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Sample records for hypercalciuric stone-forming ghs

  1. Pathophysiology of the Hypercalciuria in the Genetic Hypercalciuric Stone-Forming Rats

    NASA Astrophysics Data System (ADS)

    Bushinsky, David A.

    2007-04-01

    Given evidence for a genetic cause of hypercalciuria, we screened adult male and female Sprague-Dawley (SD) rats for hypercalciuria and used those with the highest urinary calcium excretion to breed the next generation, followed by subsequent selection and inbreeding of their most hypercalciuric progeny. By the 30th generation, and continuing to the present, the GHS rats (for Genetic Hypercalciuric Stone-forming rats) excrete 8-10 times as much calcium as simultaneously studied control rats The GHS rats were found to have defects in calcium transport in the intestine, kidneys and bone, similar to abnormalities found in many patients with idiopathic hypercalciuria. The GHS rats also form kidney stones. By the conclusion of an 18 wk study, all of the GHS rats formed stones, while there was no stone formation in similarly treated SD controls. The GHS rats, when fed a standard 1.2% calcium diet, form only poorly crystalline apatite stones. However, when 5% hydroxyproline is added to the diet of the GHS rats, they form only calcium oxalate stones.

  2. Integrative microRNA-gene expression network analysis in genetic hypercalciuric stone-forming rat kidney

    PubMed Central

    Lu, Yuchao; Qin, Baolong; Hu, Henglong; Zhang, Jiaqiao; Wang, Yufeng; Wang, Qing

    2016-01-01

    Background. MicroRNAs (miRNAs) influence a variety of biological functions by regulating gene expression post-transcriptionally. Aberrant miRNA expression has been associated with many human diseases. Urolithiasis is a common disease, and idiopathic hypercalciuria (IH) is an important risk factor for calcium urolithiasis. However, miRNA expression patterns and their biological functions in urolithiasis remain unknown. Methods and Results. A multi-step approach combining microarray miRNA and mRNA expression profile and bioinformatics analysis was adopted to analyze dysregulated miRNAs and genes in genetic hypercalciuric stone-forming (GHS) rat kidneys, using normal Sprague-Dawley (SD) rats as controls. We identified 2418 mRNAs and 19 miRNAs as significantly differentially expressed, over 700 gene ontology (GO) terms and 83 KEGG pathways that were significantly enriched in GHS rats. In addition, we constructed an miRNA-gene network that suggested that rno-miR-674-5p, rno-miR-672-5p, rno-miR-138-5p and rno-miR-21-3p may play important roles in the regulatory network. Furthermore, signal-net analysis suggested that NF-kappa B likely plays a crucial role in hypercalciuria urolithiasis. Conclusions. This study presents a global view of mRNA and miRNA expression in GHS rat kidneys, and suggests that miRNAs may be important in the regulation of hypercalciuria. The data provide valuable insights for future research, which should aim at validating the role of the genes featured here in the pathophysiology of hypercalciuria. PMID:27069814

  3. 1,25(OH)₂D₃-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet.

    PubMed

    Frick, Kevin K; Asplin, John R; Krieger, Nancy S; Culbertson, Christopher D; Asplin, Daniel M; Bushinsky, David A

    2013-10-15

    The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 ± 0.1 to 9.3 ± 0.9 mg/day and increased more in GHS from 4.7 ± 0.3 to 21.5 ± 0.9 mg/day (P < 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption.

  4. Prophylactic effects of quercetin and hyperoside in a calcium oxalate stone forming rat model.

    PubMed

    Zhu, Wei; Xu, Yun-fei; Feng, Yuan; Peng, Bo; Che, Jian-ping; Liu, Min; Zheng, Jun-hua

    2014-12-01

    Quercetin and hyperoside (QH) are the two main constituents of the total flavone glycosides of Flos Abelmoschus manihot, which has been prescribed for treating chronic kidney disease for decades. This study aimed to investigate the effect of QH on calcium oxalate (CaOx) formation in ethylene glycol (EG)-fed rats. Rats were divided into three groups: an untreated stone-forming group, a QH-treated stone-forming group (20 mg/kg/day) and a potassium citrate-treated stone-forming group (potassium citrate was a worldwide-recognized calculi-prophylactic medicine). Ethylene glycol (0.5 %) was administered to the rats during the last week, and vitamin D3 was force-fed to induce hyperoxaluria and kidney calcium oxalate crystal deposition. 24 h urine samples were collected before and after inducing crystal deposits. Rats were killed and both kidneys were harvested after 3 weeks. Bisected kidneys were examined under a polarized light microscope for semi-quantification of the crystal-formation. The renal tissue superoxide dismutase and catalase levels were measured by Western blot. QH and potassium citrate have the ability to alkalinize urine. The number of crystal deposits decreased significantly in the QH-treated stone-forming group as compared to the other groups. Superoxide dismutase and catalase levels also increased significantly in the QH-treated stone-forming group, as compared with the untreated stone-forming group. QH administration has an inhibitory effect on the deposition of CaOx crystal in EG-fed rats and may be effective for preventing stone-forming disease.

  5. Integrating GHS into the Ghrelin System

    PubMed Central

    Veldhuis, Johannes D.; Bowers, Cyril Y.

    2010-01-01

    Oligopeptide derivatives of metenkephalin were found to stimulate growth-hormone (GH) release directly by pituitary somatotrope cells in vitro in 1977. Members of this class of peptides and nonpeptidyl mimetics are referred to as GH secretagogues (GHSs). A specific guanosine triphosphatate-binding protein-associated heptahelical transmembrane receptor for GHS was cloned in 1996. An endogenous ligand for the GHS receptor, acylghrelin, was identified in 1999. Expression of ghrelin and homonymous receptor occurs in the brain, pituitary gland, stomach, endothelium/vascular smooth muscle, pancreas, placenta, intestine, heart, bone, and other tissues. Principal actions of this peptidergic system include stimulation of GH release via combined hypothalamopituitary mechanisms, orexigenesis (appetitive enhancement), insulinostasis (inhibition of insulin secretion), cardiovascular effects (decreased mean arterial pressure and vasodilation), stimulation of gastric motility and acid secretion, adipogenesis with repression of fat oxidation, and antiapoptosis (antagonism of endothelial, neuronal, and cardiomyocyte death). The array of known and proposed interactions of ghrelin with key metabolic signals makes ghrelin and its receptor prime targets for drug development. PMID:20798846

  6. Assessing applicants to the NASA flight program for their renal stone-forming potential

    NASA Technical Reports Server (NTRS)

    Pak, Charles Y. C.; Hill, Kathy; Cintron, Nitza M.; Huntoon, Carolyn

    1989-01-01

    Because spaceflight can provoke the formation of kidney stones, 24-hour urine samples for 104 male applicants were analyzed for stone-forming risk factors prior to their selection into the NASA astronaut-mission specialist corps. A high level of supersaturation (with either calcium oxalate, brushite, or monosodium urate) was noted in these applicants which predisposes them to the crystallization of stone-forming calcium salts. It is suggested that most of the abnormal stone risk factors found were environmental, rather than metabolic, in origin.

  7. Prevention of hypercalciuria and stone-forming propensity during prolonged bedrest by alendronate

    NASA Technical Reports Server (NTRS)

    Ruml, L. A.; Dubois, S. K.; Roberts, M. L.; Pak, C. Y.

    1995-01-01

    The bone loss and hypercalciuria induced by immobilization or the decreased gravitational forces of space are well described. Using a model of bedrest immobilization, the ability of a potent aminobisphosphonate, alendronate, to avert hypercalciuria and stone-forming propensity was tested. Sixteen male subjects participated in a randomized, placebo-controlled trial in which they received either 20 mg of alendronate or placebo 2 weeks prior to and during 3 weeks of strict bedrest. Parameters of bone and calcium metabolism and urinary crystallization of stone-forming salts were measured before and at the end of bedrest. In the placebo group, bedrest increased urinary calcium (209 +/- 47 to 267 +/- 60 mg/day, p < 0.01) and the saturation of calcium phosphate. Before bedrest, the alendronate group had a significantly lower serum calcium (8.8 +/- 0.4 vs. 9.6 +/- 0.5 mg/dl, p < 0.01) and higher serum PTH (62.4 +/- 33.1 vs. 23.1 +/- 7.5 pg/ml, p < 0.01) compared with the placebo group. Moreover, the alendronate group had a lower urinary calcium (75 +/- 41 mg/day) and saturation of calcium oxalate and calcium phosphate. These effects of alendronate were sustained during bedrest. Following bedrest in the alendronate group, urinary calcium rose to 121 +/- 50 mg/day, a value less than that in the placebo group before or during bedrest. Similarly, urinary saturation of calcium oxalate and calcium phosphate rose with bedrest in the alendronate-treated patients but remained lower than values obtained in placebo-treated patients before or during bedrest. Alendronate inhibits bone mineral loss and averts the hypercalciuria and increased propensity for the crystallization of stone-forming calcium salts which occurs during 3 weeks of strict bedrest.

  8. Expert review for GHS classification of chemicals on health effects.

    PubMed

    Morita, Takeshi; Morikawa, Kaoru

    2011-01-01

    Intoxication as a result of chemical accidents is a major issue in industrial health. The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) provides a framework for hazard communication on chemicals using labelling or safety data sheets. The GHS will be expected to reduce the number of chemical accidents by communicating the hazards posed and prompting safety measures to be taken. One of the issues which may be a barrier to effective implementation of the GHS results from discrepancies in GHS classifications of chemicals across countries/regions. The main reasons are the differences in information sources used and in the expertise of people making the classification (Classifiers). The GHS requests expert judgment in a weight of evidence (WOE) approach in the application of the criteria of classification. A WOE approach is an assessment method that considers all available information bearing on the determination of toxicity. The quality and consistency of the data, study design, mechanism or mode of action, dose-effect relationships and biological relevance should be taken into account. Therefore, expert review should be necessary to classify chemicals accurately. However, the GHS does not provide any information on the required level of expertise of the Classifiers, definition of who qualifies as an expert, evaluation methods of WOE or data quality, and the timing of expert judgment and the need for updating/re-classification as new information becomes available. In this paper, key methods and issues in expert reviews are discussed. Examples of expert reviews and recommendations for harmonized classification are also presented.

  9. Biochemical effects in normal and stone forming rats treated with the ripe kernel juice of plantain (musa paradisiaca).

    PubMed

    Devi, V K; Baskar, R; Varalakshmi, P

    1993-01-01

    The effect of Musa paradisiaca stem kernel juice was investigated in experimental urolithiatic rats. Stone forming rats exhibited a significant elevation in the activities of two oxalate synthesizing enzymes - Glycollic acid oxidase and Lactate dehydrogenase. Deposition and excretion of stone forming constituents in kidney and urine were also increased in these rats. The enzyme activities and the level of crystalline components were lowered with the extract treatment. The extract also reduced the activities of urinary alkaline phosphatase, lactate dehydrogenase, r-glutamyl transferase, inorganic pyrophosphatase and β-glucuronidase in calculogenic rats. No appreciable changes were noticed with leucine amino peptidase activity in treated rats.

  10. Usefulness of measuring renal papillae in Hounsfield units in stone - forming patients

    PubMed Central

    Arrabal-Polo, Miguel Angel; Cano-Garcia, Maria del Carmen; Huerta-Brunel, Juan Esteban; Hidalgo-Agullo, Guillermo; Roletto-Salmo, Luis; Arrabal-Martín, Miguel

    2016-01-01

    ABSTRACT Introduction: The aim of this work is to study the density of the renal papillae in stone-forming patients and to determine its usefulness. Materials and Methods: This study included a total of 79 patients diagnosed with renal stones and on whom a computed tomography without contrast was performed from June 2014 to May 2015. The patients were divided into two groups: Group 1 (single episode) included 43 patients, and Group 2 (recurrent episodes) included 36 patients. The density of six renal papillae (3 per kidney) was measured, and the means obtained were compared between Groups 1 and 2. Statistical analysis was performed using SPSS 20.0. Results: The mean papillary density in Group 1 was 32.26 (SD 4.07) HU compared to 42.36 (SD 8.03) HU in Group 2 (P=00001). A ROC curve was constructed, obtaining an optimal cut-off point of 36.8HU [area under the curve, 0.881 (95% CI; 0.804-0.958); P=0001], with a sensitivity of 80% and a specificity of 90%. The relative risk was estimated at 40.3 (95% CI; 10.8-151.1), meaning that a patient with a mean papillary density greater than 36.8HU would have a 40 times greater risk of having recurrent renal stones. The positive predictive value (PPV) was 81% and the negative predictive value (NPV) was 90%. Conclusion: The measurement of renal papillary density could be useful in predicting recurrent stone-formers. These results need to be confirmed in future studies with a greater number of patients and a longer follow-up. PMID:27622277

  11. Similarity of urinary risk factors among stone-forming patients in five regions of the United States

    NASA Technical Reports Server (NTRS)

    Harvey, J. A.; Hill, K. D.; Pak, C. Y.

    1990-01-01

    Study Objective: To compare urinary biochemical risk factors among stone-forming patients in the Southeast (SE) or "stone belt" versus four other regions of the United States. Design: Prospective biochemical survey for regional comparisons. Setting: Referral-based nephrolithiasis clinics, urologists, nephrologists, and family practitioners. Patients: Consecutive sample of 3473 stone-forming patients who submitted 24-hour urine collections for biochemical analyses of stone-forming risk factors. Interventions: None. Subjects taking medication known to interfere with stone-forming risk factors were deleted from the final data compilation. Measurements and Main Results: Overall, the mean values for each urinary parameter spanned a narrow range without significant difference between the five regions. Among "metabolic" factors, 40% in the SE had hypercalciuria (> 6.25 mmol/d), compared to 35%-43% in other regions, and hyperuricosuria (> 4.2 mmol/d) was found in 16% in the SE versus 17%-19% elsewhere. Among "environmental" factors, low urine volume ( < 2 L/d) was found in 77% patients in the SE compared to 69%-78% elsewhere, and high sodium was encountered in 27% in the SE versus 24%-29% elsewhere. No differences were noted in occurrence of other abnormal risk factors: hyperoxaluria, hypocitraturia, low pH, high sulfate, high phosphorus, or low magnesium. Conclusions: Despite expected regional differences in nutritional and environmental influences, the results of this study showed a striking similarity in urinary biochemical risk factor profiles of stone-formers in all five regions of the United States.

  12. [Globally harmonized system of classification and labelling of chemicals (GHS) and its implementation in Japan].

    PubMed

    Miyagawa, Muneyuki

    2010-01-01

    The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) is a set of recommendations by the United Nations, first issued in 2003 as a communication tool for the sound management of chemicals, comprising harmonized classification criteria for physical, health and environmental hazards, a unified format for material safety data sheets (MSDS), and labeling elements including pictograms and hazard statements preassigned to each classification category. The GHS has been introduced into Japan and implemented in the regulatory framework for chemical safety. The Japanese Industrial Standards (JIS) adopted the GHS, and the GHS-based JIS rules have become the Japanese standards for labels and MSDS. The use of the JIS format for labels and MSDS is recommended by several competent authorities in Japan although mostly on a voluntary basis. In the workplace, however, GHS-based JIS labels and MSDS have become legal requirements by the Industrial Safety and Health Law since 2006; namely, issuing MSDS in such a format is mandatory for the 640 specified chemicals and also labeling for the 99 targeted chemicals*. Although the GHS provides definitions and classification criteria for 10 classes of health hazards (acute toxicity, skin and eye corrosion/irritation, sensitization, germ cell mutagenicity, carcinogenicity, reproductive toxicity, specific target organ toxicity single/repeated exposures, and aspiration hazard), it does not provide actual classification of chemicals, so that competent authorities and industries need to classify a number of chemicals and/or mixtures. Weight-of-evidence judgment and/or expert judgment would be necessary in many cases. In this paper, the outline of the GHS classification is described and problems of the GHS and its implementation are discussed.

  13. Nutrient intake and urine composition in calcium oxalate stone-forming dogs: comparison with healthy dogs and impact of dietary modification.

    PubMed

    Stevenson, Abigail E; Blackburn, Judith M; Markwell, Peter J; Robertson, William G

    2004-01-01

    Nutrient intake and urine composition were analyzed in calcium oxalate (CaOx)stone-forming and healthy control dogs to identify factors that contribute to CaOx urolithiasis. Stone-forming dogs had significantly lower intake of sodium, calcium, potassium, and phosphorus and significantly higher urinary calcium and oxalate concentrations, calcium excretion, and CaOx relative supersaturation (RSS). Feeding a diet used in the treatment of canine lower urinary tract disease for 1 month was associated with increased intake of moisture, sodium, and fat; reduced intake of potassium and calcium; and decreased urinary calcium and oxalate concentrations, calcium excretion, and CaOx RSS. No clinical signs of disease recurrence were observed in the stone-forming dogs when the diet was fed for an additional 11 months. The results suggest that hypercalciuria and hyperoxaluria contribute to the formation of CaOx uroliths in dogs and show that dietary modifications can alter this process.

  14. GHS-R1a constitutive activity and its physiological relevance

    PubMed Central

    Mear, Yves; Enjalbert, Alain; Thirion, Sylvie

    2013-01-01

    Abundant evidences have shown that ghrelin, by its binding to GHS-R1a, plays an important role for fundamental physiological functions. Increasing attention is given to the GHS-R1a unusually high constitutive activity and its contribution to downstream signaling and physiological processes. Here, we review recent lines of evidences showing that the interaction between ligand-binding pocket TM domains and the ECL2 could be partially responsible for this high constitutive activity. Interestingly, GHSR-1a constitutive activity activates in turn the downstream PLC, PKC, and CRE signaling pathways and this activation is reversed by the inverse agonist [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P (MSP). Noteworthy, GHSR-1a exhibits a C-terminal-dependent constitutive internalization. Non-sense GHS-R1a mutation (Ala204Glu), first discovered in Moroccan patients, supports the role of GHSR-1a constitutive activity in physiological impairments. Ala204Glu-point mutation, altering exclusively the GHSR-1a constitutive activity, was associated with familial short stature syndrome. Altogether, these findings suggest that GHS-R1a constitutive activity could contribute to GH secretion or body weight regulation. Consequently, future research on basic and clinical applications of GHS-R1a inverse agonists will be challenging and potentially rewarding. PMID:23754971

  15. The development of the globally harmonized system (GHS) of classification and labelling of hazardous chemicals.

    PubMed

    Winder, Chris; Azzi, Rola; Wagner, Drew

    2005-10-17

    The hazards of chemicals can be classified using classification criteria that are based on physical, chemical and ecotoxicological endpoints. These criteria may be developed be iteratively, based on scientific or regulatory processes. A number of national and international schemes have been developed over the past 50 years, and some, such as the UN Dangerous Goods system or the EC system for hazardous substances, are in widespread use. However, the unnecessarily complicated multiplicity of existing hazard classifications created much unnecessary confusion at the user level, and a recommendation was made at the 1992 Rio Earth summit to develop a globally harmonized chemical hazard classification and compatible labelling system, including material safety data sheets and easily understandable symbols, that could be used for manufacture, transport, use and disposal of chemical substances. This became the globally harmonized system for the Classification and Labelling of Chemicals (GHS). The developmental phase of the GHS is largely complete. Consistent criteria for categorising chemicals according to their toxic, physical, chemical and ecological hazards are now available. Consistent hazard communication tools such as labelling and material safety data sheets are also close to finalisation. The next phase is implementation of the GHS. The Intergovernmental Forum for Chemical Safety recommends that all countries implement the GHS as soon as possible with a view to have the system fully operational by 2008. When the GHS is in place, the world will finally have one system for classification of chemical hazards.

  16. Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention.

    PubMed

    Davies, Jeffrey S; Kotokorpi, Pia; Eccles, Sinan R; Barnes, Sarah K; Tokarczuk, Pawel F; Allen, Sophie K; Whitworth, Hilary S; Guschina, Irina A; Evans, Bronwen A J; Mode, Agneta; Zigman, Jeffrey M; Wells, Timothy

    2009-06-01

    Circulating ghrelin elevates abdominal adiposity by a mechanism independent of its central orexigenic activity. In this study we tested the hypothesis that peripheral ghrelin induces a depot-specific increase in white adipose tissue (WAT) mass in vivo by GH secretagogue receptor (GHS-R(1a))-mediated lipolysis. Chronic iv infusion of acylated ghrelin increased retroperitoneal and inguinal WAT volume in rats without elevating superficial sc fat, food intake, or circulating lipids and glucose. Increased retroperitoneal WAT mass resulted from adipocyte enlargement probably due to reduced lipid export (ATP-binding cassette transporter G1 mRNA expression and circulating free fatty acids were halved by ghrelin infusion). In contrast, ghrelin treatment did not up-regulate biomarkers of adipogenesis (peroxisome proliferator-activated receptor-gamma2 or CCAAT/enhancer binding protein-alpha) or substrate uptake (glucose transporter 4, lipoprotein lipase, or CD36) and although ghrelin elevated sterol-regulatory element-binding protein 1c expression, WAT-specific mediators of lipogenesis (liver X receptor-alpha and fatty acid synthase) were unchanged. Adiposity was unaffected by infusion of unacylated ghrelin, and the effects of acylated ghrelin were abolished by transcriptional blockade of GHS-R(1a), but GHS-R(1a) mRNA expression was similar in responsive and unresponsive WAT. Microarray analysis suggested that depot-specific sensitivity to ghrelin may arise from differential fine tuning of signal transduction and/or lipid-handling mechanisms. Acylated ghrelin also induced hepatic steatosis, increasing lipid droplet number and triacylglycerol content by a GHS-R(1a)-dependent mechanism. Our data imply that, during periods of energy insufficiency, exposure to acylated ghrelin may limit energy utilization in specific WAT depots by GHS-R(1a)-dependent lipid retention.

  17. Process research and development for a tetrazole-based growth hormone secretagogue (GHS) pharmaceutical development candidate.

    PubMed

    Davulcu, Akin H; McLeod, Douglas D; Li, Jun; Katipally, Kishta; Littke, Adam; Doubleday, Wendel; Xu, Zhongmin; McConlogue, Cary W; Lai, Chiajen J; Gleeson, Margaret; Schwinden, Mark; Parsons, Rodney L

    2009-06-05

    BMS-317180 (1) is a potent, orally active agonist of the human growth hormone secretagogue (GHS) receptor. This manuscript details the process research and development efforts that enabled the synthesis of the phosphate salt of 1 on a multi-kilogram scale. Key considerations in the development of this process focused on safe execution and the requirement for telescoped synthetic transformations (i.e., without isolation of intermediate products) to contend with a lack of suitably crystalline products.

  18. Pathophysiological studies in idiopathic hypercalciuria: use of an oral calcium tolerance test to characterize distinctive hypercalciuric subgroups.

    PubMed

    Broadus, A E; Dominguez, M; Bartter, F C

    1978-10-01

    hyperparathyroidism in these patients was physiological or secondary, including the near normalization of parathyroid function on the daily 1000-mg calcium intake. A steep slope of calcium excretion on calcium intake (due to increased calcium absorption) was noted in all hypercalciuric patients and accounted for the significantly improved diagnostic accuracy of screening patients for hypercalciuria on the high-normal calcium intake. The simple measurement of total cAMP excretion (nanomoles per 100 ml GF) and urinary calcium on the 1000-mg daily calcium intake seemed to provide reliable separation of patients with "renal" from those with "absorptive" hypercalciuria. A physiological (350 mg) dose of oral calcium produced a 30% suppression of nephrogenous cAMP in normal subjects; this suggests that dietary calcium exerts an important control of parathyroid function under physiological circumstances.

  19. Hypercalciuric Bone Disease

    NASA Astrophysics Data System (ADS)

    Favus, Murray J.

    2008-09-01

    Hypercalciuria plays an important causal role in many patients with calcium oxalate (CaOx) stones. The source of the hypercalciuria includes increased intestinal Ca absorption and decreased renal tubule Ca reabsorption. In CaOx stone formers with idiopathic hypercalciuria (IH), Ca metabolic balance studies have revealed negative Ca balance and persistent hypercalciuria in the fasting state and during low dietary Ca intake. Bone resorption may also contribute to the high urine Ca excretion and increase the risk of bone loss. Indeed, low bone mass by DEXA scanning has been discovered in many IH patients. Thiazide diuretic agents reduce urine Ca excretion and may increase bone mineral density (BMD), thereby reducing fracture risk. Dietary Ca restriction that has been used unsuccessfully in the treatment of CaOx nephrolithiasis in the past may enhance negative Ca balance and accelerate bone loss. DEXA scans may demonstrate low BMD at the spine, hip, or forearm, with no predictable pattern. The unique pattern of bone histologic changes in IH differs from other causes of low DEXA bone density including postmenopausal osteoporosis, male hypogonadal osteoporosis, and glucocorticoid-induced osteoporosis. Hypercalciuria appears to play an important pathologic role in the development of low bone mass, and therefore correction of urine Ca losses should be a primary target for treatment of the bone disease accompanying IH.

  20. Extensive review of fish embryo acute toxicities for the prediction of GHS acute systemic toxicity categories.

    PubMed

    Scholz, Stefan; Ortmann, Julia; Klüver, Nils; Léonard, Marc

    2014-08-01

    Distribution and marketing of chemicals require appropriate labelling of health, physical and environmental hazards according to the United Nations global harmonisation system (GHS). Labelling for (human) acute toxicity categories is based on experimental findings usually obtained by oral, dermal or inhalative exposure of rodents. There is a strong societal demand for replacing animal experiments conducted for safety assessment of chemicals. Fish embryos are considered as alternative to animal testing and are proposed as predictive model both for environmental and human health effects. Therefore, we tested whether LC50s of the fish embryo acute toxicity test would allow effectively predicting of acute mammalian toxicity categories. A database of published fish embryo LC50 containing 641 compounds was established. For these compounds corresponding rat oral LD50 were identified resulting in 364 compounds for which both fish embryo LC50 and rat LD50 was available. Only a weak correlation of fish embryo LC50 and rat oral LD50 was obtained. Fish embryos were also not able to effectively predict GHS oral acute toxicity categories. We concluded that due to fundamental exposure protocol differences (single oral dose versus water-borne exposure) a reverse dosimetry approach is needed to explore the predictive capacity of fish embryos.

  1. Molecular identification of ghrelin receptor (GHS-R1a) and its functional role in the gastrointestinal tract of the guinea-pig.

    PubMed

    Kitazawa, Takio; Nakamura, Tatsuro; Saeki, Atsuki; Teraoka, Hiroki; Hiraga, Takeo; Kaiya, Hiroyuki

    2011-09-01

    Ghrelin stimulates gastric motility in vivo in the guinea-pig through activation of growth hormone secretagogue receptor (GHS-R). In this study, we identified GHS-R1a in the guinea-pig, and examined its distribution and cellular function and compared them with those in the rat. Effects of ghrelin in different regions of gastrointestinal tract were also examined. GHS-R1a was identified in guinea-pig brain cDNA. Amino acid identities of guinea-pig GHS-R1a were 93% to horses and 85% to dogs. Expression levels of GHS-R1a mRNA were high in the pituitary and hypothalamus, moderate in the thalamus, cerebral cortex, pons, medulla oblongata and olfactory bulb, and low in the cerebellum and peripheral tissues including gastrointestinal tract. Comparison of GHS-R1a expression patterns showed that those in the brain were similar but the expression level in the gastrointestinal tract was higher in rats than in guinea-pigs. Guinea-pig GHS-R1a expressed in HEK 293 cells responded to rat ghrelin and GHS-R agonists. Rat ghrelin was ineffective in inducing mechanical changes in the stomach and colon but caused a slight contraction in the small intestine. 1,1-Dimethyl-4-phenylpiperazinium and electrical field stimulation (EFS) caused cholinergic contraction in the intestine, and these contractions were not affected by ghrelin. Ghrelin did not change spontaneous and EFS-evoked [(3)H]-efflux from [(3)H]-choline-loaded ileal strips. In summary, guinea-pig GHS-R1a was identified and its functions in isolated gastrointestinal strips were characterized. The distribution of GHS-R1a in peripheral tissues was different from that in rats, suggesting that the functional role of ghrelin in the guinea-pig is different from that in other animal species.

  2. The Expression of GHS-R in Primary Neurons Is Dependent upon Maturation Stage and Regional Localization

    PubMed Central

    Tonna, Noemi; Casnici, Claudia; Benfante, Roberta; Fornasari, Diego; Bianco, Fabio; Longhi, Renato; Marelli, Ornella

    2013-01-01

    Ghrelin is a hormone with a crucial role in the regulation of appetite, regulation of inflammation, glucose metabolism and cell proliferation. In the brain ghrelin neurons are located in the cortex (sensorimotor area, cingular gyrus), and the fibres of ghrelin neurons in hypothalamus project directly to the dorsal vagal complex (DVC). Ghrelin binds the growth hormone secretagogue receptor (GHS-R) a G-protein-coupled receptor with a widespread tissue distribution, indeed these receptors are localized both in nonnervous, organs/tissues (i.e. adipose tissue, myocardium, adrenals, gonads, lung, liver, arteries, stomach, pancreas, thyroid, and kidney) as well as in central nervous system (CNS) and higher levels of expression in the pituitary gland and the hypothalamus and lower levels of expression in other organs, including brain. A GHS-R specific monoclonal antibody has been developed and characterized and through it we demonstrate that GHS-R is expressed in primary neurons and that its expression is dependent upon their developmental stage and shows differences according to the brain region involved, with a more pronounced expression in hippocampal rather than cortical neurons. A characterization of GHS-R within the central nervous system is of extreme importance in order to gain insights on its role in the modulation of neurodegenerative events such as Alzheimer’s disease. PMID:23755116

  3. Synthesis, growth and characterization of a new nonlinear optical crystal: glycinium hydrogen squarate (GHS).

    PubMed

    Paramasivam, P; Ramachandra Raja, C

    2012-07-01

    Single crystals of glycinium hydrogen squarate (GHS) have been successfully synthesized and purity of the material has been increased by repeated recrystallization process. Single crystals were grown by slow evaporation solution growth technique using water and ethanol as solvents at room temperature. Then the grown crystal was characterized by different techniques for finding its suitability for device fabrications. The grown crystal was characterized by single crystal XRD, powder XRD, FT-IR, UV-Vis-NIR, (1)H NMR, (13)C NMR, SHG and DTA/TGA analyses respectively. From the single crystal XRD diffraction, the crystal system was identified as monoclinic. The presence of functional groups were identified by FT-IR analysis. The UV transparency cut-off wavelength of the grown crystal occurs at 342nm. (1)H NMR and (13)C NMR spectroscopic studies were employed to elucidate the structure of the grown crystal. The second harmonic generation efficiency test by Kurtz-Perry technique showed positive result. The decomposition temperature of the grown crystal was studied by DTA/TGA analysis. The results observed from the characterization analyses show its suitability for NLO applications.

  4. Hazard banding in compliance with the new Globally Harmonised System (GHS) for use in control banding tools.

    PubMed

    Arnone, Mario; Koppisch, Dorothea; Smola, Thomas; Gabriel, Stefan; Verbist, Koen; Visser, Remco

    2015-10-01

    Many control banding tools use hazard banding in risk assessments for the occupational handling of hazardous substances. The outcome of these assessments can be combined with advice for the required risk management measures (RMMs). The Globally Harmonised System of Classification and Labelling of Chemicals (GHS) has resulted in a change in the hazard communication elements, i.e. Hazard (H) statements instead of Risk-phrases. Hazard banding schemes that depend on the old form of safety information have to be adapted to the new rules. The purpose of this publication is to outline the rationales for the assignment of hazard bands to H statements under the GHS. Based on this, this publication proposes a hazard banding scheme that uses the information from the safety data sheets as the basis for assignment. The assignment of hazard bands tiered according to the severity of the underlying hazards supports the important principle of substitution. Additionally, the set of assignment rules permits an exposure-route-specific assignment of hazard bands, which is necessary for the proposed route-specific RMMs. Ideally, all control banding tools should apply the same assignment rules. This GHS-compliant hazard banding scheme can hopefully help to establish a unified hazard banding strategy in the various control banding tools.

  5. The GHS-R blocker D-[Lys3] GHRP-6 serves as CCR5 chemokine receptor antagonist.

    PubMed

    Patel, Kalpesh; Dixit, Vishwa Deep; Lee, Jun Ho; Kim, Jie Wan; Schaffer, Eric M; Nguyen, Dzung; Taub, Dennis D

    2012-01-01

    [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS) is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R) antagonist. This antagonist is one of the most common antagonists utilized in vivo to block GHS-R function and activity. Here, we found that DLS also has the ability to modestly block chemokine function and ligand binding to the chemokine receptor CCR5. The DLS effects on RANTES binding and Erk signaling as well as calcium mobilization appears to be much stronger than its effects on MIP-1α and MIP-1β. CCR5 have been shown to act as major co-receptor for HIV-1 entry into the CD4 positive host cells. To this end, we also found that DLS blocks M-tropic HIV-1 propagation in activated human PBMCs. These data demonstrate that DLS may not be a highly selective GHS-R1a inhibitor and may also effects on other G-protein coupled receptor (GPCR) family members. Moreover, DLS may have some potential clinical applications in blocking HIV infectivity and CCR5-mediated migration and function in various inflammatory disease states.

  6. Effect of inhibitor and activator of ghrelin receptor (GHS-R1a) on porcine ovarian granulosa cell functions.

    PubMed

    Sirotkin, Alexander V; Meszarošová, Monika; Grossmann, Roland; Benčo, Andrej; Valenzuela, Francisco

    2011-08-01

    It was previously shown, that ghrelin and its agonistic analogue, ghrelin 1-18, can be a stimulator of ovarian cell functions (promoter of proliferation, inhibitor of apoptosis and stimulator of hormones release). The aim of our studies was to compare the action of two ghrelin analogues - ghrelin 1-18, activator of ghrelin receptors (GHS-R1a), and (D-Lys3)-GHRP-6, its inhibitor, on porcine ovarian granulosa cell functions. Effects of (D-Lys3)-GHRP-6 added at doses of 0, 1, 10 or 100 ng/ml on the expression of markers of proliferation (PCNA, cyclin B1, MAPK/ERK1,2), apoptosis (bax, p53, caspase 3) and release of steroid hormones (progesterone, testosterone, estradiol) were examined. In addition, some effect of ghrelin 1-8 on some of these parameters (expression of MAPK/ERK1,2, bax, p53) were verified. It was shown, that (D-Lys3)-GHRP-6 promotes all markers of granulosa cell proliferation, inhibits all markers of apoptosis and stimulates the release of all three steroid hormones. Similar effects of (D-Lys3)-GHRP-6 (inhibitor of GHS-R1a) and ghrelin 1-18 (its stimulator) suggest that the examined effects of these substances on porcine ovaries are not mediated by GHS-R1a. Both chemical analogues could be potentially useful for stimulation of reproductive processes, at least in in vitro conditions.

  7. [Trp3, Arg5]-ghrelin(1-5) stimulates growth hormone secretion and food intake via growth hormone secretagogue (GHS) receptor.

    PubMed

    Ohinata, Kousaku; Kobayashi, Kanako; Yoshikawa, Masaaki

    2006-07-01

    Ghrelin, a 28 amino acid peptide identified as an endogenous ligand for growth hormone secretagogue (GHS) receptor, stimulates food intake and growth hormone (GH) secretion. We designed low molecular weight peptides with affinity for the GHS receptor based on the primary structure of ghrelin. We found that [Trp3, Arg5]-ghrelin(1-5) (GSWFR), a novel pentapeptide composed of all L-amino acids, had affinity for the GHS receptor (IC50 = 10 microM). GSWFR stimulated GH secretion after intravenous or oral administration. Centrally administered GSWFR increased food intake in non-fasted mice. The orexigenic action of GSWFR was inhibited by a GHS receptor antagonist, [D-Lys3]-GH-releasing peptide-6, suggesting that GSWFR stimulated food intake through the GHS receptor. The orexigenic action of GSWFR was also inhibited by a neuropeptide Y (NPY) Y1 receptor antagonist, BIBO3304. These results suggest that the GSWFR-induced feeding is mediated by the NPY Y1 receptor.

  8. Unacylated ghrelin promotes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R1a activity: evidence for target cell-induced acylation

    PubMed Central

    Hopkins, Anna L.; Nelson, Timothy A. S.; Guschina, Irina A.; Parsons, Lydia C.; Lewis, Charlotte L.; Brown, Richard C.; Christian, Helen C.; Davies, Jeffrey S.; Wells, Timothy

    2017-01-01

    Despite being unable to activate the cognate ghrelin receptor (GHS-R), unacylated ghrelin (UAG) possesses a unique activity spectrum that includes promoting bone marrow adipogenesis. Since a receptor mediating this action has not been identified, we re-appraised the potential interaction of UAG with GHS-R in the regulation of bone marrow adiposity. Surprisingly, the adipogenic effects of intra-bone marrow (ibm)-infused acylated ghrelin (AG) and UAG were abolished in male GHS-R-null mice. Gas chromatography showed that isolated tibial marrow adipocytes contain the medium-chain fatty acids utilised in the acylation of UAG, including octanoic acid. Additionally, immunohistochemistry and immunogold electron microscopy revealed that tibial marrow adipocytes show prominent expression of the UAG-activating enzyme ghrelin O-acyl transferase (GOAT), which is located in the membranes of lipid trafficking vesicles and in the plasma membrane. Finally, the adipogenic effect of ibm-infused UAG was completely abolished in GOAT-KO mice. Thus, the adipogenic action of exogenous UAG in tibial marrow is dependent upon acylation by GOAT and activation of GHS-R. This suggests that UAG is subject to target cell-mediated activation – a novel mechanism for manipulating hormone activity. PMID:28361877

  9. Ghrelin receptor (GHS-R1A) antagonism alters preference for ethanol and sucrose in a concentration-dependent manner in prairie voles.

