sethi, Jaswinder K.; Stewart, Paul M.; Smith, David M.; Tomlinson, Jeremy W.

2009-01-01

OBJECTIVE Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11β-HSD1 inhibitors improve insulin sensitivity. RESEARCH DESIGN AND METHODS Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11β-HSD1 inhibition upon insulin signaling and action. RESULTS Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer307 insulin receptor substrate (IRS)-1. 11β-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11β-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer307 IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11β-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer307 IRS1 decreased and pThr308 Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression. CONCLUSIONS Prereceptor facilitation of glucocorticoid action via 11β-HSD1 increases pSer307 IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11β-HSD1 inhibition decreases pSer307 IRS1, increases pThr308 Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action. PMID:19675138

De Quervain tendinopathy: survivorship and prognostic indicators of recurrence following a single corticosteroid injection.

PubMed

Earp, Brandon E; Han, Carin H; Floyd, W Emerson; Rozental, Tamara D; Blazar, Philip E

2015-06-01

To determine short- and long-term success rates of a single corticosteroid injection for de Quervain tendinopathy while identifying prognostic indicators for symptom recurrence and repeat intervention. Fifty consecutive patients with de Quervain tendinopathy treated with corticosteroid injections (lidocaine plus triamcinolone acetonide or dexamethasone) were prospectively enrolled. Patients with inflammatory arthritis, carpometacarpal osteoarthritis, or a previous distal radius fracture affecting the symptomatic wrist were excluded. Demographic data and information on existing comorbidities were recorded. Patients were seen in clinic at 6 weeks after injection and contacted at 3, 6, 9, and 12 months following injection to determine symptom recurrence and further intervention. Medical records were also reviewed for this purpose. Kaplan-Meier survival analysis and Cox regression modeling were used to estimate recurrence rates and identify predictors of symptom recurrence and repeat intervention. Fifty wrists in 50 patients (average age, 49 y) were included. One patient was lost to follow-up. Eighty-two percent of patients had resolved symptoms 6 weeks after a steroid injection. Twenty-four patients had a recurrence of symptoms at a median of 84 days after the injection. Eleven patients underwent additional intervention (7 surgical releases and 4 repeat injections) at a median of 129 days (range, 42-365) after the injection. Estimated freedom from symptom recurrence was 52% at 6 and 12 months. Estimated freedom from repeat intervention was 81% at 6 months and 77% at 12 months. Two of 3 patients with a history of trigger finger required subsequent de Quervain surgery. We demonstrated that a single cortisone injection was effective in alleviating symptoms of de Quervain tendinopathy in 82% of patients and that over half remained symptom-free for at least 12 months. All patients with recurring symptoms developed them within the first 6 months. Prognostic IV. Copyright © 2015 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Elevation of 11β-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: evidence for an intergenerational effect of maternal trauma exposure

PubMed Central

Bierer, Linda M.; Bader, Heather N.; Daskalakis, Nikolaos P.; Lehrner, Amy; Makotkine, Iouri; Seckl, Jonathan R.; Yehuda, Rachel

2014-01-01

Background Adult offspring of Holocaust survivors comprise an informative cohort in which to study intergenerational transmission of the effects of trauma exposure. Lower cortisol and enhanced glucocorticoid sensitivity have been previously demonstrated in Holocaust survivors with PTSD, and in offspring of Holocaust survivors in association with maternal PTSD. In other work, reduction in the activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), which inactivates cortisol, was identified in Holocaust survivors in comparison to age-matched, unexposed Jewish controls. Therefore, we investigated glucocorticoid metabolism in offspring of Holocaust survivors to evaluate if similar enzymatic decrements would be observed that might help to explain glucocorticoid alterations previously shown for Holocaust offspring. Methods Holocaust offspring (n=85) and comparison subjects (n=27) were evaluated with clinical diagnostic interview and self-rating scales, and asked to collect a 24-hr urine sample from which concentrations of cortisol and glucocorticoid metabolites were assayed by GCMS. 11β-HSD-2 activity was determined as the ratio of urinary cortisone to cortisol. Results Significantly reduced cortisol excretion was observed in Holocaust offspring compared to controls (p=.046), as had been shown for Holocaust survivors. However, 11β-HSD-2 activity was elevated for offspring compared to controls (p=.008), particularly among those whose mothers had been children, rather than adolescents or adults, during World War II (p=.032). The effect of paternal Holocaust exposure could not be reliably investigated in the current sample. Conclusions The association of offspring 11β-HSD-2 activity with maternal age at Holocaust exposure is consistent with the influence of glucocorticoid programming. Whereas a long standing reduction in 11β-HSD-2 activity among survivors is readily interpreted in the context of Holocaust related deprivation, understanding the directional effect on offspring will require replication and further exploration. PMID:24971590

Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: a novel therapeutic approach.

PubMed

de Quervain, Dominique J-F; Margraf, Jürgen

2008-04-07

Post-traumatic stress disorder (PTSD) and phobias belong to the most common anxiety disorders and to the most common psychiatric illnesses in general. In both disorders, aversive memories are thought to play an important role in the pathogenesis and symptomatology. Previously, we have reported that elevated glucocorticoid levels inhibit memory retrieval in animals and healthy humans. We therefore hypothesized that the administration of glucocorticoids might also inhibit the retrieval of aversive memory, thereby reducing symptoms in patients with PTSD and phobias. In recent clinical studies, we found first evidence to support this hypothesis. In patients with PTSD, low-dose cortisol treatment for one month reduced symptoms of traumatic memories without causing adverse side effects. Furthermore, we found evidence for a prolonged effect of the cortisol treatment. Persistent retrieval and reconsolidation of traumatic memories is a process that keeps these memories vivid and thereby the disorder alive. By inhibiting memory retrieval, cortisol may weaken the traumatic memory trace, and thus reduce symptoms even beyond the treatment period. In patients with social phobia, we found that a single oral administration of cortisone 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation-, exposure-, and recovery phase of the stressor. In subjects with spider phobia, repeated oral administration of cortisol 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again two days after the last cortisol administration, indicating that cortisol facilitated the extinction of phobic fear. In conclusion, by a common mechanism of reducing the retrieval of aversive memories, glucocorticoids may be suited for the treatment of PTSD as well as phobias. More studies are needed to further evaluate the therapeutic efficacy of glucocorticoids in the treatment of anxiety disorders and to explore the potential of combining glucocorticoid treatment with psychotherapy.

Multisteroid LC–MS/MS assay for glucocorticoids and androgens and its application in Addison's disease

PubMed Central

Methlie, Paal; Hustad, Steinar; Kellman, Ralf; Almås, Bjørg; Erichsen, Martina M; Husebye, Eystein S; Løvås, Kristian

2013-01-01

Objective Liquid chromatography–tandem mass spectrometry (LC–MS/MS) offers superior analytical specificity compared with immunoassays, but it is not available in many regions and hospitals due to expensive instrumentation and tedious sample preparation. Thus, we developed an automated, high-throughput LC–MS/MS assay for simultaneous quantification of ten endogenous and synthetic steroids targeting diseases of the hypothalamic–pituitary–adrenal axis and gonads. Methods Deuterated internal standards were added to 85 μl serum and processed by liquid–liquid extraction. Cortisol, cortisone, prednisolone, prednisone, 11-deoxycortisol, dexamethasone, testosterone, androstenedione and progesterone were resolved by ultra-high-pressure chromatography on a reversed-phase column in 6.1 min and detected by triple-quadrupole mass spectrometry. The method was used to assess steroid profiles in women with Addison's disease (AD, n=156) and blood donors (BDs, n=102). Results Precisions ranged from 4.5 to 10.1% relative standard deviations (RSD), accuracies from 95 to 108% and extraction recoveries from 60 to 84%. The method was practically free of matrix effects and robust to individual differences in serum composition. Most postmenopausal AD women had extremely low androstenedione concentrations, below 0.14 nmol/l, and median testosterone concentrations of 0.15 nmol/l (interquartile range 0.00–0.41), considerably lower than those of postmenopausal BDs (1.28 nmol/l (0.96–1.64) and 0.65 nmol/l (0.56–1.10) respectively). AD women in fertile years had androstenedione concentrations of 1.18 nmol/l (0.71–1.76) and testosterone concentrations of 0.44 nmol/l (0.22–0.63), approximately half of those found in BDs of corresponding age. Conclusion This LC–MS/MS assay provides highly sensitive and specific assessments of glucocorticoids and androgens with low sample volumes and is suitable for endocrine laboratories and research. Its utility has been demonstrated in a large cohort of women with AD, and the data suggest that women with AD are particularly androgen deficient after menopause. PMID:23825158

AB69. Phyto-androgenic androgens in men’s health, sex and aging FX

PubMed Central

Adimoelja, Arif; Siauw, Ali Fuchih

2014-01-01

Protodioscin is a Herbal Steroid Saponin extract derived mainly from Tribulus terristris L. grown mainly in Bulgaria. This herbal plant begun well known in main stream medicine since the periods around 1972 in Indonesia when this phyto-steroid compound has been proven of having the ability to be converted to DHEA and further to another androgenic androgen (T) in hypogonadal men in the presence of 5-alpha-dehydrogenase (A. Adimoelja, 1976, 1978). Biogenic androgens and androgenic androgens Testosterone as a product of the male gonads from blood serum cholesterol. Cholesterol is further converted to DHEA. This product is identified as one of the biogenic or endogenic androgens (testosterone, pregnenolone, progesterone, aldosterone, androstendione). Health disorders are often hampered by the tendencies of men or women to conceal their health (sexual health) conditions due to fear and/or embarrassments. If these conditions are not being soonest medically diagnosed and left to be untreated, another un-healthy condition may appear. (hypertension, high blood serum cholesterol, decrease HDL, CVD). Decrease libido, sex arousal and ED are the first expression of the down-degraded health conditions which may appear (A. Adimoelja 1985). Prescription of phytopharmaceuticals in mainstream medicine Surprisingly more phyto-pharmaceuticals in mainstream medicine were unconsciously prescribed by physicians (25% of prescriptions, WHO, 1908). Prescriptions were made to support health conditions and promote sexual health problems, most common as aphrodisiacs. Prtodioscin and health enhancers Protodioscin indeed promote health condition in hypogonadic men (A.Adimoelja and Tjahjo Djojo Tanojo, 2009). Regretfully most herbal products whih has been promoted as health foods in the market, or sex-tonics are combined with other chemical product(s), some of which combined with erectogenics (W. Pangkahila, 2010). Sharlip ID (USA) too reported in the “Newark Star Ledger in 2002” that 9 out of 10 randomly surveyed herbal extracts on sex performance enhancers did not contain the right compositions as stated in the manual brochures. The addition of illegal chemicals to herbal extracts and traditional herbs which has been proclaimed as sex tonics (erectogenics) or other health conditions (analgetics, cortisone) found in the market.

Effects of 2G on Gene Expression of Stress-Related Hormones in Rat Placenta

NASA Technical Reports Server (NTRS)

Benson, S.; Talyansky, Y.; Moyer, E. L.; Lowe, M.; Baer, L. A.; Ronca, A. E.