    PubMed

    Stevenson, J R; Francomacaro, L M; Bohidar, A E; Young, K A; Pesarchick, B F; Buirkle, J M; McMahon, E K; O'Bryan, C M

    2016-03-01

    Ghrelin receptor (GHS-R1A) activity has been implicated in reward for preferred foods and drugs; however, a recent study in our laboratory indicated that GHS-R1A antagonism reduces early (after only four exposures) preference for 20% ethanol, but not 10% sucrose in prairie voles, a genetically diverse high alcohol-consuming species. The purpose of the present study was to determine if these effects of GHS-R1A antagonism depend on the concentration of the rewarding solution being consumed. We first characterized preference for varying concentrations of ethanol and sucrose. Two bottle tests of each ethanol concentration versus water indicated that 10% and 20% ethanol are less preferred than 3% ethanol, and a follow-up direct comparison of 10% vs. 20% showed that 10% was preferred over 20%. Direct two-bottle comparisons of 2% vs. 5%, 2% vs. 10%, and 5% vs. 10% sucrose showed that 10% sucrose was most preferred, and 2% sucrose was least preferred. The effects of JMV 2959, a GHS-R1A antagonist, on preference for each concentration of ethanol and sucrose were then tested. In a between groups design prairie voles were given four two-hour drinking sessions in which animals had access to ethanol (3, 10, or 20%) versus water, or sucrose (2, 5, or 10%) versus water every other day. Saline habituation injections were given 30 min before the third drinking session. JMV 2959 (i.p.; 9 mg/kg), a GHS-R1A antagonist, or saline was administered 30 min before the fourth drinking session. JMV 2959 reduced preference for 20% ethanol and 2% sucrose, but had no significant effect on preference for the other ethanol and sucrose concentrations. These data identify constraints on the role of GHS-R1A in early preference for ethanol and sucrose, and the concentration-dependent effects suggest strong preference for a reward may limit the importance of GHS-R1A activity.

  10. In Situ Localization and Rhythmic Expression of Ghrelin and ghs-r1 Ghrelin Receptor in the Brain and Gastrointestinal Tract of Goldfish (Carassius auratus)

    PubMed Central

    Unniappan, Suraj; Kah, Olivier; Gueguen, Marie-M.; Bertucci, Juan I.; Alonso-Gómez, Ángel L.; Valenciano, Ana I.; Isorna, Esther; Delgado, María J.

    2015-01-01

    Ghrelin is a gut-brain peptide hormone, which binds to the growth hormone secretagogue receptor (GHS-R) to regulate a wide variety of biological processes in fish. Despite these prominent physiological roles, no studies have reported the anatomical distribution of preproghrelin transcripts using in situ hybridization in a non-mammalian vertebrate, and its mapping within the different encephalic areas remains unknown. Similarly, no information is available on the possible 24-h variations in the expression of preproghrelin and its receptor in any vertebrate species. The first aim of this study was to investigate the anatomical distribution of ghrelin and GHS-R1a ghrelin receptor subtype in brain and gastrointestinal tract of goldfish (Carassius auratus) using immunohistochemistry and in situ hybridization. Our second aim was to characterize possible daily variations of preproghrelin and ghs-r1 mRNA expression in central and peripheral tissues using real-time reverse transcription-quantitative PCR. Results show ghrelin expression and immunoreactivity in the gastrointestinal tract, with the most abundant signal observed in the mucosal epithelium. These are in agreement with previous findings on mucosal cells as the primary synthesizing site of ghrelin in goldfish. Ghrelin receptor was observed mainly in the hypothalamus with low expression in telencephalon, pineal and cerebellum, and in the same gastrointestinal areas as ghrelin. Daily rhythms in mRNA expression were found for preproghrelin and ghs-r1 in hypothalamus and pituitary with the acrophase occurring at nighttime. Preproghrelin, but not ghs-r1a, displayed a similar daily expression rhythm in the gastrointestinal tract with an amplitude 3-fold higher than the rest of tissues. Together, these results described for the first time in fish the mapping of preproghrelin and ghrelin receptor ghs-r1a in brain and gastrointestinal tract of goldfish, and provide the first evidence for a daily regulation of both genes

  11. Expression, Functional Characterization, and Solid-State NMR Investigation of the G Protein-Coupled GHS Receptor in Bilayer Membranes

    PubMed Central

    Schrottke, Stefanie; Kaiser, Anette; Vortmeier, Gerrit; Els-Heindl, Sylvia; Worm, Dennis; Bosse, Mathias; Schmidt, Peter; Scheidt, Holger A.; Beck-Sickinger, Annette G.; Huster, Daniel

    2017-01-01

    The expression, functional reconstitution and first NMR characterization of the human growth hormone secretagogue (GHS) receptor reconstituted into either DMPC or POPC membranes is described. The receptor was expressed in E. coli. refolded, and reconstituted into bilayer membranes. The molecule was characterized by 15N and 13C solid-state NMR spectroscopy in the absence and in the presence of its natural agonist ghrelin or an inverse agonist. Static 15N NMR spectra of the uniformly labeled receptor are indicative of axially symmetric rotational diffusion of the G protein-coupled receptor in the membrane. In addition, about 25% of the 15N sites undergo large amplitude motions giving rise to very narrow spectral components. For an initial quantitative assessment of the receptor mobility, 1H-13C dipolar coupling values, which are scaled by molecular motions, were determined quantitatively. From these values, average order parameters, reporting the motional amplitudes of the individual receptor segments can be derived. Average backbone order parameters were determined with values between 0.56 and 0.69, corresponding to average motional amplitudes of 40–50° of these segments. Differences between the receptor dynamics in DMPC or POPC membranes were within experimental error. Furthermore, agonist or inverse agonist binding only insignificantly influenced the average molecular dynamics of the receptor. PMID:28387359

  12. A GHS-consistent approach to health hazard classification of petroleum substances, a class of UVCB substances.

    PubMed

    Clark, Charles R; McKee, Richard H; Freeman, James J; Swick, Derek; Mahagaokar, Suneeta; Pigram, Glenda; Roberts, Linda G; Smulders, Chantal J; Beatty, Patrick W

    2013-12-01

    The process streams refined from petroleum crude oil for use in petroleum products are among those designated by USEPA as UVCB substances (unknown or variable composition, complex reaction products and biological materials). They are identified on global chemical inventories with unique Chemical Abstract Services (CAS) numbers and names. The chemical complexity of most petroleum substances presents challenges when evaluating their hazards and can result in differing evaluations due to the varying level of hazardous constituents and differences in national chemical control regulations. Global efforts to harmonize the identification of chemical hazards are aimed at promoting the use of consistent hazard evaluation criteria. This paper discusses a systematic approach for the health hazard evaluation of petroleum substances using chemical categories and the United Nations (UN) Globally Harmonized System (GHS) of classification and labeling. Also described are historical efforts to characterize the hazard of these substances and how they led to the development of categories, the identification of potentially hazardous constituents which should be considered, and a summary of the toxicology of the major petroleum product groups. The use of these categories can increase the utility of existing data, provide better informed hazard evaluations, and reduce the amount of animal testing required.

  13. Association of cord blood des-acyl ghrelin with birth weight, and placental GHS-R1 receptor expression in SGA, AGA, and LGA newborns.

    PubMed

    González-Domínguez, Martha I; Lazo-de-la-Vega-Monroy, Maria-Luisa; Zaina, Silvio; Sabanero, Myrna; Daza-Benítez, Leonel; Malacara, Juan Manuel; Barbosa-Sabanero, Gloria

    2016-07-01

    Although ghrelin in cord blood has been associated to birth weight, its role in fetal and postnatal growth has not been elucidated. The aim of this study was to analyze total ghrelin, acyl ghrelin (AG), and des-acyl ghrelin (DAG) in cord blood of newborns with idiopathic birth weight alterations, and to evaluate protein expression of placental GHS-R1, in order to investigate their correlation with birth weight and placental weight. We performed a cross-sectional comparative study in umbilical cord blood and placentas from healthy mothers of SGA, AGA, and LGA (small, adequate and large for gestational age) term newborns (n = 20 per group). Cord blood total ghrelin, AG, and DAG were measured by ELISA, and placental GHS-R1 expression was evaluated by Western blot. Cord blood DAG was higher in SGA compared to AGA newborns (902.1 ± 109.1 and 597.4 ± 58.2 pg/ml, respectively, p = 0.01) while LGA and AGA showed similar values (627.2 ± 76.4 pg/ml for LGA, p = 0.80). DAG negatively correlated with birthweight (r = -0.31, p = 0.02) and placental weight (r = -0.33, p = 0.02). No differences in AG or total ghrelin were found. GHS-R1 protein in placenta was not differentially expressed among SGA, AGA, and LGA. Our results suggest a role of DAG in intrauterine growth. Further studies are needed in order to elucidate the mechanisms by which DAG participates in fetal growth.

  14. Ghrelin accelerates wound healing through GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways in combined radiation and burn injury in rats

    PubMed Central

    Liu, Cong; Huang, Jiawei; Li, Hong; Yang, Zhangyou; Zeng, Yiping; Liu, Jing; Hao, Yuhui; Li, Rong

    2016-01-01

    The therapeutic effect of ghrelin on wound healing was assessed using a rat model of combined radiation and burn injury (CRBI). Rat ghrelin, anti-rat tumor necrosis factor (TNF) α polyclonal antibody (PcAb), or selective antagonists of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and growth hormone secretagogue receptor (GHS-R) 1a (SB203580, SP600125, and [D-Lys3]-GHRP-6, respectively), were administered for seven consecutive days. Levels of various signaling molecules were assessed in isolated rat peritoneal macrophages. The results showed that serum ghrelin levels and levels of macrophage glucocorticoid receptor (GR) decreased, while phosphorylation of p38MAPK, JNK, and p65 nuclear factor (NF) κB increased. Ghrelin inhibited the serum induction of proinflammatory mediators, especially TNF-α, and promoted wound healing in a dose-dependent manner. Ghrelin treatment decreased phosphorylation of p38MAPK, JNK, and p65NF-κB, and increased GR levels in the presence of GHS-R1a. SB203580 or co-administration of SB203580 and SP600125 decreased TNF-α level, which may have contributed to the inactivation of p65NF-κB and increase in GR expression, as confirmed by western blotting. In conclusion, ghrelin enhances wound recovery in CRBI rats, possibly by decreasing the induction of TNF-α or other proinflammatory mediators that are involved in the regulation of GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways. PMID:27271793

  15. Ghrelin accelerates wound healing through GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways in combined radiation and burn injury in rats.

    PubMed

    Liu, Cong; Huang, Jiawei; Li, Hong; Yang, Zhangyou; Zeng, Yiping; Liu, Jing; Hao, Yuhui; Li, Rong

    2016-06-07

    The therapeutic effect of ghrelin on wound healing was assessed using a rat model of combined radiation and burn injury (CRBI). Rat ghrelin, anti-rat tumor necrosis factor (TNF) α polyclonal antibody (PcAb), or selective antagonists of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and growth hormone secretagogue receptor (GHS-R) 1a (SB203580, SP600125, and [D-Lys3]-GHRP-6, respectively), were administered for seven consecutive days. Levels of various signaling molecules were assessed in isolated rat peritoneal macrophages. The results showed that serum ghrelin levels and levels of macrophage glucocorticoid receptor (GR) decreased, while phosphorylation of p38MAPK, JNK, and p65 nuclear factor (NF) κB increased. Ghrelin inhibited the serum induction of proinflammatory mediators, especially TNF-α, and promoted wound healing in a dose-dependent manner. Ghrelin treatment decreased phosphorylation of p38MAPK, JNK, and p65NF-κB, and increased GR levels in the presence of GHS-R1a. SB203580 or co-administration of SB203580 and SP600125 decreased TNF-α level, which may have contributed to the inactivation of p65NF-κB and increase in GR expression, as confirmed by western blotting. In conclusion, ghrelin enhances wound recovery in CRBI rats, possibly by decreasing the induction of TNF-α or other proinflammatory mediators that are involved in the regulation of GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways.

  16. Short Time Exposure (STE) test in conjunction with Bovine Corneal Opacity and Permeability (BCOP) assay including histopathology to evaluate correspondence with the Globally Harmonized System (GHS) eye irritation classification of textile dyes.

    PubMed

    Oliveira, Gisele Augusto Rodrigues; Ducas, Rafael do Nascimento; Teixeira, Gabriel Campos; Batista, Aline Carvalho; Oliveira, Danielle Palma; Valadares, Marize Campos

    2015-09-01

    Eye irritation evaluation is mandatory for predicting health risks in consumers exposed to textile dyes. The two dyes, Reactive Orange 16 (RO16) and Reactive Green 19 (RG19) are classified as Category 2A (irritating to eyes) based on the UN Globally Harmonized System for classification (UN GHS), according to the Draize test. On the other hand, animal welfare considerations and the enforcement of a new regulation in the EU are drawing much attention in reducing or replacing animal experiments with alternative methods. This study evaluated the eye irritation of the two dyes RO16 and RG19 by combining the Short Time Exposure (STE) and the Bovine Corneal Opacity and Permeability (BCOP) assays and then comparing them with in vivo data from the GHS classification. The STE test (first level screening) categorized both dyes as GHS Category 1 (severe irritant). In the BCOP, dye RG19 was also classified as GHS Category 1 while dye RO16 was classified as GHS no prediction can be made. Both dyes caused damage to the corneal tissue as confirmed by histopathological analysis. Our findings demonstrated that the STE test did not contribute to arriving at a better conclusion about the eye irritation potential of the dyes when used in conjunction with the BCOP test. Adding the histopathology to the BCOP test could be an appropriate tool for a more meaningful prediction of the eye irritation potential of dyes.

  17. Actions of Agonists and Antagonists of the ghrelin/GHS-R Pathway on GH Secretion, Appetite, and cFos Activity

    PubMed Central

    Hassouna, Rim; Labarthe, Alexandra; Zizzari, Philippe; Videau, Catherine; Culler, Michael; Epelbaum, Jacques; Tolle, Virginie

    2012-01-01

    The stimulatory effects of ghrelin, a 28-AA acylated peptide originally isolated from stomach, on growth hormone (GH) secretion and feeding are exclusively mediated through the growth hormone secretagogue 1a receptor (GHS-R1a), the only ghrelin receptor described so far. Several GHS-R1a agonists and antagonists have been developed to treat metabolic or nutritional disorders but their mechanisms of action in the central nervous system remain poorly understood. In the present study, we compared the activity of BIM-28163, a GHS-R1a antagonist, and of several agonists, including native ghrelin and the potent synthetic agonist, BIM-28131, to modulate food intake, GH secretion, and cFos activity in arcuate nucleus (ArcN), nucleus tractus solitarius (NTS), and area postrema (AP) in wild-type and NPY-GFP mice. BIM-28131 was as effective as ghrelin in stimulating GH secretion, but more active than ghrelin in inducing feeding. It stimulated cFos activity similarly to ghrelin in the NTS and AP but was more powerful in the ArcN, suggesting that the super-agonist activity of BIM-28131 is mostly mediated in the ArcN. BIM-28163 antagonized ghrelin-induced GH secretion but not ghrelin-induced food consumption and cFos activation, rather it stimulated food intake and cFos activity without affecting GH secretion. The level of cFos activation was dependent on the region considered: BIM-28163 was as active as ghrelin in the NTS, but less active in the ArcN and AP. All compounds also induced cFos immunoreactivity in ArcN NPY neurons but BIM-28131 was the most active. In conclusion, these data demonstrate that two peptide analogs of ghrelin, BIM-28163, and BIM-28131, are powerful stimulators of appetite in mice, acting through pathways and key brain regions involved in the control of appetite that are only partially superimposable from those activated by ghrelin. A better understanding of the molecular pathways activated by these compounds could be useful in devising future therapeutic

  18. Reduced vertebral bone density in hypercalciuric nephrolithiasis

    NASA Technical Reports Server (NTRS)

    Pietschmann, F.; Breslau, N. A.; Pak, C. Y.

    1992-01-01

    Dual-energy x-ray absorptiometry and single-photon absorptiometry were used to determine bone density at the lumbar spine and radial shaft in 62 patients with absorptive hypercalciuria, 27 patients with fasting hypercalciuria, and 31 nonhypercalciuric stone formers. Lumbar bone density was significantly lower in patients with absorptive (-10%) as well as in those with fasting hypercalciuria (-12%), with 74 and 92% of patients displaying values below the normal mean, whereas only 48% of the nonhypercalciuric stone formers had bone density values below the normal mean. In contrast, radial bone density was similar in all three groups of renal stone formers investigated. The comparison of urinary chemistry in patients with absorptive hypercalciuria and low normal bone density compared to those with high normal bone density showed a significantly increased 24 h urinary calcium excretion on random diet and a trend toward a higher 24 h urinary uric acid excretion and a higher body mass index in patients with low normal bone density. Moreover, among the patients with absorptive hypercalciuria we found a statistically significant correlation between the spinal bone density and the 24 h sodium and sulfate excretion and the urinary pH. These results gave evidence for an additional role of environmental factors (sodium and animal proteins) in the pathogenesis of bone loss in absorptive hypercalciuria. In conclusion, our data suggest an osteopenia of trabecular-rich bone tissues in patients with fasting and absorptive hypercalciurias.

  19. A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice.

    PubMed

    Engel, Jörgen A; Nylander, Ingrid; Jerlhag, Elisabet

    2015-12-01

    Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Met-enkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leu-enkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959׳s ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GHS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction.

  20. Functional homology of gHs and gLs from EBV-related gamma-herpesviruses for EBV-induced membrane fusion.

    PubMed

    Omerović, Jasmina; Longnecker, Richard

    2007-08-15

    Epstein-Barr virus (EBV) is a human gamma-herpesvirus that primarily infects B lymphocytes and epithelial cells. Entry of EBV into B cells requires the viral glycoproteins gp42, gH/gL and gB, while gp42 is not necessary for infection of epithelial cells. In EBV, gH and gL form two distinct complexes, a bipartite complex that contains only gH and gL, used for infection of epithelial cells, and a tripartite complex that additionally includes gp42, used for infection of B cells. The gH/gL complex is conserved within the herpesvirus family, but its exact role in entry and mechanism of fusion is not yet known. To understand more about the functionality of EBVgH/gL, we investigated the functional homology of gHs and gLs from human herpesvirus 8 (HHV8) and two primate (rhesus and marmoset) gamma-herpesviruses in EBV-mediated virus-free cell fusion assay. Overall, gHs and gLs from the more homologous primate herpesviruses were better at complementing EBV gH and gL in fusion than HHV8 gH and gL. Interestingly, marmoset gH was able to complement fusion with epithelial cells, but not B cells. Further investigation of this led to the discovery that EBVgH is the binding partner of gp42 in the tripartite complex and the absence of fusion with B cells in the presence of marmoset gH/gL is due to its inability to bind gp42.

  1. Functional homology of gHs and gLs from EBV-related {gamma}-herpesviruses for EBV-induced membrane fusion

    SciTech Connect

    Omerovic, Jasmina; Longnecker, Richard . E-mail: r-longnecker@northwestern.edu

    2007-08-15

    Epstein-Barr virus (EBV) is a human {gamma}-herpesvirus that primarily infects B lymphocytes and epithelial cells. Entry of EBV into B cells requires the viral glycoproteins gp42, gH/gL and gB, while gp42 is not necessary for infection of epithelial cells. In EBV, gH and gL form two distinct complexes, a bipartite complex that contains only gH and gL, used for infection of epithelial cells, and a tripartite complex that additionally includes gp42, used for infection of B cells. The gH/gL complex is conserved within the herpesvirus family, but its exact role in entry and mechanism of fusion is not yet known. To understand more about the functionality of EBVgH/gL, we investigated the functional homology of gHs and gLs from human herpesvirus 8 (HHV8) and two primate (rhesus and marmoset) {gamma}-herpesviruses in EBV-mediated virus-free cell fusion assay. Overall, gHs and gLs from the more homologous primate herpesviruses were better at complementing EBV gH and gL in fusion than HHV8 gH and gL. Interestingly, marmoset gH was able to complement fusion with epithelial cells, but not B cells. Further investigation of this led to the discovery that EBVgH is the binding partner of gp42 in the tripartite complex and the absence of fusion with B cells in the presence of marmoset gH/gL is due to its inability to bind gp42.

  2. Sub-categorisation of skin corrosive chemicals by the EpiSkin™ reconstructed human epidermis skin corrosion test method according to UN GHS: revision of OECD Test Guideline 431.

    PubMed

    Alépée, N; Grandidier, M H; Cotovio, J

    2014-03-01

    The EpiSkin™ skin corrosion test method was formally validated and adopted within the context of OECD TG 431 for identifying corrosive and non-corrosive chemicals. The EU Classification, Labelling and Packaging Regulation (EU CLP) system requires the sub-categorisation of corrosive chemicals into the three UN GHS optional subcategories 1A, 1B and 1C. The present study was undertaken to investigate the usefulness of the validated EpiSkin™ test method to identify skin corrosive UN GHS Categories 1A, 1B and 1C using the original and validated prediction model and adapted controls for direct MTT reduction. In total, 85 chemicals selected by the OECD expert group on skin corrosion were tested in three independent runs. The results obtained were highly reproducible both within (>80%) and between (>78%) laboratories when compared with historical data. Moreover the results obtained showed that the EpiSkin™ test method is highly sensitive (99%) and specific (80%) in discriminating corrosive from non-corrosive chemicals and allows reliable and relevant identification of the different skin corrosive UN GHS subcategories, with high accuracies being obtained for both UN GHS Categories 1A (83%) and 1B/1C (76%) chemicals. The overall accuracy of the test method to subcategorise corrosive chemicals into three or two UN GHS subcategories ranged from 75% to 79%. Considering those results, the revised OECD Test Guideline 431 permit the use of EpiSkin™ for subcategorising corrosive chemicals into at least two classes (Category 1A and Category 1B/1C).

  3. Epigenetic regulation of BMP2 by 1,25-dihydroxyvitamin D3 through DNA methylation and histone modification.

    PubMed

    Fu, Baisheng; Wang, Hongwei; Wang, Jinhua; Barouhas, Ivana; Liu, Wanqing; Shuboy, Adam; Bushinsky, David A; Zhou, Dongsheng; Favus, Murray J

    2013-01-01

    Genetic hypercalciuric stone-forming (GHS) rats have increased intestinal Ca absorption, decreased renal tubule Ca reabsorption and low bone mass, all of which are mediated at least in part by elevated tissue levels of the vitamin D receptor (VDR). Both 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and bone morphogenetic protein 2 (BMP2) are critical for normal maintenance of bone metabolism and bone formation, respectively. The complex nature of bone cell regulation suggests a potential interaction of these two important regulators in GHS rats. In the present study, BMP2 expression is suppressed by the VDR-1,25(OH)2D3 complex in Bone Marrow Stromal Cells (BMSCs) from GHS and SD rat and in UMR-106 cell line. We used chromatin immunoprecipitation (ChIP) assays to identify VDR binding to only one of several potential binding sites within the BMP2 promoter regions. This negative region also mediates suppressor reporter gene activity. The molecular mechanisms underlying the down-regulation of BMP2 by 1,25(OH)2D3 were studied in vitro in BMSCs and UMR-106 cells using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) and the histone deacetylase inhibitor trichostatin A (TSA). Both DAC and TSA activate BMP2 expression in combination with 1,25(OH)2D3. Bisulfite DNA pyrosequencing reveals 1,25(OH)2D3 to completely hypermethylate a single CpG site in the same BMP2 promoter region identified by the ChIP and reporter gene assays. ChIP assays also show that 1,25(OH)2D3 can increase the repressive histone mark H3K9me2 and reduce the acetylation of histone H3 at the same BMP2 promoter region. Taken together, our results indicate that 1,25(OH)2D3 binding to VDR down-regulates BMP2 gene expression in BMSCs and osteoblast-like UMR-106 cells by binding to the BMP2 promoter region. The mechanism of this 1,25(OH)2D3-induced transcriptional repression of BMP2 involves DNA methylation and histone modification. The study provides novel evidence that 1,25(OH)2D3 represses bone

  4. The EpiOcular™ Eye Irritation Test is the Method of Choice for the In Vitro Eye Irritation Testing of Agrochemical Formulations: Correlation Analysis of EpiOcular Eye Irritation Test and BCOP Test Data According to the UN GHS, US EPA and Brazil ANVISA Classification Schemes.

    PubMed

    Kolle, Susanne N; Rey Moreno, Maria Cecilia; Mayer, Winfried; van Cott, Andrew; van Ravenzwaay, Bennard; Landsiedel, Robert

    2015-07-01

    The Bovine Corneal Opacity and Permeability (BCOP) test is commonly used for the identification of severe ocular irritants (GHS Category 1), but it is not recommended for the identification of ocular irritants (GHS Category 2). The incorporation of human reconstructed tissue model-based tests into a tiered test strategy to identify ocular non-irritants and replace the Draize rabbit eye irritation test has been suggested (OECD TG 405). The value of the EpiOcular™ Eye Irritation Test (EIT) for the prediction of ocular non-irritants (GHS No Category) has been demonstrated, and an OECD Test Guideline (TG) was drafted in 2014. The purpose of this study was to evaluate whether the BCOP test, in conjunction with corneal histopathology (as suggested for the evaluation of the depth of the injury( and/or the EpiOcular-EIT, could be used to predict the eye irritation potential of agrochemical formulations according to the UN GHS, US EPA and Brazil ANVISA classification schemes. We have assessed opacity, permeability and histopathology in the BCOP assay, and relative tissue viability in the EpiOcular-EIT, for 97 agrochemical formulations with available in vivo eye irritation data. By using the OECD TG 437 protocol for liquids, the BCOP test did not result in sufficient correct predictions of severe ocular irritants for any of the three classification schemes. The lack of sensitivity could be improved somewhat by the inclusion of corneal histopathology, but the relative viability in the EpiOcular-EIT clearly outperformed the BCOP test for all three classification schemes. The predictive capacity of the EpiOcular-EIT for ocular non-irritants (UN GHS No Category) for the 97 agrochemical formulations tested (91% sensitivity, 72% specificity and 82% accuracy for UN GHS classification) was comparable to that obtained in the formal validation exercise underlying the OECD draft TG. We therefore conclude that the EpiOcular-EIT is currently the best in vitro method for the prediction

  5. The Wnt11 Signaling Pathway in Potential Cellular EMT and Osteochondral Differentiation Progression in Nephrolithiasis Formation.

    PubMed

    He, Deng; Lu, Yuchao; Hu, Henglong; Zhang, Jiaqiao; Qin, Baolong; Wang, Yufeng; Xing, Shuai; Xi, Qilin; Wang, Shaogang

    2015-07-17

    The molecular events leading to nephrolithiasis are extremely complex. Previous studies demonstrated that calcium and transforming growth factor-β1 (TGF-β1) may participate in the pathogenesis of stone formation, but the explicit mechanism has not been defined. Using a self-created genetic hypercalciuric stone-forming (GHS) rat model, we observed that the increased level of serous/uric TGF-β1 and elevated intracellular calcium in primary renal tubular epithelial cells (PRECs) was associated with nephrolithiasis progression in vivo. In the setting of high calcium plus high TGF-β1 in vitro, PRECs showed great potential epithelial to mesenchymal transition (EMT) progression and osteochondral differentiation properties, representing the multifarious increased mesenchymal and osteochondral phenotypes (Zeb1, Snail1, Col2A1, OPN, Sox9, Runx2) and decreased epithelial phenotypes (E-cadherin, CK19) bythe detection of mRNAs and corresponding proteins. Moreover, TGF-β-dependent Wnt11 knockdown and L-type Ca2+ channel blocker could greatly reverse EMT progression and osteochondral differentiation in PRECs. TGF-β1 alone could effectively promote EMT, but it had no effect on osteochondral differentiation in NRK cells (Rat kidney epithelial cell line). Stimulation with Ca2+ alone did not accelerate differentiation of NRK. Co-incubation of extracellular Ca2+ and TGF-β1 synergistically promotes EMT and osteochondral differentiation in NRK control cells. Our data supplied a novel view that the pathogenesis of calcium stone development may be associated with synergic effects of TGF-β1 and Ca2+, which promote EMT and osteochondral differentiation via Wnt11 and the L-type calcium channel.

  6. Lacking applicability of in vitro eye irritation methods to identify seriously eye irritating agrochemical formulations: Results of bovine cornea opacity and permeability assay, isolated chicken eye test and the EpiOcular™ ET-50 method to classify according to UN GHS.

    PubMed

    Kolle, Susanne N; Van Cott, Andrew; van Ravenzwaay, Bennard; Landsiedel, Robert

    2017-04-01

    In vitro methods have gained regulatory acceptance for the prediction of serious eye damage (UN GHS Cat 1). However, the majority of in vitro methods do not state whether they are applicable to agrochemical formulations. This manuscript presents a study of up to 27 agrochemical formulations tested in three in vitro assays (three versions of the bovine corneal opacity and permeability test (BCOP, OECD TG 437) assay, the isolated chicken eye test (ICE, OECD TG 438) and the EpiOcular™ ET-50 assay). The results were compared with already-available in vivo data. In the BCOP only one of the four, one of five in the ICE and six of eleven tested formulations in the EpiOcular™ ET-50 Neat Protocol resulted in the correct UN GHS Cat 1 prediction. Overpredictions occurred in all assays. These data indicate a lack of applicability of the three in vitro methods to reliably predict UN GHS Cat 1 of agrochemical formulations. In order to ensure animal-free identification of seriously eye damaging agrochemical formulations testing protocols and/or prediction models need to be modified or classification rules should be tailored to in vitro testing rather than using in vivo Draize data as a standard.

  7. Potential etiologic role of brushite in the formation of calcium (renal) stones

    NASA Astrophysics Data System (ADS)

    Pak, Charles Y. C.

    1981-05-01

    Brushite may play an important regulatory role in the formation of calcium -containing renal stones. The urinary environment from patients with hypercalciuric nephrolithiasis is typically supersaturated and shows an increased propensity for the spontaneous nucleation of brushite. Brushite has been identified in "stone-forming" urine and in stones. This crystalline phase may undergo phase transformation to hydroxyapatite or cause heterogeneous nucleation or epitaxial growth of calcium oxalate. Thus, brushite may also participate in the formation of stones of hydroxypatite or calcium oxalate.

  8. Calcium Oxalate Stone Agglomeration Inhibition [tm] Reflects Renal Stone-Forming Activity.

    PubMed

    Lindberg, J S; Cole, F E; Romani, W; Husserl, F E; Fuselier, H A; Kok, D J; Erwin, D T

    2000-04-01

    Louisiana and other Gulf South states comprise a "Stone Belt" where calcium oxalate stone formers (CaOx SFs) are found at a high rate of approximately 5%. In these patients, the agglomeration of small stone crystals, which are visible in nearly all morning urine collections, forms stones that can become trapped in the renal parenchyma and the renal pelvis. Without therapy, about half of CaOx SFs repeatedly form kidney stones, which can cause excruciating pain that can be relieved by passage, fragmentation (lithotripsy), or surgical removal. The absence of stones in "normal" patients suggests that there are stone inhibitors in "normal" urines.At the Ochsner Renal Stone Clinic, 24-hour urine samples are collected by the patient and sent to the Ochsner Renal Stone Research Program where calcium oxalate stone agglomeration inhibition [tm] measurements are performed. Urine from healthy subjects and inactive stone formers has demonstrated strongly inhibited stone growth [tm] in contrast to urine from recurrent CaOx SFs. [tm] data from 1500 visits of 700 kidney stone patients have been used to evaluate the risk of recurrence in Ochsner's CaOx SF patients. These data have also been used to demonstrate the interactive roles of certain identified urinary stone-growth inhibitors, citrate and Tamm-Horsfall protein (THP), which can be manipulated with medication to diminish recurrent stone formation. Our goal is to offer patients both financial and pain relief by reducing their stones with optimized medication, using medical management to avoid costly treatments.

  9. Bone Disease and Idiopathic Hypercalciuria

    PubMed Central

    Zerwekh, Joseph E.

    2008-01-01

    Observational and epidemiological studies alike have demonstrated that idiopathic hypercalciuric (IH) stone-forming patients typically demonstrate bone mineral density scores significantly less than those observed for age- and gender-matched normal subjects or those for non-hypercalciuric stone-forming patients. Most of these studies have relied on changes in bone mineral density (BMD) and have not explored the mechanism(s) involved. There have been a small number of studies that have relied on dynamic bone histomorphometry to ascertain the nature of the bone defect in IH patients. When performed, these studies have clearly demonstrated increased bone resorption and high bone turnover in patients with fasting hypercalciuria while suppressed bone formation indices are the most consistent finding in patients with the absorptive variant of IH. The causes of this apparent difference in bone remodeling between the two variants of IH is still uncertain. Available evidence suggests that potential mechanisms may be dependent in large part to genetic, metabolic, and nutritional causes of hypercalciuria and bone loss in patients with IH. PMID:18359394

  10. Hazard Communication Standard for Chemical Labels and Safety Data Sheets In GHS Format

    EPA Pesticide Factsheets

    This fact sheet provides an overview of the required contents of Safety Data Sheets (SDSs) and chemical hazard labels, and includes tips on how these materials can be used to better protect health and the environment.

  11. The Peptidic GHS-R antagonist [D-Lys(3)]GHRP-6 markedly improves adiposity and related metabolic abnormalities in a mouse model of postmenopausal obesity.

    PubMed

    Maletínská, L; Matyšková, R; Maixnerová, J; Sýkora, D; Pýchová, M; Spolcová, A; Blechová, M; Drápalová, J; Lacinová, Z; Haluzík, M; Zelezná, B

    2011-08-22

    It was demonstrated that estrogen deficiency and consuming high fat (HF) diet enhanced orexigenic activity of ghrelin. Therefore, we hypothesized that antagonizing of ghrelin action would attenuate food intake and body weight in mice obese both from ovariectomy (OVX) and feeding a HF diet. Ghrelin receptor antagonist [D-Lys(3)]GHRP-6 after seven days of subcutaneous treatment markedly decreased food intake in OVX mice fed both HF and standard diets; furthermore, it reduced body weight and blood glucose, insulin and leptin, and increased β-hydroxybutyrate level and uncoupling-protein-1 mRNA in brown adipose tissue. Pair-feeding revealed that effect of [D-Lys(3)]GHRP-6 was primary anorexigenic. Estrogen supplementation reduced anorexigenic effects of [D-Lys(3)]GHRP-6. OVX [D-Lys(3)]GHRP-6 treatment in mice on HF diet resulted in markedly increased circulating level and liver expression of a major metabolic regulator, fibroblast growth factor 21. Our data suggest that ghrelin antagonists could be especially beneficial in individuals with common obesity combined with estrogen deficiency.

  12. Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi Syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms ...

  13. Medullary Sponge Kidney

    MedlinePlus

    ... thus increase the chance of calciumcontaining kidney stones forming. Foods rich in animal proteins such as meat, ... chance of uric acid stones and calcium stones forming. People who form stones should limit their meat ...

  14. Negative Goos-Hänchen shift on a concave dielectric interface.

    PubMed

    Zhou, L-M; Zou, C-L; Han, Z-F; Guo, G-C; Sun, F-W

    2011-03-01

    We study the Goos-Hänchen shift (GHS) on a curved surface through numerical simulation by the boundary element method. A negative GHS is first discovered on a concave dielectric interface below the critical angle, accompanied by a large positive GHS on the convexity. The simulation shows that the GHS on a planar interface is the composition of the GHS from a concave and the corresponding convex interface. This work will enrich the study of the GHS for different curved surfaces, which will have potential applications in micro-optics and near-field optics.

  15. Mixtures Equation Pilot Program to Reduce Animal Testing

    EPA Pesticide Factsheets

    EPA is announcing the start of a pilot program to evaluate the usefulness and acceptability of a mathematical tool (the GHS Mixtures Equation), which is used in the Globally Harmonized System of Classification and Labeling of Chemicals (GHS).

  16. 78 FR 54871 - Procurement List; Proposed Additions and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-06

    ... production by the nonprofit agencies listed: Products Safety Data Sheet Organizer Binder NSN: 7520-00-NIB-0357--Kit, Mounting Board, GHS, SDS Information Center NSN: 7520-00-NIB-0360--Binder, GHS, Safety Data... Administration NSN: 7520-00-NIB-0358--Kit, Mounting Board, GHS Information Center NSN:...

  17. Sequence, genomic organization and expression of two channel catfish, Ictalurus punctatus, ghrelin receptors.

    PubMed

    Small, Brian C; Quiniou, Sylvie M A; Kaiya, Hiroyuki

    2009-12-01

    Two ghrelin receptor (GHS-R) genes were isolated from channel catfish tissue and a bacterial artificial chromosome (BAC) library. The two receptors were characterized by determining tissue distribution, ontogeny of receptor mRNA expression, and effects of exogenous homologous ghrelin administration on target tissue mRNA expression. Analysis of sequence similarities indicated two genes putatively encoding GHS-R1 and GHS-R2, respectively, which have been known to be present in zebrafish. Organization and tissue expression of the GHS-R1 gene was similar to that reported for other species, and likewise yielded two detectable mRNA products as a result of alternative splicing. Expression of both full-length, GHS-R1a, and splice variant, GHS-R1b, mRNA was highest in the pituitary. Gene organization of GHS-R2 was similar to GHS-R1, but no splice variant was identified. Expression of GHS-R2a mRNA was highest in the Brockmann bodies. GHS-R1a mRNA was detected in unfertilized eggs and throughout embryogenesis, whereas GHR-R2a mRNA was not expressed in unfertilized eggs or early developing embryos and was the highest at the time of hatching. Catfish intraperitoneally injected with catfish ghrelin-Gly had greater mRNA expression of GHS-R1a in pituitaries at 2 h and Brockmann bodies at 4 h, and of GHS-R2a in Brockmann bodies at 6 h post injection. Amidated catfish ghrelin (ghrelin-amide) had no observable effect on expression of either pituitary receptor; however, GHS-R1a and GHS-R2a mRNA expression levels were increased 4 h post injection of ghrelin-amide in Brockmann bodies. This is the first characterization of GHS-R2a and suggests regulatory and functional differences between the two catfish receptors.

  18. Identification, tissue distribution and functional characterization of the ghrelin receptor in West African lungfish, Protopterus annectens.