2017-01-01

Understanding the effects of spaceflight on mammalian reproductive and developmental physiology is important to future human space exploration and permanent settlement beyond Earth orbit. Fetal developmental programming, including modulation of the HPA axis, is thought to originate at the placental-uterine interface, where both transfer of maternal hormones to the fetus and synthesis of endogenous hormones occurs. In healthy rats, fetal corticosterone levels are kept significantly lower by 11BetaHSD-2, which inactivates corticosterone by conversion into cortisone. Placental tissues express endogenous HPA axis-associated hormones including corticotropin-releasing hormone (CRH), pre-opiomelanocortin (POMC), and vasopressin, which may contribute to fetal programming alongside maternal hormones. DNA methylase 3A, 11BetaHSD-2, and 11BetaHSD-1, which are involved in the regulation of maternal cortisol transfer and modulation of the HPA axis, are also expressed in placental tissues along with glucocorticoid receptor and may be affected by differential gravity exposure during pregnancy. Fetuses may respond differently to maternal glucocorticoid exposure during gestation through sexually dimorphic expression of corticosterone-modulating hormones. To elucidate effects of altered gravity on placental gene expression, here we present a ground-based analogue study involving continuous centrifugation to produce 2g hypergravity. We hypothesized that exposure to 2g would induce a decrease in 11BetaHSD-2 expression through the downregulation of DNA methylase 3a and GC receptor, along with concurrent upregulation in endogenous CRH, POMC, and vasopressin expression. Timed pregnant female rats were exposed to 2G from Gestational day 6 to Gestational day 20, and comparisons made with Stationary Control (SC) and Vivarium Control (VC) dams at 1G. Dams were euthanized and placentas harvested on G20. We homogenized placental tissues, extracted and purified RNA, synthesized cDNA, and quantified the expression levels of the genes of interest relative to the GAPDH housekeeping gene, using RT-qPCR and gene-specific cDNA probes. Elucidation of glucocorticoid transfer and synthesis in the placenta can provide new insights into the unique dynamics of mammalian development in microgravity and guide future multi-generational studies in space.

Biological Roles of Hydroxysteroid (11-Beta) Dehydrogenase 1 (HSD11B1), HSD11B2, and Glucocorticoid Receptor (NR3C1) in Sheep Conceptus Elongation.

PubMed

Brooks, Kelsey; Burns, Gregory; Spencer, Thomas E

2015-08-01

In sheep, the elongating conceptus synthesizes and secretes interferon tau (IFNT) as well as prostaglandins (PGs) and cortisol. The enzymes, hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1) and HSD11B2 interconvert cortisone and cortisol. In sheep, HSD11B1 is expressed and active in the conceptus trophectoderm as well as in the endometrial luminal epithelia; in contrast, HSD11B2 expression is most abundant in conceptus trophectoderm. Cortisol is a biologically active glucocorticoid and ligand for the glucocorticoid receptor (NR3C1 or GR) and mineralocorticoid receptor (NR3C2 or MR). Expression of MR is not detectable in either the ovine endometrium or conceptus during early pregnancy. In tissues that do not express MR, HSD11B2 protects cells from the growth-inhibiting and/or proapoptotic effects of cortisol, particularly during embryonic development. In study one, an in utero loss-of-function analysis of HSD11B1 and HSD11B2 was conducted in the conceptus trophectoderm using morpholino antisense oligonucleotides (MAOs) that inhibit mRNA translation. Elongating, filamentous conceptuses were recovered on Day 14 from ewes infused with control morpholino or HSD11B2 MAO. In contrast, HSD11B1 MAO resulted in severely growth-retarded conceptuses or conceptus fragments with apoptotic trophectoderm. In study two, clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing was used to determine the role of GR in conceptus elongation and development. Elongating, filamentous-type conceptuses (12-14 cm in length) were recovered from ewes gestating control embryos (n = 7/7) and gestating GR-edited embryos (n = 6/7). These results support the idea that the effects of HSD11B1-derived cortisol on conceptus elongation are indirectly mediated by the endometrium and are not directly mediated through GR in the trophectoderm. © 2015 by the Society for the Study of Reproduction, Inc.

Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2.

PubMed

Cirillo, Nicola; Morgan, David J; Pedicillo, Maria Carmela; Celentano, Antonio; Lo Muzio, Lorenzo; McCullough, Michael J; Prime, Stephen S

2017-09-26

Recent studies have shown that production of cortisol not only takes place in several non-adrenal peripheral tissues such as epithelial cells but, also, the local inter-conversion between cortisone and cortisol is regulated by the 11β-hydroxysteroid dehydrogenases (11β-HSDs). However, little is known about the activity of this non-adrenal glucocorticoid system in cancers. The presence of a functioning glucocorticoid system was assessed in human skin squamous cell carcinoma (SCC) and melanoma and further, in 16 epithelial cell lines from 8 different tissue types using ELISA, western blotting and immunofluorescence. 11β-HSD2 was inhibited both pharmacologically and by siRNA technology. Naïve CD8 + T cells were used to test the paracrine effects of cancer-derived cortisol on the immune system in vitro. Functional assays included cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical data of 11β-HSD expression were generated using tissue microarrays of 40 cases of human SCCs as well as a database featuring 315 cancer cases from 15 different tissues. We show that cortisol production is a common feature of malignant cells and has paracrine functions. Cortisol production correlated with the magnitude of glucocorticoid receptor (GR)-dependent inhibition of tumour-specific CD8 + T cells in vitro. 11β-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11β-HSDs demonstrated that 11β-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11β-HSD2 activity by 18β-glycyrrhetinic acid (GA) and silencing by specific siRNAs modulated the bioavailability of cortisol. Cortisol also acted in an autocrine manner and promoted cell invasion in vitro and cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical analyses using tissue microarrays showed that expression of 11β-HSD2 was significantly reduced in human SCCs of the skin. The results demonstrate evidence of a cancer-associated glucocorticoid system and show for the first time, the functional significance of cancer-derived cortisol in tumour progression.

Trace analysis of 28 steroids in surface water, wastewater and sludge samples by rapid resolution liquid chromatography-electrospray ionization tandem mass spectrometry.

PubMed

Liu, Shan; Ying, Guang-Guo; Zhao, Jian-Liang; Chen, Feng; Yang, Bin; Zhou, Li-Jun; Lai, Hua-Jie

2011-03-11

A sensitive rapid resolution liquid chromatography-tandem mass spectrometry (RRLC-MS/MS) method, combined with solid-phase extraction, ultrasonic extraction and silica gel cartridge cleanup, was developed for 28 steroids including 4 estrogens (estrone (E1), 17β-estradiol (E2), 17α-ethynyl estradiol (EE2), diethylstilbestrol (DES)), 14 androgens (androsta-1,4-diene-3,17-dione (ADD), 17α-trenbolone, 17β-trenbolone, 4-androstene-3,17-dione, 19-nortestoserone, 17β-boldenone, 17α-boldenone, testosterone (T), epi-androsterone (EADR), methyltestosterone (MT), 4-hydroxy-androst-4-ene-17-dione (4-OHA), 5α-dihydrotestosterone (5α-DHT), androsterone (ADR), stanozolol (S)), 5 progestagens (progesterone (P), ethynyl testosterone (ET), 19-norethindrone, norgestrel, medroxyprogesterone (MP)), and 5 glucocorticoids (cortisol, cortisone, prednisone, prednisolone, dexamethasone) in surface water, wastewater and sludge samples. The recoveries of surface water, influents, effluents and sludge samples were 90.6-119.0% (except 5α-DHT was 143%), 44.0-200%, 60.7-123% and 62.6-138%, respectively. The method detection limits for the 28 analytes in surface water, influents, effluents and freeze-dried sludge samples were 0.01-0.24 ng/L, 0.02-1.44 ng/L, 0.01-0.49 ng/L and 0.08-2.06 ng/g, respectively. This method was applied in the determination of the residual steroidal hormones in two surface water of Danshui River, 12 wastewater and 8 sludge samples from two wastewater treatment plants (Meihu and Huiyang WWTPs) in Guangdong (China). Ten analytes were detected in surface water samples with concentrations ranging between 0.4 ng/L (17β-boldenone) and 55.3 ng/L (5α-DHT); twenty analytes in the wastewater samples with concentrations ranging between 0.3 ng/L (P) and 621 ng/L (5α-DHT); and 12 analytes in the sludge samples with concentrations ranging between 1.6 ng/g (E1) and 372 ng/g (EADR). Copyright © 2011 Elsevier B.V. All rights reserved.

Non-steroidal anti-inflammatory drugs. Current status and rational therapeutic use.

PubMed

Hart, F D; Huskisson, E C

1984-03-01

Aspirin (acetylsalicylic acid), the first of the NSAIDs (introduced in 1899), was initially never referred to as an anti-inflammatory agent. It was the advent of cortisone in 1949 that demonstrated dramatically that corticosteroids had anti-inflammatory properties and the term 'non-steroidal anti-inflammatory drug' was first used when phenylbutazone was introduced 3 years later. Since then, the NSAIDs have proliferated. There is to date no good evidence that they halt progression of rheumatoid disease, but by easing pain and diminishing swelling they make life much easier in osteoarthrosis, rheumatoid arthritis and many other types of arthritis, and are the drugs of first choice in acute gout. Their mode (or modes) of action are obscure and though inhibition of cyclo-oxygenase (prostaglandin synthetase) is clearly important, other mechanisms are also involved. The assessment of the anti-inflammatory action of these agents has received considerable attention in clinical trials because, whatever their action may be in experimental animal models, their action in inflamed joints in human patients must be ascertained, since there may be little parallel between the two. Different experimental animal models give different results with various agents and often bear little relation to their therapeutic action in man. No attempt has been made here to review in depth all the NSAIDs that have appeared since 1952. All have anti-inflammatory and analgesic activity and all can cause gastrointestinal side effects, though effectiveness and toxicity vary from drug to drug and patient to patient, there being very great interpatient variability. Non-reactors, patients who apparently fail to respond to certain agents, need further study, for it seems that these subjects may metabolise these agents differently from others. Considerable ingenuity has been shown not only in evolving new NSAIDs but in finding new ways of administering them. The number and variety of NSAIDs in their various forms varies greatly from country to country, depending largely on the regulatory bodies of those countries. In the meantime, the search for a better, less toxic compound continues with the hope that one may be found which has a deeper and more basic action on the underlying disease process.

Control of the immune response by DHEA and its metabolites.

PubMed

Loria, R M; Padgett, D A

1998-06-01

The 17 keto steroid, Dehydroepiandrosterone (5-androsten-3 beta-17-one, DHEA) has been shown to protect mice from a variety of lethal infections. This includes, but is not limited to, infection with viruses (herpesvirus type 2, coxsackievirus B4-CVB4),bacteria (Enterococcus faecalis, Pseudomonas aeruginosa), and a parasite (Cryptosporidium parvum). We have reported that androstenediol (5-androsten-3 beta-17 beta-diol, beta AED), which is derived from DHEA, is at least 100x more effective in up-regulating systemic resistance against CVB4-infection than its precursor. Furthermore, androstenetriol (5-androstene-3 beta-7 beta-17 beta-triol beta AET) which is formed by 7 beta hydroxylation of beta AED, was more effective against CVB4-infection than its precursor beta AED. Neither steroid however has shown any significant direct antiviral effects. The in-vitro influences of DHEA, beta AED, and beta AET on a mitogen-induced mixed splenocyte proliferation assay were determined. The results showed that DHEA suppressed the proliferation of concanavalin A (Con A) or lipopolysaccharide (LPS) activated cultures in a dose dependent manner. beta AED had little influence on the activation response. However, beta AET potentiated the response to both mitogens significantly above control. The regulation of interleukin-2 and interleukin-3 secretion from Con A-activated lymphocytes was analogous to these observations. These functions were suppressed by DHEA, unaffected by beta AED, and potently increased by beta AET. Moreover, the classic immuno-suppressive effects of hydro-cortisone on Con A-induced lymphocyte proliferation, as well as IL-2 and IL-3 production were unaffected by co-cultured with DHEA and only minimally counteracted by beta AED. In contrast, beta AET significantly counteracted the effect of hydrocortisone when co-cultured together. These results show that while in-vivo, DHEA, beta AED, and beta AET each function in a similar manner. In-vitro, their effects are dramatically different from one another with only beta AET potentiating the cellular response by increasing lymphocyte activation and counteracting the immuno-suppressive activity of hydrocortisone.

Endocrine system dynamics and MS epidemiology.

PubMed

Moynihan, James; Moore, Helena

2010-05-01

In the kidney there is a co-transport relationship in the nephron between the reabsorption of positive Na(+) ions and the reabsorption of negative ions such as uric acid anions. Uric acid acts as an anti-oxidant and it has been shown to have a sealing effect on the blood-brain barrier. The theory developed here is that chronic neurological vasoconstriction in cool environmental conditions injects an offset into the rennin-angiotensin-aldosterone system (RAAS) blood pressure control loop and reduces demand for angiotensin and aldosterone. (Aldosterone is produced in the adrenal gland and has a direct effect on renal reabsorption of Na(+) ions.) Via co-transport these conditions will reduce the body's ability to reabsorb uric acid and this in turn will weaken the integrity of the blood-brain barrier. Also, in cool environments, where levels of vasopressin (ADH) and aldosterone are lower, the gain of the hypothalamus-pituitary-adrenal gland (HPA) axis is reduced so that the production average levels of ACTH, cortisone and aldosterone will be biased at a lower level and the kidney-local levels of aldosterone in particular will remain lower. This paper develops these ideas and suggests that they can help explain the traditionally-recognized latitudinal gradient in MS epidemiology. Also, acclimatization to heat encourages sweating, which should create a greater demand for the renal reabsorption of Na(+) ions which enables greater reabsorption of uric acid. Therefore people living at low latitudes should have a lower chance of hypouricemia and a lower chance of developing MS. In fact people who spend their first fifteen years in the tropics almost never go onto develop MS. And MS patients in relapse are consistently hypouricemic. This hypothesis can explain both of these facts. The paper goes onto show how the MS condition will tend to progress because of a number of self-sustaining effects: over time the immune system becomes more targeted to myelin, MS patients are unlikely to become acclimatized to heat because they tend to avoid heat since demyelinated nerve function is worsened by elevated temperature, and the normal circadian excitation of the HPA axis gets weaker under the benign environmental conditions typically adopted by MS patients as the disease develops.

Isotope Inversion Experiment evaluating the suitability of calibration in surrogate matrix for quantification via LC-MS/MS-Exemplary application for a steroid multi-method.

PubMed

Suhr, Anna Catharina; Vogeser, Michael; Grimm, Stefanie H

2016-05-30

For quotable quantitative analysis of endogenous analytes in complex biological samples by isotope dilution LC-MS/MS, the creation of appropriate calibrators is a challenge, since analyte-free authentic material is in general not available. Thus, surrogate matrices are often used to prepare calibrators and controls. However, currently employed validation protocols do not include specific experiments to verify the suitability of a surrogate matrix calibration for quantification of authentic matrix samples. The aim of the study was the development of a novel validation experiment to test whether surrogate matrix based calibrators enable correct quantification of authentic matrix samples. The key element of the novel validation experiment is the inversion of nonlabelled analytes and their stable isotope labelled (SIL) counterparts in respect to their functions, i.e. SIL compound is the analyte and nonlabelled substance is employed as internal standard. As a consequence, both surrogate and authentic matrix are analyte-free regarding SIL analytes, which allows a comparison of both matrices. We called this approach Isotope Inversion Experiment. As figure of merit we defined the accuracy of inverse quality controls in authentic matrix quantified by means of a surrogate matrix calibration curve. As a proof-of-concept application a LC-MS/MS assay addressing six corticosteroids (cortisol, cortisone, corticosterone, 11-deoxycortisol, 11-deoxycorticosterone, and 17-OH-progesterone) was chosen. The integration of the Isotope Inversion Experiment in the validation protocol for the steroid assay was successfully realized. The accuracy results of the inverse quality controls were all in all very satisfying. As a consequence the suitability of a surrogate matrix calibration for quantification of the targeted steroids in human serum as authentic matrix could be successfully demonstrated. The Isotope Inversion Experiment fills a gap in the validation process for LC-MS/MS assays quantifying endogenous analytes. We consider it a valuable and convenient tool to evaluate the correct quantification of authentic matrix samples based on a calibration curve in surrogate matrix. Copyright © 2016 Elsevier B.V. All rights reserved.

In vitro maturation of immature thymocytes into immunocompetent T cells in the absence of direct thymic influence.

PubMed

Irlé, C; Piguet, P F; Vassalli, P

1978-07-01

Peanut lectin (PNL) binds to a majority of mouse thymocytes (Thc) in suspension. By using cell affinity chromatography on a column of anti-PNL antibody, Thc populations at least 96 percent pure in PNL + or - cells, as judged by immunofluorescence, were obtained. PNL(+) cells are rich in Thy 1 and poor in H(2) antigens, cortisone sensitive, unresponsive to phytohemagglutinin (PHA), and immunologically incompetent, as judged by mixed lymphocyte reaction, popliteal lymph node graft-versus-host assay, and by testing helper activity in a primary in vitro antibody response to sheep erythrocytes; the converse is true of PNL(-) cells. Thus, PNL(+) and (-) cells appear to correspond to cortical and medullary Thc, respectively, as previously suggested. In culture, PNL(+) Thc show poor viability and a weak proliferative response to concanavalin A (Con A), except when supernate (SUP) of 24 h Con A stimulated lymph node lymphocyte cultures, or irradiated lymph node cells, are added, in which cases a strong proliferative response to the mitogen is observed. A variety of control experiments showed that the proliferating cells did not result from preferential stimulation of a few contaminating PNL(-) Thc present in the PNL(+) Thc cultures. The blasts resulting from PNL(+) Thc proliferation display mitogen-induced cytotoxicity, and give rise to a population of medium-sized lymphocytes, mostly PNL(-), poor in Thy 1 and rich in H(2) antigens, PHA responsive, and immunologically competent in the above-mentioned assays. Fresh PNL(+) Thc responded in mixed lymphocyte reaction in the presence of SUP (lectin depleted) and since incubation in SUP alone did not confer reactivity on PNL(+) Thc, it appears therefore that (a) immature Thc possess alloantigen and mitogen-specific surface receptors but lack the capacity to respond by proliferation to receptor triggering without the help of extracellular factor(s) released by mature lymphoid cells stimulated by mitogens (b) cell division is associated with the acquisition of immunological responsiveness, characteristic of mature T lymphocytes. The implications of these findings for the ontogenesis of thymus-derived lymphocytes, and for the possible traffic of Thc within and from the thymus, are discussed.

Identification of plasma glucocorticoids in pallid sturgeon in response to stress

USGS Publications Warehouse

Webb, M.A.H.; Allert, J.A.; Kappenman, K.M.; Marcos, J.; Feist, G.W.; Schreck, C.B.; Shackleton, C.H.

2007-01-01

Compared to teleosts, little is known about the stress response in chondrosteans, and the glucocorticoid(s) most responsive to stress have never been definitively determined in sturgeon. In terms of cortisol production, pallid sturgeon (Scaphirhynchus albus) have a low physiological response to stress compared to other sturgeons (Acipenser sp.). Because of this, our null hypothesis was that cortisol is not the predominant glucocorticoid secreted in response to stress in pallid sturgeon. Our objective was to identify the putative glucocorticoids present in the plasma of pallid sturgeon during the stress response. Pallid sturgeon were subjected to a severe confinement stress (12 h) with an additional handling stressor for the first 6 h. Control fish were not subjected to confinement but were handled only to collect blood. Blood plasma was collected at time 0, 6, and 12 h. Gas chromatography/mass spectrometry was used to screen the plasma for the spectrum of glucocorticoids and determine the putative steroid secreted during the stress response. Cortisol was the primary glucocorticoid detected in stressed pallid sturgeon. In addition, the cortisol metabolites cortisone, alloTHE (5??-pregnane-3??,17??,21-triol-11,20-dione), allo-??-cortolone (3??,17??,20??,21-tetrahydro-5??-pregnan-11-one), and allo-??-cortolone (3??,17??,20??,21-tetrahydro-5??-pregnan-11-one) were detected. Plasma cortisol increased from a resting concentration of 0.67 ng/ml to 10.66 ng/ml at 6 h followed by a decrease to 6.78 ng/ml by 12 h. Plasma glucose increased significantly by time 6 and 12 h in both stressed and unstressed groups and remained elevated at time 12 h, while resting lactate concentrations were low to non-detectable and did not increase significantly with the stressor over time. Cortisol was the primary glucocorticoid synthesized and secreted in response to a stressor in pallid sturgeon. Though the proportional increase in plasma cortisol in stressed pallid sturgeon was lower than many other species of sturgeon, the concentration was high enough to elicit a secondary stress response as seen by changes in plasma glucose. ?? 2007 Elsevier Inc. All rights reserved.

Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion.

PubMed

Debono, Miguel; Harrison, Robert F; Chadarevian, Rita; Gueroult, Carole; Abitbol, Jean-Louis; Newell-Price, John

2017-09-01

Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death. We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers. In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index-matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11β-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed. Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 pm to 10 pm [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 pm to 2 am (AUC difference: 0.86 nmol/L/h; P < 0.001). In light of these findings, patients with ACS received metyrapone 500 mg at 6 pm and 250 mg at 10 pm, and cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 pm to 10 pm (AUC difference: -0.06 nmol/L/h; P = 0.85); 10 pm to 2 am (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 pm to 2 pm (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment. In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6. Copyright © 2017 Endocrine Society

Characterization of new recombinant 3-ketosteroid-Δ1-dehydrogenases for the biotransformation of steroids.

PubMed

Wang, Xiaojun; Feng, Jinhui; Zhang, Dalong; Wu, Qiaqing; Zhu, Dunming; Ma, Yanhe

2017-08-01

3-Ketosteroid-Δ 1 -dehydrogenases (KstDs [EC 1.3.99.4]) catalyze the Δ 1 -dehydrogenation of steroids and are a class of important enzymes for steroid biotransformations. In this study, we cloned 12 putative KstD-encoding (kstd) genes from both fungal and Gram-positive microorganisms and attempted to overproduce the recombinant proteins in E. coli BL21(DE3). Five successful recombinant enzymes catalyzed the Δ 1 -desaturation of a variety of steroidal compounds such as 4-androstene-3,17-dione (AD), 9α-hydroxy-4-androstene-3,17-dione (9-OH-AD), hydrocortisone, cortisone, and cortexolone. However, the substrate specificity and catalytic efficiency of the enzymes differ depending on their sources. The purified KstD from Mycobacterium smegmatis mc 2 155 (MsKstD1) displayed high catalytic efficiency toward hydrocortisone, progesterone, and 9-OH-AD, where it had the highest affinity (K m 36.9 ± 4.6 μM) toward 9-OH-AD. On the other hand, the KstD from Rhodococcus erythropolis WY 1406 (ReKstD) exhibited high catalytic efficiency toward androst-4,9(11)-diene-3,17-dione (Diene), 21-acetoxy-pregna-4,9(11),16-triene-3,20-dione (Triene), and cortexolone, where in all three cases the K m values (12.3 to 17.8 μM) were 2.5-4-fold lower than that toward hydrocortisone (46.3 μM). For both enzymes, AD was a good substrate although ReKstD had a 3-fold higher affinity than MsKstD1. Reaction conditions were optimized for the biotransformation of AD or hydrocortisone in terms of pH, temperature, and effects of hydrogen peroxide, solvent, and electron acceptor. For the biotransformation of hydrocortisone with 20 g/L wet resting E. coli cells harboring MsKstD1 enzyme, the yield of prednisolone was about 90% within 3 h at the substrate concentration of 6 g/L, demonstrating the application potential of the newly cloned KstDs.