    PubMed

    Kaiya, Hiroyuki; Konno, Norifumi; Kangawa, Kenji; Uchiyama, Minoru; Miyazato, Mikiya

    2014-12-01

    We identified two ghrelin receptor isoforms, the ghrelin receptor type-1a (GHS-R1a) and its alternative splice form (GHS-R1b) for West African lungfish, Protopterus annectens. Lungfish GHS-R1a and 1b comprised 361 and 281 amino acids, respectively. Lungfish GHS-R1a showed the highest identity to coelacanth GHS-R1a (80.4%). The highest expression of GHS-R1a mRNAs was seen in the brain, liver, ovary, heart, intestine, and gills. GHS-R1b mRNAs were also detected in the same tissues with GHS-R1a, but their expression level was 1/20 that of GHS-R1a. In human embryonic kidney 293 cells transiently expressing lungfish GHS-R1a, rat and bullfrog ghrelin, and two GHS-R1a agonists, GHRP-6 and hexarelin, increased intracellular Ca(2+) concentrations. The intensity of the Ca(2+) increases induced by GHS-R1a agonists was twice when compared to that induced by ghrelin, although the median effective doses (ED50) were similar, suggesting a long-lasting effect of GHS-R1a agonists with similar affinity. We also examined changes in the GHS-R gene expression during an eight-week estivation. Body weight was slightly lowered, but plasma sodium and glucose concentrations decreased; plasma urea concentration increased significantly 4weeks after the start of estivation. Overall, expression of GHS-R1a mRNA decreased, but changes in GHS-R1b mRNA expression were inconsistent with those of GHS-R1a during estivation, suggesting an involvement of GHS-R in energy homeostasis, as seen in mammals. Our results suggest that the ghrelin-GHS-R1a system is present in this lungfish although ghrelin has not yet been found. The structure of GHS-R1a is closer to that of tetrapods than Actinopterygian fish, indicating a process of evolution that follows the Crossopterygii such as coelacanth.

  19. The atypical antipsychotic, olanzapine, potentiates ghrelin-induced receptor signaling: An in vitro study with cells expressing cloned human growth hormone secretagogue receptor.

    PubMed

    Tagami, Keita; Kashiwase, Yohei; Yokoyama, Akinobu; Nishimura, Hitomi; Miyano, Kanako; Suzuki, Masami; Shiraishi, Seiji; Matoba, Motohiro; Ohe, Yuichiro; Uezono, Yasuhito

    2016-08-01

    The growth hormone secretagogue receptor (GHS-R) belongs to Gαq-coupled G protein-coupled receptor (GPCR) that mediates growth hormone release, food intake, appetite, glucose metabolism and body composition. Ghrelin has been identified as an endogenous ligand for GHS-R, and it is the only orexigenic peptide found in the peripheral organs. Olanzapine, an atypical antipsychotic agent that binds to and inhibits the activation of GPCR for several neurotransmitters, has metabolic side effects such as excessive appetite and weight gain. Recently, studies have revealed that the orexigenic mechanism of olanzapine is mediated via GHS-R signaling, although the precise mechanisms have not been clarified. In this study, we investigated the effect of olanzapine on ghrelin-mediated GHS-R signaling by using an electrical impedance-based receptor biosensor assay system (CellKey™). Olanzapine at concentrations of 10(-7) and 10(-6)mol/L enhanced ghrelin-induced (10(-10)-10(-8)mol/L) GHS-R activation. A Ca(2+) imaging assay revealed that olanzapine (10(-7) and 10(-6)mol/L) enhanced ghrelin (10(-7) M)-induced GHS-R activity. In contrast, haloperidol (an antipsychotic agent) failed to enhance this ghrelin-mediated GHS-R activation, as demonstrated by both the CellKey™ and Ca(2+) imaging assays. Together, these results suggest that olanzapine, but not haloperidol, promotes appetite by enhancing ghrelin-mediated GHS-R signaling.

  20. 77 FR 17573 - Hazard Communication

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-26

    ... with the GHS will improve worker understanding of the hazardous chemicals they encounter every day... System of Classification and Labelling of Chemicals (GHS). OSHA has determined that the modifications... information provided to employers and employees regarding chemical hazards and associated protective...

  1. Characteristics of Participants in Australia's Get Healthy Telephone-Based Lifestyle Information and Coaching Service: Reaching Disadvantaged Communities and Those Most at Need

    ERIC Educational Resources Information Center

    O'Hara, Blythe J.; Phongsavan, Philayrath; Venugopal, Kamalesh; Bauman, Adrian E.

    2011-01-01

    To address increasing rates of overweight and obesity, a population-based telephone intervention was introduced in New South Wales, Australia. The Get Healthy Information and Coaching Service[R] (GHS) offered participants a 6-month coaching program or detailed self-help information. Determining the population reach of GHS is of public health…

  2. Development of a Geriatric Scale of Hopelessness: Implications for Counseling and Intervention with the Depressed Elderly.

    ERIC Educational Resources Information Center

    Fry, P. S.

    1984-01-01

    Evaluated hopelessness, depression, and self-esteem among depressed elderly people (N=78) and developed a Geriatric Hopelessness Scale (GHS). As predicted, elderly subjects who scored high on the GHS showed significantly higher depression and lower self-esteem scores. (JAC)

  3. Thermogenic characterization of ghrelin receptor null mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is the only known circulating orexigenic hormone that increases food intake and promotes adiposity, and these physiological functions of ghrelin are mediated through its receptor growth hormone secretagogue receptor (GHS-R). Ghrelin/GHS-R signaling plays a crucial role in energy homeostasis....

  4. Effect of ghrelin receptor agonist and antagonist on the activity of arcuate nucleus tyrosine hydroxylase containing neurons in C57BL/6 male mice exposed to normal or high fat diet.

    PubMed

    Pirnik, Z; Majercikova, Z; Holubova, M; Pirnik, R; Zelezna, B; Maletinska, L; Kiss, A

    2014-08-01

    Catecholamines participate in the food intake regulation, however, there are no literature data available, dealing with the activity of tyrosine hydroxylase (TH) neurons in response to stimulation or inhibition of GHS-R (growth hormone secretagogue receptor) in the hypothalamic arcuate nucleus (ARC). The present study was focused to reveal whether [Dpr(N-octanoyl) 3ghrelin], a stable GHS-R agonist, itself in doses of 5 or 10 mg/kg (s.c.) or in combination with GHS-R receptor antagonist ([DLys3]GHRP-6) in dose of 10 mg/kg (s.c.), may affect the activity of ARC TH-containing neurons in C57BL/6 male mice fed either with standard (SD) or high fat diet (HFD) that developed a diet-induced obesity (DIO). The data of the present study clearly indicate that both doses of GHS-R agonist stimulated food intake in SD mice and GHS-R antagonist significantly reduced GHS-R agonist orexinergic effect in SD mice and suppressed the voluntary food intake in HFD mice. Both doses of the GHS-R agonist stimulated Fos expression in ARC neurons in both diet groups of mice which was not abolished by GHS-R antagonist pretreatment. Moreover, both doses of the GHS-R agonist significantly influenced the activation of TH neurons in the ARC of SD mice. The GHS-R antagonist also significantly increased TH neurons activation after GHS-R agonist although this effect was less powerful in HFD mice. This is the first study demonstrating response of local ARC TH neurons to peripherally applied GHS-R agonist and antagonist. The present data point out that the response of TH neurons to GHS-R agonist and antagonist is different in normal and DIO mice and extend our knowledge about the further ARC neuronal phenotype responding to peripheral ghrelin. To bring insight into the understanding of the functional significance of the activated TH neurons in ARC, in the context of the ghrelin peripheral increase, further studies are required.

  5. Kidney stones

    MedlinePlus Videos and Cool Tools

    ... ureter. As urine can become very concentrated as it passes through the kidneys. When the urine becomes ... being stretched, and when stones form and distend it, the stretching can be very painful. Often, people ...

  6. Kidney Stones (For Parents)

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Kidney Stones KidsHealth > For Parents > Kidney Stones Print A ... other treatments to help remove the stones. How Kidney Stones Form It's the kidneys' job to remove ...

  7. Kidney Stones (For Parents)

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Kidney Stones KidsHealth > For Parents > Kidney Stones A A ... other treatments to help remove the stones. How Kidney Stones Form It's the kidneys' job to remove ...

  8. New active series of growth hormone secretagogues.

    PubMed

    Guerlavais, Vincent; Boeglin, Damien; Mousseaux, Delphine; Oiry, Catherine; Heitz, Annie; Deghenghi, Romano; Locatelli, Vittorio; Torsello, Antonio; Ghé, Corrado; Catapano, Filomena; Muccioli, Giampiero; Galleyrand, Jean-Claude; Fehrentz, Jean-Alain; Martinez, Jean

    2003-03-27

    New growth hormone secretagogue (GHS) analogues were synthesized and evaluated for growth hormone releasing activity. This series derived from EP-51389 is based on a gem-diamino structure. Compounds that exhibited higher in vivo GH-releasing potency than hexarelin in rat (subcutaneous administration) were then tested per os in beagle dogs and for their binding affinity to human pituitary GHS receptors and to hGHS-R 1a. Compound 7 (JMV 1843, H-Aib-(d)-Trp-(d)-gTrp-formyl) showed high potency in these tests and was selected for clinical studies.(1)

  9. EPA Releases Guidance on a Voluntary Pilot Program to Reduce Animal Testing

    EPA Pesticide Factsheets

    EPA is announcing the start of a voluntary pilot program to evaluate the usefulness and acceptability of a mathematical tool that estimates the toxicological classification of a chemical, which is used in the GHS.

  10. 75 FR 69472 - Preparations for December UN Meetings on the Globally Harmonized System of Classification and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-12

    ... maintaining and updating the GHS. The U.S has been an active member of the UNSCEGHS for many years, and OSHA... direction of David Michaels, PhD, MPH, Assistant Secretary of Labor for Occupational Safety and Health,...

  11. Fact Sheet: Revisions to the Occupational Safety and Health Administration Hazard Communication Standards (HCS)

    EPA Pesticide Factsheets

    On March 26, 2012, Occupational Safety and Health Administration (OSHA) modified its HCS to conform to the United Nations’ (UN) Globally Harmonized System of Classification and Labeling of Chemicals (GHS), to improve consistency and quality of information.

  12. Temperature-dependent Goos-Hänchen shift on the interface of metal/dielectric composites.

    PubMed

    Zhao, Bin; Gao, Lei

    2009-11-23

    The temperature-dependent Goos-Hänchen shift (GHS) for an electromagnetic wave reflected from a metal/dielectric composite material is investigated. With the stationary-phase method, we theoretically show that the effect of the temperature on GHS is significant near the Brewster angle for the dielectric composites and at the grazing angle for the metallic composites. For dielectric composites, the lateral shift can be negative as well as positive. And GHS may become much negative, much positive, and nonmonotonic variation with increasing the temperature under different conditions. Moreover, through the suitable adjustment of the temperature, one may realize the reversal of the GHS. To support the above results, numerical simulations for Gaussian incident beams based on the momentum method and COMSOL Multiphysics software are provided, and reasonable agreement between the theoretical results and numerical simulations is found.

  13. Role of calcium in the regulation of bone morphogenetic protein 2, runt-related transcription factor 2 and Osterix in primary renal tubular epithelial cells by the vitamin D receptor.

    PubMed

    Jia, Zhaohui; Wang, Shaogang; He, Deng; Cui, Lei; Lu, Yuchao; Hu, Henglong; Qin, Baolong; Zhao, Zhenyu

    2015-08-01

    The aim of the present study was to investigate the effect of 1,25(OH)2D3/vitamin D receptor (VDR) and calcium on the expression levels of osteogenic factors in primary renal tubular epithelial cells (RTECs) using genetic hypercalciuric rats. The basal levels of osteogenic factors were detected in Sprague Dawley and genetic hypercalciuric rats. The gene and protein levels of bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (Runx2) and osterix were detected in the RTECs transduced with Lenti-VDR-sh and were incubated with calcium. Using the o-cresolphthalein complexone method, the calcium levels of the primary RTECs cultured with Lenti-VDR-sh and with 1,25(OH)2D3 were assessed. The basal levels of BMP2, Runx2 and Osterix in the cells were significantly higher in the genetic hypercalciuric rats compared with the control rats. VDR knockdown in the RTECs reduced the expression levels of BMP2, Runx2 and Osterix. The calcium depositions in the primary RTECs were also decreased following exposure to Lenti-VDR-sh, but increased following treatment with 1,25(OH)2D3. The expression levels of BMP2, Runx2 and Osterix were markedly increased in the cells incubated with calcium compared with the cells treated with normal saline and the untreated cells. These findings indicated that osteogenic factors, including BMP2, Runx2 and Osterix may be important in renal stone formation in idiopathic hypercalciuria. VDR may mediate the increased expression levels of BMP2, Runx2 and Osterix by positively regulating calcium levels in primary RTECs.

  14. Ghrelin does not affect gastrointestinal contractility in rainbow trout and goldfish in vitro.

    PubMed

    Kitazawa, Takio; Itoh, Kentaro; Yaosaka, Noriko; Maruyama, Keisuke; Matsuda, Kouhei; Teraoka, Hiroki; Kaiya, Hiroyuki

    2012-09-15

    Ghrelin has been identified in rainbow trout and goldfish, and it has been shown to regulate growth hormone release and food intake in these species as seen in mammals. The aim of this study was to investigate the functional role of ghrelin in regulation of gastrointestinal contractility in both fishes. Neither rainbow trout ghrelin nor rat ghrelin affected the contractility of gastrointestinal strips of rainbow trout. Similarly, goldfish ghrelin-17 and rat ghrelin did not cause marked contraction in the goldfish intestinal bulb. Detail examinations using the goldfish intestine revealed that human neurotensin, substance-P, goldfish neuromedine-U and carbachol showed apparent contractile activities in the intestinal strips. Electrical field stimulation (EFS, 1-20 Hz) caused a frequency-dependent contraction of the intestinal bulb. Atropine partially inhibited and tetrodotoxin abolished the EFS-induced contraction. Pretreatments with goldfish ghrelin-17 and rat ghrelin did not modify the EFS-induced contraction. The mRNAs of two types of growth hormone secretagogue receptor (GHS-R), GHS-R1a-1 and GHS-R1a-2, were detected in the goldfish intestine, and the expression level of GHS-R1a-2 was 4-times higher than that of GHS-R1a-1. The expression levels of GHS-R1a-1 and GHS-R1a-2 in four regions of the goldfish intestine (intestinal bulb, intestine-1, intestine-2 and intestine-3) were almost the same. In conclusion, ghrelin does not affect gastrointestinal contractility of the rainbow trout and goldfish, although GHSR-like receptor/GHS-R1a is expressed entire intestine. These results suggest diversity of ghrelin function in vertebrates.

  15. Second-phase validation study of short time exposure test for assessment of eye irritation potency of chemicals.

    PubMed

    Kojima, Hajime; Hayashi, Kazuhiko; Sakaguchi, Hitoshi; Omori, Takashi; Otoizumi, Takuya; Sozu, Takashi; Kuwahara, Hirofumi; Hayashi, Takumi; Sakaguchi, Mayumi; Toyoda, Akemi; Goto, Haruka; Watanabe, Shinichi; Ahiko, Kyoko; Nakamura, Tsuneaki; Morimoto, Takashi

    2013-09-01

    A Short Time Exposure (STE) test is a cytotoxicity test that uses SIRC cells (rabbit corneal cell line) to assess eye irritation potency following a 5-min chemical exposure. This second-phase validation study assessed the predictive capacity of the STE test using 40 coded test substances at three laboratories. A Validation Management Team (VMT) then evaluated the predictivity of the STE test for United Nation (UN) Globally Harmonized System (GHS) categories using 63 test substances including the results of the first-phase validation study. The STE test can assess not only the severe or corrosive ocular irritants (corresponding to the UN GHS Category 1) but also non-irritant (corresponding to UN GHS Non Category) from other toxicity classes, especially for limited types of test substances. The predictivity by STE test, however, was insufficient for identification of UN GHS categories (Category 1, Category 2, or Non Category). These results suggest that the STE test can be recommended as an initial step in a top-down approach to identification of severe irritants and test substances that require classification for eye irritation (UN GHS Category 1) as well as an initial step in a bottom-up approach to identification of test substances that do not require classification for eye irritation (UN GHS Non Category) from other toxicity classes, especially for limited types of test substances. On the other hand, the STE test is not considered adequate for the identification of mild or moderate irritants (i.e., UN GHS Categories 2A and 2B) and severe irritants (UN GHS Category 1).

  16. Characteristics of participants in Australia's Get Healthy telephone-based lifestyle information and coaching service: reaching disadvantaged communities and those most at need.

    PubMed

    O'Hara, Blythe J; Phongsavan, Philayrath; Venugopal, Kamalesh; Bauman, Adrian E

    2011-12-01

    To address increasing rates of overweight and obesity, a population-based telephone intervention was introduced in New South Wales, Australia. The Get Healthy Information and Coaching Service® (GHS) offered participants a 6-month coaching program or detailed self-help information. Determining the population reach of GHS is of public health importance to ensure that the program reaches disadvantaged groups. This paper describes the socio-demographic and risk profile of participants (n = 4828) in the first 18 months of operations, determines how representative they are of the population, assesses changes in participants' socio-demographic profile and compares 'information-only' and 'coaching' participants. The results show that GHS users are representative of the adult population in relation to education, employment status, Aboriginal status, fruit and vegetable consumption and alcohol use. However, more female, middle-aged, English-speaking, rural and socially disadvantaged adults participated in GHS. Coaching Participants were more likely to be overweight and to be ex-smokers than the general population. There was substantial variability in GHS recruitment, when mass-reach television advertising was used, participants enrolled from a major city and from more disadvantaged communities. The GHS has broader population reach than many local interventions, but further efforts are needed to increase reach by Aboriginal communities, other minorities and men.

  17. Longer term impact of the mass media campaign to promote the Get Healthy Information and Coaching Service®: increasing the saliency of a new public health program.

    PubMed

    O'Hara, Blythe J; Phongsavan, Philayrath; Gebel, Klaus; Banovic, Debbie; Buffett, Kym M; Bauman, Adrian E

    2014-11-01

    The Get Healthy Information and Coaching Service® (GHS) was introduced in New South Wales in February 2009. It used mass reach media advertising and direct mail and/or proactive marketing to recruit participants. This article reports on the long-term impact of the campaign on GHS participation from July 2011 to June 2012. A stand-alone population survey collected awareness, knowledge, and behavioral variables before the first advertising phase, (n = 1,544, August-September 2010), during the advertising period (n = 1,500, February-March 2011; n = 1,500, June-July 2011; n = 1,500, February 2012), and after the advertising period (n = 1,500, June-July 2012). GHS usage data (n = 6,095) were collated during July 2011-June 2012. Unprompted and prompted awareness of GHS mass media significantly increased (0% to 8.0%, p < .001; and 14.1% to 43.9%, p < .001, respectively) as well as knowledge and perceived effectiveness of the GHS. Those from the lowest three quintiles of socioeconomic disadvantage and respondents who were overweight or obese were significantly more likely to report prompted campaign awareness. The majority (84.4%) of new GHS calls occurred when television advertising was present. Participants who cited mass media as their referral source were significantly more likely to enroll in the intensive coaching program. Mass media campaigns remain an effective method of promoting a telephone-based statewide lifestyle program.

  18. Tiered application of the neutral red release and EpiOcular™ assays for evaluating the eye irritation potential of agrochemical formulations.

    PubMed

    Settivari, Raja S; Amado, Ricardo Acosta; Corvaro, Marco; Visconti, Nicolo R; Kan, Lynn; Carney, Edward W; Boverhof, Darrell R; Gehen, Sean C

    2016-11-01

    Agrochemical formulations have been underrepresented in validation efforts for implementing alternative eye irritation approaches but represent a significant opportunity to reduce animal testing. This study assesses the utility of the neutral red release assay (NRR) and EpiOcular™ assay (EO) for predicting the eye irritation potential of 64 agrochemical formulations relative to Draize data. In the NRR, formulations with an NRR50 value ≤ 50 mg/mL were categorized as UN GHS Cat 1 and those >250 mg/mL were classified as UN GHS Non Classified (NC). The accuracy, sensitivity, and specificity were 78, 85 and 76% and 73, 85 and 61% for identifying UN GHS 1 and NC formulations, respectively. Specificity was poor for formulations with NRR50 > 50 to ≤250 mg/mL. The EO (ET-40 method) was explored to differentiate formulations that were UN GHS 1/2 and UN GHS NC. The EO resulted in accuracy, sensitivity, and specificity of 65%, 58% and 75% for identifying UN GHS NC formulations. To improve the overall performance, the assays were implemented using a tiered-approach where the NRR was run as a first-tier followed by the EO. The tiered-approach resulted in improved accuracy (75%) and balanced sensitivity (73%) and specificity (77%) for distinguishing between irritating and non-irritating agrochemical formulations.

  19. Food restriction, ghrelin, its antagonist and obestatin control expression of ghrelin and its receptor in chicken hypothalamus and ovary.

    PubMed

    Sirotkin, Alexander V; Pavlova, Silvia; Tena-Sempere, Manuel; Grossmann, Roland; Jiménez, Magdalena Romero; Rodriguez, Juan Manuel Castellano; Valenzuela, Francisco

    2013-01-01

    The purpose of the present study was to identify the role of age, nutritional state and some metabolic hormones in control of avian hypothalamic and ovarian ghrelin/ghrelin receptor system. We examined the effect of food restriction, administration of ghrelin 1-18, ghrelin antagonistic analogue (D-Lys-3)-GHRP-6, obestatin and combinations of them on the expression of ghrelin and ghrelin receptor (GHS-R1a) in hypothalamus and ovary of old (23months of age) and young (7months of age) chickens. Expression of mRNAs for ghrelin and GHS-R1a in both hypothalamus and largest ovarian follicle was measured by RT-PCR. It was observed that food restriction could promote the expression of ghrelin and GHS-R1a in hypothalamus and ovary of the old chickens, but in the young chickens it reduced expression of ghrelin and did not affect expression of GHS-R1a in the ovary. Administration of ghrelin 1-18 did not affect hypothalamic or ovarian ghrelin mRNA, but significantly increased the expression of GHS-R1a in hypothalamus, but not in ovary. (D-Lys-3)-GHRP-6, significantly stimulated accumulation of ghrelin, but not GHS-R1a mRNA in hypothalamus or ghrelin or GHS-R1a in the ovary. Ghrelin 1-18 and (D-Lys-3)-GHRP-6, when given together, were able either to prevent or to induce effect of these hormones. Obestatin administration increased expression of ghrelin gene in the hypothalamus, but not expression of hypothalamic GHS-R1a, ovarian ghrelin and GHS-R1a. Furthermore, obestatin was able to modify effect of both ghrelin and fasting on hypothalamic and ovarian mRNA for ghrelin GHS-R1a. Our results (1) confirm the existence of ghrelin and its functional receptors GHS-R1a in the chicken hypothalamus and ovary (2) confirm the age-dependent control of ovarian ghrelin by feeding, (3) demonstrate, that nutritional status can influence the expression of both ghrelin and GHS-R1a in hypothalamus and in the ovary (3) demonstrates for the first time, that ghrelin can promote generation of its

  20. The role of vitamin D receptor gene polymorphisms in Turkish infants with urolithiasis.

    PubMed

    Goknar, Nilufer; Öktem, Faruk; Torun, Emel; Gok, Ozlem; Demir, Aysegul Dogan; Kucukkoc, Mehmet; Kilic, Ulkan

    2016-01-01

    Polymorphisms in the vitamin D receptor (VDR) gene have recently been reported to be associated with urinary calculi in pediatric and adult cases, but no studies have looked at the youngest period of life. The purpose of this study was to investigate the role of VDR gene polymorphisms in infantile urolithiasis in a Turkish population. We compared a study group of 104 infants (55 girls and 49 boys, mean age 6.94 ± 3.81 months) with a control group of 96 infants (51 girls and 45 boys, mean age 7.51 ± 3.23) to evaluate their demographics and metabolic risk factors. PCR-based restriction analysis of the polymorphisms on the VDR gene (BsmI and TaqI) showed statistically significant differences between study and control groups (p = 0.001 and 0.043, respectively). In addition, the prevalence of the BsmI genotype was significantly different between the hypercalciuric and normocalciuric stone formers (p = 0.007). Allelic frequencies were similar between the urolithiasis and control groups (p > 0.05). The B allele of BsmI and the A allele of ApaI were more prevalent in the hypercalciuric stone formers than in the normocalciuric stone formers (p = 0.018 vs.0.036, respectively). These results suggest that the BsmI and TaqI VDR genotypes could be candidate genes leading to infantile urolithiasis.

  1. Effects of ghrelin on anorexia in tumor-bearing mice with eicosanoid-related cachexia.

    PubMed

    Wang, Wenhua; Andersson, Marianne; Iresjö, Britt-Marie; Lönnroth, Christina; Lundholm, Kent

    2006-06-01

    Ghrelin is a novel brain-gut peptide that stimulates food intake and may secondarily increase body weight via a growth hormone secretagogue receptor (GHS-R). Tumor-bearing mice (MCG101), characterized by anorexia, fat loss and muscle wasting due to increased concentration of PGE2 and proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha), were provided ghrelin i.p. at a low (20 microg/day) and high dose (40 microg/day) to examine the ability of ghrelin to counteract tumor-induced anorexia. Immunohistochemical staining and Western blot analyses were used to identify GHS-R expression in the brain as well as its relationship to NPY expression in hypothalamic neurons. GHS-R mRNA in hypothalamus and ghrelin mRNA in gastric fundus were quantified by RT-PCR. Body composition was determined by carcass extractions. GHS-R expression in hypothalamus and plasma ghrelin levels were significantly increased in freely-fed tumor-bearing mice, while gastric fundus expression of ghrelin was unaltered compared to non-tumor-bearing mice (controls). Ghrelin treatment increased food intake, body weight and whole body fat at both low and high doses of ghrelin in normal controls, while tumor-bearing mice showed improved intake and body composition at the high dose of ghrelin only. Exogenous ghrelin normalized the GHS-R expression in hypothalamus from tumor-bearing mice without alterations in the gastric fundus expression of ghrelin. Tumor growth was not altered by exogenous ghrelin. Our results indicate that MCG 101-bearing mice became ghrelin resistant despite upregulation of hypothalamic GHS-R expression, which confirms similar indirect observations in cancer patients. Thus, other factors downstream of the ghrelin-GHS-R system appear to be more important than ghrelin to explain cancer-induced anorexia.

  2. Evidence for a far-traveled thrust sheet in the Greater Himalayan thrust system, and an alternative model to building the Himalaya

    NASA Astrophysics Data System (ADS)

    Khanal, S.; Robinson, D. M.; Kohn, M. J.; Mandal, S.

    2015-01-01

    The Galchhi shear zone underlies the Kathmandu klippe in central Nepal and has emerged as a key structure for discriminating competing models for the formation of the Himalayan orogenic wedge. New chronologic data from the Galchhi area suggest a new structural and orogenic interpretation. Zircons from quartzites and an orthogneiss restrict protolith deposition to between 467 + 7/ - 10 Ma and ~570 Ma, with metamorphic zircon growth at 23-29 Ma. Comparable data from the Greater Himalayan Sequence (GHS) at the intra-GHS Langtang thrust, north of Galchhi, similarly restrict GHS deposition to between 475 + 7/ - 3 and ~660 Ma. Undeformed pegmatites near Galchhi constrain movement of the Galchhi shear zone to ≥22.5 ± 2.3 Ma, long before slip of the Main Central Thrust in the region (≤17 Ma). Shear sense indicators in the Galchhi area indicate both top-to-the-south and top-to-the-north shears. The old age of movement, Neoproterozoic youngest detrital zircons, occurrence of top-to-the-south shear sense indicators, and intrusive Paleozoic granites, all suggest that the Galchhi shear zone is an intra-GHS top-to-the-south thrust, rather than either a thrust involving Lesser Himalayan rocks, or a top-to-the-north shear zone that juxtaposed Tethyan and GHS rocks during coeval movement of the Main Central Thrust. The GHS in Nepal was not emplaced as a single body of rock but consists of at least two ductile "thrust sheets," present in both the hinterland at Langtang and toward the foreland at Galchhi. GHS thrust sheets sequentially underplated during southward propagation of the thrust belt.

  3. Tissue-specific expression of ghrelinergic and NUCB2/nesfatin-1 systems in goldfish (Carassius auratus) is modulated by macronutrient composition of diets.

    PubMed

    Blanco, Ayelén M; Bertucci, Juan I; Delgado, María J; Valenciano, Ana I; Unniappan, Suraj

    2016-05-01

    The macronutrient composition of diets is a very important factor in the regulation of body weight and metabolism. Several lines of research in mammals have shown that macronutrients differentially regulate metabolic hormones, including ghrelin and nesfatin-1 that have opposing effects on energy balance. This study aimed to determine whether macronutrients modulate the expression of ghrelin and the nucleobindin-2 (NUCB2) encoded nesfatin-1 in goldfish (Carassius auratus). Fish were fed once daily on control, high-carbohydrate, high-protein, high-fat and very high-fat diets for 7 (short-term) or 28 (long-term) days. The expression of preproghrelin, ghrelin O-acyl transferase (goat), growth hormone secretagogue receptor 1 (ghs-r1) and nucb2/nesfatin-1 mRNAs was quantified in the hypothalamus, pituitary, gut and liver. Short-term feeding with fat-enriched diets significantly increased nucb2 mRNA levels in hypothalamus and liver, preproghrelin, goat and ghs-r1 expression in pituitary, and ghs-r1 expression in gut. Fish fed on a high-protein diet exhibited a significant reduction in preproghrelin and ghs-r1 mRNAs in the liver. After long-term feeding, fish fed on high-carbohydrate and very high-fat diets had significantly increased preproghrelin, goat and ghs-r1 expression in pituitary. Feeding on a high-carbohydrate diet also upregulated goat and ghs-r1 transcripts in gut, while feeding on a high-fat diet elicited the same effect only for ghs-r1 in liver. Nucb2 expression increased in pituitary, while it decreased in gut after long-term feeding of a high-protein diet. Collectively, these results show for the first time in fish that macronutrients differentially regulate the expression of ghrelinergic and NUCB2/nesfatin-1 systems in central and peripheral tissues of goldfish.

  4. Correlation of ghrelin concentration and ghrelin, ghrelin-O-acetyltransferase (GOAT) and growth hormone secretagogue receptor 1a mRNAs expression in the proventriculus and brain of the growing chicken.

    PubMed

    Kitazawa, Takio; Hiraga, Takeo; Teraoka, Hiroki; Yaosaka, Noriko; Kaiya, Hiroyuki

    2015-01-01

    To determine mechanisms for age-related decrease of GHS-R1a expression in the chicken proventriculus, changes in mRNA expression of ghrelin and ghrelin-O-acetyltransferase (GOAT) as well as ghrelin concentrations in the proventriculus and plasma were examined in growing chickens. Changes in expression levels of ghrelin, GOAT and GHS-R1a mRNAs were also examined in different brain regions (pituitary, hypothalamus, thalamus, cerebellum, cerebral cortex, olfactory bulb, midbrain and medulla oblongata). Ghrelin concentrations in the proventriculus and plasma increased with aging and reached plateaus at 30-50 days after hatching. High level of ghrelin mRNA decreased at 3 days after hatching, and it became stable at half of the initial level. Expression levels of GHS-R1a and GOAT decreased 3 or 5 days after hatching and became stable at low levels. Significant negative correlations were found between plasma ghrelin and mRNA levels of GOAT and GHS-R1a. Expression levels of ghrelin mRNA were different in the brain regions, but a significant change was not seen with aging. GHS-R1a expression was detected in all brain regions, and age-dependent changes were observed in the pituitary and cerebellum. Different from the proventriculus, the expression of GOAT in the brain increased or did not change with aging. These results suggest that decreased GHS-R1a and GOAT mRNA expression in the proventriculus is due to endogenous ghrelin-induced down-regulation. Expression levels of ghrelin, GOAT and GHS-R1a in the brain were independently regulated from that in the proventriculus, and age-related and region-dependent regulation pattern suggests a local effect of ghrelin system in chicken brain.

  5. Exhumation of the Greater Himalayan Sequence Along the Zanskar Shear Zone, NW India

    NASA Astrophysics Data System (ADS)

    Basta, S.; Beck, E.; Burlick, T.

    2013-12-01

    The Zanskar Shear Zone (ZSZ), the western extent of the South Tibetan Detachment System, exposes high-grade metamorphic rocks of the Greater Himalayan Sequence (GHS) in its footwall. Granites and metapelites collected along the the ZSZ in the Suru River valley provide how and when the GHS rocks exhumed and were deformed. There are two suits of Paleozoic granites deformed within the ZSZ: Pan-African Cambrian-Ordovician granites at the cores of gneiss domes and Mississippian-Permian granites related to Panjal Traps magmatism. Age of Himalayan granites indicates 28-16 Ma which is concurrent with anatectic leucogranite crystallization. The metamorphic mineral assemblage indicates increasing metamorhic grade from NE to SW and comprises Qtz × Kfs + Pl + Bt × Ms × Sil × Ky × Grt × St × Chl × Tur × Rt. In addition to macroscopic evidence, strongly deformed quartz grains, deformation twins, pressure shadows, and kink bands have been observed to demonstrate micro-tectonics evidence. There are two different method to explain exhumation and deformation of the GHS metapelites: Electron backscatter diffraction (EBSD) crystallographic mapping and pseudosection modeling. While EBSD indicates the potential temperature of deformation, pseudosection modeling with Perple_X specifically presents the exhumation path of the GHS rocks. Pseudosection modeling with Perple_X , based on whole-rock geochemical analysis, is set pressure and temperature to 0.4-1.2 GPa and 300-900°C, and uses specific solution models, Bio(TCC), Chl(HP), St(HP), feldspar, Mica(CHA), Gt(HP), and hCrd, namely. These two methods are used by combining with geo/thermochronology data from U-Pb, 40Ar/39Ar, and (U-Th)/He, constraining the age of metamorphism, the cooling and exhumation time of the GHS rocks, and the end of shearing of deformation, respectively. 40Ar/39Ar dating on muscovite and biotite constrains cooling and exhumation ages of the GHS as ~20-19 Ma and 15 Ma, respectively. A metamorphic pressure

  6. Ghrelin receptor in Japanese fire belly newt, Cynops pyrrhogaster.

    PubMed

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2015-11-01

    We identified cDNA encoding a functional ghrelin receptor (growth hormone secretagogue-receptor 1a (GHS-R1a)) in a urodele amphibian, the Japanese fire belly newt (Cynops pyrrhogaster). Two functional receptor proteins, composed of 378- and 362-amino acids, were deduced from the identified cDNA because two candidate initiation methionine sites were found. The long-chain receptor protein shared 80%, 69%, and 59% identities with the bullfrog GHS-R1a, human GHS-R1a and tilapia GHS-R1a-like receptor, respectively. Phylogenetic analysis suggested that the newt receptor is grouped to the clade of the tetrapod homologs, and very closed to anuran amphibians. In functional analyses, homologous newt ghrelin, heterologous bullfrog and rat ghrelin, and a GHS-R1a agonist, GHRP-6 increased intracellular Ca(2+) concentration in human embryonic kidney (HEK) 293 cells stably expressed newt GHS-R1a. The responsiveness was much greater in the short-chain receptor than in the long-chain receptor. Both receptors preferred to bind Ser(3)-ghrelin including newt and rat ghrelin than Thr(3)-ghrelin with bullfrog ghrelin. GHRP-6 has a similar affinity to bullfrog ghrelin. GHS-R1a mRNA was expressed in the brain, pituitary, intestine, pancreas, testis and fat body with high level, and eyes, heart, stomach, liver, gall bladder, kidney and dorsal skin with low level. In a fasting experiment, gene expression of GHS-R1a in the brain and pituitary increased 4days after fasting, and the increased level decreased to the initial level 2weeks after fasting. These changes are consistent with the change in ghrelin mRNA. In contrast, expression of ghrelin and GHS-R1a mRNA in the stomach decreased on day 4 after fasting, and increased 2weeks after fasting. These results indicate that ghrelin and its receptor system are present and altered by energy states in this newt.

  7. Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward

    PubMed Central

    Schellekens, Harriët; Dinan, Timothy G.; Cryan, John F.

    2013-01-01

    The gut hormone, ghrelin, is the only known peripherally derived orexigenic signal. It activates its centrally expressed receptor, the growth hormone secretagogue receptor (GHS-R1a), to stimulate food intake. The ghrelin signaling system has recently been suggested to play a key role at the interface of homeostatic control of appetite and the hedonic aspects of food intake, as a critical role for ghrelin in dopaminergic mesolimbic circuits involved in reward signaling has emerged. Moreover, enhanced plasma ghrelin levels are associated with conditions of physiological stress, which may underline the drive to eat calorie-dense “comfort-foods” and signifies a role for ghrelin in stress-induced food reward behaviors. These complex and diverse functionalities of the ghrelinergic system are not yet fully elucidated and likely involve crosstalk with additional signaling systems. Interestingly, accumulating data over the last few years has shown the GHS-R1a receptor to dimerize with several additional G-protein coupled receptors (GPCRs) involved in appetite signaling and reward, including the GHS-R1b receptor, the melanocortin 3 receptor (MC3), dopamine receptors (D1 and D2), and more recently, the serotonin 2C receptor (5-HT2C). GHS-R1a dimerization was shown to affect downstream signaling and receptor trafficking suggesting a potential novel mechanism for fine-tuning GHS-R1a receptor mediated activity. This review summarizes ghrelin's role in food reward and stress and outlines the GHS-R1a dimer pairs identified to date. In addition, the downstream signaling and potential functional consequences of dimerization of the GHS-R1a receptor in appetite and stress-induced food reward behavior are discussed. The existence of multiple GHS-R1a heterodimers has important consequences for future pharmacotherapies as it significantly increases the pharmacological diversity of the GHS-R1a receptor and has the potential to enhance specificity of novel ghrelin-targeted drugs. PMID

  8. Tectonic and metamorphic discontinuities in the Greater Himalayan Sequence in Central Himalaya: in-sequence shearing by accretion from the Indian plate

    NASA Astrophysics Data System (ADS)

    Carosi, Rodolfo

    2016-04-01

    The Greater Himalayan Sequence (GHS) is the main metamorphic unit of the Himalayas, stretching for over 2400 km, bounded to the South by the Main Central Thrust (MCT) and to the North by the South Tibetan Detachment (STD) whose contemporanous activity controlled its exhumation between 23 and 17 Ma (Godin et al., 2006). Several shear zones and/or faults have been recognized within the GHS, usually regarded as out of sequence thrusts. Recent investigations, using a multitechnique approach, allowed to recognize a tectonic and metamorphic discontinuity, localized in the mid GHS, with a top-to-the SW sense of shear (Higher Himalayan Discontinuity: HHD) (Carosi et al., 2010; Montomoli et al., 2013). U-(Th)-Pb in situ monazite ages provide temporal constraint of the acitivity of the HHD from ~ 27-25 Ma to 18-17 Ma. Data on the P and T evolution testify that this shear zone affected the tectono-metamorphic evolution of the belt and different P and T conditions have been recorded in the hanging-wall and footwall of the HHD. The HHD is a regional tectonic feature running for more than 700 km, dividing the GHS in two different portions (Iaccarino et al., 2015; Montomoli et al., 2015). The occurrence of even more structurally higher contractional shear zone in the GHS (above the HHD): the Kalopani shear zone (Kali Gandaki valley, Central Nepal), active from ~ 41 to 30 Ma (U-Th-Pb on monazite) points out to a more complex deformation pattern in the GHS characterized by in sequence shearing. The actual proposed models of exhumation of the GHS, based exclusively on the MCT and STD activities, are not able to explain the occurrence of the HHD and other in-sequence shear zones. Any model of the tectonic and metamorphic evolution of the GHS should account for the occurrence of the tectonic and metamorphic discontinuities within the GHS and its consequences on the metamorphic paths and on the assembly of Himalayan belt. References Godin L., Grujic D., Law, R. D. & Searle, M. P. 2006

  9. Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus

    PubMed Central

    Ribeiro, Luís F.; Catarino, Tatiana; Santos, Sandra D.; Benoist, Marion; van Leeuwen, J. Fiona; Esteban, José A.; Carvalho, Ana Luísa

    2014-01-01

    Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary. However, GHS-R1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. Herein we explore the molecular mechanism underlying the action of ghrelin on hippocampal-dependent memory. Our data show that GHS-R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-type receptors (AMPARs) to synapses, producing functional modifications at excitatory synapses. Moreover, GHS-R1a activation enhances two different paradigms of long-term potentiation in the hippocampus, activates the phosphatidylinositol 3-kinase, and increases GluA1 AMPAR subunit and stargazin phosphorylation. We propose that GHS-R1a activation in the hippocampus enhances excitatory synaptic transmission and synaptic plasticity by regulating AMPAR trafficking. Our study provides insights into mechanisms that may mediate the cognition-enhancing effect of ghrelin, and suggests a possible link between the regulation of energy metabolism and learning. PMID:24367106

  10. Ghrelin receptor regulates adipose tissue inflammation in aging

    PubMed Central

    Buras, Eric D.; Yu, Kaijiang; Wang, Ruitao; Smith, C. Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

    2016-01-01

    Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr−/− mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsr−/− mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsr−/− mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance. PMID:26837433

  11. Genetic control of the humoral immune response to avian egg white lysozymes in the chicken

    SciTech Connect

    Flanagan, M.P.

    1987-01-01

    Chickens from two closely related sublines, GHs-B6 and GHs-B13, differing serologically at the major histocompatibility complex, were significantly different in their humoral response to three avian egg white lysozymes. Specific antisera levels were measured by radioimmunoassay using /sup 125/I-labeled lysozymes. Antibodies elicited in response to these lysozymes are assumed to be directed against sites on these lysozymes where their amino acid sequence differs from that of the recipient G. domesticus egg white lysozyme (HEL). GHs-B6 birds produced a high level of antibody in response to immunization of turkey (TEL), pheasant (PhL) and guinea hen (GHL) lysozymes. GHs-B13 birds produced no detectable antibody to TEL, were intermediate in their response to PhL and equaled the antibody production of GHs-B6 birds in response to GHL. Antisera to each lysozyme were examined for crossreactivity with all other lysozymes by use of a competitive binding assay.

  12. Ghrelin receptor regulates adipose tissue inflammation in aging.

    PubMed

    Lin, Ligen; Lee, Jong Han; Buras, Eric D; Yu, Kaijiang; Wang, Ruitao; Smith, C Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

    2016-01-01

    Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr(-/-) mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsrp(-/-) mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsrp(-/-) mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.

  13. Analysis of the comprehensibility of chemical hazard communication tools at the industrial workplace.

    PubMed

    Ta, Goh Choo; Mokhtar, Mazlin Bin; Mohd Mokhtar, Hj Anuar Bin; Ismail, Azmir Bin; Abu Yazid, Mohd Fadhil Bin Hj

    2010-01-01

    Chemical classification and labelling systems may be roughly similar from one country to another but there are significant differences too. In order to harmonize various chemical classification systems and ultimately provide consistent chemical hazard communication tools worldwide, the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) was endorsed by the United Nations Economic and Social Council (ECOSOC). Several countries, including Japan, Taiwan, Korea and Malaysia, are now in the process of implementing GHS. It is essential to ascertain the comprehensibility of chemical hazard communication tools that are described in the GHS documents, namely the chemical labels and Safety Data Sheets (SDS). Comprehensibility Testing (CT) was carried out with a mixed group of industrial workers in Malaysia (n=150) and factors that influence the comprehensibility were analysed using one-way ANOVA. The ability of the respondents to retrieve information from the SDS was also tested in this study. The findings show that almost all the GHS pictograms meet the ISO comprehension criteria and it is concluded that the underlying core elements that enhance comprehension of GHS pictograms and which are also essential in developing competent persons in the use of SDS are training and education.

  14. Salmonella Degrades the Host Glycocalyx Leading to Altered Infection and Glycan Remodeling

    PubMed Central

    Arabyan, Narine; Park, Dayoung; Foutouhi, Soraya; Weis, Allison M.; Huang, Bihua C.; Williams, Cynthia C.; Desai, Prerak; Shah, Jigna; Jeannotte, Richard; Kong, Nguyet; Lebrilla, Carlito B.; Weimer, Bart C.

    2016-01-01

    Complex glycans cover the gut epithelial surface to protect the cell from the environment. Invasive pathogens must breach the glycan layer before initiating infection. While glycan degradation is crucial for infection, this process is inadequately understood. Salmonella contains 47 glycosyl hydrolases (GHs) that may degrade the glycan. We hypothesized that keystone genes from the entire GH complement of Salmonella are required to degrade glycans to change infection. This study determined that GHs recognize the terminal monosaccharides (N-acetylneuraminic acid (Neu5Ac), galactose, mannose, and fucose) and significantly (p < 0.05) alter infection. During infection, Salmonella used its two GHs sialidase nanH and amylase malS for internalization by targeting different glycan structures. The host glycans were altered during Salmonella association via the induction of N-glycan biosynthesis pathways leading to modification of host glycans by increasing fucosylation and mannose content, while decreasing sialylation. Gene expression analysis indicated that the host cell responded by regulating more than 50 genes resulting in remodeled glycans in response to Salmonella treatment. This study established the glycan structures on colonic epithelial cells, determined that Salmonella required two keystone GHs for internalization, and left remodeled host glycans as a result of infection. These data indicate that microbial GHs are undiscovered virulence factors. PMID:27389966

  15. A chronic high fat diet alters the homologous and heterologous control of appetite regulating peptide receptor expression.

    PubMed

    Kentish, Stephen J; Wittert, Gary A; Blackshaw, L Ashley; Page, Amanda J

    2013-08-01

    Leptin, ghrelin and neuropeptide W (NPW) modulate vagal afferent activity, which may underlie their appetite regulatory actions. High fat diet (HFD)-induced obesity induces changes in the plasma levels of these peptides and alters the expression of receptors on vagal afferents. We investigated homologous and heterologous receptor regulation by leptin, ghrelin and NPW. Mice were fed (12 weeks) a standard laboratory diet (SLD) or HFD. Nodose ganglia were cultured overnight in the presence or absence of each peptide. Leptin (LepR), ghrelin (GHS-R), NPW (GPR7) and cholecystokinin type-1 (CCK1R) receptor mRNA, and the plasma leptin, ghrelin and NPW levels were measured. SLD: leptin reduced LepR, GPR7, increased GHS-R and CCK1R mRNA; ghrelin increased LepR, GPR7, CCK1R, and decreased GHS-R. HFD: leptin decreased GHS-R and GPR7, ghrelin increased GHS-R and GPR7. NPW decreased all receptors except GPR7 which increased with HFD. Plasma leptin was higher and NPW lower in HFD. Thus, HFD-induced obesity disrupts inter-regulation of appetite regulatory receptors in vagal afferents.

  16. Telescoping of isotherms beneath the South Tibetan Detachment System, Mount Everest Massif

    NASA Astrophysics Data System (ADS)

    Law, R. D.; Jessup, M. J.; Searle, M. P.; Francsis, M. K.; Waters, D. J.; Cottle, J. M.

    2011-11-01

    Petrologic and microstructural/crystal fabric data indicate that isotherms recorded in Greater Himalayan Series (GHS) schists and gneisses in the footwall to the South Tibetan Detachment System (STDS) have undergone extreme telescoping during penetrative flow associated with southward extrusion of the GHS. In the Rongbuk Valley, to the north of Mount Everest, we have made three vertical sampling traverses from the STDS down into the GHS and estimated temperatures associated with penetrative deformation using the opening angles of quartz c-axis fabrics measured on dynamically recrystallized grains. From north to south, the deformation temperature data indicate apparent thermal field gradients of 369, 385 and 420 °C per km for our three traverses, traced over a maximum vertical sampling distance of 0.5 km. Adopting a differential flow path model, simple geometric analysis using sections drawn parallel to the local transport direction indicates that detachment-parallel transport magnitudes of 25-170 km are needed to explain the extreme telescoping of isotherms in the immediate footwall to the STDS, depending on assumed original geothermal gradient, dip of detachment, etc. These particle transport estimates are similar to those previously calculated from barometry data of GHS rocks in the Everest region and are compatible with channel flow models for extrusion and exhumation of the GHS.

  17. A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo

    PubMed Central

    Pastor-Cavada, Elena; Pardo, Leticia M.; Kandil, Dalia; Torres-Fuentes, Cristina; Clarke, Sarah L.; Shaban, Hamdy; McGlacken, Gerard P.; Schellekens, Harriet

    2016-01-01

    Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. In vivo tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand. PMID:27819353

  18. A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo

    NASA Astrophysics Data System (ADS)

    Pastor-Cavada, Elena; Pardo, Leticia M.; Kandil, Dalia; Torres-Fuentes, Cristina; Clarke, Sarah L.; Shaban, Hamdy; McGlacken, Gerard P.; Schellekens, Harriet

    2016-11-01

    Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. In vivo tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand.

  19. Identification and localization of gastrointestinal hormones in the skin of the bullfrog Rana catesbeiana during periods of activity and hibernation.

    PubMed

    Wang, Huan; Zhou, Naizhen; Zhang, Rui; Wu, Yuanyuan; Zhang, Ruidong; Zhang, Shengzhou

    2014-10-01

    Amphibian skin and its secretions contain a wide variety of biogenic amines and biologically active peptides, some of which are either identical or highly homologous to gastrointestinal hormones (GHs) of higher vertebrates. This study investigated the distribution density and immunoreactive (IR) intensity of 5-hydroxytryptamine (5-HT), gastrin (GAS), somatostatin (SS), pancreatic polypeptide (PP), neuropeptide Y (NPY) and glucagon (GLU) IR cells in the skin of the bullfrog Rana catesbeiana during periods of activity and hibernation. The results indicated that the six types of GHs were all present in the bullfrog skin and were most predominant in the epidermis and mucous glands. In dorsal skin, the density of the GHs-IR cells in mucous glands was higher than that in epidermis except for GAS-IR cells. In ventral skin, the density of 5-HT, PP and NPY-IR cells in mucous glands was also higher than that in the epidermis. During hibernation, the density of the six types of GHs-IR cells and the IR intensity of GAS, SS, NPY and GLU-IR cells in the epidermis of dorsal skin increased significantly. The IR intensity of SS, PP and NPY-IR cells in granular glands of ventral skin also increased significantly during hibernation. These results suggested that multiple types of GHs-IR cells present in the skin of R. catesbeiana, may play important roles in the regulation of the physiological functions of skin. Also, adaptive changes in the density and IR intensity of GHs-IR cells occurred during hibernation.

  20. GHRP-6 mimics ghrelin-induced stimulation of food intake and suppression of locomotor activity in goldfish.

    PubMed

    Yahashi, Satowa; Kang, Ki Sung; Kaiya, Hiroyuki; Matsuda, Kouhei

    2012-04-01

    Ghrelin was first identified and characterized from rat stomach as an endogenous ligand for the growth hormone secretagogue (GHS) receptor (GHS-R). Ghrelin also acts as an orexigenic factor and regulates energy balance in rodents. In goldfish, native ghrelin consists of 11 molecular variants, the major form being a 17-residue peptide with n-octanoic acid modification (n-octanoyl ghrelin17), and intraperitoneal (IP) administration of n-octanoyl ghrelin17 induces central actions such as stimulation of food intake and suppression of locomotor activity through capsaicin-sensitive afferents. Four types of GHS-Rs (1a-1, 1a-2, 2a-1 and 2a-2) have been identified in goldfish, and one GHS, GHRP-6, can activate only GHS-R2a-1 in vitro. However, there is no information about the effect of GHRP-6 on food intake and locomotor activity in goldfish in vivo. Therefore, in the present study, we examined whether IP-administered GHRP-6 would mimic the orexigenic action of n-octanoyl ghrelin17 and its suppression of locomotor activity. IP administration of GHRP-6 at 1pmol/g body weight (BW) stimulated food intake, and was equipotent to the orexigenic action of n-octanoyl ghrelin17 at 10 pmol/g BW. IP-injected GHRP-6 at 1 pmol/g BW also induced a significant decrease of locomotor activity, as was the case for IP-injected n-octanoyl ghrelin17 at 10 pmol/g BW. The action of GHRP-6 was blocked by IP-preinjected capsaicin at 160 nmol/g BW. These results suggest that the central action of GHRP-6 might be mediated via the GHS-R2a-1-signaling pathway, and subsequently through capsaicin-sensitive afferents in goldfish.

  1. A quantitative in silico model for predicting skin sensitization using a nearest neighbours approach within expert-derived structure-activity alert spaces.

    PubMed

    Canipa, Steven J; Chilton, Martyn L; Hemingway, Rachel; Macmillan, Donna S; Myden, Alun; Plante, Jeffrey P; Tennant, Rachael E; Vessey, Jonathan D; Steger-Hartmann, Thomas; Gould, Janet; Hillegass, Jedd; Etter, Sylvain; Smith, Benjamin P C; White, Angela; Sterchele, Paul; De Smedt, Ann; O'Brien, Devin; Parakhia, Rahul

    2017-02-28

    Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU. A Nearest Neighbours in silico model was developed using an in-house dataset of 1096 murine local lymph node (LLNA) studies. The EC3 value (the effective concentration of the test substance producing a threefold increase in the stimulation index compared to controls) of a given chemical was predicted using the weighted average of EC3 values of up to 10 most similar compounds within the same mechanistic space (as defined by activating the same Derek skin sensitization alert). The model was validated using previously unseen internal (n = 45) and external (n = 103) data and accuracy of predictions assessed using a threefold error, fivefold error, European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classifications. In particular, the model predicts the GHS skin sensitization category of compounds well, predicting 64% of chemicals in an external test set within the correct category. Of the remaining chemicals in the previously unseen dataset, 25% were over-predicted (GHS 1A predicted: GHS 1B experimentally) and 11% were under-predicted (GHS 1B predicted: GHS 1A experimentally). Copyright © 2017 John Wiley & Sons, Ltd.

  2. Using mass-media communications to increase population usage of Australia’s Get Healthy Information and Coaching Service®

    PubMed Central

    2012-01-01

    Background Global obesity prevalence is increasing and population health programs are required to support changes to modifiable lifestyle risk factors. Such interventions benefit from mass-communications to promote their use. The Get Healthy Information and Coaching Service ® (GHS) utilised mass-reach media advertising to recruit participants to an Australian state-wide program. Methods A stand alone population survey collected awareness, knowledge and behavioural variables before the first advertising phase, (n = 1,544; August -September 2010), during (n = 1,500; February - March 2011) and after the advertising period (n = 1,500; June-July 2011). GHS usage data (n = 6,375) was collated during July 2010 – June 2011. Results The results showed that television-lead mass-media significantly increased unprompted awareness (0% to 31.8%, p < 0.001); prompted awareness (2.5% to 23.7%, p < 0.001); and understanding (10.2% to 32.2%, p < 0.001). Mass-media (television, print and mail out information) was more often cited as the source of referral by males, those aged 18 – 49 years, employed, and from the lowest socio-economic groups. During the weeks when mass-media advertising was present, 4 and 2.5 times more information and coaching participants respectively registered than when there was no advertising present. Participants who cited television and print were less likely to enrol in GHS coaching, but this was not the case for mail out information and secondary referral sources. Conclusions GHS mass-communications campaigns are effective at increasing awareness and usage of the GHS, especially among hard-to-reach population groups. Television advertising provides universal reach, but should be supplemented by health professional referrals and targeted mail-out information to recruit participants to the intensive GHS coaching program. PMID:22967230

  3. Novel analogs of ghrelin: physiological and clinical implications.

    PubMed

    Halem, Heather A; Taylor, John E; Dong, Jesse Z; Shen, Yeelana; Datta, Rakesh; Abizaid, Alfonso; Diano, Sabrina; Horvath, Tamas; Zizzari, Philippe; Bluet-Pajot, Marie-Thèrèse; Epelbaum, Jacques; Culler, Michael D

    2004-08-01

    Ghrelin, the 28 amino acid peptide recently identified as the natural ligand for the growth hormone (GH) secretagogue (GHS) receptor, has multiple activities in addition to stimulation of GH secretion, including stimulation of feeding and weight gain. To utilize these actions for potential therapeutic benefit, we have produced analogs of human ghrelin with enhanced metabolic stability, affinity for the GHS receptor, and efficacy in stimulating weight gain. We have also discovered an analog of ghrelin, BIM-28163, that is an antagonist at the GHS receptor and that fully inhibits GHS receptor activation induced by native ghrelin. In vivo, BIM-28163 does not increase GH secretion but fully blocks ghrelin-induced GH secretion. In contrast, BIM-28163 acts as a full agonist with regard to the ghrelin actions of stimulating weight gain and food intake. These results suggest that a receptor other than the GHS receptor mediates the actions of ghrelin on feeding and weight gain. This concept is strengthened by our observation that at certain hypothalamic sites, BIM-28163 acts as an antagonist of ghrelin-induced neuronal activation, while at other sites, both ghrelin and BIM-28163 induce neuronal activation via the same receptor. Collectively, these results indicate the existence of a novel ghrelin receptor that may regulate the feeding activity of ghrelin. Using BIM-28163 as a tool to define the endogenous role of ghrelin in normal GH secretion, we have demonstrated that antagonism of the GHS receptor in normal rats does not impair the pulsatility of GH secretion but lowers the pulse amplitude and mean GH level. These results demonstrate that endogenous ghrelin acts to amplify the basic pattern of GH secretion established by the interplay of hypothalamic GH-releasing hormone and somatostatin. These studies demonstrate the feasibility of creating ghrelin analogs that are selective for specific activities, as well as their utility in dissecting the role of ghrelin in both

  4. Urolithiasis in animals.

    PubMed

    McIntosh, G H

    1978-06-01

    Urolithiasis is a disease of multifactorial origin. Prominent amongst the causes of disease outbreaks are nutritional factors. Alteration of diet is probably one of the most effective means of prevention, depending of course on the nature of the uroliths formed. In this regard analysis of the stones formed is an essential prelude to understanding, adequately treating the disease and preventing its recurrence.

  5. Dexamethasone regulates expression of BRUCE/Apollon and the proliferation of neural progenitor cells.

    PubMed

    Sippel, Maria; Rajala, Raili; Korhonen, Laura; Bornhauser, Beat; Sokka, Anna-Leena; Naito, Mikihiko; Lindholm, Dan

    2009-07-07

    Glucocorticoid hormones (GHs) regulate cell proliferation of neural progenitor cells (NPCs) contributing to reduction of neurogenesis after stress. We show here that dexamethasone (Dex) decreases BRUCE/Apollon (BRUCE) in cultured NPCs in a GH-receptor-dependent manner. Downregulation of BRUCE by Dex or using silencing RNA reduced the number of proliferating NPCs, whilst overexpression of BRUCE counteracted the effect of Dex. Dex also elevated the deubiquitinating enzyme, Usp8/Ubpy, which via Nrdp1 decreases BRUCE. The results show that BRUCE is a target for GHs in the NPCs, and that BRUCE controls cell division of NPCs and possibly of other stem cells.

  6. Microstructural analysis of the Greater Himalayan Sequence, Annapurna-Dhaulagiri Himalaya, central Nepal: Channel Flow and Orogen-parallel deformation.

    NASA Astrophysics Data System (ADS)

    Parsons, A. J.; Phillips, R. J.; Lloyd, G. E.; Searle, M. P.; Law, R. D.

    2014-12-01

    Knowledge of deformation processes that occur in the lithosphere during orogenesis can be gained from microstructural analysis of exhumed terranes and shear zones. Here, we use Crystallographic Preferred Orientation (CPO) and Anisotropy of Magnetic Susceptibility (AMS) data to reveal the kinematic evolution of the metamorphic core of the Himalayan orogen, the Greater Himalayan Sequence (GHS). The Himalayan orogen is commonly explained with models of channel flow, which describe the GHS as a partially molten, rheologically weak mid crustal channel. Extrusion of the channel was facilitated by coeval reverse- and normal-sense shear zones, at the lower and upper channel margins respectively. Whilst many thermobarometric studies support the occurrence of channel flow, the spatial and temporal distribution of strain within the GHS is one aspect of the model that is yet to be fully resolved. We present a quantified strain proxy profile for the GHS in the Annapurna-Dhaulagiri region of central Nepal and compare our results with the kinematic predictions of the channel flow model. Samples were collected along a NS transect through the Kali Gandaki valley of central Nepal for CPO and AMS analysis. Variations in CPO strength are used as a proxy for relative strain magnitude, whilst AMS data provide a proxy for strain ellipsoid shape. Combining this information with field and microstructural observations and thermobarometric constraints reveals the kinematic evolution of the GHS in this region. Low volumes of leucogranite and sillimanite bearing rocks and evidence of reverse-sense overprinting normal-sense shearing at the top of the GHS suggest that channel flow was not as intense as model predictions. Additionally, observed EW mineral lineations and oblate strain ellipsoid proxies in the Upper GHS, indicative of three dimensional flattening and orogen parallel stretching, cannot be explained by current channel flow models. Whilst the results do not refute the occurrence of

  7. Tectono-metamorphic discontinuities in the Greater Himalayan Sequence and their role in the exhumation of crystalline units

    NASA Astrophysics Data System (ADS)

    Carosi, Rodolfo; Montomoli, Chiara; Iaccarino, Salvatore; Visonà, Dario

    2013-04-01

    The Greater Himalayan Sequence (GHS) shows an impressive continuity running for more than 2000 kilometers. Large volumes of granites were intruded in its upper portion, below the South Tibetan Detachment System. The deformation within the crystalline rocks is referable to pervasive non-coaxial deformation mainly related to a top-to-the south sense of shear developed in the time span of activity of the STDS and MCT. Several shear zones/faults have been recognized within the GHS, usually regarded as out of sequence thrusts with respect to the MCT. However, geological investigations in Western Nepal allow the authors to identify different generations of shear zones with different kinematics and, moreover, different ages. A high-temperature top-to-the SW shear zone (Toijem shear zone) has been documented in the core of the GHS in lower Dolpo (western Nepal), whose activity has been constrained at ~ 26 Ma by U-Pb on monazite (Carosi et al., 2010) before the onset of shearing of the MCT. Going in the Mugu-Karnali valley an even thicker (up to 4 km) and top-to-the SW shear zone (Mangri shear zone) has been recently detected in the middle part of the GHS. It separates the upper part of the GHS (with the occurrence of sillimanite along the main foliation) from a lower part mainly made by kyanite-bearing gneiss and micaschist. The age has been constrained by U-Pb on monazite at ~ 25-17 Ma. The difference in Pressure experienced by the hanging-wall and footwall rock is at least ~ 2 Kbar. The two shear zones are responsible for the exhumation of the hanging wall rocks before the well-known period of exhumation by extrusion or channel flow of the GHS by the contemporaneous activity of the Main Central Thrust and South Tibetan Detachment System. By connecting the study shear zone with similar tectonic-metamorphic discontinuities in central Himalaya it is evident the occurrence of a regional-scale feature, the High Himalayan Discontinuity, separating the sillimanite

  8. Episodic exhumation of the Greater Himalayan Sequence since the Miocene constrained by fission track thermochronology in Nyalam, central Himalaya

    NASA Astrophysics Data System (ADS)

    Wang, An; Garver, John I.; Wang, Guocan; Smith, Jacqueline A.; Zhang, Kexin

    2010-12-01

    The Greater Himalayan Sequence (GHS), which makes up the core of the Himalayan orogen, has an uppermost tectonic contact defined by the South Tibetan Detachment System (STDS) and a lower tectonic contact defined by the Main Central Thrust (MCT). The GHS occurs as one of the most important tectostratigraphic units for deciphering processes related to tectonic and climatic exhumation across the orogen. Zircon and apatite fission track (ZFT, AFT) dating were carried out along a transect in Nyalam, central Himalaya in southern Tibet to constrain cooling driven by orogenic process since the middle Miocene. The hanging wall of the STDS yields an essentially unreset Jurassic ZFT age in the Jurassic strata. However, below the STDS within the GHS there is a clear and distinct thermal signal of cooling related to exhumation. In the footwall and within the GHS, the rocks have ZFT ages of middle Miocene to Pliocene, and AFT ages of late Miocene to Quaternary that get younger downward and away from the STDS. In combination with thermal structure modeling, a two-part episodic model, which is widely compatible with existing thermochronological data, is proposed for cooling and exhumation of the GHS since the middle Miocene: [1] middle Miocene; and [2] Pliocene to Quaternary (Recent). The middle Miocene cooling is suggested to have resulted from a rapid tectonic unroofing by down-to-the-north slip on the STDS. The tectonic exhumation was also recorded by several other thermochronological systems (e.g. biotite 40Ar/ 39Ar) with concordant middle Miocene cooling ages in different structural positions across the GHS. Post middle Miocene ZFT and AFT cooling ages in the lower part of the GHS suggest accelerated cooling by climate-enhanced erosional exhumation, which was initiated in the late Miocene to Pliocene and was dramatic in the Quaternary to Recent. Thermochronological data and modeling further imply that the present Himalayan topographic front may have been shaped essentially by

  9. Numerical validation of the generalized Harvey-Shack surface scatter theory

    NASA Astrophysics Data System (ADS)

    Choi, Narak; Harvey, James E.

    2013-11-01

    The generalized Harvey-Shack (GHS) surface scatter theory is numerically compared to the classical small perturbation method, the Kirchhoff approximation method, and the rigorous method of moments for one-dimensional ideally conducting surfaces whose surface power spectral density function is Gaussian or exhibits an inverse power law (fractal) behavior. In spite of its simple analytic form, our numerical comparison shows that the new GHS theory is valid (with reasonable accuracy) over a broader range of surface parameter space than either of the two classical surface scatter theories.

  10. Hybrid channel flow-type mechanisms in the Greater Himalayan Sequence (West Nepal): new constraints from vorticity of flow and quartz petrofabric analyses.

    NASA Astrophysics Data System (ADS)

    Frassi, Chiara

    2016-04-01

    Three main tectono-metamorphic units are classically recognized along the Himalayan belt: the Lesser Himalayan (LH), the Greater Himalayan sequence (GHS) and the Tibetan Sedimentary sequence (TSS). The GHS may be interpreted as a low-viscosity tabular body of mid-crustal rocks extruded southward in Miocene times beneath the Tibetan plateau between two parallel and opposite-sense crustal-scale shear zones: the Main Central thrust at the base, and the South Tibetan Detachment system at the top. The pre-/syn-shearing mineral assemblage documented within these crustal-scale shear zones indicates that the metamorphic grade increases toward the core of the GHS producing an inverted and a normal thermal gradient respectively on the top and on the bottom of the slab. In addition, thermal profiles estimated using both petrology- and microstructures/fabrics-based thermometers indicate that the metamorphic isograds are condensed. Although horizontal extension and vorticity estimates collected across the GHS could be strongly biased by the criteria used to define the map position of the MCT, published vorticity data document general shear flow (1>Wk>0) within the slab with a pure-shear component of flow slightly predominant within the core of the GHS whereas the simple-shear component seems to dominate at the top of the slab. The lower boundary of the GHS records a general shear flow with a comparable contribution of simple and pure shearing. The associated crustal extrusion is compatible with Couette - Poiseuille velocity flow profile as assumed in crustal-scale channel flow-type models In this study, the quartz c-axis petrofabrics, vorticity and deformation-temperature studies are integrated with microstructures and metamorphic studies to individuate the location of the MCT and to document the spatial distribution of ductile deformation patterns across the lower portion of the GHS exposed in the Chaudabise river valley in western Nepal. My results indicate that the Main

  11. Drinking water for stone formers: is the calcium content relevant?

    PubMed

    Jaeger, P; Portmann, L; Jacquet, A F; Burckhardt, P

    1984-01-01

    Stone formers are often told to select a drinking water with low Ca content. To see whether this measure has a rational biochemical background, 4 Ca hyperabsorbers were asked to drink, first tap water ad libitum, then 2 liters/day of tap water, then 2 liters/day of a low Ca water (A) and finally 2 liters/day of a high Ca water (B). On A, subjects were normocalciuric but hyperoxaluric; whereas on B, they were markedly hypercalciuric but normooxaluric. Therefore, Ca . Ox concentration products were similar on B and A. However, on A as well as on B, Ca . Ox products were much lower than on tap water ad libitum due to the high fluid intake which had thus been imposed. It is concluded that, in the prevention of the recurrence of nephrolithiasis, 'have a high fluid intake' is probably a more relevant advice than 'select a water with a particularly low Ca content'.

  12. Genotype-phenotype correlations in normotensive patients with primary renal tubular hypokalemic metabolic alkalosis.

    PubMed

    Bettinelli, A; Vezzoli, G; Colussi, G; Bianchetti, M G; Sereni, F; Casari, G

    1998-01-01

    Among the different forms of hereditary renal tubulopathies associated with hypokalemia, metabolic alkalosis and normotension, two main types of disorders have been identified: Gitelman disease, which appears to be a homogeneous post-Henle's loop disorder, and Bartter syndrome, a heterogeneous Henle loop disorder. A specific gene has been found responsible for Gitelman disease, encoding the thiazide-sensitive Na-Cl cotransporter (TSC) of the distal convoluted tubule. From a phenotypic point of view the characteristic findings of this disease are hypocalciuria, hypomagnesemia and tetanic crises appearing during childhood or later. Many subjects are asymptomatic. At least three different genes have been shown to be responsible for Bartter syndrome, characterized by mutations in the proteins encoding respectively the bumetanide-sensitive Na-K-2Cl cotransporter, the inwardly-rectifying renal potassium channel and a renal chloride channel, all protein transports located in the ascending limb of Henle's loop. Mutations in the first two transport proteins have been demonstrated in patients with the hypercalciuric forms of Bartter syndrome associated with nephrocalcinosis (respectively Bartter syndrome type I and II), who were often born after pregnancies complicated by polyhydramnios and premature delivery. Mutations in the gene encoding a renal chloride channel were recently recognized in patients with a Henle tubular defect not associated with nephrocalcinosis (Bartter syndrome type III). Most of the latter group of patients were normo-hypercalciuric and presented dehydration and life-threatening hypotension in the first year of life. However, these three genes do not explain all the patients with Bartter syndrome which unlike Gitelman disease, appears to be a very heterogeneous disorder. Clearance studies, especially if done during furosemide and/or hydrochlorothiazide administration, have been helpful in identifying the site of tubular involvement. Considering both

  13. When and how to evaluate a patient with nephrolithiasis.

    PubMed

    Rivers, K; Shetty, S; Menon, M

    2000-05-01

    Nephrolithiasis is a common disorder that afflicts up to 12% of the population and continues to be a significant cause of patient injury. Evaluation of these patients should include the assessment of their comorbidities and underlying medical conditions. Patients who form stones can undergo a streamlined evaluation. A cause can be found in more than 90% of these patients. With medical treatment, stone-recurrence rates can be decreased by 85% for calcium oxalate stone formation, which affects a large proportion of patients. Introduction of nonspecific medical therapy in uncomplicated calcium stone disease may improve the quality of life for these patients and allow utilization a simple diagnostic protocol. This is in contrast to the previous recommendations of disease-specific therapy. Because patients without complications represent the majority of those who form stones, a simplified approach greatly reduces the cost of evaluation and treatment. Underlying medical conditions, however, require disease-specific therapy. The protocol represented here should aid physicians and patients in the approach to management of stone disease. The fasting calcium-load test is not required, and the entire evaluation can be performed in an ambulatory setting in two visits. Two 24-hour urine samples should be obtained on a random and restricted diet. Patients who form calcium stones can be subdivided into those who form hypercalciuric and normocalciuric stones. Patients who form normocalciuric stones are treated with conservative measures (increased fluid intake) and potassium and magnesium citrate. Patients who form hypercalciuric stones are treated with a combination of thiazides and potassium and magnesium citrate.

  14. Relationship and interaction between sodium and potassium.

    PubMed

    Morris, R Curtis; Schmidlin, Olga; Frassetto, Lynda A; Sebastian, Anthony

    2006-06-01

    Compared with the Stone Age diet, the modern human diet is both excessive in NaCl and deficient in fruits and vegetables which are rich in K+ and HCO3- -yielding organates like citrate. With the modern diet, the K+/Na+ ratio and the HCO3-/Cl- ratio have both become reversed. Yet, the biologic machinery that evolved to process these dietary electrolytes remains largely unchanged, genetically fixed in Paleolithic time. Thus, the electrolytic mix of the modern diet is profoundly mismatched to its processing machinery. Dietary potassium modulates both the pressor and hypercalciuric effects of the modern dietary excess of NaCl. A marginally deficient dietary intake of potassium amplifies both of these effects, and both effects are dose-dependently attenuated and may be abolished either with dietary potassium or supplemental KHCO3. The pathogenic effects of a dietary deficiency of potassium amplify, and are amplified by, those of a dietary excess of NaCl and in some instances a dietary deficiency of bicarbonate precursors. Thus, in those ingesting the modern diet, it may not be possible to discern which of these dietary electrolytic dislocations is most determining of salt-sensitive blood pressure and hypercalciuria, and the hypertension, kidney stones, and osteoporosis they may engender. Obviously abnormal plasma electrolyte concentrations rarely characterize these dietary electrolytic dislocations, and when either dietary potassium or supplemental KHCO3 corrects the pressor and hypercalciuric effects of these dislocations, the plasma concentrations of sodium, potassium, bicarbonate and chloride change little and remain well within the normal range.

  15. Twisting of glycosidic bonds by hydrolases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Patterns of scissile bond twisting have been found in crystal structures of glycoside hydrolases (GHs) that are complexed with substrates and inhibitors. To estimate the increased potential energy in the substrates that results from this twisting, we have plotted torsion angles for the scissile bond...

  16. Neuronal deletion of ghrelin receptor almost completely prevents diet-induced obesity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin signaling has major effects on energy- and glucose-homeostasis, but it is unknown whether ghrelin's functions are centrally and/or peripherally mediated. The ghrelin receptor, Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in brain and detectable in some peripheral tissues...

  17. Ghrelin Facilitates GLUT2-, SGLT1- and SGLT2-mediated Intestinal Glucose Transport in Goldfish (Carassius auratus)

    PubMed Central

    Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Ramesh, Naresh; Delgado, María Jesús; Valenciano, Ana Isabel; Unniappan, Suraj

    2017-01-01

    Glucose homeostasis is an important biological process that involves a variety of regulatory mechanisms. This study aimed to determine whether ghrelin, a multifunctional gut-brain hormone, modulates intestinal glucose transport in goldfish (Carassius auratus). Three intestinal glucose transporters, the facilitative glucose transporter 2 (GLUT2), and the sodium/glucose co-transporters 1 (SGLT1) and 2 (SGLT2), were studied. Immunostaining of intestinal sections found colocalization of ghrelin and GLUT2 and SGLT2 in mucosal cells. Some cells containing GLUT2, SGLT1 and SGLT2 coexpressed the ghrelin/growth hormone secretagogue receptor 1a (GHS-R1a). Intraperitoneal glucose administration led to a significant increase in serum ghrelin levels, as well as an upregulation of intestinal preproghrelin, ghrelin O-acyltransferase and ghs-r1 expression. In vivo and in vitro ghrelin treatment caused a concentration- and time-dependent modulation (mainly stimulatory) of GLUT2, SGLT1 and SGLT2. These effects were abolished by the GHS-R1a antagonist [D-Lys3]-GHRP-6 and the phospholipase C inhibitor U73122, suggesting that ghrelin actions on glucose transporters are mediated by GHS-R1a via the PLC/PKC signaling pathway. Finally, ghrelin stimulated the translocation of GLUT2 into the plasma membrane of goldfish primary intestinal cells. Overall, data reported here indicate an important role for ghrelin in the modulation of glucoregulatory machinery and glucose homeostasis in fish. PMID:28338019

  18. Physiological roles revealed by ghrelin and ghrelin receptor deficient mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neur...

  19. Ghrelin Facilitates GLUT2-, SGLT1- and SGLT2-mediated Intestinal Glucose Transport in Goldfish (Carassius auratus).

    PubMed

    Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Ramesh, Naresh; Delgado, María Jesús; Valenciano, Ana Isabel; Unniappan, Suraj

    2017-03-24

    Glucose homeostasis is an important biological process that involves a variety of regulatory mechanisms. This study aimed to determine whether ghrelin, a multifunctional gut-brain hormone, modulates intestinal glucose transport in goldfish (Carassius auratus). Three intestinal glucose transporters, the facilitative glucose transporter 2 (GLUT2), and the sodium/glucose co-transporters 1 (SGLT1) and 2 (SGLT2), were studied. Immunostaining of intestinal sections found colocalization of ghrelin and GLUT2 and SGLT2 in mucosal cells. Some cells containing GLUT2, SGLT1 and SGLT2 coexpressed the ghrelin/growth hormone secretagogue receptor 1a (GHS-R1a). Intraperitoneal glucose administration led to a significant increase in serum ghrelin levels, as well as an upregulation of intestinal preproghrelin, ghrelin O-acyltransferase and ghs-r1 expression. In vivo and in vitro ghrelin treatment caused a concentration- and time-dependent modulation (mainly stimulatory) of GLUT2, SGLT1 and SGLT2. These effects were abolished by the GHS-R1a antagonist [D-Lys3]-GHRP-6 and the phospholipase C inhibitor U73122, suggesting that ghrelin actions on glucose transporters are mediated by GHS-R1a via the PLC/PKC signaling pathway. Finally, ghrelin stimulated the translocation of GLUT2 into the plasma membrane of goldfish primary intestinal cells. Overall, data reported here indicate an important role for ghrelin in the modulation of glucoregulatory machinery and glucose homeostasis in fish.