Impact of HSD11B1 polymorphisms on BMI and components of the metabolic syndrome in patients receiving psychotropic treatments.

PubMed

Quteineh, Lina; Vandenberghe, Frederik; Saigi Morgui, Nuria; Delacrétaz, Aurélie; Choong, Eva; Gholam-Rezaee, Mehdi; Magistretti, Pierre; Bondolfi, Guido; Von Gunten, Armin; Preisig, Martin; Castelao, Enrique; Vollenweider, Peter; Waeber, Gerard; Bochud, Murielle; Kutalik, Zoltán; Conus, Philippe; Eap, Chin B

2015-05-01

Metabolic syndrome (MetS) associated with psychiatric disorders and psychotropic treatments represents a major health issue. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that catalyzes tissue regeneration of active cortisol from cortisone. Elevated enzymatic activity of 11β-HSD1 may lead to the development of MetS. We investigated the association between seven HSD11B1 gene (encoding 11β-HSD1) polymorphisms and BMI and MetS components in a psychiatric sample treated with potential weight gain-inducing psychotropic drugs (n=478). The polymorphisms that survived Bonferroni correction were analyzed in two independent psychiatric samples (nR1=168, nR2=188) and in several large population-based samples (n1=5338; n2=123 865; n3>100 000). HSD11B1 rs846910-A, rs375319-A, and rs4844488-G allele carriers were found to be associated with lower BMI, waist circumference, and diastolic blood pressure compared with the reference genotype (Pcorrected<0.05). These associations were exclusively detected in women (n=257) with more than 3.1 kg/m, 7.5 cm, and 4.2 mmHg lower BMI, waist circumference, and diastolic blood pressure, respectively, in rs846910-A, rs375319-A, and rs4844488-G allele carriers compared with noncarriers (Pcorrected<0.05). Conversely, carriers of the rs846906-T allele had significantly higher waist circumference and triglycerides and lower high-density lipoprotein-cholesterol exclusively in men (Pcorrected=0.028). The rs846906-T allele was also associated with a higher risk of MetS at 3 months of follow-up (odds ratio: 3.31, 95% confidence interval: 1.53-7.17, Pcorrected=0.014). No association was observed between HSD11B1 polymorphisms and BMI and MetS components in the population-based samples. Our results indicate that HSD11B1 polymorphisms may contribute toward the development of MetS in psychiatric patients treated with potential weight gain-inducing psychotropic drugs, but do not play a significant role in the general population.

Parental management of adrenal crisis in children with congenital adrenal hyperplasia

PubMed Central

Fleming, Louise; Knafl, Kathleen; Knafl, George; Van Riper, Marcia

2018-01-01

Purpose Congenital adrenal hyperplasia (CAH) requires parents to inject their child with hydro-cortisone intramuscularly during times of illness and adrenal crisis. The purpose of this study was to describe circumstances surrounding adrenal crisis events in children with CAH; to explore parents’ perceptions of the consequences of having a child with a life-threatening condition; and to examine a relationship between parents’ perceived management ability and the impact CAH has on the family. Methods In Phase 1 of this mixed-methods, cross-sectional study, 77 parents were asked to complete questionnaires comprising measures of family life in the context of childhood illness. Descriptive statistics were computed with four separate analyses using linear mixed models allowing for correlation between responses from parents of the same family and for the variance to be different for fathers and mothers. The following relationships were examined: (1) parental management ability and type of provider instruction on how to manage adrenal crises; (2) parental management ability and child age; (3) the perceived impact of the condition on the family and management ability; and (4) the age of the child and number of adrenal crisis events. In Phase 2, 16 semi-structured interviews were conducted to elicit detailed descriptions of parents’ experiences in managing crises. Results There was a significant, positive relationship between detailed provider instruction to parents on adrenal crisis management and perceived management ability (p = .02), additionally the stronger the perceived management ability, the less impact CAH had on the family (p < .001). From birth to age 5, parents reported more frequent crisis events and less perceived ability to manage the condition when compared with parents of older children (p = .009). The threat of an adrenal crisis event is a pervasive concern for parents, especially when they are not being properly prepared by providers. Practice Implications Provider support is needed for these parents throughout childhood, but especially in the first 5 years of life when parents are adjusting to having a child with a life-threatening condition. Identifying gaps in parent education by healthcare providers is necessary to promote positive family outcomes. PMID:28771930

Expression of 11beta-hydroxysteroid dehydrogenase 1 and 2 in subcutaneous adipose tissue of lean and obese women with and without polycystic ovary syndrome.

PubMed

Svendsen, P F; Madsbad, S; Nilas, L; Paulsen, S K; Pedersen, S B

2009-11-01

To investigate the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and 2 and hexose-6-phosphate dehydrogenase (H6PDH) mRNA in subcutaneous abdominal tissue from lean and obese women with and without polycystic ovary syndrome (PCOS), and to investigate the association between these enzymes and different measures of insulin sensitivity. Cross-sectional study. A total of 60 women, 36 women with PCOS, 17 lean (lean PCOS, LP) and 19 obese (obese PCOS, OP) and 24 age- and weight-matched control women, 8 lean (lean controls, LC) and 16 obese (obese controls, OC). Subcutaneous adipose tissue was collected from the abdomen. Peripheral insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp and determined as glucose disposal rate and insulin sensitivity index. Whole-body insulin sensitivity was calculated using homeostasis model assessment insulin resistance index. Body composition was evaluated by dual X-ray absorptiometry. Adipose mRNA expression of leptin and adiponectin were determined by real-time PCR. Polycystic ovary syndrome (P<0.05) and obesity (P<0.05) were independently associated with increased expression of 11beta-HSD1 mRNA. The subgroups LP and OC had increased 11beta-HSD1 and 11beta-HSD2 mRNA expression compared with LC (P<0.05, P<0.05). There were no effects of PCOS or obesity on11beta-HSD2 or H6PDH mRNA expression. Decreased peripheral insulin sensitivity (P<0.001) and increased upper body fat distribution (P<0.01) were associated with increased expression of 11beta-HSD1, but neither 11beta-HSD2 nor H6PDH. Polycystic ovary syndrome and obesity are independently associated with increased expression of 11beta-HSD1. This may lead to increased conversion of cortisone to cortisol in the peripheral adipose tissue and subsequently increased glucocorticoid activity. Decreased peripheral insulin sensitivity and central obesity was associated with increased expression of 11beta-HSD1.

11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Itoi, Saori; Terao, Mika, E-mail: mterao@derma.med.osaka-u.ac.jp; Murota, Hiroyuki

Highlights: •We investigate the role of 11β-HSD1 in skin inflammation. •Various stimuli increase expression of 11β-HSD1 in keratinocytes. •11β-HSD1 knockdown by siRNA decreases cortisol levels in media. •11β-HSD1 knockdown abrogates the response to pro-inflammatory cytokines. •Low-dose versus high-dose cortisol has opposing effects on keratinocyte inflammation. -- Abstract: The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactivemore » cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10{sup −13} M cortisol, whereas 1 × 10{sup −5} M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations by 11β-HSD1 appears to modulate expression of inflammatory cytokines in NHEKs.« less

Amount of systemic steroid medication is a strong predictor for the use of complementary and alternative medicine in patients with inflammatory bowel disease: results from a German national survey.

PubMed

Langhorst, Jost; Anthonisen, Inga B; Steder-Neukamm, Ulf; Lüdtke, Rainer; Spahn, Guenther; Michalsen, Andreas; Dobos, Gustav J

2005-03-01

Previous studies have suggested that inflammatory bowel disease (IBD) patients rank high among users of complementary and alternative medicine (CAM). To further elucidate this phenomenon, we sent questionnaires to a large sample of IBD patients in Germany to determine the patterns and predictors of their CAM use. Pretested 73-item questionnaires were mailed to a randomly selected representative sample of 1000 IBD patients from the approximately 16,000 members and associates of the German Crohn's and Colitis Association. Predictors of CAM use were evaluated by logistic regression models. Completed questionnaires were returned by 684 patients (female patients, 61.4%; Crohn's disease patients, 58.3%; ulcerative colitis patients, 38.2%). Of the 671 adult respondents, 344 (51.3%) had experience with CAM, and significantly more of the ulcerative colitis patients (59.8%) than the Crohn's disease patients (48.3%) had experience with CAM. There was no difference by gender. Homeopathy (52.9%) and herbal medicine (43.6%) were the most commonly used types of CAM. The most frequent personal reasons for CAM use were the search for an "optimum treatment" (78.9%) and the wish to stop taking steroids (63.8%). Using logistic regression, we found that total cortisone intake (P = 0.0077), but not duration of disease, was a strong predictor of CAM use. Other predictors were experience with psychosomatic and psychotherapeutic support (P = 0.0029), relaxation techniques (P = 0.0284), an academic education (P = 0.0173), a diet utilizing whole grains (P = 0.0123), and a normal body weight (P = 0.0215). Although 80% of patients indicated that they were interested in using CAM in the future, only 24.7% felt sufficiently informed about it. More than 50% of a large group of German IBD patients had used CAM. Prolonged or intensive steroid treatment, an academic education, active ways of coping, and a health-conscious life-style are associated with CAM use. Given the potential side effects and interactions, the treating physician should focus on thorough information about the benefits and limitations of conventional and complementary treatment options, especially for IBD patients who have received prolonged or intensive steroid treatment.

[Possible pathogenetic role of 11 beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) gene polymorphisms in arterial hypertension].