  20. Ghrelin and obestatin: different role in fetal lung development?

    PubMed

    Nunes, Susana; Nogueira-Silva, Cristina; Dias, Emanuel; Moura, Rute S; Correia-Pinto, Jorge

    2008-12-01

    Ghrelin and obestatin are two proteins that originate from post-translational processing of the preproghrelin peptide. Various authors claim an opposed role of ghrelin and obestatin in several systems. Preproghrelin mRNA is significantly expressed in airway epithelium throughout lung development, predominantly during the earliest stages. The aim of this study was to evaluate the role of ghrelin and obestatin in fetal lung development in vitro. Immunohistochemistry studies were performed at different gestational ages in order to clarify the expression pattern of ghrelin, GHS-R1a, obestatin and GPR39 during fetal lung development. Fetal rat lung explants were harvested at 13.5 days post-conception (dpc) and cultured during 4 days with increasing doses of total ghrelin, acylated ghrelin, desacyl-ghrelin, ghrelin antagonist (D-Lys(3)-GHRP-6) or obestatin. Immunohistochemistry studies demonstrated that ghrelin, GHS-R1a, obestatin and GPR39 proteins were expressed in primitive rat lung epithelium throughout all studied gestational ages. Total and acylated ghrelin supplementation significantly increased the total number of peripheral airway buds, whereas desacyl-ghrelin induced no effect. Moreover, GHS-R1a antagonist significantly decreased lung branching. Finally, obestatin supplementation induced no significant effect in the measured parameters. The present study showed that ghrelin has a positive effect in fetal lung development through its GHS-R1a receptor, whereas obestatin has no effect on lung branching.

  1. Dominant simple-shear deformation during peak metamorphism for the lower portion of the Greater Himalayan Sequence in West Nepal: New implications for hybrid channel flow-type mechanisms in the Dolpo region

    NASA Astrophysics Data System (ADS)

    Frassi, Chiara

    2015-12-01

    I conducted new vorticity and deformation temperatures studies to test competing models of the exhumation of the mid-crustal rocks exposed in the Dolpo region (West Nepal). My results indicate that the Main Central Thrust is located ∼5 km structurally below the previous mapped locations. Deformation temperature increasing up structural section from ∼450 °C to ∼650 °C and overlap with peak metamorphic temperature indicating that penetrative shearing was responsible for the exhumation of the GHS occurred at "close" to peak metamorphic conditions. I interpreted the telescoping and the inversion of the paleo-isotherms at the base of the GHS as produced mainly by a sub-simple shearing (Wm = 0.88-1) pervasively distributed through the lower portion of the GHS. My results are consistent with hybrid channel flow-type models where the boundary between lower and upper portions of the GHS, broadly corresponding to the tectonometamorphic discontinuity recently documented in west Nepal, represents the limit between buried material, affected by dominant simple shearing, and exhumed material affected by a general flow dominates by pure shearing. This interpretation is consistent with the recent models suggesting the simultaneous operation of channel flow- and critical wedge-type processes at different structural depth.

  2. Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin ("Ghrl"), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that "Gh...

  3. Ghrelin: much more than a hunger hormone

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is a multifaceted gut hormone that activates its receptor, growth hormone secretagogue receptor (GHS-R). Ghrelin's hallmark functions are its stimulatory effects on growth hormone release, food intake and fat deposition. Ghrelin is famously known as the 'hunger hormone'. However, ample recen...

  4. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are ...

  5. Ghrelin receptor regulates appetite and satiety during aging in mice by regulating meal frequency and portion size but not total food intake

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aging is often associated with overweight and obesity. There exists a long-standing debate about whether meal pattern also contributes to the development of obesity. The orexigenic hormone ghrelin regulates appetite and satiety by activating its receptor, growth hormone secretagogue receptor (GHS-R)...

  6. Amylose recognition and ring-size determination of amylomaltase

    PubMed Central

    Roth, Christian; Weizenmann, Nicole; Bexten, Nicola; Saenger, Wolfram; Zimmermann, Wolfgang; Maier, Timm; Sträter, Norbert

    2017-01-01

    Starch is a major carbon and energy source throughout all kingdoms of life. It consists of two carbohydrate polymers, branched amylopectin and linear amylose, which are sparingly soluble in water. Hence, the enzymatic breakdown by glycoside hydrolases (GHs) is of great biological and societal importance. Amylomaltases (AMs) are GHs specialized in the hydrolysis of α-1,4–linked sugar chains such as amylose. They are able to catalyze an intramolecular transglycosylation of a bound sugar chain yielding polymeric sugar rings, the cycloamyloses (CAs), consisting of 20 to 100 glucose units. Despite a wealth of data on short oligosaccharide binding to GHs, no structural evidence is available for their interaction with polymeric substrates that better represent the natural polysaccharide. We have determined the crystal structure of Thermus aquaticus AM in complex with a 34-meric CA—one of the largest carbohydrates resolved by x-ray crystallography and a mimic of the natural polymeric amylose substrate. In total, 15 glucose residues interact with the protein in an extended crevice with a length of more than 40 Å. A modified succinimide, derived from aspartate, mediates protein-sugar interactions, suggesting a biological role for this nonstandard amino acid. The structure, together with functional assays, provides unique insights into the interaction of GHs with their polymeric substrate and reveals a molecular ruler mechanism for minimal ring-size determination of CA products. PMID:28097217

  7. Vancouver Coastal Health's Second Generation Health Strategy: A need for a reboot?

    PubMed

    Masuda, Jeffrey R; Chan, Sophy

    2017-03-01

    In this commentary, we consider the motivations and implications of Vancouver Coastal Health's place-based population health strategy called the Downtown Eastside Second Generation Health Strategy (2GHS) in light of a broader historical view of shifting values in population and public health and structural health reforms in Canada over the past three decades. We argue that the tone and content of the 2GHS signals a shift towards a neoliberal clientelist model of health that treats people as patients and the DTES as a site of clinical encounter rather than as a community in its own right. In its clinical emphasis, the 2GHS fails to recognize the political dimension of health and well-being in the DTES, a community that faces compounding health risks associated with colonialism, gentrification, human displacement, the criminalization of poverty, sex work, and the street economy. Furthermore, we suggest that in its emphasis on allocating funding based on a rationalist model of health system access, the 2GHS undermines well-established insights and best practices from community-driven health initiatives. Our aim is to provide a provocation that will encourage public health policy-makers to embrace community-based leadership as well as the broader structural health determinants that are at the root of the current circumstances of people in the DTES and other marginalized communities in Canada.

  8. Localizing gene regulation reveals a staggered wood decay mechanism for the brown rot fungus Postia placenta

    SciTech Connect

    Zhang, Jiwei; Presley, Gerald N.; Hammel, Kenneth E.; Ryu, Jae-San; Menke, Jon R.; Figueroa, Melania; Hu, Dehong; Orr, Galya; Schilling, Jonathan S.

    2016-09-12

    The fungi that cause brown rot of wood are essential contributors to biomass recycling in forest ecosystems. Their highly efficient cellulolytic systems, which may have practical applications, apparently depend on a combination of two mechanisms: nonselective oxidation of the lignocellulose by reactive oxygen species (ROS) coupled with hydrolysis of the polysaccharide components by a limited set of glycoside hydrolases (GHs). Since the production of strongly oxidizing ROS appears incompatible with the operation of GHs, it has been proposed that the fungi regulate ROS production by maintaining concentration gradients of the chelated metal ions they use to generate extracellular oxidants. However, calculations have indicated that this protective mechanism is physically infeasible. We examined a different hypothesis, that expression of ROS and GH components is temporally staggered by brown rot fungi in wood. We sectioned thin wafers of spruce and aspen that had been colonized directionally by Postia placenta and measured expression of relevant genes and some of the encoded enzymes, thus using the spatial distribution of fungal hyphae to resolve a fine-scale temporal sequence. Hierarchical clustering of gene expression for eight oxidoreductases thought to have a role in ROS production and of eight GHs revealed a zone of oxidoreductase upregulation at the hyphal front that persisted about 48 h before upregulation of the GHs. Additional evidence for differential expression was provided by localization of endoglucanase, xylanase, mannanase, and laccase activities in the colonized wood. Our results support a two-step mechanism for brown rot, in which substrate oxidation precedes enzymatic hydrolysis.

  9. Field Collection Methods for an EPA Pilot Study Evaluating Personal, Housing, and Community Factors Influencing Children’s Potential Exposures to Indoor Contaminants at Various Lifestages (EPA Pilot Study Add-On to the GreenHousing Study)

    EPA Science Inventory

    This compilation of field collection standard operating procedures (SOPs) was assembled for the U.S. Environmental Protection Agency’s (EPA) Pilot Study add-on to the Green Housing Study (GHS). A detailed description of this add-on study can be found in the peer reviewed research...

  10. 77 FR 68152 - Preparations for the 24th Session of the UN Sub-committee of Experts on the Globally Harmonized...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-15

    ... meeting to discuss proposals in preparation for the 24th session of the United Nations Sub-committee of.... Background The GHS was formally adopted by the United Nations Committee of Experts on the Transport of... from previous sessions, can be found on the United Nations Economic Commission for Europe...

  11. Methane Hydrate Dissociation and Gas Seepage on Global Upper Continental Slopes Driven by Intermediate Ocean Warming

    NASA Astrophysics Data System (ADS)

    Ruppel, C. D.; Weber, T.; Kessler, J. D.; Pohlman, J.; Skarke, A. D.

    2014-12-01

    Evidence suggests that the short-term temporal pattern of seafloor gas emissions may be largely driven by tidal/barometric pressure fluctuations. However, thermal perturbations in the overlying intermediate waters are a key factor leading to gas hydrate dissociation that liberates methane to feed cold seeps near the updip limit of gas hydrate stability (GHS) on upper continental slopes. Over the past 5 years, studies have documented temperature-driven methane release at intraseasonal to century-long timescales on the West Spitsbergen margin. Our data on the US Arctic margin show that bottom water temperature (BWT) perturbations over ~2.5 months cause the theoretical updip GHS limit to migrate ~1.5 km upslope, a level of dynamism that may manifest as the observed elevated methane concentrations over the upper slope. Given the documented decades-long increase in oceanic heat content due to global warming, it is not surprising that evidence is emerging that upper slope hydrate dissociation is a global, not merely arctic, phenomenon. On the northern US Atlantic margin, most of the ~600 newly-discovered methane seeps mapped between Cape Hatteras and Georges Bank occur on the upper continental slope near the updip limit of GHS (505-575 m). A BWT database based on ~35,000 CTD casts reveals subtle along-margin variations in the theoretical updip GHS limit and first-order agreement with the observed onset of seepage. Other historical datasets provide evidence for short-term BWT variations of >1ºC on the upper slope. Hudson Canyon, the largest US Atlantic margin shelf-break canyon, has reversing current patterns that amplify short-term BWT variations, making this location an apt laboratory for study of possible gas hydrate degradation processes. Hudson Canyon surveys conducted in 2014 identified dozens more seeps than the ~50 described in Skarke et al. (Fall Meeting 2013), particularly at the updip limit of GHS At this depth, CTDs show that BWTs were initially within GHS

  12. Th-Pb Monazite-in-Garnet Ages From the Greater Himalayan Sequence of Central Nepal

    NASA Astrophysics Data System (ADS)

    Gehrels, G.; Decelles, P.; Martin, A.

    2007-12-01

    431 new Th-Pb ages have been determined from rocks of the Greater Himalayan Sequence (GHS) of central Nepal. Some of these ages are reported by Martin et al. (2007, Chem. Geol.), most have not been reported previously. 42 samples were collected from transects along Kali Gandaki, Modi Khola, Seti Nadi, Madi Nadi, Nayu Ridge, and Marsyangdi Nadi in the Annapurna region, with three transects extending across the GHS and three transects concentrated near the base of the sequence. Garnet crystals were extracted from the samples, and monazite inclusions were identified by BSE imaging and then analyzed by LA-MC-ICPMS with a 10 micron laser beam. Where possible, inclusions were sampled from both cores and rims of the garnet crystals. The resulting ages belong to four groups: (1) 3 ages (all cores) between 801 Ma and 1407 Ma that are inherited from GHS protoliths, (2) 42 ages (all cores) from 550 Ma to 400 Ma (peak age of 487 Ma) that record early Paleozoic prograde metamorphism, (3) 102 ages (nearly all cores) scattered between 400 Ma and ~50 Ma that are interpreted as early Paleozoic grains which have experienced either Pb loss or overgrowth of Tertiary monazite, and (4) 284 ages (2/3 cores, 1/3 rims) between ca. 50 Ma and ca. 10 Ma, with cores only slightly (avg of 1.5 m.y.) older than rims. The Tertiary ages consistently young northward/upsection from ca. 35 to ca. 18 Ma, and in Marsyangdi Nadi define two separate panels that are interpreted to be imbricated along a north-dipping thrust fault. This fault is near the base of sillimanite-bearing rocks, similar to the Langtang thrust (Kohn et al. 2005, JMG), and may be partly responsible for the inverted metamorphic gradient discussed by many previous workers. Our preferred structural scenario is that the Tertiary monazite ages record progressive burial of the GHS by shortening in the Tethyan thrust belt between ca. 35 and ca. 18 Ma, termination of this metamorphism due to onset of motion along the MCT, and ca. 10 Ma

  13. Orogenic superstructure behaviour and mid-crustal plastic flow in the central Nepal Himalaya

    NASA Astrophysics Data System (ADS)

    Godin, L.; Kellett, D. A.; Larson, K. P.

    2007-12-01

    In the central Nepal Himalaya, the Tethyan sedimentary sequence (TSS) forms the superstructure to mid-crustal infrastructure rocks of the Greater Himalayan sequence (GHS); the top-to-the-north South Tibetan detachment system (STDS) defines their contact. North-verging folds, opposite to the main orogenic vergence, structurally dominate the TSS. Although the absolute age of this folding is unknown, structural observations and 40Ar/39Ar thermochronology indicate that it formed between 50-23 Ma, predating the dominant Miocene motion on the STDS. The GHS records a two-stage post-collisional history, marked by ca. 35 Ma burial metamorphism, followed by high-T, low-P, ca. 22 Ma metamorphism. Dominant top-to-the-south shear fabrics developed at peak temperatures at ca. 22 Ma pervasively transpose linear and planar features within the GHS. Vorticity analyses yield kinematic vorticity numbers between 0.29 and 0.80 (81-41% pure shear), with a significant amount of stretch parallel to the flow plane (34-53%). 40Ar/39Ar thermochronological data indicate that southward extrusion of the GHS terminated with cessation of movement on the STDS at 19 Ma. Our data suggest that the orogenic superstructure actively influenced the behaviour of the infrastructure in the early stages of orogenesis through fold-thrust belt formation leading to prograde 35 Ma metamorphism in the GHS. Associated melt weakening in the infrastructure allowed the initiation of southward plastic flow of the GHS, locally modifying the vergence of superstructural folds towards the north. As melt weakening in the middle crust intensified and the rheological contrast between superstructure and infrastructure increased, the upper crust decoupled from the middle crust and deformation in the upper crust temporarily ceased. By 17 Ma the extruded mid-crustal rocks cooled sufficiently to require the upper, brittle component of the STDS to become active. As cooling continued (17-14 Ma), the superstructure and underlying

  14. Kinematic evolution, metamorphism, and exhumation of the Greater Himalayan Series, Sutlej River and Zanskar regions of NW India

    NASA Astrophysics Data System (ADS)

    Stahr, Donald William, III

    The Himalayan orogen provides a natural laboratory to test models of orogenic development due to large-scale continental collision. The Greater Himalayan Series (GHS), a lithotectonic unit continuous along the entire length of the belt, comprises the metamorphic core of the Himalayan orogen and underlies the highest topography. GHS rocks are exposed as a moderately northdipping slab bounded below by the Main Central Thrust (MCT) and above by the South Tibetan Detachment System (STDS) of normal faults. Coeval reverse- and normal-sense motion on the crustal-scale MCT and STDS ductile shear zones allows the GHS to be modeled as an extruded wedge or channel of mid-crustal material. Due to this unique tectonic setting, the deformation path of rocks within the bounding shear zones and throughout the core of the GHS profoundly influences the efficiency of extrusion and exhumation processes. Attempts to quantify GHS deformation and metamorphic evolution have provided significant insight into Himalayan orogenic development, but these structural and petrologic studies are often conducted in isolation. Penetrative deformation fabrics developed under mid-upper amphibolite facies conditions within the GHS argue that deformation and metamorphism were coupled, and this should be considered in studies aimed at quantifying GHS teconometamorphic evolution. This work focuses on two projects related to the coupled deformation, thermal and metamorphic evolution during extrusion and exhumation of the GHS, focused on the lower and upper margins of the slab. A detailed examination of the P--T history of a schist collected from within the MCT zone of the Sutlej River, NW India, provides insight into the path experienced by these rocks as they traveled through the crust in response to the extreme shortening related to India-Asia collision. Combined forward thermodynamic and diffusion modeling indicates compositional zoning preserved in garnet has remained unmodified since growth and can be

  15. Validation study on the Ocular Irritection assay for eye irritation testing.

    PubMed

    Eskes, Chantra; Hoffmann, Sebastian; Facchini, Davide; Ulmer, Rich; Wang, Amy; Flego, Manuela; Vassallo, Marco; Bufo, Monica; van Vliet, Erwin; d'Abrosca, Federica; Wilt, Nathan

    2014-08-01

    Both a prospective and a retrospective validation study were undertaken to assess the suitability of the Ocular Irritection assay to discriminate ocular hazards as defined by the OECD and UN Globally Harmonized System (UN GHS) for classification. The primary focus of the study was to evaluate the usefulness of the Ocular Irritection assay to reliably discriminate chemicals not requiring classification (UN GHS non-classified), from classified chemicals (UN GHS Categories 1 and 2). Furthermore a post-hoc evaluation was carried out to evaluate the usefulness of the assay to discriminate chemicals inducing serious eye damage (UN GHS Category 1) from other classes. The prospective validation study was conducted between 2009 and 2012 following internationally agreed principles. A set of 56 coded test chemicals for which quality and/or peer-reviewed in vivo data were available were used to obtain prospective data on the assay's reliability (reproducibility within and between laboratories) and relevance (predictive capacity). The assay showed good within-laboratory variability, transferability including to a naïve laboratory, and between-laboratory concordance of classifications (82% for the discrimination of non-classified from classified chemicals, and 83% for the discrimination of Category 1 from other classes). The obtained prospective data were then combined with existing data on the Ocular Irritection collected from various sources, totaling 88 chemicals with parallel in vivo and in vitro data to obtain a comprehensive assessment of the test method performances. The enlarged dataset comprised 43 non-classified, 25 Category 2 and 20 Category 1 chemicals according to the UN GHS classification. When used for the identification of UN GHS non-classified versus classified materials (based on the existing cut-off of 12.5) the Ocular Irritection assay showed an overall a sensitivity of 93% and a specificity of 58%. An evaluation on possible reasons for misclassification

  16. Ghrelin Modulates Lateral Amygdala Neuronal Firing and Blocks Acquisition for Conditioned Taste Aversion

    PubMed Central

    Liu, Tianwei; Yu, Ming; Xiao, Kewei; Kong, Qingnuan; Zhao, Renliang; Li, Guo-Dong; Zhou, Yu

    2013-01-01

    Ghrelin is an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents. An increasing number of studies have reported that ghrelin and its identified receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), produces remarkably wide and complex functions and biological effects on specific populations of neurons in central nervous system. In this study, we sought to explore the in vivo effects of acute ghrelin exposure on lateral amygdala (LA) neurons at the physiological and behavioral levels. In vivo extracellular single-unit recordings showed that ghrelin with the concentration of several nanomolars (nM) stimulated spontaneous firing of the LA neurons, an effect that was dose-dependent and could be blocked by co-application of a GHS-R1a antagonist D-Lys3-GHRP-6. We also found that D-Lys3-GHRP-6 inhibited spontaneous firing of the LA neurons in a dose-dependent manner, revealing that tonic GHS-R1a activity contributes to orchestrate the basal activity of the LA neurons. Behaviorally, we found that microinfusion of ghrelin (12 ng) into LA before training interfered with the acquisition of conditioned taste aversion (CTA) as tested at 24 h after conditioning. Pre-treatment with either purified IgG against GHS-R1a or GHS-R1a antagonist blocked ghrelin’s effect on CTA memory acquisition. Ghrelin (12 ng) had no effect on CTA memory consolidation or the expression of acquired CTA memory; neither did it affect the total liquid consumption of tested rats. Altogether, our data indicated that ghrelin locally infused into LA blocks acquisition of CTA and its modulation effects on neuronal firing may be involved in this process. PMID:23762368

  17. Central responsiveness to a ghrelin mimetic (GHRP-6) is rapidly altered by acute changes in nutritional status in rats.

    PubMed

    Tung, Y C L; Hewson, A K; Carter, R N; Dickson, S L

    2005-06-01

    The hypothalamus appears to be more responsive to ghrelin and growth hormone secretagogues (GHS) in fasting, as reflected by a two- to three-fold increase in the number of cells detected that express Fos protein in the arcuate nucleus, in 48-h fasted rats compared to fed controls. Moreover, this increased hypothalamic responsiveness to GHS in fasting is regulated by the central action of exogenous leptin and insulin, although it is unknown whether these hormones mediate the changes in hypothalamic responsiveness to GHS associated with the fasting/fed state. In the present study, we show that refeeding with normal rat chow for only 2 h at the end of a 48-h fast reversed the potentiation of the Fos response to GHRP-6 observed in fasted rats. Circulating leptin and insulin levels remained significantly lower in refed rats compared to ad lib-fed rats, suggesting that the change in the hypothalamic sensitivity brought about by refeeding was independent of these hormones. By contrast, 2 h of chow refeeding at the end of a fast restored plasma glucose levels to those of the fed state. Refeeding with sugar alone for 2 h at the end of a 48-h fast also reduced the potentiated Fos response in fasting, indicating that elevated blood glucose can influence the central responsiveness to ghrelin/GHS. By contrast, infusion of the ileal satiety factor, PYY(3-36) (known to increase postprandially) did not alter the central responsiveness to GHRP-6, although it suppressed feeding and body weight as expected. This study highlights the importance of nutritional status in regulating the action of exogenous GHS (and presumably endogenous ghrelin) on the hypothalamic circuits controlling food intake.

  18. Desacyl-ghrelin and synthetic GH-secretagogues modulate the production of inflammatory cytokines in mouse microglia cells stimulated by beta-amyloid fibrils.

    PubMed

    Bulgarelli, Ilaria; Tamiazzo, Laura; Bresciani, Elena; Rapetti, Daniela; Caporali, Simona; Lattuada, Donatella; Locatelli, Vittorio; Torsello, Antonio

    2009-09-01

    Data from Alzheimer's disease (AD) patients and AD animal models demonstrate the accumulation of inflammatory microglia at sites of insoluble fibrillar beta-amyloid protein (fAbeta) deposition. It is known that fAbeta binds to CD36, a type B scavenger receptor also involved in internalization of oxidized low-density lipoprotein (LDL), and initiate a signaling cascade that regulates microglial recruitment, activation, and secretion of inflammatory mediators leading to neuronal dysfunction and death. The recent demonstration of a binding site for the growth hormone secretagogues (GHS) on CD36 prompted us to ascertain whether ghrelin and synthetic GHS could modulate the synthesis of inflammatory cytokines in fAbeta-activated microglia cells. We demonstrate that N9 microglia cells express the CD36 and are a suitable model to study the activation of inflammatory cytokines synthesis. In fact, in N9 cells exposed to fAbeta(25-35) for 24 hr, the expression of interleukin (IL)-1beta and IL-6 mRNA significantly increased. Interestingly, 10(-7) M desacyl-ghrelin, hexarelin, and EP80317 in the nanomolar range effectively counteracted fAbeta(25-35) stimulation of IL-6 mRNA levels, whereas ghrelin was ineffective. Similarly, the effects of fAbeta(25-35) on IL-1beta mRNA levels were attenuated by desacyl-ghrelin, hexarelin, and EP80317, but not ghrelin. Because we have observed that the specific GHS receptor GHS-R1a is not expressed in N9 cells, the actions of GHS should be mediated by different receptors. Reportedly, hexarelin and EP80317 are capable of binding the CD36 in mouse macrophages and reducing atherosclerotic plaque deposition in mice. We conclude that desacyl-ghrelin, hexarelin, and EP80317 might interfere with fAbeta activation of CD36 in microglia cells.

  19. Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues.

    PubMed

    Lin, Ligen; Saha, Pradip K; Ma, Xiaojun; Henshaw, Iyabo O; Shao, Longjiang; Chang, Benny H J; Buras, Eric D; Tong, Qiang; Chan, Lawrence; McGuinness, Owen P; Sun, Yuxiang

    2011-12-01

    Aging is associated with increased adiposity in white adipose tissues and impaired thermogenesis in brown adipose tissues; both contribute to increased incidences of obesity and type 2 diabetes. Ghrelin is the only known circulating orexigenic hormone that promotes adiposity. In this study, we show that ablation of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) improves insulin sensitivity during aging. Compared to wild-type (WT) mice, old Ghsr(-/-) mice have reduced fat and preserve a healthier lipid profile. Old Ghsr(-/-) mice also exhibit elevated energy expenditure and resting metabolic rate, yet have similar food intake and locomotor activity. While GHS-R expression in white and brown adipose tissues was below the detectable level in the young mice, GHS-R expression was readily detectable in visceral white fat and interscapular brown fat of the old mice. Gene expression profiles reveal that Ghsr ablation reduced glucose/lipid uptake and lipogenesis in white adipose tissues but increased thermogenic capacity in brown adipose tissues. Ghsr ablation prevents age-associated decline in thermogenic gene expression of uncoupling protein 1 (UCP1). Cell culture studies in brown adipocytes further demonstrate that ghrelin suppresses the expression of adipogenic and thermogenic genes, while GHS-R antagonist abolishes ghrelin's effects and increases UCP1 expression. Hence, GHS-R plays an important role in thermogenic impairment during aging. Ghsr ablation improves aging-associated obesity and insulin resistance by reducing adiposity and increasing thermogenesis. Growth hormone secretagogue receptor antagonists may be a new means of combating obesity by shifting the energy balance from obesogenesis to thermogenesis.

  20. Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference.

    PubMed

    Bahi, Amine; Tolle, Virginie; Fehrentz, Jean-Alain; Brunel, Luc; Martinez, Jean; Tomasetto, Catherine-Laure; Karam, Sherif M

    2013-05-01

    Recent work suggests that stomach-derived hormone ghrelin receptor (GHS-R1A) antagonism may reduce motivational aspects of ethanol intake. In the current study we hypothesized that the endogenous GHS-R1A agonist ghrelin modulates alcohol reward mechanisms. For this purpose ethanol-induced conditioned place preference (CPP), ethanol-induced locomotor stimulation and voluntary ethanol consumption in a two-bottle choice drinking paradigm were examined under conditions where ghrelin and its receptor were blocked, either using ghrelin knockout (KO) mice or the specific ghrelin receptor (GHS-R1A) antagonist "JMV2959". We showed that ghrelin KO mice displayed lower ethanol-induced CPP than their wild-type (WT) littermates. Consistently, when injected during CPP-acquisition, JMV2959 reduced CPP-expression in C57BL/6 mice. In addition, ethanol-induced locomotor stimulation was lower in ghrelin KO mice. Moreover, GHS-R1A blockade, using JMV2959, reduced alcohol-stimulated locomotion only in WT but not in ghrelin KO mice. When alcohol consumption and preference were assessed using the two-bottle choice test, both genetic deletion of ghrelin and pharmacological antagonism of the GHS-R1A (JMV2959) reduced voluntary alcohol consumption and preference. Finally, JMV2959-induced reduction of alcohol intake was only observed in WT but not in ghrelin KO mice. Taken together, these results suggest that ghrelin neurotransmission is necessary for the stimulatory effect of ethanol to occur, whereas lack of ghrelin leads to changes that reduce the voluntary intake as well as conditioned reward by ethanol. Our findings reveal a major, novel role for ghrelin in mediating ethanol behavior, and add to growing evidence that ghrelin is a key mediator of the effects of multiple abused drugs.

  1. Endogenous ghrelin regulates episodic growth hormone (GH) secretion by amplifying GH Pulse amplitude: evidence from antagonism of the GH secretagogue-R1a receptor.

    PubMed

    Zizzari, P; Halem, H; Taylor, J; Dong, J Z; Datta, R; Culler, M D; Epelbaum, J; Bluet-Pajot, M T

    2005-09-01

    Ghrelin was purified from rat stomach as an endogenous ligand for the GH secretagogue (GHS) receptor. As a GHS, ghrelin stimulates GH release, but it also has additional activities, including stimulation of appetite and weight gain. Plasma GH and ghrelin secretory patterns appear unrelated, whereas many studies have correlated ghrelin variations with food intake episodes. To evaluate the role of endogenous ghrelin, GH secretion and food intake were monitored in male rats infused sc (6 mug/h during 10 h) or intracerebroventricularly (5 microg/h during 48 h) with BIM-28163, a full competitive antagonist of the GHS-R1a receptor. Subcutaneous BIM-28163 infusion significantly decreased GH area under the curve during a 6-h sampling period by 54% and peak amplitude by 46%. Twelve hours after the end of treatment these parameters returned to normal. Central treatment was similarly effective (-37 and -42% for area under the curve and -44 and -49% for peak amplitude on the first and second days of infusion, respectively). Neither peripheral nor central BIM-28163 injection modified GH peak number, GH nadir, or IGF-I levels. In this protocol, food intake is not strongly modified and water intake is unchanged. Subcutaneous infusion of BIM-28163 did not change plasma leptin and insulin levels evaluated at 1200 and 1600 h. On the contrary, central BIM-28163 infusion slightly increased leptin and significantly increased insulin concentrations. Thus, endogenous ghrelin, through GHS-R1a, acts as a strong endogenous amplifier of spontaneous GH peak amplitude. The mechanisms by which ghrelin modifies food intake remain to be defined and may involve a novel GHS receptor.

  2. Hazard Classification of Household Chemical Products in Korea according to the Globally Harmonized System of Classification and labeling of Chemicals

    PubMed Central

    2013-01-01

    Objectives This study was conducted to review the validity of the need for the application of the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) to household chemical products in Korea. The study also aimed to assess the severity of health and environmental hazards of household chemical products using the GHS. Methods 135 products were classified as ‘cleaning agents and polishing agents’ and 98 products were classified as ‘bleaches, disinfectants, and germicides.’ The current status of carcinogenic classification of GHS and carcinogenicity was examined for 272 chemical substances contained in household chemical products by selecting the top 11 products for each of the product categories. In addition, the degree of toxicity was assessed through analysis of whether the standard of the Republic of Korea’s regulations on household chemical products had been exceeded or not. Results According to GHS health and environmental hazards, “acute toxicity (oral)” was found to be the highest for two product groups, ‘cleaning agents and polishing agents’, and ‘bleaches, disinfectants, and germicides’ (result of classification of 233 household chemical products) at 37.8% and 52.0% respectively. In an analysis of carcinogenicity assuming a threshold of IARC 2B for the substances in household chemical products, we found ‘cleaning agents and polishing agents’ to contain 12 chemical substances and ‘bleaches, disinfectants, and germicides’ 11 chemical substances. Conclusion Some of the household chemical products were found to have a high hazard level including acute toxicity and germ cell mutagenicity, carcinogenicity, and reproductive toxicity. Establishing a hazard information delivery system including the application of GHS to household chemical products in Korea is urgent as well. PMID:24472347

  3. Evaluation of Musa (Paradisiaca Linn. cultivar)--"Puttubale" stem juice for antilithiatic activity in albino rats.

    PubMed

    Prasad, K V; Bharathi, K; Srinivasan, K K

    1993-10-01

    The fresh juice of Musa stem (Puttubale) was tested for its antilithiatic activity. Zinc discs were implanted in the urinary bladder of albino rats to induce urolithiasis. The stones formed were mainly of magnesium ammonium phosphate with traces of calcium oxalate. Musa stem juice (3 mL/rat/day orally) was found to be effective in reducing the formation and also in dissolving the pre-formed stones.

  4. [Correlations between the metastable solutions of calculus-forming salts and crystals from coexistent insoluble urinary components].

    PubMed

    Leskovar, P; Hartung, R

    1978-09-01

    The correlations between the individual stone-forming systems, expecially the induction of heterogeneous crystallization from metastable solutions of one stone-forming system by preformed crystals of the other stone-forming system, were measured semiquantitatively by the Coulter-Counter-Size Distribution Analyzer technique. It has been found out that Ca-oxalate crystals may represent potent triggers and accelerators of the phosphate precipitation from metastable Ca-phosphate solutions. The importance of this phenomenon could be attributed especially to the induction of crystal rich phosphate crystalluria at moderate pH values (6,5--6,8) by the preceding Ca-oxalate crystalluria (,,starter "resp." primer "crystalluria). The favouring, promoting influence of uric acid on the stone formation and growth of Ca-oxalate crystals could be observed with the same experiments under changed conditions. This mechanism could be of some importance in the case when Ca-oxalate precipitates from the urine, saturated by uric acid, at low pH values (5,0--6,0). Uric acid resp. sodium urate crystals showed a moderate by clear favouring effect on the formation of Ca-phosphate crystals from metastable solutions. The influence of Ca-phosphate crystals upon the growth of Ca-oxalate crystals proved to be very limited.

  5. Upregulation of Voltage-Gated Calcium Channel Cav1.3 in Bovine Somatotropes Treated with Ghrelin

    PubMed Central

    Salinas Zarate, V. M.; Magdaleno Méndez, A.; Domínguez Mancera, B.; Rodríguez Andrade, A.; Barrientos Morales, M.; Cervantes Acosta, P.; Hernández Beltrán, A.; Romero Salas, D.; Flores Hernández, J. L. V.; Monjaraz Guzmán, E.; Félix Grijalva, D. R.

    2013-01-01

    Activation of the growth hormone (GH) secretagogue receptor (GHS-R) by synthetic GH releasing peptides (GHRP) or its endogenous ligand (Ghrelin) stimulates GH release. Though much is known about the signal transduction underlying short-term regulation, there is far less information on the mechanisms that produce long-term effects. In the current report, using an enzyme-linked immunosorbent assay for GH detection and whole-cell patch-clamp recordings, we assessed the long-term actions of such regulatory factors on voltage-activated Ca2+ currents in bovine somatotropes (BS) separated on a Percoll gradient and detected by immunohistochemistry. After 24 h of treatment with Ghrelin (10 nM) or GHRP-6 (100 nM) enhanced BS secretory activity; GH secretion stimulated by GHS through the activation of GHS-R because treatment with the antagonist of GHS-R (D-Lys3-GHRP-6, 10 μM) blocked the GH secretion, and the effect was dose and time dependent (24, 48, and 72 h). GH secretion stimulated by GHRP-6 was abolished by nifedipine (0.5 μM), a blocker of L-type HVA Ca2+ channels, and KN-62 (10 μM), an inhibitor of Ca2+/CaM-KII. After 72 h in culture, all recorded BS exhibited two main Ca2+ currents: a low voltage-activated (LVA; T-type) and a high voltage-activated (HVA; mostly dihydropyridine-sensitive L-type) current. Interestingly, HVA and LVA channels were differentially upregulated by Ghrelin. Chronic treatment with the GHS induced a significant selective increase on the Ba2+ current through HVA Ca2+ channels, and caused only a small increase of currents through LVA channels. The stimulatory effect on HVA current density was accompanied by an augment in maximal conductance with no apparent changes in the kinetics and the voltage dependence of the Ca2+ currents, suggesting an increase in the number of functional channels in the cell membrane. Lastly, in consistency with the functional data, quantitative real-time RT-PCR revealed transcripts encoding for the Cav

  6. Empirical Constraints on Extrusion Mechanisms Derived From Pressure-Temperature-Time Histories From the Himalayan Metamorphic Core (Sutlej Valley, NW India)

    NASA Astrophysics Data System (ADS)

    Chambers, J.; Caddick, M.; Argles, T.; Horstwood, M.; Harris, N.; Parrish, R.; Ahmad, T.

    2007-12-01

    The exhumed Himalayan core in the Sutlej Valley comprises the Greater Himalayan Sequence (GHS), bounded by the Main Central Thrust and the South Tibetan Detachment, and tectonically distinct metamorphosed units above (the Haimanta Group) and below (the Jutogh Group). While pressure-temperature-time (P-T-t) data from the GHS are broadly compatible with predictions of the channel flow model presented by Jamieson et al. (2004), corresponding data for the units bounding the putative channel are not: The underlying Jutogh Group experienced a tightly closed P-T path featuring upper-amphibolite prograde metamorphism at c. 11 Ma, followed by rapid cooling and exhumation. These data are consistent with a) prograde metamorphism during overthrusting (along the Main Central Thrust) and b) subsequent exhumation via accretion to the extruding GHS channel above. However, muscovite cooling ages from the GHS pre-date those from the Jutogh Group by at least 10 Ma, clearly indicating decoupled exhumation of the two crystalline units. Alongside evidence that motion on the Main Central Thrust had ceased by c. 16 Ma, concomitant extrusion of the Jutogh Group as part of a single widening GHS `channel' seems impossible. The Haimanta Group, considered uppermost in the GHS sequence and/or basal to the Tethyan Sedimentary Sequence, also reached upper-amphibolite grade during the Himalayan orogeny. As for the Jutogh Group, exhumation and cooling rapidly followed peak metamorphism. Coupled U-Pb monazite data and detailed textural and pseudosection analyses constrain prograde metamorphism at c. 35 to 30 Ma, the timing of which is compatible with channel flow model predictions. Importantly, however, P-T paths do not match numerical simulations, which imply shallower burial, lower peak temperatures and a distinct phase of isobaric heating. We conclude that the Sutlej Valley presents a tectonically complex metamorphic core for which a single, widening channel flow model does not accurately predict

  7. Titanite petrochronology supports protracted transport along a high-level thrust within the Greater Himalayan Sequence, Central Nepal.

    NASA Astrophysics Data System (ADS)

    Walters, J.; Kohn, M. J.

    2015-12-01

    Zr-in-titanite thermometry and U-Pb geochronology offer potential to recover prograde and retrograde temperature-time (T-t) histories from moderate- to high-grade metamorphic rocks, which in turn can elucidate tectonic processes. In this study, titanite-based T-t paths were determined along a transect across the proposed trace of the ductile South Tibetan Detachment System (STDS) in central Nepal. Titanite-bearing calcsilicates were sampled from the upper Greater Himalayan Sequence (GHS) through the putative lower Tethyan Himalayan Sequence (THS) along the Marsyandi River in the Annapurna Himal. T's decrease from 800 ºC to 650 ºC with increasing structural level, consistent with previous work that shows decreasing T structurally upwards towards the STDS. T-t trends separate into three groups, from structurally lowest to highest: I. increasing T from ~27 to ~15 Ma, II. constant T from ~50 to ~10 Ma, and III. Decreasing T from ~ 25 Ma to ~ 10 Ma. These data are consistent with synmetamorphic thrusting from ~25 Ma to ~15 Ma: Group I (structurally low) heated during burial, Group II (structurally intermediate) resided in the shear zone at quasi-static T, and Group III (structurally high) cooled during emplacement. After ~ 15 Ma, Groups I-III exhumed coherently, supported by decreasing T-t trends at all structural levels. These data are consistent with (a) titanite T-t paths from elsewhere in the Annapurna Himal, (b) the timing of heating of structurally lower GHS rocks from other Central Nepal locations, and (c) the occurrence of intra-GHS thrusts within the orogen. High-grade GHS transport more likely occurred through a series of in sequence thrusts, rather than ductile flow. Our data do not support a ductile STDS at this location, and instead indicate a GHS origin for rocks previously assigned to the Tethyan. Significant extensional throw appears absent at this structural level, whereas shortening within the GHS and Himalaya is greater than commonly assumed.

  8. P-T-t-d History of the Lahul Valley, NW Indian Himalaya

    NASA Astrophysics Data System (ADS)

    Nieblas, A.; Leech, M. L.

    2015-12-01

    The Lahul Valley of NW India is located between the Zanskar Shear zone to the northwest and the Sangla detachment to the southeast. This region contains three east-trending, laterally-continuous tectonostratigraphic units separated by two major fault zones. To the south, low-grade metasediments of the Lesser Himalayan Sequence (LHS) are separated from high-grade crystalline rocks of the Greater Himalayan Sequence (GHS) by the north dipping Main Central Thrust (MCT). The northern extent of the GHS is separated from overlying low-grade sedimentary rocks of the Tethyan Himalayan Sequence (THS) along the north dipping South Tibetan Detachment System (STDS). There is controversy over the location and type of shear motion for the STDS in the ~50 km strip running through Lahul Valley where the STD is interpreted as a discrete fault, a dextral shear zone, and is unidentified in some areas along the trend of the STDS. This study focuses on understanding the pressure-temperature-time-deformation (P-T-t-d) evolution of THS and GHS rocks in Lahul Valley to better understand regional Cenozoic deformation and the location and role of the STDS in the extrusion of the GHS. Deformed granitics, migmatites, and leucogranites from the GHS contain a dominant mineralogy of Qz + Kfs + Pl + Bt + Ms ± Grt ± Ky ± St. Schists and phyllites from the THS contain a dominant mineralogy of Qz + Kfs + Pl + Bt + Ms ± Grt. Isochemical phase equilibria diagrams (pseudosections) are calculated in Perple_X using whole-rock chemistry data with solution models based on these mineral assemblages. Ti-in-quartz thermometry and the Fe-Mg exchange thermometry from garnet-biotite pairs used with mineral growth relationships constrain conditions during deformation and to establish P-T paths. U-Pb SHRIMP dating of zircon constrains peak metamorphic conditions and 40Ar/39Ar thermochronology of micas provide the cooling history along the valley and across the STDS. This multi-component approach to understand

  9. Acylated and unacylated ghrelin protect MC3T3-E1 cells against tert-butyl hydroperoxide-induced oxidative injury: pharmacological characterization of ghrelin receptor and possible epigenetic involvement.

    PubMed

    Dieci, Elisa; Casati, Lavinia; Pagani, Francesca; Celotti, Fabio; Sibilia, Valeria

    2014-07-01

    Increasing evidence suggests a role for oxidative stress in age-related decrease in osteoblast number and function leading to the development of osteoporosis. This study was undertaken to investigate whether ghrelin, previously reported to stimulate osteoblast proliferation, counteracts tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in MC3T3-E1 osteoblastic cells as well as to characterize the ghrelin receptor (GHS-R) involved in such activity. Pretreatment with ghrelin (10(-7)-10(-11)M) significantly increased viability and reduced apoptosis of MC3T3-E1 cells cultured with t-BHP (250 μM) for three hours at the low concentration of 10(-9)M as shown by MTT assay and Hoechst-33258 staining. Furthermore, ghrelin prevented t-BHP-induced osteoblastic dysfunction and changes in the cytoskeleton organization evidenced by the staining of the actin fibers with Phalloidin-FITC by reducing reactive oxygen species generation. The GHS-R type 1a agonist, EP1572 (10(-7)-10(-11)M), had no effect against t-BHP-induced cytotoxicity and pretreatment with the selective GHS-R1a antagonist, D-Lys(3)-GHRP-6 (10(-7)M), failed to remove ghrelin (10(-9) M)-protective effects against oxidative injury, indicating that GHS-R1a is not involved in such ghrelin activity. Accordingly, unacylated ghrelin (DAG), not binding GHS-R1a, displays the same protective actions of ghrelin against t-BHP-induced cytotoxicity. Preliminary observations indicate that ghrelin increased the trimethylation of lys4 on histones H3, a known epigenetic mark activator, which may regulate the expression of some genes limiting oxidative damage. In conclusion, our data demonstrate that ghrelin and DAG promote survival of MC3T3-E1 cell exposed to t-BHP-induced oxidative damage. Such effect is independent of GHS-R1a and is likely mediated by a common ghrelin/DAG binding site.

  10. Recent Advances in Potential Clinical Application of Ghrelin in Obesity

    PubMed Central

    Delporte, Christine

    2012-01-01

    Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a 28 amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by ghrelin O-acyltransferase (GOAT). Ghrelin stimulates growth hormone secretion, but also appetite, food intake, weight gain, and gastric emptying. Ghrelin is involved in weight regulation, obesity, type 2 diabetes, and metabolic syndrome. Furthermore, a better understanding of ghrelin biology led to the identification of molecular targets modulating ghrelin levels and/or its biological effects: GOAT, ghrelin, and GHS-R1a. Furthermore, a recent discovery, showing the involvement of bitter taste receptor T2R in ghrelin secretion and/or synthesis and food intake, suggested that T2R could represent an additional interesting molecular target. Several classes of ghrelin-related pharmacological tools for the treatment of obesity have been or could be developed to modulate the identified molecular targets. PMID:22523666

  11. Reaction Mechanisms in Carbohydrate-Active Enzymes: Glycoside Hydrolases and Glycosyltransferases. Insights from ab Initio Quantum Mechanics/Molecular Mechanics Dynamic Simulations.

    PubMed

    Ardèvol, Albert; Rovira, Carme

    2015-06-24

    Carbohydrate-active enzymes such as glycoside hydrolases (GHs) and glycosyltransferases (GTs) are of growing importance as drug targets. The development of efficient competitive inhibitors and chaperones to treat diseases related to these enzymes requires a detailed knowledge of their mechanisms of action. In recent years, sophisticated first-principles modeling approaches have significantly advanced in our understanding of the catalytic mechanisms of GHs and GTs, not only the molecular details of chemical reactions but also the significant implications that just the conformational dynamics of a sugar ring can have on these mechanisms. Here we provide an overview of the progress that has been made in the past decade, combining molecular dynamics simulations with density functional theory to solve these sweet mysteries of nature.

  12. Identification of DLK1 variants in pituitary- and neuroendocrine tumors.

    PubMed

    Altenberger, T; Bilban, M; Auer, M; Knosp, E; Wolfsberger, S; Gartner, W; Mineva, I; Zielinski, C; Wagner, L; Luger, A

    2006-02-17

    In a gene chip analysis of common pituitary tumor types, one of the genes with the most impressive tissue-specific expression regulation was delta-like 1 (DLK1), which was strongly expressed in GH-secreting (GH-S) pituitary tumors. In addition to pituitary adenomas, various endocrine tumors were subjected to real-time-quantitative PCR revealing high expression of DLK1 in normal pituitary tissue, in GH-S-, in one prolactin-secreting pituitary adenoma and in pheochromocytomas. Additionally, three DLK1 gene-derived subvariants were identified. The first, lacking 204 bp--coding for epidermal growth factor-like domain 6 and parts of the juxtamembrane region--was named Secredeltin. In the other two splice variants (named Brevideltin and Brevideltinin), a stop codon is introduced due to a frame-shift, leading to truncated proteins of 204 and 213 aas, respectively.

  13. Enhanced alcohol-drinking behavior associated with active ghrelinergic and serotoninergic neurons in the lateral hypothalamus and amygdala.

    PubMed

    Yoshimoto, Kanji; Nagao, Masataka; Watanabe, Yoshihisa; Yamaguchi, Takashi; Ueda, Shuichi; Kitamura, Yoshihisa; Nishimura, Kaneyasu; Inden, Masatoshi; Marunaka, Yoshinori; Hattori, Hiroyuki; Murakami, Kaori; Tokaji, Megumi; Ochi, Kozo

    2017-02-01

    Central ghrelin is required for the rewarding properties of drug abuse. We investigated whether alcohol affects ghrelinergic, dopaminergic, and serotoninergic neurons and growth hormone secretagogue receptor 1A (GHS-R1A) levels in the reward system of the brain. Alcohol-naïve C57BL/6J mice received 2g/kg ethanol (EtOH) intraperitoneally (i.p.). Plasma ghrelin levels decreased between 1 and 4h. We investigated the effects of EtOH administration on plasma ghrelin levels in two different animal models at 1, 3, and 10months of age. Plasma ghrelin levels decreased following the EtOH treatment in 1- and 3-month-old short-term (1-day) alcohol vapor-exposed (STA) mice. In contrast, EtOH administration increased plasma ghrelin levels in 1- and 3-month-old long-term (20-day) alcohol vapor-exposed (LTA) mice. In vivo ghrelin release in the lateral hypothalamus (LH) increased in STA and LTA mice after the i.p. administration of EtOH. EtOH increased in vivo dopamine (DA), but not serotonin (5-HT) release in the LH of STA mice, and increased in vivo DA and 5-HT release in the LH of LTA mice. GHS-R1A mRNA expression and GHS-R1A protein levels in the LH were increased in LTA mice. The number of GHS-R1A-immunoreactive cells was greater in the LH and amygdala of LTA mice. These results support the neurobiological correlation between the development of drinking behavior and activation of ghrelinergic and serotonergic neurons in the LH. The activation of ghrelinergic systems in the amygdala may also induce an increase in 5-HT release in the LH during long-term alcohol intake.

  14. Effects of retinoic acid on growth hormone-releasing hormone receptor, growth hormone secretagogue receptor gene expression and growth hormone secretion in rat anterior pituitary cells.

    PubMed

    Maliza, Rita; Fujiwara, Ken; Tsukada, Takehiro; Azuma, Morio; Kikuchi, Motoshi; Yashiro, Takashi

    2016-06-30

    Retinoic acid (RA) is an important signaling molecule in embryonic development and adult tissue. The actions of RA are mediated by the nuclear receptors retinoic acid receptor (RAR) and retinoid X receptor (RXR), which regulate gene expression. RAR and RXR are widely expressed in the anterior pituitary gland. RA was reported to stimulate growth hormone (GH) gene expression in the anterior pituitary cells. However, current evidence is unclear on the role of RA in gene expression of growth hormone-releasing hormone receptor (Ghrh-r), growth hormone secretagogue receptor (Ghs-r) and somatostatin receptors (Sst-rs). Using isolated anterior pituitary cells of rats, we examined the effects of RA on gene expression of these receptors and GH release. Quantitative real-time PCR revealed that treatment with all-trans retinoic acid (ATRA; 10(-6) M) for 24 h increased gene expression levels of Ghrh-r and Ghs-r; however, expressions of Sst-r2 and Sst-r5 were unchanged. Combination treatment with the RAR-agonist Am80 and RXR-agonist PA024 mimicked the effects of ATRA on Ghrh-r and Ghs-r gene expressions. Exposure of isolated pituitary cells to ATRA had no effect on basal GH release. In contrast, ATRA increased growth hormone-releasing hormone (GHRH)- and ghrelin-stimulated GH release from cultured anterior pituitary cells. Our results suggest that expressions of Ghrh-r and Ghs-r are regulated by RA through the RAR-RXR receptor complex and that RA enhances the effects of GHRH and ghrelin on GH release from the anterior pituitary gland.

  15. Devil's Claw to Suppress Appetite—Ghrelin Receptor Modulation Potential of a Harpagophytum procumbens Root Extract

    PubMed Central

    Torres-Fuentes, Cristina; Theeuwes, Wessel F.; McMullen, Michael K.; McMullen, Anna K.; Dinan, Timothy G.; Cryan, John F.; Schellekens, Harriët

    2014-01-01

    Ghrelin is a stomach-derived peptide that has been identified as the only circulating hunger hormone that exerts a potent orexigenic effect via activation of its receptor, the growth hormone secretagogue receptor (GHS-R1a). Hence, the ghrelinergic system represents a promising target to treat obesity and obesity-related diseases. In this study we analysed the GHS-R1a receptor activating potential of Harpagophytum procumbens, popularly known as Devil's Claw, and its effect on food intake in vivo. H. procumbens is an important traditional medicinal plant from Southern Africa with potent anti-inflammatory and analgesic effects. This plant has been also used as an appetite modulator but most evidences are anecdotal and to our knowledge, no clear scientific studies relating to appetite modulation have been done to this date. The ghrelin receptor activation potential of an extract derived from the dried tuberous roots of H. procumbens was analysed by calcium mobilization and receptor internalization assays in human embryonic kidney cells (Hek) stably expressing the GHS-R1a receptor. Food intake was investigated in male C57BL/6 mice following intraperitoneal administration of H. procumbens root extract in ad libitum and food restricted conditions. Exposure to H. procumbens extract demonstrated a significant increased cellular calcium influx but did not induce subsequent GHS-R1a receptor internalization, which is a characteristic for full receptor activation. A significant anorexigenic effect was observed in male C57BL/6 mice following peripheral administration of H. procumbens extract. We conclude that H. procumbens root extract is a potential novel source for potent anti-obesity bioactives. These results reinforce the promising potential of natural bioactives to be developed into functional foods with weight-loss and weight maintenance benefits. PMID:25068823

  16. Decreased GH secretion and enhanced ACTH and cortisol release after ghrelin administration in Cushing's disease: comparison with GH-releasing peptide-6 (GHRP-6) and GHRH.

    PubMed

    Correa-Silva, Silvia Regina; Nascif, Sérgio Oliva; Lengyel, Ana-Maria Judith

    2006-01-01

    GH responsiveness to GH secretagogues (GHS) is blunted in Cushing's disease (CD), while ACTH/cortisol responses are enhanced, by mechanisms still unclear. Ghrelin, the endogenous ligand for GHS-receptors (GHS-R), increases GH, ACTH, cortisol and glucose levels in humans. This study evaluated the GH, ACTH, cortisol and glucose-releasing effects of ghrelin in CD in comparison with GHRP-6. GHRH-induced GH release was also studied. Ten patients with CD (BMI 26.9+/-1.0 kg/m(2)) and ten controls (BMI 24.4+/-1.1 kg/m(2)) received ghrelin (1 microg/kg), GHRP-6 (1 microg/kg) and GHRH (100 microg) separately. GH, ACTH, cortisol and glucose levels were measured. In CD ghrelin-induced GH (microg/L; mean +/- SE) release (peak: 7.2+/-3.0) was higher than seen with GHRP-6 (2.7+/-1.0) and GHRH (0.7+/-0.2), but lower than in controls (ghrelin: 58.3+/-12.1; GHRP-6: 22.9+/-4.8; GHRH: 11.3+/-3.7). In controls ACTH (pg/mL) release after ghrelin (79.2+/-26.8) was higher than after GHRP-6 (23.6+/-5.7). In CD these responses (ghrelin: 192+/-43; GHRP-6: 185+/-56) were similar, and enhanced compared to controls. The same was observed with cortisol. Glucose levels failed to increase after ghrelin in CD, differently than in controls. Our data suggests that hypothalamic and pituitary pathways of GH release activated by ghrelin, GHRP-6 and GHRH are deranged in chronic hypercortisolism. The increased ACTH/cortisol responses to ghrelin and GHRP-6 in CD could be mediated by overexpression of GHS-R in ACTH-secreting adenomas. Hypercortisolism apparently impairs the ability of ghrelin to increase glucose levels.

  17. Upregulation of voltage-gated Na+ channels by long-term activation of the ghrelin-growth hormone secretagogue receptor in clonal GC somatotropes.

    PubMed

    Dominguez, Belisario; Felix, Ricardo; Monjaraz, Eduardo

    2009-05-01

    A central question in adenohypophyseal cell physiology concerns the role of transmembrane ionic fluxes in the initiation of the hormone secretion process. In the current report, we investigated the effects of the growth hormone (GH) secretagogues ghrelin and GH-releasing peptide-6 (GHRP-6) on the regulation of the functional expression of voltage-gated Na(+) channels using the tumoral somatotrope GC cell line as a model. Cells were cultured under control conditions or in presence of the GH secretagogues (GHS) for 96 h, and Na(+) currents (I(Na)) were characterized in whole cell patch-clamp experiments. GHS treatment significantly increased I(Na) density in a dose-dependent manner. The effects of GHRP-6 were accompanied by an augment in conductance without changes in the kinetics and the voltage dependence of the currents, suggesting an increase in the number of channels in the cell membrane. Sustained inhibition of L-type Ca(2+) channel activity decreased I(Na) density and prevented the effects of the GHS, whereas long-term exposure to an L-channel agonist increased I(Na) density and enhanced the actions of GHRP-6, indicating that Ca(2+) entry through these channels plays a role in the regulation of Na(+) channel expression. Likewise, GHRP-6 failed to enhance Na(+) channel expression in the presence of membrane-permeable inhibitors of protein kinases A and C, as well as the Ca(2+)/calmodulin-dependent kinase II. Conversely, treatment with a cAMP analog or a protein kinase C activator enhanced both basal and GHS-induced secretion of GH measured by enzyme-linked immunoassay, suggesting that GHRP-6 acting through the ghrelin receptor and different signaling pathways enhances Na(+) channel membrane expression, which favors hormone release from GC somatotropes.

  18. Attenuation of systemic morphine-induced analgesia by central administration of ghrelin and related peptides in mice.

    PubMed

    Zeng, Ping; Chen, Jia-Xiang; Yang, Bei; Zhi, Xing; Guo, Fa-Xian; Sun, Meng-Li; Wang, Jing-Lei; Wei, Jie

    2013-12-01

    Ghrelin, an acylated 28-amino peptide secreted in the gastric endocrine cells, has been demonstrated to stimulate the release of growth hormone, increase food intake, and inhibit pro-inflammatory cascade, etc. Ghrelin mainly combines with its receptor (GHS-R1α) to play the role in physiological and pathological functions. It has been reported that ghrelin plays important roles in the control of pain through interaction with the opioid system in inflammatory pain and acute pain. However, very few studies show the effect of supraspinal ghrelin system on antinociception induced by intraperitoneal (i.p.) administration of morphine. In the present study, intracerebroventricular (i.c.v.) injection of ghrelin (0.1, 1, 10 and 100 nmol/L) produced inhibition of systemic morphine (6 mg/kg, i.p.) analgesia in the tail withdrawal test. Similarly, i.c.v. injection GHRP-6 and GHRP-2 which are the agonists of GHS-R1α, also decreased analgesia effect induced by morphine injected intraperitoneally in mice. Furthermore, these anti-opioid activities of ghrelin and related peptides were not blocked by pretreatment with the GHS-R1α selective antagonist [d-Lys(3)]-GHRP-6 (100 nmol/L, i.c.v.). These results demonstrated that central ghrelin and related peptides could inhibit the analgesia effect induced by intraperitoneal (i.p.) administration of morphine. The anti-opioid effects of ghrelin and related peptides do not interact with GHS-R1a. These findings may pave the way for a new strategy on investigating the interaction between ghrelin system and opioids on pain modulation.

  19. Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts

    PubMed Central

    Mrak, Emanuela; Casati, Lavinia; Pagani, Francesca; Rubinacci, Alessandro; Zarattini, Guido; Sibilia, Valeria

    2015-01-01

    Ghrelin, by binding growth hormone secretagogue receptor (GHS-R), promotes osteoblast proliferation but the signaling mechanism of GHS-R on these cells remains unclear. Since canonical Wnt/β-catenin pathway is critically associated with bone homeostasis, we investigated its involvement in mediating ghrelin effects in osteoblasts and in osteoblast-osteoclast cross talk. Ghrelin (10−10M) significantly increased β-catenin levels in rat osteoblasts (rOB). This stimulatory action on β-catenin involves a specific interaction with GHS-R1a, as it is prevented by the selective GHS-R1a antagonist, D-Lys3-GHRP-6 (10−7M). The effect of ghrelin on β-catenin involves the phosphorylation and inactivation of GSK-3β via protein kinase A (PKA). Inhibition of PKA activity reduces the facilitatory action of ghrelin on β-catenin stabilization. Ghrelin treatment of rOB significantly increases the expression of osteoprotegerin (OPG), which plays an important role in the regulation of osteoclastogenesis, and this effect is blocked by D-Lys3-GHRP-6. Furthermore, ghrelin reduced RANKL/OPG ratio thus contrasting osteoclastogenesis. Accordingly, conditioned media from rOB treated with ghrelin decreased the number of multinucleated TRAcP+ cells as compared with the conditioned media from untreated-control rOB. Our data suggest new roles for ghrelin in modulating bone homeostasis via a specific interaction with GHSR-1a in osteoblasts with subsequent enhancement of both β-catenin levels and OPG expression. PMID:25866509

  20. Ghrelin and obestatin modulate growth hormone-releasing hormone release and synaptic inputs onto growth hormone-releasing hormone neurons.

    PubMed

    Feng, Dan D; Yang, Seung-Kwon; Loudes, Catherine; Simon, Axelle; Al-Sarraf, Tamara; Culler, Michael; Alvear-Perez, Rodrigo; Llorens-Cortes, Catherine; Chen, Chen; Epelbaum, Jacques; Gardette, Robert

    2011-09-01

    Ghrelin, a natural ligand of the growth hormone secretagogue receptor (GHS-R), is synthesized in the stomach but may also be expressed in lesser quantity in the hypothalamus where the GHS-R is located on growth hormone-releasing hormone (GHRH) neurons. Obestatin, a peptide derived from the same precursor as ghrelin, is able to antagonize the ghrelin-induced increase of growth hormone (GH) secretion in vivo but not from pituitary explants in vitro. Thus, the blockade of ghrelin-induced GH release by obestatin could be mediated at the hypothalamic level by the neuronal network that controls pituitary GH secretion. Ghrelin increased GHRH and decreased somatostatin (somatotropin-releasing inhibitory factor) release from hypothalamic explants, whereas obestatin only reduced the ghrelin-induced increase of GHRH release, thus indicating that the effect of ghrelin and obestatin is targeted to GHRH neurons. Patch-clamp recordings on mouse GHRH-enhanced green fluorescent protein neurons indicated that ghrelin and obestatin had no significant effects on glutamatergic synaptic transmission. Ghrelin decreased GABAergic synaptic transmission in 44% of the recorded neurons, an effect blocked in the presence of the GHS-R antagonist BIM28163, and stimulated the firing rate of 78% of GHRH neurons. Obestatin blocked the effects of ghrelin by acting on a receptor different from the GHS-R. These data suggest that: (i) ghrelin increases GHRH neuron excitability by increasing their action potential firing rate and decreasing the strength of GABA inhibitory inputs, thereby leading to an enhanced GHRH release; and (ii) obestatin counteracts ghrelin actions. Such interactions on GHRH neurons probably participate in the control of GH secretion.

  1. Minimalist Medical Diplomacy - Do Engagements Achieve US National Strategy Global Health Security Objectives?

    DTIC Science & Technology

    2015-04-01

    Form ApprovedOMB No. 0704-0188 Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time...ABSTRACT unclassified c. THIS PAGE unclassified Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 i    Disclaimer The views...Health Initiatives GHS Global Health Security HA Humanitarian Assistance HE Health Engagement HN Host Nation HSS Health Services Support

  2. 49 CFR 172.401 - Prohibited labeling.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Chemicals (GHS) (IBR, see § 171.7 of this subchapter). (d) The provisions of paragraph (a) of this section... consignee. [Amdt. 172-9, 41 FR 15996, Apr. 15, 1976, as amended by Amdt. 172-75, 47 FR 44471, Oct. 7, 1982; Amdt. 172-77, 47 FR 54822, Dec. 6, 1982; Amdt. 172-94, 49 FR 38134, Sept. 27, 1984; Amdt. 172-100,...

  3. AFRL’s New Tool for HAZCOM Compliance at R&D Level: CHAMP (Chemical Hazard Analysis & Management Program)

    DTIC Science & Technology

    2012-03-01

    Unclassified SAR 29 19b. TELEPHONE NUMBER (include area code) N/A Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. 239.18 Mike Verlinden...Distribution Statement A: Approved for public release, distribution unlimited; PA# _________________ Modern Standards ∞ Hazard Communication Standard ...specific information through hazard labels and (M)SDS ∞ New (GHS) Hazcom waiting at OMB ∞ Adopted to UN Standards – revision after ~25 years 5 243

  4. Where Do You Think You’re Going with That? Challenges for Hazardous Material Management in Europe

    DTIC Science & Technology

    2011-11-29

    E) C50 (mg/L) Degradation Accumulation Pictogram/ code/signal word Aquatic Acute 1 ; H400 < 1 - Not relevant - - Not relevant - GHS09/Warning Aquatic...Workshop November 29 – December 1 , 2011, Washington Hilton in Washington, D.C. Challenges for Hazardous Material Management in Europe “Where Do You...Form ApprovedOMB No. 0704-0188 Public reporting burden for the collection of information is estimated to average 1 hour per response, including the

  5. Exploring the use of social network analysis to measure communication between disease programme and district managers at sub-national level in South Africa.

    PubMed

    Kawonga, Mary; Blaauw, Duane; Fonn, Sharon

    2015-06-01

    With increasing interest in maximising synergies between disease control programmes (DCP) and general health services (GHS), methods are needed to measure interactions between DCP and GHS actors. In South Africa, administrative integration reforms make GHS managers at decentralised level (district managers) responsible for the oversight of DCP operations within districts, with DCP managers (programme managers) providing specialist support. The reforms necessitate interdependence, but these actors work together ineffectively. Communication is crucial for joint working, but no research to assess communication between these actors has been done. This study explores the use of social network analysis (SNA) to measure the extent to which programme and district managers in South Africa communicate, using HIV monitoring and evaluation (M&E) as an exemplar. Data were collected from fifty one managers in two provinces during 2010-2011, to measure: a) one-on-one task-related communication - talking about the collation (verification, reporting) and use of HIV data for monitoring HIV interventions; and b) group communication through co-participating in management committees where HIV data are used for monitoring HIV interventions in districts. SNA measures were computed to describe actor centrality, network density (cohesion), and communication within and between respective manager groups. Block modelling was applied to identify management committees that connect respective manager groups. Results show HIV programme managers located at higher level communicated largely amongst themselves as a group (homophily), seldom talked to the district managers to whom they are supposed to provide specialist HIV M&E support, and rarely participated with them in management committees. This research demonstrates the utility of SNA as a tool for measuring the extent of communication between DCP and GHS actors at sub-national level. Actions are needed to bridge observed communication gaps in

  6. The influence of the Goos-Hänchen effect on seismic data processing and AVO in attenuating media

    NASA Astrophysics Data System (ADS)

    Wang, Zhiyong

    2015-11-01

    The Goos-Hänchen (GH) effect induced by the total reflection of an incident beam of P-wave from a low-impedance medium to a high-impedance medium at near- and post-critical angles was theoretically simulated and discussed. For both PP- and PSV-waves, there may be large GH shifts (GHS) and penetration depths (PD) for both lossless and attenuating media. As the Q-factor increases, or the frequency of the seismic wave decreases, the GH effect is increased. However, in attenuating media, there may be non-zero GHS and PD at all non-zero incident angles, not just post-critical angles. GHS may be either positive or negative, while PD is positive only. Compared to the Q-factor in the incident medium, the Q-factor in the transmission medium may play a more dominant role in the determination of reflection coefficients, GHS, and PD. The GH-induced normal moveout (NMO) discrepancy of the PSV-wave may be larger than that of the PP-wave. Due to the GH effect, there may be an angle discrepancy (at fixed offset) between the GH-modified incident angle and the traditional incident angle. In addition, the GH effect at a given offset may produce two or three reflected waves, from different incident angles. These results suggest that, within their assumptions, the GH effect may lead to errors in NMO estimates and the vertical location of the reflector. Furthermore, there may be errors in offsets, incident angles, and reflection amplitudes, in the analyses of the amplitude variation with offset (AVO). These GH effects might be more important for seismic data at fixed offsets and shallow layers, and for sonic log data, which might fall into the post-critical angle regime. Therefore, there may be a necessity to take into account the GH effect in the interpretation of wide-angle reflection data in NMO and AVO analyses.

  7. Transformation/dissolution characteristics of a nickel matte and nickel concentrates for acute and chronic hazard classification.

    PubMed

    Skeaff, James M; Beaudoin, Robert

    2015-01-01

    For the purposes of aquatic hazard classification under the United Nations Globally Harmonized System of Classification (UNGHS), we have examined the transformation/dissolution (T/D) characteristics of a Ni matte and 4 Ni concentrates at pH 6 using the United Nations (UN) Transformation/Dissolution Protocol (T/DP) for metals and sparingly soluble metal compounds. Among the analytes Ni, Co, and Cu, Ni was released into the T/D solutions in the highest concentrations and was thus the main driver in establishing the hazard classification. We applied an extrapolation-scaling approach to obtain concentrations of total dissolved Ni at low loadings of 0.1 and 0.01 mg/L for derivation of chronic classification outcomes in the European Union (EU) classification, labeling, and packaging (CLP) scheme. The T/D data would classify the Ni matte as Acute 2-Chronic 2 under the Globally Harmonized System (GHS) scheme, and Chronic 1 under the EU CLP. Three of the 4 Ni concentrates would classify as GHS Acute 2-Chronic 2 and EU CLP Chronic 2, whereas the 4th would classify as GHS Acute 3-Chronic 3 and EU CLP Chronic 3. In applying the critical surface area (CSA) approach to the Ni concentrates, acute and chronic hazard classification outcomes were the same as those derived from direct application of the T/D data to the GHS and EU schemes. Such agreement provided confidence that the CSA approach could yield scientifically defensible acute and chronic hazard classification outcomes.

  8. Impaired bone formation in male idiopathic osteoporosis: further reduction in the presence of concomitant hypercalciuria

    NASA Technical Reports Server (NTRS)

    Zerwekh, J. E.; Sakhaee, K.; Breslau, N. A.; Gottschalk, F.; Pak, C. Y.

    1992-01-01

    We present iliac bone histomorphometric data and related biochemical data from 16 nonalcoholic men (50 +/- 11 (SD) years) referred for evaluation of spontaneous skeletal and/or appendicular fractures and reduced spinal bone density. All men were eugonadal and had no known underlying disorder associated with osteopenia. For the group, mean serum chemistry values were within normal limits including immunoreactive parathyroid hormone, osteocalcin and serum 1,25-dihydroxyvitamin D [1,25(OH)2D]. Nine men demonstrated hypercalciuria (greater than or equal to 0.1 mmol/kg per day) while on a constant metabolic diet of 20 mmol/day Ca. Their 24-hour urinary calcium was significantly greater than that for the remaining 7 men (7.4 +/- 1.6 vs. 5.0 +/- 0.8 mmol/day, p = 0.003), as was their calciuric response to a 1 g oral calcium load (0.23 +/- 0.06 vs. 0.15 +/- 0.05 Ca/creatinine, p = 0.042). Serum parameters (including parathyroid hormone and 1,25(OH)2D) of hypercalciuric and normocalciuric men were not significantly different. Histomorphometric indices for cancellous bone demonstrated significant differences between the entire group of osteoporotic men and age-adjusted normal values for bone volume (11.4 +/- 4.0% vs. 23.2 +/- 4.4%), osteoid surface (5.6 +/- 3.9% vs. 12.1 +/- 4.6%), osteoblastic surface (2.0 +/- 2.3% vs. 3.9 +/- 1.9%), and mineralizing surface (1.9 +/- 2.4% vs. 5.1 +/- 2.7%); there were also significant differences in bone formation rate (total surface referent) (0.004 +/- 0.001 vs. 0.011 +/- 0.006 mm3/mm2 per year). Compared with the normocalciuric group the 9 hypercalciuric men had significantly lower osteoblastic surfaces (1.6 +/- 1.9% vs. 2.5 +/- 2.6%) and mineralizing surfaces (1.4 +/- 1.5% vs. 2.7 +/- 3.2%).(ABSTRACT TRUNCATED AT 250 WORDS).

  9. A new approach for continuous estimation of baseflow using discrete water quality data: Method description and comparison with baseflow estimates from two existing approaches

    USGS Publications Warehouse

    Miller, Matthew P.; Johnson, Henry M.; Susong, David D.; Wolock, David M.

    2015-01-01

    Understanding how watershed characteristics and climate influence the baseflow component of stream discharge is a topic of interest to both the scientific and water management communities. Therefore, the development of baseflow estimation methods is a topic of active research. Previous studies have demonstrated that graphical hydrograph separation (GHS) and conductivity mass balance (CMB) methods can be applied to stream discharge data to estimate daily baseflow. While CMB is generally considered to be a more objective approach than GHS, its application across broad spatial scales is limited by a lack of high frequency specific conductance (SC) data. We propose a new method that uses discrete SC data, which are widely available, to estimate baseflow at a daily time step using the CMB method. The proposed approach involves the development of regression models that relate discrete SC concentrations to stream discharge and time. Regression-derived CMB baseflow estimates were more similar to baseflow estimates obtained using a CMB approach with measured high frequency SC data than were the GHS baseflow estimates at twelve snowmelt dominated streams and rivers. There was a near perfect fit between the regression-derived and measured CMB baseflow estimates at sites where the regression models were able to accurately predict daily SC concentrations. We propose that the regression-derived approach could be applied to estimate baseflow at large numbers of sites, thereby enabling future investigations of watershed and climatic characteristics that influence the baseflow component of stream discharge across large spatial scales.

  10. Caldicellulosiruptor Core and Pangenomes Reveal Determinants for

    SciTech Connect

    Blumer-Schuette, Sara E.; Giannone, Richard J; Zurawski, Jeffrey V; Ozdemir, Inci; Ma, Qin; Yin, Yanbin; Xu, Ying; Kataeva, Irena; Poole, Farris; Adams, Michael W. W.; Hamilton-Brehm, Scott; Elkins, James G; Larimer, Frank W; Land, Miriam L; Hauser, Loren John; Cottingham, Robert W; Hettich, Robert {Bob} L; Kelly, Robert M

    2012-01-01

    Extremely thermophilic bacteria of the genus Caldicellulosiruptor utilize carbohydrate components of plant cell walls, including cellulose and hemicellulose, facilitated by a diverse set of glycoside hydrolases (GHs). From a biofuel perspective, this capability is crucial for deconstruction of plant biomass into fermentable sugars. While all species from the genus grow on xylan and acidpretreated switchgrass, growth on crystalline cellulose is variable. The basis for this variability was examined using microbiological, genomic, and proteomic analyses of eight globally diverse Caldicellulosiruptor species. The open Caldicellulosiruptor pangenome (4,009 open reading frames [ORFs]) encodes 106 GHs, representing 43 GH families, but only 26 GHs from 17 families are included in the core (noncellulosic) genome (1,543 ORFs). Differentiating the strongly cellulolytic Caldicellulosiruptor species from the others is a specific genomic locus that encodes multidomain cellulases from GH families 9 and 48, which are associated with cellulose-binding modules. This locus also encodes a novel adhesin associated with type IV pili, which was identified in the exoproteome bound to crystalline cellulose. Taking into account the core genomes, pangenomes, and individual genomes, the ancestral Caldicellulosiruptor was likely cellulolytic and evolved, in some cases, into species that lost the ability to degrade crystalline cellulose while maintaining the capacity to hydrolyze amorphous cellulose and hemicellulose.

  11. Thermo-kinematic evolution of the Annapurna-Dhaulagiri Himalaya, central Nepal: The Composite Orogenic System

    NASA Astrophysics Data System (ADS)

    Parsons, A. J.; Law, R. D.; Lloyd, G. E.; Phillips, R. J.; Searle, M. P.

    2016-04-01

    The Himalayan orogen represents a "Composite Orogenic System" in which channel flow, wedge extrusion, and thrust stacking operate in separate "Orogenic Domains" with distinct rheologies and crustal positions. We analyze 104 samples from the metamorphic core (Greater Himalayan Sequence, GHS) and bounding units of the Annapurna-Dhaulagiri Himalaya, central Nepal. Optical microscopy and electron backscatter diffraction (EBSD) analyses provide a record of deformation microstructures and an indication of active crystal slip systems, strain geometries, and deformation temperatures. These data, combined with existing thermobarometry and geochronology data are used to construct detailed deformation temperature profiles for the GHS. The profiles define a three-stage thermokinematic evolution from midcrustal channel flow (Stage 1, >700°C to 550-650°C), to rigid wedge extrusion (Stage 2, 400-600°C) and duplexing (Stage 3, <280-400°C). These tectonic processes are not mutually exclusive, but are confined to separate rheologically distinct Orogenic Domains that form the modular components of a Composite Orogenic System. These Orogenic Domains may be active at the same time at different depths/positions within the orogen. The thermokinematic evolution of the Annapurna-Dhaulagiri Himalaya describes the migration of the GHS through these Orogenic Domains and reflects the spatial and temporal variability in rheological boundary conditions that govern orogenic systems.

  12. Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP

    PubMed Central

    Shi, Chang-He; Schisler, Jonathan C.; Rubel, Carrie E.; Tan, Song; Song, Bo; McDonough, Holly; Xu, Lei; Portbury, Andrea L.; Mao, Cheng-Yuan; True, Cadence; Wang, Rui-Hao; Wang, Qing-Zhi; Sun, Shi-Lei; Seminara, Stephanie B.; Patterson, Cam; Xu, Yu-Ming

    2014-01-01

    Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms. PMID:24113144

  13. Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity.