PubMed

Morales, Mauricio A; Carvajal, Cristián A; Ortiz, Eugenia; Mosso, Lorena M; Artigas, Rocío A; Owen, Gareth I; Fardella, Carlos E

2008-06-01

Cortisol has been implicated in hypertension and lately reported to be regulated at the pre-receptor level by the 11betaHSD1 enzyme, which converts cortisone (E) to cortisol (F). Over-expression of this enzyme in adipose tissue could determine an increase in available cortisol that interacts with the mineralocorticoid receptor (MR) in renal, brain and heart tissue, leading to similar hypertensive effects as in 11betaHSD2 impaired patients. Several polymorphisms have been reported in HSDl IB 1 gene (CAI5, CAI9 and InsA83557), which could modify HSDl IB 1 gene expression or activity. To determine the distribution and prevalence of CAI5, CAI9 and InsA83557 in the HSDl IBl gene, and to correlate these results with biochemical parameters in cortisol/ ACTH (HPA) and renin-angiotensin-aldosterone (RAA) axis in patients with essential hypertension (EH). We studied 113 EH patients (76 non-obese and 37 obese, with a body mass índex >30 kg/m(2)) and 30 normotensive adults (NT). In each patient, we measured serum levels of E E, serum aldosterone (SA), plasma renin activity (PRA), adrenocorticotrophic hormone (ACTH), the urinary free cortisol/creatinine (UFF/Cr), F/ACTH and SA/PRA ratios. Each polymorphism was studied by PCR and 8% polyacrylamide gel electrophoresis. Statistical associations were evaluated by Pearson correlations and the genetic equilibrium by the Hardy-Weinberg (H-W) equation. We found all three polymorphisms in the EH and the NT group, both in genetic equilibrium. In obese essential hypertensives, the CAI5 polymorphism showed association with SA/PRA ratio (r =0.189, p =0.012) and F/ACTH (r =0.301, p 0.048); CA19 also showed correlation with F/ACTH in obese EH (r = 0.220, p 0.009). The InsA83557polymorphism correlated with UFF/Cr in both EH (r =0.206; p =0.03), and in obese EH (r =0.354; p =0.05). The CAI5 and CAI9 polymorphism correlated with changes in biochemical parameters in HPA and RAA axis of obese essential hypertensives. These changes may result in modifications in the expression of 11betaHSD1, leading to increased cortisol and aldosterone levels independent of ACTH and renin control, respectively.

Health Knowledge, Cosmetic Interests, Attitude, and the Need for Health Education Regarding the Use of Topical Bleaching Agents Among Women in West Saudi Arabia: A Cross-Sectional Study.

PubMed

Alanzi, Mariam Eid; Alghamdi, Riyadh A; Alsharif, Osama Mohammed; Alghamdi, Khaled S; El Sayed, Salah Mohammed

We aimed at investigating the cosmetic interests, public confidence in cosmetic industry, health knowledge, practice, and need for health education regarding using topical bleaching agents (TPAs) among a relatively big sample size in Al-Madinah (west Saudi Arabia, a conservative eastern society that acquires its social customs from Islam). Islamic values increased women respect and esteem in this society. This is reflected on cosmetic practices and attitude, e.g. women use face cover outdoors. This issue is vital for both women health and beauty, and is rarely discussed. TPAs use is affected by culture, social customs, and health awareness regarding TPAs chemical constituents, e.g. hydroquinone, mercury, steroids that may harm skin and general health. Ethical committee approval was done for our study that included 531 women (attending the outpatient clinics in March-April 2016) of targeted 571 (response rate was 89.8%). 43.3% (230 women) are current TPAs users. Three hundred and eight-nine women (73.3%) regularly used TPAs to heal pigmented areas like freckles (75.8%) and just to lighten skin color (58.7%). Side effects of discontinuation were restoration of normal skin color (44.3%) or even darker skin (27%), skin dryness (20%) and rash (9.6%). Mercury is recognized as harmful to human health by 30.2%, whereas cortisone was chosen by others (53.2%). Unexpectedly, minority of investigated women (10%) considered using TPAs safe and recognized harms of some ingredients as mercury whereas the majority (70.2%) does not encourage others for TPAs use although they themselves kept using TPAs for different reasons. Cosmetic interest is high among women using TPAs, highest among the middle age (26-40 years), and lowest among women more than 40 years (50% versus 17.9%) ( p < 0.001). Using skin TPAs in west Saudi Arabia is comparable with international standards, higher among educated women, house wives and employed women. This denotes care of married employed women to use TPAs to express beauty to husbands. This is not reduced by work duties and is controlled by conservative Islamic modesty. Health education is mandatory regarding TPAs components and use during pregnancy and lactation. Cosmetic science and industry needs more research to improve TPAs use through providing better safe alternatives for many TPAs components, e.g. mercury and hydroquinone.

In vitro influence of light radiation on hair steroid concentrations.

PubMed

Grass, Juliane; Miller, Robert; Carlitz, Esther H D; Patrovsky, Fabian; Gao, Wei; Kirschbaum, Clemens; Stalder, Tobias

2016-11-01

Hair cortisol concentrations (hairF) are considered to be relatively robust to various confounding influences. However, a potentially important covariate factor that has received little attention in this context is hair exposure to ultraviolet/sunlight radiation. We conducted a detailed experimental investigation to examine the effects of light exposure on hair cortisol. In study I, a hydrocortisone-containing solution was subjected to short-term artificial light irradiation for 1, 3, 5, 10, 15, or 30min to evaluate the stability of cortisol molecules due to radiant energy. In study II, hair samples (N=12) were subjected to single short-term artificial light irradiation for 0, 1, or 5h to examine light-induced effects in the hair matrix. In study III, hair samples (N=25) were subjected to long-term naturalistic sunlight radiation over a period of two months (during summer) with daily exposure times of 0, 1, 3, or 6h, respectively. Besides cortisol, studies II & III also examined concentrations of cortisone (hairE), dehydroepiandrosterone (hairDHEA) and progesterone (hairP) in hair, quantified using LC-MS/MS technology. Results across the three studies consistently revealed effects of light irradiation on hair steroid concentrations: Longer light exposure resulted in a decrease of dissolved hydrocortisone (study I) as well as of hairF and hairE (studies II and III). Conversely, hairDHEA and hairP increased with longer natural sunlight exposure times (study III), while this effect was not observed for short-term artificial light irradiation (study II). Combined, our findings imply sunlight exposure as a potential confound in hair steroid research. Given the experimental character of this investigation, the magnitude of this effect under real-life testing conditions is difficult to estimate. To support future investigation into this, we designed a 'sunlight-exposure' questionnaire to share with the research community. The assessment and statistical accounting for sunlight exposure-related effects in future hair steroid research (using this or a similar questionnaire) may help to reduce the potential influence of this unwanted error source and could thus lead to more valid and reliable results. In addition, our data strongly suggest that hair samples for steroid analyses need to be stored in a dark environment. Copyright © 2016. Published by Elsevier Ltd.

Methodological Considerations for Hair Cortisol Measurements in Children

PubMed Central

Slominski, Radomir; Rovnaghi, Cynthia R.; Anand, Kanwaljeet J. S.

2015-01-01

Background Hair cortisol levels are used increasingly as a measure for chronic stress in young children. We propose modifications to the current methods used for hair cortisol analysis to more accurately determine reference ranges for hair cortisol across different populations and age groups. Methods The authors compared standard (finely cutting hair) vs. milled methods for hair processing (n=16), developed a 4-step extraction process for hair protein and cortisol (n=16), and compared liquid chromatography-mass spectrometry (LCMS) vs. ELISA assays for measuring hair cortisol (n=28). The extraction process included sequential incubations in methanol and acetone, repeated twice. Hair protein was measured via spectrophotometric ratios at 260/280 nm to indicate the hair dissolution state using a BioTek® plate reader and dedicated software. Hair cortisol was measured using an ELISA assay kit. Individual (n=13), pooled hair samples (n=12) with high, intermediate, and low cortisol values and the ELISA assay internal standards (n=3) were also evaluated by LCMS. Results Milled and standard methods showed highly correlated hair cortisol (rs=0.951, p<0.0001) and protein values (rs=0.902, p=0.0002), although higher yields of cortisol and protein were obtained from the standard method in 13/16 and 14/16 samples respectively (p<0.05). Four sequential extractions yielded additional amounts of protein (36.5%, 27.5%, 30.5%, 3.1%) and cortisol (45.4%, 31.1%, 15.1%, 0.04%) from hair samples. Cortisol values measured by LCMS and ELISA were correlated (rs=0.737; p<0.0001), although cortisol levels (median [IQR]) detected in the same samples by LCMS (38.7 [14.4, 136] ng/ml) were lower than by ELISA (172.2 [67.9, 1051] ng/ml). LCMS also detected cortisone, which comprised 13.4% (3.7%, 25.9%) of the steroids detected. Conclusion Methodological studies suggest that finely cutting hair with sequential incubations in methanol and acetone, repeated twice, extracts greater yields of cortisol than does milled hair. Based on these findings, at least three incubations may be required to extract most of the cortisol in human hair samples. In addition, ELISA-based assays showed greater sensitivity for measuring hair cortisol levels than LCMS-based assays. PMID:25811341

Battling the hematological malignancies: the 200 years' war.

PubMed

Lichtman, Marshall A

2008-02-01

The delineation of the hematological malignancies began near the end of the first third of the 19th century with the recognition of the similarity among cases with lymph node tumors and an enlarged spleen (Hodgkin's disease). Descriptions of chronic and acute leukemia and myeloma followed thereafter. In the first years of the 20th century the discovery of x-radiation permitted palliative orthovoltage radiation therapy of Hodgkin's disease. Following World War II, legitimate drug therapy for the hematological malignancies was introduced: nitrogen mustard, adrenocorticotropic hormone and cortisone acetate, and anti-folic acid derivatives, initially aminopterin. Today, about 14 classes of drugs (different mechanisms of action) and >50 individual agents are being used, with others under study. Several examples of agents targeting specific transcription factors or oncoproteins have been introduced. Despite remarkable progress, including the ability to cure acute leukemia in about 70% of children, cure several genetic variants of acute myelogenous leukemia in younger adults, cure some cases of lymphoma in children and younger adults, and induce prolonged remission in many affected persons, the majority of patients face an uncertain outcome and shortened life. Thus, we have much to do in the next several decades. The significant hurdles we must overcome include: the apparent infrequency of an exogenous cause that can be avoided, the exponential increase in incidence rates with age and the dramatic negative effect of aging on the results of treatment, the challenge of one trillion or more disseminated cancer cells among which are a smaller population of cancer stem cells, the profound genetic diversity of the hematological malignancies (apparently hundreds of unique genetic primary lesions), the redundant growth and survival pathways defining the cancer phenotype, the decreasing market for pharmaceutical companies as therapy becomes more specific (fewer target patients) and drug development costs become more expensive, and the significant negative long-term effects of current therapy on both children and adults. These challenges will be gradually overcome, if we (a) develop new models of cooperation among academia, industry, and government, (b) continue the growth of international participation in cancer research (more keen minds to the task), and (c) convince the governments of the world, including that of the U.S., that an investment in minimizing the effects of cancer is as important as defending against other threats to the welfare and longevity of their citizens.

Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline

PubMed Central

Bornstein, Stefan R.; Allolio, Bruno; Arlt, Wiebke; Barthel, Andreas; Don-Wauchope, Andrew; Hammer, Gary D.; Husebye, Eystein S.; Merke, Deborah P.; Murad, M. Hassan; Stratakis, Constantine A.; Torpy, David J.

2016-01-01

Objective: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. Participants: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence. Consensus Process: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. Conclusions: We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 μg) as the “gold standard” diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15–25 mg/d) or cortisone acetate replacement (20–35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (∼8 mg/m2/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease. PMID:26760044

11-Hydroxy-β-steroid dehydrogenase gene expression in canine adipose tissue and adipocytes: stimulation by lipopolysaccharide and tumor necrosis factor α.