    PubMed

    Wiedemann, Tobias; Bielohuby, Maximilian; Müller, Timo D; Bidlingmaier, Martin; Pellegata, Natalia S

    2016-02-01

    Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes.

  14. On the central mechanism underlying ghrelin's chronic pro-obesity effects in rats: new insights from studies exploiting a potent ghrelin receptor antagonist.

    PubMed

    Salomé, N; Hansson, C; Taube, M; Gustafsson-Ericson, L; Egecioglu, E; Karlsson-Lindahl, L; Fehrentz, J A; Martinez, J; Perrissoud, D; Dickson, S L

    2009-09-01

    In the present study, we explore the central nervous system mechanism underlying the chronic central effects of ghrelin with respect to increasing body weight and body fat. Specifically, using a recently developed ghrelin receptor antagonist, GHS-R1A (JMV2959), we investigate the role of GHS-R1A in mediating the effects of ghrelin on energy balance and on hypothalamic gene expression. As expected, in adult male rats, chronic central treatment with ghrelin for 14 days, when compared to vehicle-treated control rats, resulted in an increased body weight, lean mass and fat mass (assessed by dual X-ray absorptiometry), dissected white fat pad weight, cumulative food intake, food efficiency, respiratory exchange ratio and a decrease of energy expenditure. Co-administration of the ghrelin receptor antagonist JMV2959 suppressed/blocked the majority of these effects, with the notable exception of ghrelin-induced food intake and food efficiency. The hypothesis emerging from these data, namely that GHS-R1A mediates the chronic effects of ghrelin on fat accumulation, at least partly independent of food intake, is discussed in light of the accompanying data regarding the hypothalamic genes coding for peptides and receptors involved in energy balance regulation, which were found to have altered expression in these studies.

  15. Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the growth hormone secretagogue receptor 1a.

    PubMed

    Proulx, Caroline; Picard, Émilie; Boeglin, Damien; Pohankova, Petra; Chemtob, Sylvain; Ong, Huy; Lubell, William D

    2012-07-26

    The synthetic hexapeptide growth hormone releasing peptide-6 (GHRP-6) exhibits dual affinity for the growth hormone secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogues have been synthesized, exhibiting micromolar affinity to the CD36 receptor with reduced affinity toward the GHS-R1a. A combinatorial split-and-mix approach furnished aza-GHRP-6 leads, which were further examined by alanine scanning. Incorporation of an aza-amino acid residue respectively at the D-Trp(2), Ala(3), or Trp(4) position gave aza-GHRP-6 analogues with reduced affinity toward the GHS-R1a by at least a factor of 100 and in certain cases retained affinity for the CD36 receptor. In the latter cases, the D-Trp(2) residue proved important for CD36 receptor affinity; however, His(1) could be replaced by Ala(1) without considerable loss of binding. In a microvascular sprouting assay using a choroid explant, [azaTyr(4)]-GHRP-6 (15), [Ala(1), azaPhe(2)]-GHRP-6 (16), and [azaLeu(3), Ala(6)]-GHRP-6 (33) all exhibited antiangiogenic activity.

  16. Ghrelin receptor signaling: a promising therapeutic target for metabolic syndrome and cognitive dysfunction

    PubMed Central

    Cong, Wei-na; Golden, Erin; Pantaleo, Nick; White, Caitlin M.; Maudsley, Stuart; Martin, Bronwen

    2010-01-01

    The neuroendocrine hormone ghrelin is an octanoylated 28-residue peptide that exerts numerous physiological functions. Ghrelin exerts its effects on the body mainly through a highly conserved G protein-coupled receptor known as the growth hormone secretagagogue receptor subtype 1a (GHS-R1a). Ghrelin and GSH-R1a are widely expressed in both peripheral and central tissues/organs, and ghrelin signaling plays a critical role in maintaining energy balance and neuronal health. The multiple orexigenic effects of ghrelin and its receptor have been studied in great detail, and GHS-R1a-mediated ghrelin signaling has long been a promising target for the treatment of metabolic disorders, such as obesity. In addition to its well-characterized metabolic effects, there is also mounting evidence that ghrelin-mediated GHS-R1a signaling exerts neuroprotective effects on the brain. In this review, we will summarize some of the effects of ghrelin-mediated GSH-R1a signaling on peripheral energy balance and cognitive function. We will also discuss the potential pharmacotherapeutic role of GSH-R1a-mediated ghrelin signaling for the treatment of complex neuroendocrine disorders. PMID:20632971

  17. In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display

    PubMed Central

    Ueno, Shingo; Yoshida, Sayaka; Mondal, Anupom; Nishina, Kazuya; Koyama, Makoto; Sakata, Ichiro; Miura, Kenju; Hayashi, Yujiro; Nemoto, Naoto; Nishigaki, Koichi; Sakai, Takafumi

    2012-01-01

    G protein-coupled receptors (GPCRs) are major drug targets, and their ligands are currently being explored and developed by many pharmaceutical companies and independent researchers. Class A (rhodopsin-like) GPCRs compose a predominant GPCR family; therefore, class A GPCR ligands are in demand. Growth hormone secretagogue receptor (GHS-R) is a class A GPCR that stimulates food intake by binding to its peptide ligand, ghrelin. Therefore, antagonists of GHS-R are expected to exert antiobesity function. In this article, we describe the use of cDNA display to screen for successfully and identify an antagonistic peptide of GHS-R. The antagonistic peptide inhibited the ghrelin-induced increase in intracellular Ca2+ in vitro (IC50 = approximately 10 μM) and repressed the contraction of isolated animal stomach in response to ghrelin. Furthermore, peripheral administration of the peptide inhibited the food intake of mice. This work provides new insight into the development of antiobesity drugs and describes a method for the discovery of unique peptide ligands for class A GPCRs. PMID:22723348

  18. Growing degree hours - a simple, accurate, and precise protocol to approximate growing heat summation for grapevines

    NASA Astrophysics Data System (ADS)

    Gu, S.

    2016-08-01

    Despite its low accuracy and consistency, growing degree days (GDD) has been widely used to approximate growing heat summation (GHS) for regional classification and phenological prediction. GDD is usually calculated from the mean of daily minimum and maximum temperatures (GDDmm) above a growing base temperature ( T gb). To determine approximation errors and accuracy, daily and cumulative GDDmm was compared to GDD based on daily average temperature (GDDavg), growing degree hours (GDH) based on hourly temperatures, and growing degree minutes (GDM) based on minute-by-minute temperatures. Finite error, due to the difference between measured and true temperatures above T gb is large in GDDmm but is negligible in GDDavg, GDH, and GDM, depending only upon the number of measured temperatures used for daily approximation. Hidden negative error, due to the temperatures below T gb when being averaged for approximation intervals larger than measuring interval, is large in GDDmm and GDDavg but is negligible in GDH and GDM. Both GDH and GDM improve GHS approximation accuracy over GDDmm or GDDavg by summation of multiple integration rectangles to reduce both finite and hidden negative errors. GDH is proposed as the standardized GHS approximation protocol, providing adequate accuracy and high precision independent upon T gb while requiring simple data recording and processing.

  19. Ghrelin increases intracellular Ca²⁺ concentration in the various hormone-producing cell types of the rat pituitary gland.

    PubMed

    Yamazaki, Mami; Aizawa, Sayaka; Tanaka, Toru; Sakai, Takafumi; Sakata, Ichiro

    2012-09-20

    Ghrelin, isolated from the stomach as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), has potent growth hormone release ability in vivo and in vitro. Although GHS-R is abundantly expressed in the pituitary gland, there is no direct evidence of a relationship between hormone-producing cells and functional GHS-R in the pituitary gland. The aim of this study was to determine which anterior pituitary cells respond to ghrelin stimulation in male rats. We performed Fura-2 Ca(2+) imaging analysis using isolated pituitary cells, and performed immunocytochemistry to identify the type of pituitary hormone-producing cells. In Fura-2 Ca(2+) imaging analysis, ghrelin administration increased the intracellular Ca(2+) concentration in approximately 50% of total isolated anterior pituitary cells, and 20% of these cells strongly responded to ghrelin. Immunocytochemical analysis revealed that 82.9 ± 1.3% of cells that responded to ghrelin stimulation were GH-immunopositive. On the other hand, PRL-, LH-, and ACTH-immunopositive cells constituted 2.0 ± 0.3%, 12.6 ± 0.3%, and 2.5 ± 0.8% of ghrelin-responding pituitary cells, respectively. TSH-immunopositive cells did not respond to ghrelin treatment. These results suggest that ghrelin directly acts not only on somatotrophs, but also on mammotrophs, gonadotrophs, and corticotrophs in the rat pituitary gland.

  20. Fungal glycoside hydrolases for saccharification of lignocellulose: outlook for new discoveries fueled by genomics and functional studies

    SciTech Connect

    Jovanovic, Iva; Magnuson, Jon K.; Collart, Frank R.; Robbertse, Barbara; Adney, William S.; Himmel, Michael E.; Baker, Scott E.

    2009-08-01

    Genome sequencing of a variety of fungi is a major initiative currently supported by the Department of Energy’s Joint Genome Institute. Encoded within the genomes of many fungi are upwards of 200+ enzymes called glycoside hydrolases (GHs). GHs are known for their ability to hydrolyze the polysaccharide components of lignocellulosic biomass. Production of ethanol and “next generation” biofuels from lignocellulosic biomass represents a sustainable route to biofuels production. However this process has to become more economical before large scale operations are put into place. Identifying and characterizing GHs with improved properties for biomass degradation is a key factor for the development of cost effective processes to convert biomass to fuels and chemicals. With the recent explosion in the number of GH encoding genes discovered by fungal genome sequencing projects, it has become apparent that improvements in GH gene annotation processes have to be developed. This will enable more informed and efficient decision making with regard to selection and utilization of these important enzymes in bioprocess that produce fuels and chemicals from lignocellulosic feedstocks.

  1. Motivations and challenges of community-based surveillance volunteers in the northern region of Ghana.

    PubMed

    Dil, Yasemin; Strachan, Daniel; Cairncross, Sandy; Korkor, Andrew Seidu; Hill, Zelee

    2012-12-01

    Community health workers (CHWs) are an important element of many health systems and programmes for the promotion and delivery of a wide range of health interventions and disease surveillance. Understanding the motivation and retention of CHWs is recognized as essential but there are few data from sub-Saharan Africa. This qualitative study explored factors that motivate, and the challenges faced by community-based surveillance volunteers (CBSVs) in the Northern Region of Ghana through semi-structured interviews with 28 CBSVs, 12 zonal coordinators, nine Ghana Health Service (GHS) sub-district level staff, ten GHS district level staff and two GHS regional level staff in the administrative capital. The community emerged as an important motivating factor in terms of altruism, a sense of duty to the community and gaining community respect and pride. This was enhanced by community selection of the volunteers. Major challenges included incorrect community perceptions of CBSVs, problems with transportation and equipment, difficulties conducting both volunteer and farm work and late or lack of payment for ad hoc tasks such as National Immunization Days. Most CBSVs recognized that they were volunteers, understood the constraints of the health system and were not demanding remuneration. However, CBSVs strongly desired something tangible to show that their work is recognized and appreciated and described a number of low cost items that could be used. They also desired equipment such as raincoats and identifiers such as tee-shirts and certificates.

  2. Effects of ghrelin and des-acyl ghrelin on neurogenesis of the rat fetal spinal cord

    SciTech Connect

    Sato, Miho; Nakahara, Keiko; Goto, Shintaro; Kaiya, Hiroyuki; Miyazato, Mikiya . E-mail: a0d201u@cc.miyazaki-u.ac.jp; Date, Yukari; Nakazato, Masamitsu; Kangawa, Kenji; Murakami, Noboru

    2006-11-24

    Expressions of the growth hormone secretagogue receptor (GHS-R) mRNA and its protein were confirmed in rat fetal spinal cord tissues by RT-PCR and immunohistochemistry. In vitro, over 3 nM ghrelin and des-acyl ghrelin induced significant proliferation of primary cultured cells from the fetal spinal cord. The proliferating cells were then double-stained using antibodies against the neuronal precursor marker, nestin, and the cell proliferation marker, 5-bromo-2'-deoxyuridine (BrdU), and the nestin-positive cells were also found to be co-stained with antibody against GHS-R. Furthermore, binding studies using [{sup 125}I]des-acyl ghrelin indicated the presence of a specific binding site for des-acyl ghrelin, and confirmed that the binding was displaced with unlabeled des-acyl ghrelin or ghrelin. These results indicate that ghrelin and des-acyl ghrelin induce proliferation of neuronal precursor cells that is both dependent and independent of GHS-R, suggesting that both ghrelin and des-acyl ghrelin are involved in neurogenesis of the fetal spinal cord.

  3. A novel GH secretagogue, A233, exhibits enhanced growth activity and innate immune system stimulation in teleosts fish.

    PubMed

    Martinez, Rebeca; Ubieta, Kenia; Herrera, Fidel; Forellat, Alina; Morales, Reynold; de la Nuez, Ania; Rodriguez, Rolando; Reyes, Osvaldo; Oliva, Ayme; Estrada, Mario P

    2012-09-01

    In teleosts fish, secretion of GH is regulated by several hypothalamic factors that are influenced by the physiological state of the animal. There is an interaction between immune and endocrine systems through hormones and cytokines. GH in fish is involved in many physiological processes that are not overtly growth related, such as saltwater osmoregulation, antifreeze synthesis, and the regulation of sexual maturation and immune functions. This study was conducted to characterize a decapeptide compound A233 (GKFDLSPEHQ) designed by molecular modeling to evaluate its function as a GH secretagogue (GHS). In pituitary cell culture, the peptide A233 induces GH secretion and it is also able to increase superoxide production in tilapia head-kidney leukocyte cultures. This effect is blocked by preincubation with the GHS receptor antagonist [d-Lys(3)]-GHRP6. Immunoneutralization of GH by addition of anti-tilapia GH monoclonal antibody blocked the stimulatory effect of A233 on superoxide production. These experiments propose a GH-mediated mechanism for the action of A233. The in vivo biological action of the decapeptide was also demonstrated for growth stimulation in goldfish and tilapia larvae (P<0.001). Superoxide dismutase levels, antiprotease activity, and lectin titer were enhanced in tilapia larvae treated with this novel molecule. The decapeptide A233 designed by molecular modeling is able to function as a GHS in teleosts and enhance parameters of the innate immune system in the fish larvae.

  4. Diversity of glycosyl hydrolases from cellulose-depleting communities enriched from casts of two earthworm species.

    PubMed

    Beloqui, Ana; Nechitaylo, Taras Y; López-Cortés, Nieves; Ghazi, Azam; Guazzaroni, María-Eugenia; Polaina, Julio; Strittmatter, Axel W; Reva, Oleg; Waliczek, Agnes; Yakimov, Michail M; Golyshina, Olga V; Ferrer, Manuel; Golyshin, Peter N

    2010-09-01

    The guts and casts of earthworms contain microbial assemblages that process large amounts of organic polymeric substrates from plant litter and soil; however, the enzymatic potential of these microbial communities remains largely unexplored. In the present work, we retrieved carbohydrate-modifying enzymes through the activity screening of metagenomic fosmid libraries from cellulose-depleting microbial communities established with the fresh casts of two earthworm species, Aporrectodea caliginosa and Lumbricus terrestris, as inocula. Eight glycosyl hydrolases (GHs) from the A. caliginosa-derived community were multidomain endo-beta-glucanases, beta-glucosidases, beta-cellobiohydrolases, beta-galactosidase, and beta-xylosidases of known GH families. In contrast, two GHs derived from the L. terrestris microbiome had no similarity to any known GHs and represented two novel families of beta-galactosidases/alpha-arabinopyranosidases. Members of these families were annotated in public databases as conserved hypothetical proteins, with one being structurally related to isomerases/dehydratases. This study provides insight into their biochemistry, domain structures, and active-site architecture. The two communities were similar in bacterial composition but significantly different with regard to their eukaryotic inhabitants. Further sequence analysis of fosmids and plasmids bearing the GH-encoding genes, along with oligonucleotide usage pattern analysis, suggested that those apparently originated from Gammaproteobacteria (pseudomonads and Cellvibrio-like organisms), Betaproteobacteria (Comamonadaceae), and Alphaproteobacteria (Rhizobiales).

  5. Prevalence and Cardiovascular Associations of Diabetic Retinopathy and Maculopathy: Results from the Gutenberg Health Study

    PubMed Central

    Raum, Philipp; Lamparter, Julia; Ponto, Katharina A.; Peto, Tunde; Hoehn, René; Schulz, Andreas; Schneider, Astrid; Wild, Philipp S.; Pfeiffer, Norbert; Mirshahi, Alireza

    2015-01-01

    Objective Diabetic retinopathy (DR) is the leading cause of blindness in people of working age. The purpose of this paper is to report the prevalence and cardiovascular associations of diabetic retinopathy and maculopathy (DMac) in Germany. Research Design and Methods The Gutenberg Health Study (GHS) is a population-based study with 15,010 participants aged between 35 at 74 years from the city of Mainz and the district of Mainz-Bingen. We determined the weighted prevalence of DR and DMac by assessing fundus photographs of persons with diabetes from the GHS data base. Diabetes was defined as HbA1c ≥ 6.5%, known diagnosis diabetes mellitus or known diabetes medication. Furthermore, we analysed the association between DR and cardiovascular risk factors and diseases. Results Overall, 7.5% (1,124/15,010) of the GHS cohort had diabetes. Of these, 27.7% were unaware of their disease and thus were newly diagnosed by their participation in the GHS. The prevalence of DR and DMac was 21.7% and 2.3%, respectively among patients with diabetes. Vision-threatening disease was present in 5% of the diabetic cohort. In the multivariable analysis DR (all types) was associated with age (Odds Ratio [95% confidence interval]: 0.97 [0.955–0.992]; p = 0.006) arterial hypertension (1.90 [1.190–3.044]; p = 0.0072) and vision-threatening DR with obesity (3.29 [1.504–7.206]; p = 0.0029). DR (all stages) and vision-threatening DR were associated with duration of diabetes (1.09 [1.068–1.114]; p<0.0001 and 1.18 [1.137–1.222]; p<0.0001, respectively). Conclusions Our calculations suggest that more than a quarter-million persons have vision-threatening diabetic retinal disease in Germany. Prevalence of DR was lower in the GHS compared to East-Asian studies. Associations were found with age, arterial hypertension, obesity, and duration of diabetes mellitus. PMID:26075604

  6. Simultaneous detection of recombinant growth hormones in equine plasma by liquid chromatography/high-resolution tandem mass spectrometry for doping control.

    PubMed

    Wong, Kin-Sing; Chan, George H M; Ho, Emmie N M; Wan, Terence S M

    2016-12-23

    Growth hormone (GH), or somatotropin, is a protein that may enhance physical performance and facilitate growth and wound healing. For this reason, growth hormones and their recombinant analogues are prohibited in human sports by the World Anti-Doping Agency (WADA) and in horseracing under Article 6 of the International Agreement on Breeding, Racing and Wagering published by the International Federation of Horse Racing Authorities (IFHA). Identifying the illicit use of GHs in both human athletes and racehorses is challenging, especially when differentiating between endogenous and exogenous GHs, and between analogues of GH from different species. This paper describes a multiplexed mass spectrometric method for the simultaneous detection of three recombinant GHs, namely recombinant equine GH (reGH), recombinant human GH (rhGH) and recombinant porcine GH (rpGH), in equine plasma. Recombinant chicken GH (rcGH) was used as an internal standard. The recombinant GHs were extracted from equine plasma by automated C4 solid-phase extraction after ammonium sulfate precipitation, and then cleaned up by chloroform/methanol precipitation before trypsination. Proteotypic peptides were analyzed by liquid chromatography/high-resolution tandem mass spectrometry (LC-MS/HRMS). The limits of detection were estimated to be approximately 0.5ng/mL for reGH, 2.5ng/mL for rhGH and 1.25ng/mL for rpGH. Confirmation at 1ng/mL for reGH and 5ng/mL each for rhGH and rpGH was successfully achieved by comparing the retention times and relative abundances of three major product-ions of the respective standards in accordance with industry criteria published by the Association of Official Racing Chemists. The developed method requires less plasma (2mL) and has a shorter turnaround time as compared with other published mass spectrometric methods, and demonstrates good precision and reproducibility. To our knowledge, this is the first reported method for the simultaneous detection of different

  7. A new approach to the hazard classification of alloys based on transformation/dissolution.

    PubMed

    Skeaff, James M; Hardy, David J; King, Pierrette

    2008-01-01

    Most of the metals produced for commercial application enter into service as alloys which, together with metals and all other chemicals in commerce, are subject to a hazard identification and classification initiative now being implemented in a number of jurisdictions worldwide, including the European Union Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) initiative, effective 1 June 2007. This initiative has considerable implications for environmental protection and market access. While a method for the hazard identification and classification of metals is available in the recently developed United Nations (UN) guidance document on the Globally Harmonized System of Hazard Classification and Labelling (GHS), an approach for alloys has yet to be formulated. Within the GHS, a transformation/dissolution protocol (T/ DP) for metals and sparingly soluble metal compounds is provided as a standard laboratory method for measuring the rate and extent of the release of metals into aqueous media from metal-bearing substances. By comparison with ecotoxicity reference data, T/D data can be used to derive UN GHS classification proposals. In this study we applied the T/DP for the 1st time to several economically important metals and alloys: iron powder, nickel powder, copper powder, and the alloys Fe-2Cu-0.6C (copper = 2%, carbon = 0.6%), Fe-2Ni-0.6C, Stainless Steel 304, Monel, brass, Inconel, and nickel-silver. The iron and copper powders and the iron and nickel powders had been sintered to produce the Fe-2Me-0.6C (Me = copper or nickel) alloys which made them essentially resistant to reaction with the aqueous media, so they would not classify under the GHS, although their component copper and nickel metal powders would. Forming a protective passivating film, chromium in the Stainless Steel 304 and Inconel alloys protected them from reaction with the aqueous media, so that their metal releases were minimal and would not result in GHS classification

  8. Testosterone inhibition of growth hormone release stimulated by a growth hormone secretagogue: studies in the rat and dog.

    PubMed

    Rigamonti, Antonello E; Cella, Silvano G; Giordani, Claudio; Bonomo, Sara M; Giunta, Marialuisa; Sartorio, Alessandro; Muller, Eugenio

    2006-01-01

    Anabolic steroids are frequently taken by athletes and bodybuilders together with recombinant human GH (rhGH), though there is some scientific evidence that the use of anabolic steroids reverses the rhGH-induced effects. Recently, we have shown that treatment with rhGH (0.2 IU/kg s.c., daily x 12 days) in the dog markedly reduced the canine GH (cGH) responses stimulated by EP51216, a GH secretagogue (GHS), evaluated after 3 and 5 daily rhGH injections, and that the inhibition was still present a few days after rhGH discontinuation. The aim of the present study was to evaluate in the dog the GH response to EP51216 (125 mug/kg i.v.) in a condition of enhanced androgenic function (i.e. acute injection or 15-day treatment with testosterone at the dose of 2 mg/kg i.m. on alternate days), and in the hypophysectomized rat the hypothalamic and hippocampal expression of ghrelin, the receptor of GHSs (GHS-R), GH-releasing hormone (GHRH) and somatostatin (SS) after specific hormonal replacement therapies (testosterone, 1 mg/kg/day s.c.; hydrocortisone, 500 mug/kg/day s.c.; rhGH, 400 mug/kg/day s.c.; 0.9% saline 0.1 ml/kg/day s.c.; x11 days). In the dog experiments, under baseline conditions, a single injection of EP51216 elicited an abrupt rise of plasma cGH. Twenty-four hours from the acute bolus injection of testosterone, C(max) and AUC(0-90) of the GHS-stimulated cGH response were significantly lower than baseline cGH response; 5 days later, there was still a significant decrease of either parameter versus the original values. Short-term treatment with testosterone markedly reduced the GHS-stimulated cGH responses evaluated during (5th bolus) and at the end (8th bolus) of testosterone treatment. Four and 8 days after testosterone withdrawal, the EP51216-stimulated cGH response was still significantly reduced when compared with that under baseline conditions. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were stable until the 5th bolus of testosterone and

  9. Dietary modifications alone do not improve bone mineral density in children with idiopathic hypercalciuria.

    PubMed

    Schwaderer, A L; Srivastava, T; Schueller, L; Cronin, R; Mahan, J D; Hains, D

    2011-11-01

    Prior cross-sectional studies have demonstrated an association between hypercalciuria and low bone mineral density (BMD) in children and adults. However, the natural history of BMD in children with hypercalciuria and its response to therapy has not been evaluated. The objective of this retrospective study was to determine the change over time in lumbar (L1 - L4) BMD Z-score measured on sequential DXA scans in 19 children with hypercalciuria treated with dietary recommendations without (n = 12, Group A) and with citrate (n = 7, Group B). The mean lumbar bone density Z-score/year decreased in Group A (-0.11 ±/0.41) indicating that children with hypercalciuria lose L1 - L4 BMD over time. In contrast, the L1 - L4 BMD Zscore/ year increased in Group B (0.19 ± 0.38) suggesting that pharmacologic therapy may reverse this trend. Similarly 75% of patients in Group A, but only 29% patients in Group B had a decrease in L1 - L4 BMD. There was a definite, although not significant, trend towards improved mean bone mineral density Z-score per year and a lower percentage of patients with a decreased Z-score in hypercalciuric children treated with potassium citrate. Our findings suggest the possibility that dietary recommendations alone is not adequate as the bone mineral density of children with hypercalciuria will decrease over time, potentially increasing the risk for osteoporosis as an adult.

  10. Critical role of oxalate restriction in association with calcium restriction to decrease the probability of being a stone former: insufficient effect in idiopathic hypercalciuria.

    PubMed

    Bataille, P; Pruna, A; Gregoire, I; Charransol, G; de Fremont, J F; Coevoet, B; Galy, C; Fournier, A

    1983-01-01

    The probability of being a stone former (PSF) was calculated according to the method of Robertson in three groups of idiopathic calcium stone formers (normocalciuria (NCa), dietary hypercalciuria (DH) and idiopathic hypercalciuria (IH] during four conditions: on a free diet; on a calcium and oxalate restricted diet for four days and after an oxalate load (200 g of spinach) while on a calcium unrestricted or calcium restricted diet. Combined calciuria (Ca) and oxaluria (Ox) restriction significantly decreased PSF only in NCa and DH whereas the decrease was not significant in IH because of a concomitant significant increase in oxalate excretion. Increase of PSF with the oxalate load was significantly greater on calcium restricted than on calcium unrestricted diets in all groups of patients (4-6-12 times greater in NCa, DH and IH respectively). This shows the critical role of oxalate restriction when calcium is restricted in order to decrease the PSF. Combined restriction is not sufficient in idiopathic hypercalciuric patients to decrease their probability of stone formation.

  11. Renal-Stone Risk Assessment During Space Shuttle Flights

    NASA Technical Reports Server (NTRS)

    Whitson, Peggy A.; Pietrzyk, Robert A.; Pak, Charles Y. C.

    1996-01-01

    The metabolic and environmental factors influencing renal stone formation before, during, and after Space Shuttle flights were assessed. We established the contributing roles of dietary factors in relationship to the urinary risk factors associated with renal stone formation. 24-hr urine samples were collected prior to, during space flight, and following landing. Urinary factors associated with renal stone formation were analyzed and the relative urinary supersaturation ratios of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were calculated. Food and fluid consumption was recorded for a 48-hr period ending with the urine collection. Urinary composition changed during flight to favor the crystallization of stone-forming salts. Factors that contributed to increased potential for stone formation during space flight were significant reductions in urinary pH and increases in urinary calcium. Urinary output and citrate, a potent inhibitor of calcium-containing stones, were slightly reduced during space flight. Dietary intakes were significantly reduced for a number of variables, including fluid, energy, protein, potassium, phosphorus and magnesium. This is the first in-flight characterization of the renal stone forming potential in astronauts. With the examination of urinary components and nutritional factors, it was possible to determine the factors that contributed to increased risk or protected from risk. In spite of the protective components, the negative contributions to renal stone risk predominated and resulted in a urinary environment that favored the supersaturation of stone-forming salts. The importance of the hypercalciuria was noted since renal excretion was high relative to the intake.

  12. Simulating calcium salt precipitation in the nephron using chemical speciation.

    PubMed

    Rodgers, Allen L; Allie-Hamdulay, Shameez; Jackson, Graham; Tiselius, Hans-Göran

    2011-08-01

    Theoretical modeling of urinary crystallization processes affords opportunities to create and investigate scenarios which would be extremely difficult or impossible to achieve in in vivo experiments. Researchers have previously hypothesized that calcium renal stone formation commences in the nephron. In the present study, concentrations of urinary components and pH ranges in different regions of the nephron were estimated from concentrations in blood combined with a knowledge of the renal handling of individual ions. These were used in the chemical speciation program JESS to determine the nature of the solution complexes in the different regions of the nephron and the saturation index (SI) of the stone-forming salts calcium oxalate (CaOx), brushite (Bru), hydroxyapatite (HAP) and octacalcium phosphate (OCP). The effect of independent precipitation of each of the latter on the SI values of other salts was also investigated. HAP was the only salt which was supersaturated throughout the nephron. All of the other salts were supersaturated only in the middle and distal regions of the collecting duct. Supersaturations were pH sensitive. When precipitation of CaOx, Bru and OCP was simulated in the distal part of the collecting duct, little or no effect on the SI values of the other stone forming salts was observed. However, simulation of HAP precipitation caused all other salts to become unsaturated. This suggests that if HAP precipitates, a pure stone comprising this component will ensue while if any of the other salts precipitates, a mixed CaOx/CaP stone will be formed. Application of Ostwald's Rule of Stages predicts that the mixed stone is likely to be CaOx and Bru. Our modelling demonstrates that precipitation of stone-forming salts in the nephron is highly dependent on the delicate nature of the chemical equilibria which prevail and which are themselves highly dependent on pH and component concentrations.

  13. Crystalluria

    NASA Astrophysics Data System (ADS)

    Werness, Peter G.; Bergert, Jan H.; Smith, Lynwood H.

    1981-05-01

    Crystalluria was studied in 4835 voidings in 162 subjects. Patients with primary hyperparathyroidism (with and without stones), primary hyperoxaluria, and idiopathic calcium urolithiasis were studied, as well as normal subjects. Although crystalluria was observed in all groups, stone-forming patients had a greater number of crystals in their urine than normal subjects. Therapy effective in controlling stone disease in the patients resulted in a decrease in crystalluria to the levels seen in normal subjects. Examples of common urinary crystals are shown and observations relating to crystal growth and habit in urine are presented.

  14. [Ionic calcium in blood and urine. Methods of determination and methodological difficulties].

    PubMed

    Leskovar, P

    1979-04-01

    The present paper reports about the individual fractions of the plasma and urine calcium, further about the analytical methods for the determination of the ionic Ca, as well as about the methodical difficulties of the described analytical techniques. Considerations about the real informative value of the Ca2+ -determination in the urine led us to the conclusion that only the additional knowledge of the actual concentration of the stone-forming anions, the oxalate resp. the phosphate may mediate a more complete picture about the calculogenetic "aggressivity" of the urine under investigation.

  15. Carcass composition of market weight pigs subjected to heat stress in utero and during finishing.

    PubMed

    Cruzen, S M; Boddicker, R L; Graves, K L; Johnson, T P; Arkfeld, E K; Baumgard, L H; Ross, J W; Safranski, T J; Lucy, M C; Lonergan, S M

    2015-05-01

    Objectives were to investigate the effects of prolonged gestational and/or postnatal heat stress on performance and carcass composition of market weight pigs. Pregnant gilts were exposed to gestational heat stress (GHS, 28°C to 34°C, diurnal) or thermal neutral (18°C to 22°C, diurnal) conditions during the entire gestation or during the first or second half of gestation. At 14 wk of age (58 ± 5 kg), barrows were housed in heat stress (32°C, HS) or thermal neutral (21°C, TN) conditions. Feed intake and BW were recorded weekly, and body temperature parameters were monitored twice weekly until slaughter (109 ± 5 kg). Organs were removed and weighed, and loin eye area (LEA) and back fat thickness (BF) were measured after carcass chilling. Carcass sides were separated into lean, separable fat, bone, and skin components and were weighed. Moisture, lipid, and protein content were determined in the LM at the 10th rib. Data were analyzed using a split plot with random effect of dam nested within gestational treatment. Carcass measurements included HCW as a covariate to control for weight. Planned orthogonal contrast statements were used to evaluate the overall effect of GHS in the first half, second half, or any part of gestation. Gestational heat stress did not alter postnatal performance or most body temperature parameters (P > 0.10). However, ADFI in the finishing period was increased (P < 0.05) in response to GHS, particularly in pigs receiving GHS in the first half of gestation. Gestational heat stress during the first half of gestation decreased head weight as a percent of BW (P = 0.02), whereas GHS in the second half of gestation decreased bone weight as a percent of BW (P = 0.02). Heat stress reduced ADG, BW, and HCW (P < 0.0001). Lean tissue was increased in HS pigs on both a weight and percentage basis (P < 0.0001), but LEA was similar to TN carcasses (P = 0.38). Carcasses from HS barrows also had less carcass separable fat (P < 0.01) and tended to have

  16. Two-stage bottom-up tiered approach combining several alternatives for identification of eye irritation potential of chemicals including insoluble or volatile substances.

    PubMed

    Hayashi, Kazuhiko; Mori, Taeko; Abo, Takayuki; Ooshima, Kenichi; Hayashi, Takumi; Komano, Tomoko; Takahashi, Yutaka; Sakaguchi, Hitoshi; Takatsu, Akihiko; Nishiyama, Naohiro

    2012-10-01

    For the assessment of eye irritation, one alternative test may not completely replace the rabbit Draize test. In the present study, we examined the predictive potential of a tiered approach analyzing the results from several alternatives (i.e., the Short Time Exposure (STE) test, the EpiOcular assay, the Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) assay and the Bovine Corneal Opacity and Permeability (BCOP) assay) for assessing Globally Harmonized System (GHS) eye irritation categories. Fifty-six chemicals including alcohols, surfactants, and esters were selected with a balanced GHS category and a wide range of chemical classes. From a standpoint of both assessable sample numbers and predictive accuracy, the more favorable tiered approach was considered to be the two-stage bottom-up tiered approach combining the STE test, the EpiOcular assay followed by the BCOP assay (accuracy 69.6%, under prediction rate 8.9%). Moreover, a more favorable predictive capacity (accuracy 71.4%, under prediction rate 3.6%) was obtained when high volatile alcohols/esters with vapor pressures >6 kilopascal (kPa) at 25°C were evaluated with EpiOcular assay instead of the STE test. From these results, the two-stage bottom-up tiered approach combining the STE test, the EpiOcular assay followed by the BCOP assay might be a promising method for the classification of GHS eye irritation category (Not classified (NC), Category 2 (Cat. 2), and Category 1 (Cat. 1)) for a wide range of test chemicals regardless of solubility.

  17. Ghrelin receptor agonist, GHRP-2, produces antinociceptive effects at the supraspinal level via the opioid receptor in mice.

    PubMed

    Zeng, Ping; Li, Shu; Zheng, Yue-hui; Liu, Fu-Yan; Wang, Jing-lei; Zhang, Da-lei; Wei, Jie

    2014-05-01

    GHRP-2 is a synthetic agonist of ghrelin receptor. GHRP-2 has similar physiological functions with ghrelin. In our previous study, ghrelin (i.c.v.) could induce analgesic effect through an interaction with GHS-R1α and with the central opioid system in the acute pain in mice. To date, the function of GHRP-2 in pain processing was not understood. Therefore the aim of this study was to investigate the effects of GHRP-2 on pain modulation at supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of GHRP-2 (0.1, 0.3, 1, 3 and 10 nmol/L) produced a concentration- and time-related antinociceptive effect. This effect could be fully antagonized by GHS-R1α antagonist [d-Lys(3)]-GHRP-6, indicating that the analgesic effect induced by GHRP-2 is mediated through the activation of GHS-R1α. Interestingly, naloxone, naltrindole and nor-binaltorphimine, but not β-funaltrexamine, could also block the analgesic effect markedly, suggesting that δ- and κ-opioid receptor is involved in the analgesic response evoked by GHRP-2. Moreover, i.c.v. administration of GHRP-2 potentiated the analgesic effect induced by morphine (i.c.v., 1 nmol/L) and this potentiated effect could not be reversed by [d-Lys(3)]-GHRP-6. Thus these findings may be a new strategy on investigating the interaction between ghrelin system and opioids on pain modulation. Furthermore, GHRP-2 may be a promising peptide for developing new analgesic drugs.

  18. Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation

    PubMed Central

    Li, Qingjie; Winston, John H.