PubMed

Ryan, V H; Trayhurn, P; Hunter, L; Morris, P J; German, A J

2011-10-01

The enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD-1) is expressed in a number of tissues in rodents and humans and is responsible for the reactivation of inert cortisone into cortisol. Its gene expression and activity are increased in white adipose tissue (WAT) from obese humans and may contribute to the adverse metabolic consequences of obesity and the metabolic syndrome. The extent to which 11β-HSD-1 contributes to adipose tissue function in dogs is unknown; the aim of the present study was to examine 11β-HSD-1 gene expression and its regulation by proinflammatory and anti-inflammatory agents in canine adipocytes. Real-time PCR was used to examine the expression of 11β-HSD-1 in canine adipose tissue and canine adipocytes differentiated in culture. The mRNA encoding 11β-HSD-1 was identified in all the major WAT depots in dogs and also in liver, kidney, and spleen. Quantification by real-time PCR showed that 11β-HSD-1 mRNA was least in perirenal and falciform depots and greatest in subcutaneous, omental, and gonadal depots. Greater expression was seen in the omental depot in female than in male dogs (P=0.05). Gene expression for 11β-HSD-1 was also seen in adipocytes, from both subcutaneous and visceral depots, differentiated in culture; expression was evident throughout differentiation but was generally greatest in preadipocytes and during early differentiation, declining as cells progressed to maturity. The inflammatory mediators lipopolysaccharide and tumor necrosis factor α had a main stimulatory effect on 11β-HSD-1 gene expression in canine subcutaneous adipocytes, but IL-6 had no significant effect. Treatment with dexamethasone resulted in a significant time- and dose-dependent increase in 11β-HSD-1 gene expression, with greatest effects seen at 24 h (2 nM: approximately 4-fold; 20 nM: approximately 14-fold; P=0.010 for both). When subcutaneous adipocytes were treated with the peroxisome proliferator activated receptor γ agonist rosiglitazone, similar dose- and time-dependent effects were noted. However, no effects were seen when adipocytes from the gonadal WAT depot were treated with rosiglitazone. The induction of 11β-HSD-1 expression, by the pro-inflammatory cytokine tumor necrosis factor α and by lipopolysaccharide may have implications for the pathogenesis of obesity and its associated diseases in the dog. Copyright © 2011 Elsevier Inc. All rights reserved.

Development of an LC-MS/MS method for the determination of endogenous cortisol in hair using (13)C3-labeled cortisol as surrogate analyte.

PubMed

Binz, Tina M; Braun, Ueli; Baumgartner, Markus R; Kraemer, Thomas

2016-10-15

Hair cortisol levels are increasingly applied as a measure for stress in humans and mammals. Cortisol is an endogenous compound and is always present within the hair matrix. Therefore, "cortisol-free hair matrix" is a critical point for any analytical method to accurately quantify especially low cortisol levels. The aim of this project was to modify current methods used for hair cortisol analysis to more accurately determine low endogenous cortisol concentrations in hair. For that purpose, (13)C3-labeled cortisol, which is not naturally present in hair (above 13C natural abundance levels), was used for calibration and comparative validation applying cortisol versus (13)C3-labeled cortisol. Cortisol was extracted from 20mg hair (standard sample amount) applying an optimized single step extraction protocol. An LC-MS/MS method was developed for the quantitative analysis of cortisol using either cortisol or (13)C3-cortisol as calibrators and D7-cortisone as internal standard (IS). The two methods (cortisol/(13)C3-labeled cortisol) were validated in a concentration range up to 500pg/mg and showed good linearity for both analytes (cortisol: R(2)=0.9995; (13)C3-cortisol R(2)=0.9992). Slight differences were observed for limit of detection (LOD) (0.2pg/mg/0.1pg/mg) and limit of quantification (LOQ) (1pg/mg/0.5pg/mg). Precision was good with a maximum deviation of 8.8% and 10% for cortisol and (13)C3-cortisol respectively. Accuracy and matrix effects were good for both analytes except for the quality control (QC) low cortisol. QC low (2.5pg/mg) showed matrix effects (126.5%, RSD 35.5%) and accuracy showed a deviation of 26% when using cortisol to spike. These effects are likely to be caused by the unknown amount of endogenous cortisol in the different hair samples used to determine validation parameters like matrix effect, LOQ and accuracy. No matrix effects were observed for the high QC (400pg/mg) samples. Recovery was good with 92.7%/87.3% (RSD 9.9%/6.2%) for QC low and 102.3%/82.1% (RSD 5.8%/11.4%) for QC high. After successful validation the applicability of the method could be proven. The study shows that the method is especially useful for determining low endogenous cortisol concentrations as they occur in cow hair for example. Copyright © 2016 Elsevier B.V. All rights reserved.

WITHDRAWN: Corticosteroids for Bell's palsy (idiopathic facial paralysis).

PubMed

Salinas, Rodrigo A; Alvarez, Gonzalo; Ferreira, Joaquim

2009-04-15

Inflammation and oedema of the facial nerve are implicated in causing Bell's palsy. Corticosteroids have a potent anti-inflammatory action which should minimise nerve damage and thereby improve the outcome of patients suffering from this condition. The objective of this review was to assess the effect of steroid therapy in the recovery of patients with Bell's palsy. We searched the Cochrane Neuromuscular Disease Group register (searched November 2005) for randomised trials, as well as MEDLINE (January 1966 to November 2005), EMBASE (January 1980 to November 2005) and LILACS (January 1982 to November 2005). We contacted known experts in the field to identify additional published or unpublished trials. Randomised trials comparing different routes of administration and dosage schemes of corticosteroid or adrenocorticotrophic hormone therapy versus a control group where no therapy considered effective for this condition was administered, unless it was also given in a similar way to the experimental group. Two reviewers independently assessed eligibility, trial quality, and extracted the data. Four trials with a total of 179 patients were included. One trial compared cortisone acetate with placebo; one compared prednisone plus vitamins, with vitamins alone; one compared high-dose prednisone administered intravenously against saline solution, and one, not-placebo controlled, tested the efficacy of methylprednisolone. Allocation concealment was appropriate in two trials, and the data reported allowed an intention-to-treat analysis. The data included in the meta-analyses were collected from three trials with a total of 117 patients. Overall 13/59 (22%) of the patients allocated to steroid therapy had incomplete recovery of facial motor function six months after randomisation, compared with 15/58 (26%) in the control group. This reduction was not significant (relative risk 0.86, 95% confidence interval 0.47 to 1.59). The reduction in the proportion of patients with cosmetically disabling sequelae six months after randomisation was also not significant (relative risk 0.86, 95% confidence interval 0.38 to 1.98). The trial not included in the meta-analysis showed a non-significant difference in outcomes between the arms. The available evidence from randomised controlled trials does not show significant benefit from treating Bell's palsy with corticosteroids. More randomised controlled trials with a greater number of patients are needed to determine reliably whether there is real benefit (or harm) from the use of corticosteroid therapy in patients with Bell's palsy. One trial, with 551 participants, comparing prednisolone with acyclovir with both and with neither has just been published and will be included in an update of this review.

Cortisol metabolic predictors of response to psychotherapy for symptoms of PTSD in survivors of the World Trade Center attacks on September 11, 2001.

PubMed

Yehuda, Rachel; Bierer, Linda M; Sarapas, Casey; Makotkine, Iouri; Andrew, Ruth; Seckl, Jonathan R

2009-10-01

A proportion of subjects with symptoms of posttraumatic stress disorder (PTSD) are unresponsive to specialized psychotherapy, but a biological basis for this has not been described. To observe whether differences in cortisol or its metabolites predict or correlate with response to therapy for PTSD symptoms, cortisol and its metabolites were measured from urine samples at pre-treatment, at the conclusion of psychotherapy, and at 3-month follow-up. 28 survivors of the World Trade Center attacks on September 11, 2001 seeking psychological treatment for PTSD symptoms received four sessions of either exposure therapy or supportive counseling, followed by up to 10 sessions of prolonged exposure in a specialized PTSD treatment program at a private hospital serving the New York City metropolitan area. 24-h mean integrated cortisol excretion was assessed by radioimmunoassay (RIA); urinary free cortisol and metabolites cortisone, 5alpha-tetrahydrocortisol (5alpha-THF), 5beta-tetrahydrocortisol, and tetrahydrocortisone were assessed by gas chromatography-mass spectrometry (GC-MS); and indices of enzyme activity for 5alpha- and 5beta-reductase and for the 11beta-hydroxysteroid dehydrogenases were derived from the metabolite and glucocorticoid measures. 5alpha-Reductase activity was significantly lower at pre-treatment among non-responders, whereas there were no significant pre-treatment differences between responders and non-responders in any other hormone or metabolite level. In repeated measures analyses across the three time points, 5alpha-reductase activity, as well as 5alpha-THF and total glucocorticoids, significantly differed between responders and non-responders. For urinary cortisol measured by RIA, there was a significant groupxtime interaction indicating that, although not different at pre-treatment, urinary cortisol levels declined over time in the non-responder group, such that by follow-up, lowered cortisol significantly distinguished non-responders from responders. Indices of 5alpha-reductase activity, including 5alpha-THF and total glucocorticoids, were significantly negatively correlated with avoidance symptom severity at pre-treatment. At follow-up, indices of 5alpha-reductase activity were significantly negatively correlated with severity of all three PTSD symptom clusters and with total PTSD severity scores. Lower 5alpha-reductase activity is associated with avoidance severity and predicts non-responsiveness to psychological treatment for PTSD symptomatology. Relatively diminished 5alpha-reductase activity may mark a state of primary vulnerability, perhaps via attenuated peripheral catabolism of cortisol resulting in the suppression of hypothalamic-pituitary-adrenal axis responsiveness. Lower cortisol levels appear later in the progression to chronic, treatment-resistant PTSD.

Cushing's Syndrome: Screening and Diagnosis.

PubMed

Ceccato, Filippo; Boscaro, Marco

2016-09-01

Endogenous Cushing's syndrome (CS) is a rare disease, and usually characterized by hypertension, diabetes, obesity, osteoporosis, facial rounding, dorsocervical fat pad, thin skin, purple striae, hirsutism, and mood disorders. Efficient diagnostic and screening strategies lead to the diagnosis of a significantly higher number of cases of CS. As a screening test for CS, the Endocrine Society's Clinical Practice Guidelines recommend a single test with a high diagnostic accuracy, among the 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and 24 h urinary free cortisol (UFC). In normal subjects, administering a higher than physiological dose of glucocorticoids prompts the suppression of cortisol secretion. The 1-mg DST explores this normal feedback reaction from the hypothalamic-pituitary-adrenal axis (HPA). It is a simple dynamic test, usually performed in outpatients. A morning serum cortisol level <50 nmol/L suffices to exclude CS, unless there is a strong clinical suspicion to suggest otherwise. The HPA axis reaches a nadir just after a person has fallen asleep, but its circadian rhythm is impaired in CS patients, who feature higher cortisol values at night, which are easy to measure in saliva (the LNSC assay). Saliva collection is also suitable for outpatients since cortisol is stable at room temperature and the collection device can be mailed to the laboratory for analysis. UFC levels reflect the integrated tissue exposure to free cortisol over 24 h, and thus provide a particular picture of endogenous hypercortisolism. In most cases, high UFC levels coincide with severe hypercortisolism. UFC is used not only to diagnose CS, but also to monitor its response to medical treatment. All screening tests have procedural snares: some drugs can interfere with the DST; false-positive or false-negative LNSC results may be due to an inadequate soaking of the device or to cyclic CS; and in the case of UFC it is important to ensure that patients provide complete urine collections with appropriate total volumes. Measuring cortisol with antibody-based immunoassays can also generate false-positive results due to cross-reactivity between cortisol, cortisone and other metabolites. Structurally-based assays, such as liquid chromatography with tandem mass spectrometry, only measure cortisol and have only recently become available for use in routine clinical practice. This review summarizes the recent literature on the clinical and biochemical aspects of CS diagnostics with a view to helping physicians choose the best screening test for diagnosing endogenous hypercortisolism.

Muscle 'contractures' and the 'stiff-man' syndrome.

PubMed

Slater, J D

1986-12-01

The aetiology of the clinical stiff-man syndrome is likely to be heterogenous, but until we have more precise methods of identifying an individual cause the need will continue for this rather flippant appellation in patients whose condition cannot be described in any other way. It is also important because patients may otherwise become labelled as suffering from a psychiatric disorder and may even be falsely accused of abusing diazepam (Westblom, 1978). The reverse is also true, and patients may masquerade as stiff men or women (Price and Allott, 1958; Casati and Rossi, 1969). The endocrine dimension remains and should be tested for carefully, particularly in patients with predominantly lower-limb rigidity whose spasms are a relatively minor aspect of their clinical syndrome. Clearly those patients described by George et al (1984) and Slater (1960) as suffering from the stiff-man syndrome need to be reclassified as examples of the hormonal stiff muscle syndrome, and there may be others so misclassified. An endocrine aetiology may easily be missed in a patient with relatively minor muscle stiffness, pain and cramps, such as the man described by Yunus et al (1981) whose myalgia, 'arthralgia' and muscle tenderness vanished completely within four days of taking physiological replacement doses of cortisone acetate as treatment for his hypopituitarism. The rarity of the stiff-man syndrome makes prospective studies of its aetiology and treatment impossible, yet the dramatic and devastating nature of the syndrome suggests that such cases may be extreme examples of a much more common condition. On the other hand, it is possible to argue that once the psychiatric, the overtly neurological and the endocrine cases are omitted we are left with nothing. However, this is just where Moersch and Woltman came in; they could not explain 14 of their cases. Despite modern technology, despite refinements of diagnosis and despite the increasing recognition of the stiff-man syndrome as a heterogeneous condition, there still remains--albeit very rarely--a cohort of patients with progressive proximal muscular stiffness and spasms who defy proper scientific explanation, but who are likely to suffer from a chronic myelitis which destroys normal feedback mechanisms between muscle spindles and the spinal cord. Experience over the last 30 years has served at least to alert people to the psychiatric possibilities, to remove any question of primary muscle or tendon disease and to point to the usefulness of diazepam. With hope, this chapter provides an endocrine dimension which offers an actual cure and therefore deserves to be more widely recognized.

Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. III. Higher 5 alpha-reductase activity in oligozoospermic men administered supraphysiological doses of testosterone.

PubMed

Anderson, R A; Wallace, A M; Wu, F C

1996-03-01

The administration of exogenous testosterone (T) to eugonadal men causes suppression of gonadotropin secretion and thus of spermatogenesis. This is currently being investigated as a possible method of hormonal male contraceptive, but complete suppression of spermatogenesis to azoospermia is induced in only 50-70% of Caucasian men; the remainder maintain a low rate of spermatogenesis. The basis for this polymorphism in response is unclear. The enzyme 5 alpha-reductase (5 alpha R) converts T to dihydrotestosterone (DHT) and is important in determining the magnitude of the androgen stimulus in some tissues. We investigated whether the maintenance of spermatogenesis in men remaining oligozoospermic while receiving suppressive doses of T is associated with evidence of increased 5 alpha R activity. Thirty-three normal men were given 200 mg T enanthate (TE), im, weekly in a clinical trial of hormonal male contraception. The MCR of T (MCRT) and the conversion ratio of T to DHT (CRT-DHT) were measured by infusion of [3H]T, plasma levels of DHT and androstanediol glucuronide (AdiolG) were measured by RIA, and 24-h urinary steroid metabolites were measured by capillary column gas chromatography. Sperm density decreased in all men; 18 achieved azoospermia by 20 weeks of treatment, and the remainder had a mean sperm density of 2.0 +/- 0.8 x 10(5)/mL at that time. This treatment caused increases in plasma T levels and MCRT, but with no differences between azoospermic and oligozoospermic responders. There were no differences in CRT-DHT plasma DHT, or AdiolG before treatment, but after 16 weeks, CRT-DHT had increased in the oligozoospermic responders, but not in the azoospermic responders. TE treatment increased plasma DHT and AdiolG levels in both groups, but the increases in both 5 alpha R metabolites were significantly greater in the oligozoospermic responders. Urinary excretion of etiocholanolone and androsterone was increased after 16 weeks of TE treatment, but did not differ between the two groups, andetiocholanolone/androsterone ratios did not differ greatly from unity. There was no change in urinary excretion of tetrahydrocortisol, allo-tetrahydrocortisol, or cortisone after 16 weeks of TE treatment in either group. These results suggest that after TE administration there is a selective increase in 5 alpha R activity in those men who remain oligozoospermic, but not in those becoming azoospermic. This difference in the androgenic milieu may underlie the incomplete suppression in the oligozoospermic responders, in whom a low rate of spermatogenesis is maintained despite the apparent absence of gonadotropins.

LInking EDCs in maternal Nutrition to Child health (LINC study) - protocol for prospective cohort to study early life exposure to environmental chemicals and child health.

PubMed

de Cock, Marijke; Quaak, Ilona; Sugeng, Eva J; Legler, Juliette; van de Bor, Margot

2016-02-13

The presence of chemicals in the environment is ubiquitous. Human biomonitoring studies have shown that various chemicals can be detected in the majority of the population, including pregnant women. These compounds may pass the placenta, and reach the fetus. This early life exposure in particular may be detrimental as some chemicals may disrupt the endocrine system, which is involved in various processes during development. The LINC study is a prospective birth cohort designed to study associations between early life environmental exposures and child health, including growth and neurodevelopment. The purpose of this paper is to give an overview of this cohort. Recruitment for this cohort has started in 2011 in three Dutch areas and is still ongoing. To date over 300 mother-child pairs have been included. Women are preferably included during the first trimester of pregnancy. Major congenital anomalies and twin births are reasons for exclusion. To assess exposure to environmental chemicals, cord blood, placenta, meconium and vernix are collected. Parents collect urine of the child shortly after birth and breast milk in the second month of life. Exposure to a broad range of environmental chemicals are determined in cord plasma and breast milk. Furthermore various hormones, including leptin and cortisone, are determined in cord plasma, and in heel prick blood spots (thyroxine). Data on anthropometry of the child is collected through midwives and youth health care centres on various time points until the child is 18 months of age. Furthermore cognitive development is monitored by means of the van Wiechen scheme, and information on behavioral development is collected by means of the infant behavior questionnaire and the child behavior checklist. When the child is 12 months of age, a house visit is scheduled to assess various housing characteristics, as well as hand-to-mouth behavior of the child. At this visit exposure of the child to flame retardants (with endocrine disrupting properties) in house dust is determined by means of body wipes. They are furthermore also measured in a saliva sample of the child. Next to these measurements, women receive questionnaires each trimester regarding amongst others lifestyle of the parents, general health of the parents and the child, and mental state of the mother. This study was approved by the medical ethics committee of the VU University Medical Centre. Consent for the infant is given by the mother, who is specifically required to give consent for both herself as well as her child. Results will be published regardless of the findings of this study, and will be widely disseminated among related medical stakeholders (e.g. midwives and pediatricians), policy makers, and the general public.

Cortisol metabolic predictors of response to psychotherapy for symptoms of PTSD in survivors of the World Trade Center attacks on September 11, 2001

PubMed Central

Yehuda, Rachel; Bierer, Linda M.; Sarapas, Casey; Makotkine, Iouri; Andrew, Ruth; Seckl, Jonathan R.

2009-01-01

Background A proportion of subjects with symptoms of posttraumatic stress disorder (PTSD) are unresponsive to specialized psychotherapy, but a biological basis for this has not been described. To observe whether differences in cortisol or its metabolites predict or correlate with response to therapy for PTSD symptoms, cortisol and its metabolites were measured from urine samples at pre-treatment, at the conclusion of psychotherapy, and at 3-month follow-up. Methods 28 survivors of the World Trade Center attack on September 11, 2001 seeking psychological treatment for PTSD symptoms received four sessions of either exposure therapy or supportive counseling, followed by up to 10 sessions of prolonged exposure in a specialized PTSD treatment program at a private hospital serving the New York City metropolitan area. 24-hr mean integrated cortisol excretion was assessed by radioimmunoassay (RIA); urinary free cortisol and metabolites cortisone, 5α–tetrahydrocortisol (5α-THF), 5β–tetrahydrocortisol, and tetrahydrocortisone were assessed by gas chromatography-mass spectrometry (GCMS); and indices of enzyme activities for 5α–and 5β–reductase and for the 11β–hydroxysteroid dehydrogenases were derived from the metabolite and glucocorticoid measures. Results 5α-reductase activity was significantly lower at pre-treatment among non-responders, whereas there were no significant pre-treatment differences between responders and non-responders in any other hormone or metabolite level. In repeated-measures analyses across the three time points, 5α-reductase activity, as well as 5α-THF and total glucocorticoids, significantly differed between responders and non-responders. For urinary cortisol measured by RIA, there was a significant group × time interaction indicating that, although not different at pre-treatment, urinary cortisol levels declined over time in the non-responder group, such that by follow-up, lowered cortisol significantly distinguished non-responders from responders. Indices of 5α-reductase activity, including 5α-THF and total glucocorticoids, were significantly negatively correlated with avoidance symptom severity at pre-treatment. At follow-up, indices of 5α-reductase activity were significantly negatively correlated with severity of all three PTSD symptom clusters and with total PTSD severity scores. Conclusion Lower 5α–reductase activity is associated with avoidance severity and predicts non-responsiveness to psychological treatment for PTSD symptomatology. Relatively diminished 5α–reductase activity may mark a state of primary vulnerability, perhaps via attenuated peripheral catabolism of cortisol resulting in the suppression of hypothalamic-pituitary-adrenal axis responsiveness. Lower cortisol levels appear later in the progression to chronic, treatment-resistant PTSD. PMID:19411143

The influence of hormonal and neuronal factors on rat heart adrenoceptors

PubMed Central

Kunos, George; Mucci, Lucia; O'Regan, Seana

1980-01-01

1 The influence of hormonal and neuronal factors on adrenoceptors mediating increased cardiac force and rate of contraction were studied in rat isolated atria. The pharmacological properties of these receptors were deduced from the relative potencies of agonists and from the effects of selective α- and β-adrenoceptor antagonists. The numbers and affinities of α- and β-adrenoceptors were also determined by radioligand binding to ventricular membrane fragments. 2 Hypophysectomy reduced the inotropic potency of isoprenaline and increased the potency of phenylephrine and methoxamine in left atria. The effect of phenylephrine was inhibited by propranolol less effectively and by phentolamine or phenoxybenzamine more effectively in hypophysectomized than in control rats. The difference in block was smaller at low than at high antagonist concentrations. Similar but smaller changes were observed for chronotropic responses of right atria. 3 The decreased β- and increased α-receptor response after hypophysectomy was similar to that observed earlier in thyroidectomized rats (Kunos, 1977). These changes developed slowly after hypophysectomy (>2 weeks), they were both reversed within 2 days of thyroxine treatment (0.2 mg/kg daily), but were not affected by cortisone treatment (50 mg/kg every 12 h for 4 days). 4 Treatment of hypophysectomized rats for 2 days with thyroxine increased the density of [3H]-dihydroalprenolol ([3H]-DHA) binding sites from 27.5 ± 2.7 to 45.5 ± 5.7 fmol/mg protein and decreased the density of [3H]-WB-4101 binding sites from 38.7 ± 3.1 to 18.7 ± 2.5 fmol/mg protein. The affinity of either type of binding site for agonists or antagonist was not significantly altered by thyroxine treatment and the sum total of α1- and β-receptors remained the same. 5 Sympathetic denervation of thyroidectomized rats by 6-hydroxydopamine increased the inotropic potency of isoprenaline and noradrenaline and the blocking effect of propranolol, and decreased the potency of phenylephrine and the blocking effect of phenoxybenzamine to or beyond values observed in euthyroid controls. The density of [3H]-DHA binding sites was higher and that of [3H]-WB-4101 binding sites was lower in the denervated than in the innervated hypothyroid myocardium. Depletion of endogenous noradrenaline stores by reserpine did not significantly alter the adrenoceptor response pattern of the hypothyroid preparations and did not influence the density or affinity of [3H]-DHA and [3H]-WB-4101 binding sites. 6 These results indicate that thyrotropin or steroids do not contribute to the reciprocal changes in the sensitivity of cardiac α1- and β-adrenoceptors in altered thyroid states. These thyroid hormone-dependent changes are probably due to a parallel, reciprocal change in the numbers but not the affinities of α1- and β-adrenoceptors. Reciprocal regulation of cardiac α1- and β-adrenoceptors by thyroid hormones requires intact sympathetic innervation but not the presence of normal stores of the neurotransmitter. PMID:7470752

RADIATION THERAPY IN NEOPLASTIC DISEASE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Agnew, C.H.

1962-11-01

Recent innovations in radiotherapy of various forms of cancer are reviewed, and new techniques for treating radiation sickness and injury are outlined. When larger areas of skin are treated with high dosage levels, the erythematous reaction may regress to a wet reaction with denudation. Aqueous 1% gentian violet produces a protective cover which may be soaked off two or three times daily,. followed by a new application by nebulizer or cotton applicator. It is most important to prevent additional trauma. This skin reaction will heal in about two weeks, depending upon the area and depth of involvement. Atrophic dry areasmore » should be protected from irritation. Zinc oxide paste provides an economic protection; however, large areas exhibiting atrophy and ectasia may ulcerate repeatedly. If there has been much vascular damage, adequate excision and skin grafting will probably be necessary. Careful attention must be given to the possibility of metaplasia and transformation into squamous cell carcinoma. The epithelial lining of the oropharynx and esophagas, when included in treatment fields, may develop mucositis near the end of treatment, but the peak reaction usually develops after treatment is completed. This may be easily observed in the oropharynx as a pseudomembranous reaction which looks very much like a monilia infection. This temporary reaction will not require intensive treatment and will respond to warm, normal saline irrigation. The mucous membrane reaction of the esophagus usually develops after approximates 4000 r. Thus, near the end of the 4th wk of treatment, complaints of difficulty in swallowing are expected. There is no effective treatment. Fluoroscopic examination usually does not show a detectable abnormality. The peak reaction may occur 10 days after treatment is completed, and then gradually subsides during the next three weeks. For relief from nausea and vomiting, antiemetics, vitamin B preparations, and antihistamines may be used. Yeast tablets and wine have proved very satisfactory, and a glass of wine diluted to half with water 30 min before noon and evening meals promotes appetite. If the white blood count remains above 2000 and the hemoglobin above 10 g, it is not necessary to be concerned about the hematologic picture. However, if the count falls below these levels, special consideration is required and daily hemoglobin and white blood cell determinations should be done. As a treatment policy, it is recommended that radiation be continued as long as the white blood count remains above 1000 and hemoglobin above 10 g. When hemoglobin falls below this level, transfusion is indicated. The radiation effect is dependent upon the level of tissue oxygenation. With a large field, peripheral white cell counts usually drop in about two weeks. Proctitis, a frequent complication of uterine cancer irradiation, may respond to oil enemas; however, the most effective treatment now seems to be cortisone suppositories. Sedation coupled with narcotics may have to be used for dysuria, which usually does not appear at doses >4000 r. This becomes a rather serious problem in connection with treatment of carcinoma of the bladder, but is rarely a problem in treatment of the uterine cervix. Relief from burning, urgency and frequency can usually be obtained with phenazopyridine. If retention and infection complicate the discomfort, methenamine mandelate may be used safely in combination for its antibacterial action. For postradiation vaginitis, a regimen of gentle irrigation with warm (100 deg F) water, hydrogen peroxide or sodium perborate, and normal saline assists healing. (BBB)« less

[Pathological fractures of the femoral neck in hemodialyzed patients. Apropos of 26 cases].

PubMed

Hardy, P; Benoit, J; Donneaud, B; Jehanno, P; Lortat-Jacob, A

1994-01-01

This study is based on a retrospective analysis of 26 pathological fractures of the femoral neck in 19 chronic haemodialysis patients. The purpose of this study is to analyze the epidemiological and etiological factors of these fractures in relation to osteo-arthropathy of the dialyzed patient, as well as the results of various treatments, both curative and preventive. 26 pathological fractures of the femoral neck appeared in 19 chronic haemodialysis patients, 11 men and 8 women, 6 patients presented bilateral fractures. The patient's average age at the time of the fracture was 61 years (27 to 82). The average duration of dialysis was 11 years with a minimum of 2 years and a maximum of 21 years. Hyper parathyroidism was found in 14 patients, aluminic intoxication in 6 and amyloidosis at the level of the coxo-femoral joint 18 times. Surgical treatment consisted of 6 osteosynthesis, 2 cephalic arthroplasties, 13 modular arthroplasties and 5 total hip arthroplasties. For each case, we studied the presence of necrosis of the femoral neck due to aluminic intoxication, osteoporosis due to hyperparathyroidism and also the presence of amyloidosis without aluminic intoxication. Cortisonic necrosis and porosis was found 4 times out of 26 cases, hyperparathyroidism once, aluminic osteomalacy 3 times and beta-2-microglobulin amyloid 18 times. Amyloidosis remains the most frequent etiological factor. All patients had been operated for median nerve compression in the carpal tunnel, usually 2.5 years before appearance of the pathological fracture. Non surgical treatment was used 5 times in undisplaced fractures without any sign of amyloidosis and was successful 3 times and unsuccessful twice necessitating a new operation by osteosynthesis. Out of 6 osteosynthesis performed for fractures either with little or no displacement we observed 4 failures, all of them in the cases with intra-osseous amyloidosis. Best results were obtained by arthroplasties. Modular arthroplasty has given us 11 long term excellent results in 11 of 13 cases. The analysis of etiological factors shows two very different groups. The first one consisted of 8 fractures without coxofemoral amyloidosis. The average duration of dialysis was 5 years, average age, 44 years. Etiology was 3 times aluminic osteomalacy, once the only factor found was osteoporosis and 4 times necrosis and porosis as a complication, not of haemodialysis but of renal transplantation with concomittant corticosteroid treatment. The second group consisted of 18 fractures with hip amyloidosis in 14 patients. The average age was 63.5 years, the dialysis duration was 11.5 years, the two extremes 5 and 21 years. Etiology was beta-2-microglobulin amylosis. The pathological fracture was due to the presence of voluminous subchondral amyloidosis geodes. Amyloidosis always associated with hyperparathyroidism and aluminic intoxication in one of 3 cases. Osteosynthesis gave good results only in cases presenting no intra-osseous amyloidosis. Modular arthroplasty has allowed us to obtain excellent long term functional results with simpler outcome. Total arthroplasty should be used only for evident acetabular involvement. Amyloidosis remains the etiological factor most frequently found in pathological fractures of the femoral neck in chronic haemodialysis patients. The study of the etiological factors is essential since they will guide us in the choice of the mode or treatment. It is totally licit to propose conservative treatment for non displaced fractures without osseous amylosis. In all other cases, prosthetic replacement is necessary and osteosynthesis contra-indicated. When the acetabulum is not altered a modular arthroplasty must be used. We do not recommend preventive surgical treatment for patients having a threatening geode of the femoral neck as all osteosynthesis realized on amyloidotic bone, even without any displacement, resulted

Water-filtered infrared-A (wIRA) can act as a penetration enhancer for topically applied substances

PubMed Central

Otberg, Nina; Grone, Diego; Meyer, Lars; Schanzer, Sabine; Hoffmann, Gerd; Ackermann, Hanns; Sterry, Wolfram; Lademann, Jürgen

2008-01-01

Background: Water-filtered infrared-A (wIRA) irradiation has been shown to enhance penetration of clinically used topically applied substances in humans through investigation of functional effects of penetrated substances like vasoconstriction by cortisone. Aim of the study: Investigation of the influence of wIRA irradiation on the dermatopharmacokinetics of topically applied substances by use of optical methods, especially to localize penetrating substances, in a prospective randomised controlled study in humans. Methods: The penetration profiles of the hydrophilic dye fluorescein and the lipophilic dye curcumin in separate standard water-in-oil emulsions were determined on the inner forearm of test persons by tape stripping in combination with spectroscopic measurements. Additionally, the penetration was investigated in vivo by laser scanning microscopy. Transepidermal water loss, hydration of the epidermis, and surface temperature were determined. Three different procedures (modes A, B, C) were used in a randomised order on three separate days of investigation in each of 12 test persons. In mode A, the two dyes were applied on different skin areas without water-filtered infrared-A (wIRA) irradiation. In mode B, the skin surface was irradiated with wIRA over 30 min before application of the two dyes (Hydrosun® radiator type 501, 10 mm water cuvette, orange filter OG590, water-filtered spectrum: 590–1400 nm with dominant amount of wIRA). In mode C, the two dyes were applied and immediately afterwards the skin was irradiated with wIRA over 30 min. In all modes, tape stripping started 30 min after application of the formulations. Main variable of interest was the ratio of the amount of the dye in the deeper (second) 10% of the stratum corneum to the amount of the dye in the upper 10% of the stratum corneum. Results: The penetration profiles of the hydrophilic fluorescein showed in case of pretreatment or treatment with wIRA (modes B and C) an increased penetration depth compared to the non-irradiated skin (mode A): The ratio of the amount of the dye in the deeper (second) 10% of the stratum corneum to the amount of the dye in the upper 10% of the stratum corneum showed medians and interquartile ranges for mode A of 0.017 (0.007/0.050), for mode B of 0.084 (0.021/0.106), for mode C of 0.104 (0.069/0.192) (difference between modes: p=0.0112, significant; comparison mode A with mode C: p<0.01, significant). In contrast to fluorescein, the lipophilic curcumin showed no differences in the penetration kinetics, in reference to whether the skin was irradiated with wIRA or not. These effects were confirmed by laser scanning microscopy. Water-filtered infrared-A irradiation increased the hydration of the stratum corneum: transepidermal water loss rose from approximately 8.8 g m-2 h-1 before wIRA irradiation to 14.2 g m-2 h-1 after wIRA irradiation and skin hydration rose from 67 to 87 relative units. Skin surface temperature increased from 32.8°C before wIRA to 36.4°C after wIRA irradiation. Discussion: The better penetration of the hydrophilic dye fluorescein after or during skin irradiation (modes B and C) can be explained by increased hydration of the stratum corneum by irradiation with wIRA. Conclusions: As most topically applied substances for the treatment of patients are mainly hydrophilic, wIRA can be used to improve the penetration of substances before or after application of substances – in the first case even of thermolabile substances – with a broad clinical relevance as a contact free alternative to an occlusive dressing. PMID:19675735