    2015-01-01

    Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus. PMID:26608656

  19. Do university hospitals perform better than general hospitals? A comparative analysis among Italian regions

    PubMed Central

    Grillo Ruggieri, Tommaso; Podetti, Silvia

    2016-01-01

    Objective The aim of this research was to investigate how university hospitals (UHs) perform compared with general hospitals (GHs) in the Italian healthcare system. Design and setting 27 indicators of overall performance were selected and analysed for UHs and GHs in 10 Italian regions. The data refer to 2012 and 2013 and were selected from two performance evaluation systems based on hospital discharge administrative data: the Inter-Regional Performance Evaluation System developed by the Management and Health Laboratory of the Scuola Superiore Sant'Anna of Pisa and the Italian National Outcome Evaluation Programme developed by the National Agency for Healthcare Services. The study was conducted in 2 stages and by combining 2 statistical techniques. In stage 1, a non-parametric Mann-Whitney U test was carried out to compare the performance of UHs and GHs on the selected set of indicators. In stage 2, a robust equal variance test between the 2 groups of hospitals was carried out to investigate differences in the amount of variability between them. Results The overall analysis gave heterogeneous results. In general, performance was not affected by being in the UH rather than the GH group. It is thus not possible to directly associate Italian UHs with better results in terms of appropriateness, efficiency, patient satisfaction and outcomes. Conclusions Policymakers and managers should further encourage hospital performance evaluations in order to stimulate wider competition aimed at assigning teaching status to those hospitals that are able to meet performance requirements. In addition, UH facilities could be integrated with other providers that are responsible for community, primary and outpatient services, thereby creating a joint accountability for more patient-centred and integrated care. PMID:27507233

  20. Strengthening global health security capacity--Vietnam demonstration project, 2013.

    PubMed

    Tran, Phu Dac; Vu, Long Ngoc; Nguyen, Hien Tran; Phan, Lan Trong; Lowe, Wayne; McConnell, Michelle S; Iademarco, Michael F; Partridge, Jeffrey M; Kile, James C; Do, Trang; Nadol, Patrick J; Bui, Hien; Vu, Diep; Bond, Kyle; Nelson, David B; Anderson, Lauren; Hunt, Kenneth V; Smith, Nicole; Giannone, Paul; Klena, John; Beauvais, Denise; Becknell, Kristi; Tappero, Jordan W; Dowell, Scott F; Rzeszotarski, Peter; Chu, May; Kinkade, Carl

    2014-01-31

    Over the past decade, Vietnam has successfully responded to global health security (GHS) challenges, including domestic elimination of severe acute respiratory syndrome (SARS) and rapid public health responses to human infections with influenza A(H5N1) virus. However, new threats such as Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza A(H7N9) present continued challenges, reinforcing the need to improve the global capacity to prevent, detect, and respond to public health threats. In June 2012, Vietnam, along with many other nations, obtained a 2-year extension for meeting core surveillance and response requirements of the 2005 International Health Regulations (IHR). During March-September 2013, CDC and the Vietnamese Ministry of Health (MoH) collaborated on a GHS demonstration project to improve public health emergency detection and response capacity. The project aimed to demonstrate, in a short period, that enhancements to Vietnam's health system in surveillance and early detection of and response to diseases and outbreaks could contribute to meeting the IHR core capacities, consistent with the Asia Pacific Strategy for Emerging Diseases. Work focused on enhancements to three interrelated priority areas and included achievements in 1) establishing an emergency operations center (EOC) at the General Department of Preventive Medicine with training of personnel for public health emergency management; 2) improving the nationwide laboratory system, including enhanced testing capability for several priority pathogens (i.e., those in Vietnam most likely to contribute to public health emergencies of international concern); and 3) creating an emergency response information systems platform, including a demonstration of real-time reporting capability. Lessons learned included awareness that integrated functions within the health system for GHS require careful planning, stakeholder buy-in, and intradepartmental and interdepartmental coordination and

  1. Margins of safety provided by COSHH Essentials and the ILO Chemical Control Toolkit.

    PubMed

    Jones, Rachael M; Nicas, Mark

    2006-03-01

    COSHH Essentials, developed by the UK Health and Safety Executive, and the Chemical Control Toolkit (Toolkit) proposed by the International Labor Organization, are 'control banding' approaches to workplace risk management intended for use by proprietors of small and medium-sized businesses. Both systems group chemical substances into hazard bands based on toxicological endpoint and potency. COSSH Essentials uses the European Union's Risk-phrases (R-phrases), whereas the Toolkit uses R-phrases and the Globally Harmonized System (GHS) of Classification and Labeling of Chemicals. Each hazard band is associated with a range of airborne concentrations, termed exposure bands, which are to be attained by the implementation of recommended control technologies. Here we analyze the margin of safety afforded by the systems and, for each hazard band, define the minimal margin as the ratio of the minimum airborne concentration that produced the toxicological endpoint of interest in experimental animals to the maximum concentration in workplace air permitted by the exposure band. We found that the minimal margins were always <100, with some ranging to <1, and inversely related to molecular weight. The Toolkit-GHS system generally produced margins equal to or larger than COSHH Essentials, suggesting that the Toolkit-GHS system is more protective of worker health. Although, these systems predict exposures comparable with current occupational exposure limits, we argue that the minimal margins are better indicators of health protection. Further, given the small margins observed, we feel it is important that revisions of these systems provide the exposure bands to users, so as to permit evaluation of control technology capture efficiency.

  2. The ghrelin/obestatin balance in the physiological and pathological control of growth hormone secretion, body composition and food intake.

    PubMed

    Hassouna, R; Zizzari, P; Tolle, V

    2010-07-01

    Ghrelin and obestatin are two gastrointestinal peptides obtained by post-translational processing of a common precursor, preproghrelin. Ghrelin is an orexigenic and adipogenic peptide and a potent growth hormone secretagogue (GHS) modified by the enzyme ghrelin-O-acyl-transferase to bind and activate its receptor, the GHS-R. The ghrelin/GHS-R pathway is complex and the effects of ghrelin on GH secretion, adiposity and food intake appear to be relayed by distinct mechanisms involving different transduction signals and constitutive activity for the GH-R, different cofactors as modulators of endogenous ghrelin signalling and/or alternative ghrelin receptors. The discovery of obestatin in 2005 brought an additional level of complexity to this fascinating system. Obestatin was initially identified as an anorexigenic peptide and as the cognate ligand for GPR39, but its effect on food intake and its ability to activate GPR39 are still controversial. Although several teams failed to reproduce the anorexigenic actions of obestatin, this peptide has been shown to antagonise GH secretion and food intake induced by ghrelin and could be an interesting pharmacological tool to counteract the actions of ghrelin. Ghrelin and obestatin immunoreactivities are recovered in the blood with an ultradian pulsatility and their concentrations in plasma vary with the nutritional status of the body. It is still a matter of debate whether both hormones are regulated by independent mechanisms and whether obestatin is a physiologically relevant peptide. Nevertheless, a significant number of studies show that the ghrelin/obestatin ratio is modified in anorexia nervosa and obesity. This suggests that the ghrelin/obestatin balance could be essential to adapt the body's response to nutritional challenges. Although measuring ghrelin and obestatin in plasma is challenging because many forms of the peptides circulate, more sensitive and selective assays to detect the different preproghrelin

  3. The ghrelin signalling system is involved in the consumption of sweets.

    PubMed

    Landgren, Sara; Simms, Jeffrey A; Thelle, Dag S; Strandhagen, Elisabeth; Bartlett, Selena E; Engel, Jörgen A; Jerlhag, Elisabet

    2011-03-23

    The gastric-derived orexigenic peptide ghrelin affects brain circuits involved in energy balance as well as in reward. Indeed, ghrelin activates an important reward circuit involved in natural- as well as drug-induced reward, the cholinergic-dopaminergic reward link. It has been hypothesized that there is a common reward mechanism for alcohol and sweet substances in both animals and humans. Alcohol dependent individuals have higher craving for sweets than do healthy controls and the hedonic response to sweet taste may, at least in part, depend on genetic factors. Rat selectively bred for high sucrose intake have higher alcohol consumption than non-sucrose preferring rats and vice versa. In the present study a group of alcohol-consuming individuals selected from a population cohort was investigated for genetic variants of the ghrelin signalling system in relation to both their alcohol and sucrose consumption. Moreover, the effects of GHS-R1A antagonism on voluntary sucrose-intake and operant self-administration, as well as saccharin intake were investigated in preclinical studies using rodents. The effects of peripheral grelin administration on sucrose intake were also examined. Here we found associations with the ghrelin gene haplotypes and increased sucrose consumption, and a trend for the same association was seen in the high alcohol consumers. The preclinical data show that a GHS-R1A antagonist reduces the intake and self-administration of sucrose in rats as well as saccharin intake in mice. Further, ghrelin increases the intake of sucrose in rats. Collectively, our data provide a clear indication that the GHS-R1A antagonists reduces and ghrelin increases the intake of rewarding substances and hence, the central ghrelin signalling system provides a novel target for the development of drug strategies to treat addictive behaviours.

  4. The Ghrelin Signalling System Is Involved in the Consumption of Sweets

    PubMed Central

    Landgren, Sara; Simms, Jeffrey A.; Thelle, Dag S.; Strandhagen, Elisabeth; Bartlett, Selena E.; Engel, Jörgen A.; Jerlhag, Elisabet

    2011-01-01

    The gastric-derived orexigenic peptide ghrelin affects brain circuits involved in energy balance as well as in reward. Indeed, ghrelin activates an important reward circuit involved in natural- as well as drug-induced reward, the cholinergic-dopaminergic reward link. It has been hypothesized that there is a common reward mechanism for alcohol and sweet substances in both animals and humans. Alcohol dependent individuals have higher craving for sweets than do healthy controls and the hedonic response to sweet taste may, at least in part, depend on genetic factors. Rat selectively bred for high sucrose intake have higher alcohol consumption than non-sucrose preferring rats and vice versa. In the present study a group of alcohol-consuming individuals selected from a population cohort was investigated for genetic variants of the ghrelin signalling system in relation to both their alcohol and sucrose consumption. Moreover, the effects of GHS-R1A antagonism on voluntary sucrose- intake and operant self-administration, as well as saccharin intake were investigated in preclinical studies using rodents. The effects of peripheral grelin administration on sucrose intake were also examined. Here we found associations with the ghrelin gene haplotypes and increased sucrose consumption, and a trend for the same association was seen in the high alcohol consumers. The preclinical data show that a GHS-R1A antagonist reduces the intake and self-administration of sucrose in rats as well as saccharin intake in mice. Further, ghrelin increases the intake of sucrose in rats. Collectively, our data provide a clear indication that the GHS-R1A antagonists reduces and ghrelin increases the intake of rewarding substances and hence, the central ghrelin signalling system provides a novel target for the development of drug strategies to treat addictive behaviours. PMID:21448464

  5. A role of ghrelin in canine mammary carcinoma cells proliferation, apoptosis and migration

    PubMed Central

    2012-01-01

    Background Ghrelin is a natural ligand of the growth hormone secretagogue receptor (GHS-R). They are often co-expressed in multiple human tumors and related cancer cell lines what can indicate that the ghrelin/GHS-R axis may have an important role in tumor growth and progression. However, a role of ghrelin in canine tumors remains unknown. Thus, the aim of our study was two-fold: (1) to assess expression of ghrelin and its receptor in canine mammary cancer and (2) to examine the effect of ghrelin on carcinoma cells proliferation, apoptosis, migration and invasion. The expression of ghrelin and its receptor in canine mammary cancer tissues and cell lines (isolated from primary tumors and their metastases) was examined using Real-time qPCR and immunohistochemistry. For apoptosis analysis the Annexin V and propidium iodide dual staining was applied whereas cell proliferation was evaluated by MTT assay and BrdU incorporation test. The influence of ghrelin on cancer cells migration and invasion was assessed using Boyden chamber assays and wound healing assay. Results The highest expression of ghrelin was observed in metastatic cancers whereas the lowest expression of ghrelin receptor was detected in tumors of the 3rd grade of malignancy. Higher expression of ghrelin and its receptor was detected in cancer cell lines isolated from metastases than in cell lines isolated from primary tumors. In vitro experiments demonstrated that exposure to low doses of ghrelin stimulates cellular proliferation, inhibits apoptosis and promotes motility and invasion of canine mammary cancer cells. Growth hormone secretagogue receptor inhibitor ([D-Lys3]-GHRP6) as well as RNA interference enhances early apoptosis. Conclusion The presence of ghrelin and GHS-R in all of the examined canine mammary tumors may indicate their biological role in cancer growth and development. Our experiments conducted in vitro confirmed that ghrelin promotes cancer development and metastasis. PMID:22999388

  6. Non-medical use of prescription pain relievers among high school students in China: a multilevel analysis

    PubMed Central

    Guo, Lan; Xu, Yan; Deng, Jianxiong; He, Yuan; Gao, Xue; Li, Pengsheng; Wu, Hong; Zhou, Jinhua; Lu, Ciyong

    2015-01-01

    Objectives Given the differences between general high school (GHS) and vocational high school (VHS) students, this study aimed to investigate the lifetime prevalence of non-medical use of prescription pain relievers (NMUPPR) among high school students as well as the associations between NMUPPR and individual-level factors and school category. Methods A cross-sectional study was conducted in GHS and VHS students in 2012 in Chongqing, and 11 906 students’ questionnaires were completed and qualified for the survey. Self-reported NMUPPR and information regarding individual-level determinants and school category were collected. A multilevel multivariate logistic regression model was fitted to explore independent predictors of NMUPPR. Results The total lifetime prevalence of NMUPPR was 11.3%, and NMUPPR was more prevalent among VHS students (15.8%) compared with GHS students (9.8%). Overall, the results indicated that VHS students were more likely to be involved in NMUPPR (adjusted OR (AOR)=1.64, 95% CI 1.42 to 1.89). Regarding the individual-level predictors of NMUPPR, below-average family economic status was negatively correlated with NMUPPR (AOR=0.77, 95% CI 0.60 to 0.98), and students with more pocket money were more likely to be engaged in NMUPPR. Students who had difficult family relationships, had poor relationships with teachers, had parents or friends who engaged in non-medical prescription drug use, and considered or attempted suicide were more likely to be engaged in NMUPPR. Conclusions NMUPPR among high school students is a multidetermined phenomenon. The current findings indicate that VHS students are an important subgroup of adolescents and highlight the need for additional research as well as targeted prevention and intervention programmes for NMUPPR. PMID:26169805

  7. Orogen-parallel deformation of the Himalayan midcrust: Insights from structural and magnetic fabric analyses of the Greater Himalayan Sequence, Annapurna-Dhaulagiri Himalaya, central Nepal

    NASA Astrophysics Data System (ADS)

    Parsons, A. J.; Ferré, E. C.; Law, R. D.; Lloyd, G. E.; Phillips, R. J.; Searle, M. P.

    2016-11-01

    The metamorphic core of the Himalaya (Greater Himalayan Sequence, GHS), in the Annapurna-Dhaulagiri region, central Nepal, recorded orogen-parallel stretching during midcrustal evolution. Anisotropy of magnetic susceptibility and field-based structural analyses suggest that midcrustal deformation of the amphibolite facies core of the GHS occurred under an oblate/suboblate strain regime with associated formation of low-angle northward dipping foliation. Magnetic and mineral stretching lineations lying within this foliation from the top of the GHS record right-lateral orogen-parallel stretching. We propose that oblate strain within a midcrustal flow accommodated oblique convergence between India and the arcuate orogenic front without the need for strain partitioning in the upper crust. Oblate flattening may have also promoted orogen-parallel melt migration and development of melt-depleted regions between km3 scale leucogranite culminations at 50-100 km intervals along orogen strike. Following the cessation of flow, continued oblique convergence led to upper crustal strain partitioning between orogen-perpendicular convergence on thrust faults and orogen-parallel extension on normal and strike-slip faults. In the Annapurna-Dhaulagiri Himalaya, orogen-parallel stretching lineations are interpreted as a record of transition from midcrustal orogen-perpendicular extrusion to upper crustal orogen-parallel stretching. Our findings suggest that midcrustal flow and upper crustal extension could not be maintained simultaneously and support other studies from across the Himalaya, which propose an orogen-wide transition from midcrustal orogen-perpendicular extrusion to upper crustal orogen-parallel extension during the mid-Miocene. The 3-D nature of oblate strain and orogen-parallel stretching cannot be replicated by 2-D numerical simulations of the Himalayan orogen.

  8. Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans.

    PubMed

    Bisi, G; Podio, V; Valetto, M R; Broglio, F; Bertuccio, G; Del Rio, G; Arvat, E; Boghen, M F; Deghenghi, R; Muccioli, G; Ong, H; Ghigo, E

    1999-04-01

    Reduced cardiac mass and performances are present in GH deficiency and are counteracted by rhGH replacement. GH and IGF-I possess specific myocardial receptors and have been reported able to exert an acute inotropic effect. Synthetic GH secretagogues (GHS) possess specific pituitary and hypothalamic but even myocardial receptors. In 7 male volunteers, we studied cardiac performance by radionuclide angiocardiography after iv administration of rhGH or hexarelin (HEX), a peptidyl GHS. The administration of rhGH or HEX increased circulating GH levels to the same extent (AUC: 1594.6+/-88.1 vs 1739.3+/-262.2 microg/l/min for 90 min) while aldosterone and catecholamine levels did not change; HEX, but not rhGH, significantly increased cortisol levels. Left ventricular ejection fraction (LVEF), mean blood pressure (MBP) and heart rate (HR) were unaffected by rhGH (62.4+/-2.1 vs 62.1+/-2.3%, 90.6+/-3.4 vs 92.0+/-2.5 mm Hg, 62.3+/-1.8 vs 66.7+/-2.7 bpm). HEX increased LVEF (70.7+/-3.0 vs 64.0+/-1.5%, p<0.03) without significant changes in MBP and HR (92.8+/-4.7 vs 92.4+/-3.2 mm Hg, 63.1+/-2.1 vs 67.0+/-2.9 bpm). LVEF significantly raised at 15 min, peaked at 30 min and lasted up to 60 min after HEX. These findings suggest that in man, the acute administration of Hexarelin exerts a short-lasting, positive inotropic effect. This effect seems GH-independent and might be mediated by specific GHS myocardial receptors.

  9. Effects of intraamygdaloid microinjections of acylated-ghrelin on liquid food intake of rats.

    PubMed

    Tóth, Krisztián; László, Kristóf; Bagi, Eva Eszter; Lukács, Edit; Lénárd, László

    2008-09-30

    Ghrelin (Ghr) has two main forms in the blood: the acylated (A-Ghr) and non-acylated (NA-Ghr) Ghr. A-Ghr was discovered as a potent growth hormone (GH) secretion increasing substance acting on GH secretagouge receptor (GHS-R) type 1a. A-Ghr facilitates food intake after its i.p., i.c.v. or direct hypothalamic application. Immunohistological assays identified projections of ghrelinergic neurons to the basolateral nucleus (ABL) of the amygdala (AMY). A-Ghr injected into the hypothalamus caused c-Fos overexpression in the AMY area that has an important role in food intake and body weight regulation. In separate experiments, liquid food intake of male wistar rats was measured after bilateral intraamygdalar or bilateral i.c.v. administration of A-Ghr (25, 50, 100, 250, and 500 ng/side or 500 and 1000 ng/side, A-Ghr dissolved in 0.15 M sterile NaCl/0.4 microl or 1 microl, respectively). In the ABL, A-Ghr microinjections in the 50-250 ng dose range resulted in significant decrease of food intake. The 25 and 500 ng had no effect. Action of 50 ng (14.83 pmol) or 100 ng (30.16 pmol) A-Ghr was eliminated by 15 ng (16.13 pmol) or 30 ng (32.25 pmol) GHS-R antagonist (D-Lys3-GHRP-6) pretreatment. The administration of 30 ng D-Lys3-GHRP-6 in itself had no influence on feeding. I.c.v. applied 1000 ng A-Ghr increased liquid food intake. Our results are the first ones reporting that A-Ghr injected into the ABL resulted in a decrease of liquid food consumption, within a limited dose range. This is a receptor-linked effect because it was eliminated by a GHS-R specific antagonist.

  10. The Ophthalmic Branch of the Gutenberg Health Study: Study Design, Cohort Profile and Self-Reported Diseases

    PubMed Central

    Höhn, René; Kottler, Ulrike; Peto, Tunde; Blettner, Maria; Münzel, Thomas; Blankenberg, Stefan; Lackner, Karl J.; Beutel, Manfred

    2015-01-01

    Purpose This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS). Methods The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling. Results Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively. Conclusions The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties. PMID:25775251

  11. Piloting proactive marketing to recruit disadvantaged adults to a community-wide obesity prevention program.

    PubMed

    O'Hara, Blythe J; Eggins, Dianne; Phongsavan, Philayrath; Milat, Andrew J; Bauman, Adrian E; Wiggers, John

    2015-03-30

    Population-wide obesity prevention and treatment programs are fundamental to addressing the increasing overweight and obesity rates in socioeconomically disadvantaged populations. Innovative recruitment strategies, including proactive marketing strategies, are needed to ensure such programs have universal reach and target vulnerable populations. This study aimed to determine the success of proactive recruitment to Australia's Get Healthy Information and Coaching Service® (GHS) and to assess whether the recruitment strategy influenced participants' outcomes. Sociodemographic information was collected from all GHS participants who joined the service between February 2009 and August 2013, and anthropometric information regarding behavioural risk factors was collected from all GHS coaching participants at baseline and six months. Data were analysed according to the participants' referral source (self-referral and secondary referral versus proactive recruitment). Participants recruited through proactive marketing were more likely to be male, aged 50 years or older, have high school education, not be in paid employment and be from the lowest three quintiles of socioeconomic advantage. The risk factor profile of coaching participants recruited through proactive marketing did not vary significantly from those recruited via other mechanisms, although they were less likely to be obese and less likely to have a higher 'at risk' waist circumference measurement. Proactively recruited coaching participants reported significant improvements from baseline to six months (consistent with improvements made by participants recruited through other strategies), although they were significantly more likely to withdraw from coaching before they completed the six-month program.Proactive marketing facilitated use of an obesity prevention service; similar services may have greater reach if proactive marketing recruitment strategies are used. These strategies could be encouraged to assist

  12. The role of ghrelin signalling for sexual behaviour in male mice.

    PubMed

    Egecioglu, Emil; Prieto-Garcia, Luna; Studer, Erik; Westberg, Lars; Jerlhag, Elisabet

    2016-03-01

    Ghrelin, a gut-brain signal, is well known to regulate energy homeostasis, food intake and appetite foremost via hypothalamic ghrelin receptors (GHS-R1A). In addition, ghrelin activates the reward systems in the brain, namely the mesolimbic dopamine system, and regulates thereby the rewarding properties of addictive drugs as well as of palatable foods. Given that the mesolimbic dopamine system mandates the reinforcing properties of addictive drugs and natural rewards, such as sexual behaviour, we hypothesize that ghrelin plays an important role for male sexual behaviour, a subject for the present studies. Herein we show that ghrelin treatment increases, whereas pharmacological suppression (using the GHSR-1A antagonist JMV2959) or genetic deletion of the GHS-R1A in male mice decreases the sexual motivation for as well as sexual behaviour with female mice in oestrus. Pre-treatment with L-dopa (a dopamine precursor) prior to treatment with JMV2959 significantly increased the preference for female mouse compared with vehicle treatment. On the contrary, treatment with 5-hydroxythyptohan (a precursor for serotonin) prior to treatment with JMV2959 decreased the sexual motivation compared to vehicle. In separate experiments, we show that ghrelin and GHS-R1A antagonism do not affect the time spent over female bedding as measured in the androgen-dependent bedding test. Collectively, these data show that the hunger hormone ghrelin and its receptor are required for normal sexual behaviour in male mice and that the effects of the ghrelin signalling system on sexual behaviour involve dopamine neurotransmission.

  13. Mathematical model to estimate risk of calcium-containing renal stones

    NASA Technical Reports Server (NTRS)

    Pietrzyk, R. A.; Feiveson, A. H.; Whitson, P. A.

    1999-01-01

    BACKGROUND/AIMS: Astronauts exposed to microgravity during the course of spaceflight undergo physiologic changes that alter the urinary environment so as to increase the risk of renal stone formation. This study was undertaken to identify a simple method with which to evaluate the potential risk of renal stone development during spaceflight. METHOD: We used a large database of urinary risk factors obtained from 323 astronauts before and after spaceflight to generate a mathematical model with which to predict the urinary supersaturation of calcium stone forming salts. RESULT: This model, which involves the fewest possible analytical variables (urinary calcium, citrate, oxalate, phosphorus, and total volume), reliably and accurately predicted the urinary supersaturation of the calcium stone forming salts when compared to results obtained from a group of 6 astronauts who collected urine during flight. CONCLUSIONS: The use of this model will simplify both routine medical monitoring during spaceflight as well as the evaluation of countermeasures designed to minimize renal stone development. This model also can be used for Earth-based applications in which access to analytical resources is limited.

  14. Renal stone risk assessment during Space Shuttle flights

    NASA Technical Reports Server (NTRS)

    Whitson, P. A.; Pietrzyk, R. A.; Pak, C. Y.

    1997-01-01

    PURPOSE: The metabolic and environmental factors influencing renal stone formation before, during, and after Space Shuttle flights were assessed. We established the contributing roles of dietary factors in relationship to the urinary risk factors associated with renal stone formation. MATERIALS AND METHODS: 24-hr. urine samples were collected prior to, during space flight, and following landing. Urinary and dietary factors associated with renal stone formation were analyzed and the relative urinary supersaturation of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were calculated. RESULTS: Urinary composition changed during flight to favor the crystallization of calcium-forming salts. Factors that contributed to increased potential for stone formation during space flight were significant reductions in urinary pH and increases in urinary calcium. Urinary output and citrate, a potent inhibitor of calcium-containing stones, were slightly reduced during space flight. Dietary intakes were significantly reduced for a number of variables, including fluid, energy, protein, potassium, phosphorus and magnesium. CONCLUSIONS: This is the first in-flight characterization of the renal stone forming potential in astronauts. With the examination of urinary components and nutritional factors, it was possible to determine the factors that contributed to increased risk or protected from risk. In spite of the protective components, the negative contributions to renal stone risk predominated and resulted in a urinary environment that favored the supersaturation of stone-forming salts. Dietary and pharmacologic therapies need to be assessed to minimize the potential for renal stone formation in astronauts during/after space flight.

  15. Clinical, demographic, and laboratory characteristics of children with nephrolithiasis.

    PubMed

    Sas, David J; Becton, Lauren J; Tutman, Jeffrey; Lindsay, Laura A; Wahlquist, Amy H

    2016-06-01

    While the incidence of pediatric kidney stones appears to be increasing, little is known about the demographic, clinical, laboratory, imaging, and management variables in this patient population. We sought to describe various characteristics of our stone-forming pediatric population. To that end, we retrospectively reviewed the charts of pediatric patients with nephrolithiasis confirmed by imaging. Data were collected on multiple variables from each patient and analyzed for trends. For body mass index (BMI) controls, data from the general pediatrics population similar to our nephrolithiasis population were used. Data on 155 pediatric nephrolithiasis patients were analyzed. Of the 54 calculi available for analysis, 98 % were calcium based. Low urine volume, elevated supersaturation of calcium phosphate, elevated supersaturation of calcium oxalate, and hypercalciuria were the most commonly identified abnormalities on analysis of 24-h urine collections. Our stone-forming population did not have a higher BMI than our general pediatrics population, making it unlikely that obesity is a risk factor for nephrolithiasis in children. More girls presented with their first stone during adolescence, suggesting a role for reproductive hormones contributing to stone risk, while boys tended to present more commonly at a younger age, though this did not reach statistical significance. These intriguing findings warrant further investigation.

  16. Nephrolithiasis: Molecular Mechanism of Renal Stone Formation and the Critical Role Played by Modulators

    PubMed Central

    Aggarwal, Kanu Priya; Narula, Shifa; Kakkar, Monica

    2013-01-01

    Urinary stone disease is an ailment that has afflicted human kind for many centuries. Nephrolithiasis is a significant clinical problem in everyday practice with a subsequent burden for the health system. Nephrolithiasis remains a chronic disease and our fundamental understanding of the pathogenesis of stones as well as their prevention and cure still remains rudimentary. Regardless of the fact that supersaturation of stone-forming salts in urine is essential, abundance of these salts by itself will not always result in stone formation. The pathogenesis of calcium oxalate stone formation is a multistep process and essentially includes nucleation, crystal growth, crystal aggregation, and crystal retention. Various substances in the body have an effect on one or more of the above stone-forming processes, thereby influencing a person's ability to promote or prevent stone formation. Promoters facilitate the stone formation while inhibitors prevent it. Besides low urine volume and low urine pH, high calcium, sodium, oxalate and urate are also known to promote calcium oxalate stone formation. Many inorganic (citrate, magnesium) and organic substances (nephrocalcin, urinary prothrombin fragment-1, osteopontin) are known to inhibit stone formation. This review presents a comprehensive account of the mechanism of renal stone formation and the role of inhibitors/promoters in calcium oxalate crystallisation. PMID:24151593

  17. New pathophysiological concepts underlying pathogenesis of pigment gallstones.

    PubMed

    Vítek, Libor; Carey, Martin C

    2012-04-01

    Pigment gallstones, which are much less frequent than cholesterol stones, are classified descriptively as "black" or "brown". They are composed mostly of calcium hydrogen bilirubinate, Ca(HUCB)(2), which is polymerized and oxidized in "black" stones but remains unpolymerized in "brown" stones. Black stones form in sterile gallbladder bile but brown stones form secondary to stasis and anaerobic bacterial infection in any part of the biliary tree, including the gallbladder. Other calcium salts coprecipitate in both stone types; crystalline calcium phosphate and/or carbonate in the case of "black" stones and amorphous calcium salts of long chain saturated fatty acids ("soaps") in the case of "brown" stones. Cholesterol is present in variable proportions in "brown" more than "black" stones and in the latter, the bile sterol may be totally absent. The "scaffolding" of both stone types is a mixed mucin glycoprotein matrix secreted by epithelial cells lining the biliary tree. The critical pathophysiological prerequisite for "black" stone formation is "hyperbilirubinbilia" (biliary hypersecretion of bilirubin conjugates). It is due principally to hemolysis, ineffective erythropoiesis, or pathologic enterohepatic cycling of unconjugated bilirubin. Endogenous biliary β-glucuronidase hydrolysis of bilirubin conjugates in gallbladder bile provides HUCB(-) molecules that precipitate as insoluble salts with ionized Ca. Putatively, reactive oxygen species secreted by an inflamed gallbladder mucosa are responsible for transforming the initial soft yellow precipitates into hard black [Ca(HUCB)(2)](n) polymers. Despite "brown" gallstones being soft and amenable to mechanical removal, chronic anaerobic infection of the biliary tree is often markedly resistant to eradication.

  18. Nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators.

    PubMed

    Aggarwal, Kanu Priya; Narula, Shifa; Kakkar, Monica; Tandon, Chanderdeep

    2013-01-01

    Urinary stone disease is an ailment that has afflicted human kind for many centuries. Nephrolithiasis is a significant clinical problem in everyday practice with a subsequent burden for the health system. Nephrolithiasis remains a chronic disease and our fundamental understanding of the pathogenesis of stones as well as their prevention and cure still remains rudimentary. Regardless of the fact that supersaturation of stone-forming salts in urine is essential, abundance of these salts by itself will not always result in stone formation. The pathogenesis of calcium oxalate stone formation is a multistep process and essentially includes nucleation, crystal growth, crystal aggregation, and crystal retention. Various substances in the body have an effect on one or more of the above stone-forming processes, thereby influencing a person's ability to promote or prevent stone formation. Promoters facilitate the stone formation while inhibitors prevent it. Besides low urine volume and low urine pH, high calcium, sodium, oxalate and urate are also known to promote calcium oxalate stone formation. Many inorganic (citrate, magnesium) and organic substances (nephrocalcin, urinary prothrombin fragment-1, osteopontin) are known to inhibit stone formation. This review presents a comprehensive account of the mechanism of renal stone formation and the role of inhibitors/promoters in calcium oxalate crystallisation.

  19. Regulatory assessment of chemicals within OECD member countries, EU and in Russia.

    PubMed

    Fjodorova, Natalja; Novich, Marjana; Vrachko, Marjan; Kharchevnikova, Nina; Zholdakova, Zoya; Sinitsyna, Oxana; Benfenati, Emilio

    2008-01-01

    The chemical risk assessment is essesntial part of new chemical legislation registration, evaluation, and authorization of chemicals (REACH). The article presents a review of chemical legislation policies in the European Union (EU) and in Russia, and changes in chemicals regulations to meet the requirement of REACH. The risk assessment paradigm, toxicological parameters, safe limits and classification criteria used by different agencies and authorities in different countries are reported. Our investigation also focuses on comparison of chemical risk assessment criteria used in OECD member countries and in Russia. Tendencies in harmonization in accordance with the globally harmonized system of classification and labeling of chemicals (GHS) are discussed.

  20. Role of endogenous cortistatin in the regulation of ghrelin system expression at pancreatic level under normal and obese conditions.

    PubMed

    Chanclón, Belén; Luque, Raúl M; Córdoba-Chacón, José; Gahete, Manuel D; Pozo-Salas, Ana I; Castaño, Justo P; Gracia-Navarro, Francisco; Martínez-Fuentes, Antonio J

    2013-01-01

    Ghrelin-system components [native ghrelin, In1-ghrelin, Ghrelin-O-acyltransferase enzyme (GOAT) and receptors (GHS-Rs)] are expressed in a wide variety of tissues, including the pancreas, where they exert different biological actions including regulation of neuroendocrine secretions, food intake and pancreatic function. The expression of ghrelin system is regulated by metabolic conditions (fasting/obesity) and is associated with the progression of obesity and insulin resistance. Cortistatin (CORT), a neuropeptide able to activate GHS-R, has emerged as an additional link in gut-brain interplay. Indeed, we recently reported that male CORT deficient mice (cort-/-) are insulin-resistant and present a clear dysregulation in the stomach ghrelin-system. The present work was focused at analyzing the expression pattern of ghrelin-system components at pancreas level in cort-/- mice and their control littermates (cort +/+) under low- or high-fat diet. Our data reveal that all the ghrelin-system components are expressed at the mouse pancreatic level, where, interestingly, In1-ghrelin was expressed at higher levels than native-ghrelin. Thus, GOAT mRNA levels were significantly lower in cort-/- mice compared with controls while native ghrelin, In1-ghrelin and GHS-R transcript levels remained unaltered under normal metabolic conditions. Moreover, under obese condition, a significant increase in pancreatic expression of native-ghrelin, In1-ghrelin and GHS-R was observed in obese cort+/+ but not in cort-/- mice. Interestingly, insulin expression and release was elevated in obese cort+/+, while these changes were not observed in obese cort-/- mice. Altogether, our results indicate that the ghrelin-system expression is clearly regulated in the pancreas of cort+/+ and cort -/- under normal and/or obesity conditions suggesting that this system may play relevant roles in the endocrine pancreas. Most importantly, our data demonstrate, for the first time, that endogenous CORT is essential

  1. d-Lys-GHRP-6 does not modify the endocrine response to acylated ghrelin or hexarelin in humans.

    PubMed

    Benso, A; Prodam, F; Lucatello, B; Gramaglia, E; Riganti, F; Schneider, H; van der Lely, A J; Muccioli, G; Ghigo, E; Broglio, F

    2007-02-01

    Acylated ghrelin exerts numerous endocrine and non-endocrine activities via the GH Secretagogue receptor type 1a (GHS-R1a). D-Lys-GHRP-6 has been widely studied in vitro and in vivo in animal studies as GHS-R1a antagonist; its action in humans has, however, never been tested so far. Aim of our study was to verify the antagonistic action of D-Lys-GHRP-6 on the endocrine responses to acylated ghrelin and hexarelin, a peptidyl synthetic GHS, in humans. The effects of different doses of D-Lys-GHRP-6 (2.0microg/kg iv as bolus or 2.0microg/kg/h iv as infusion) on both spontaneous and acylated ghrelin- or hexarelin (1.0microg/kg iv as bolus) -stimulated GH, PRL, ACTH and cortisol levels were studied in six normal volunteers (age [mean+/-SEM]: 25.4+/-1.2yr; BMI: 22.3+/-1.0kg/m(2)). The effects of D-Lys-GHRP-6 (2.0microg/kg iv as bolus+4.0microg/kg/h iv) on the GH response to 0.25microg/kg iv as bolus acylated ghrelin was also studied. During saline, spontaneous ACTH and cortisol decrease was observed while non changes occurred in GH and PRL levels. Acylated ghrelin and hexarelin stimulated (p<0.05) GH, PRL, ACTH and cortisol secretions. D-Lys-GHRP-6 administered either as bolus or a continuous infusion did not modify both spontaneous and acylated ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. D-Lys-GHRP-6 did not modify even the GH response to 0.25microg/kg iv acylated ghrelin. In conclusion, D-Lys-GHRP-6 does not affect the neuroendocrine response to both ghrelin and hexarelin. These findings question D-Lys-GHRP-6 as an effective GHS-R1a antagonist for human studies.

  2. Black Hole in a Model with Dilaton and Monopole Fields

    NASA Astrophysics Data System (ADS)

    Kyriakopoulos, E.

    We present an exact black hole solution in a model having besides gravity a dilaton and a monopole field. The solution has three free parameters, which can be identified with the monopole charge, the ADM mass, and the dilaton charge. The metric is asymptotically flat and has two horizons and irremovable singularity only at r = 0. The dilaton field is singular only at r = 0. The dominant and the strong energy condition are satisfied outside and on the external horizon. According to a formulation of the no hair conjecture, the solution is "hairy." Also the well-known GHS-GM solution is obtained from our solution for certain values of its parameters.

  3. National Dam Safety Program. Garnerville Dam (Inventory Number N.Y. 744), Hudson River Basin, Rockland County, New York. Phase I Inspection Report,

    DTIC Science & Technology

    1980-08-01

    aUS 80 E O-BRIEN DAC51-79-C-0001 UNCLASSIFIED NL 2 flfflfllflfflfllflf I */fllflfIflIfIflf EEEEEEEEEEllllE E-EEEIIEEEEEE .-0. SECURITY CLASIFICATION ...which constitute an immediate hazard to ’ human life or property. DD PO" 147J3 EDfIlOH Of I OIOV 65 IS OtiSOLETIEAn~ SEC C m~S CTOF GHS E (Whoen Dot...of Engineers, Washington, D.C., 20314. The purpose of a Phase I Investigation is to identify expeditiously those dams which may pose hazards to human

  4. Ghrelin Receptors in Non-Mammalian Vertebrates

    PubMed Central

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2012-01-01

    The growth hormone secretagogue-receptor (GHS-R) was discovered in humans and pigs in 1996. The endogenous ligand, ghrelin, was discovered 3 years later, in 1999, and our understanding of the physiological significance of the ghrelin system in vertebrates has grown steadily since then. Although the ghrelin system in non-mammalian vertebrates is a subject of great interest, protein sequence data for the receptor in non-mammalian vertebrates has been limited until recently, and related biological information has not been well organized. In this review, we summarize current information related to the ghrelin receptor in non-mammalian vertebrates. PMID:23882259

  5. Identifying the ionically bound cell wall and intracellular glycoside hydrolases in late growth stage Arabidopsis stems: implications for the genetic engineering of bioenergy crops

    PubMed Central

    Wei, Hui; Brunecky, Roman; Donohoe, Bryon S.; Ding, Shi-You; Ciesielski, Peter N.; Yang, Shihui; Tucker, Melvin P.; Himmel, Michael E.

    2015-01-01

    Identifying the cell wall-ionically bound glycoside hydrolases (GHs) in Arabidopsis stems is important for understanding the regulation of cell wall integrity. For cell wall proteomics studies, the preparation of clean cell wall fractions is a challenge since cell walls constitute an open compartment, which is more likely to contain a mixture of intracellular and extracellular proteins due to cell leakage at the late growth stage. Here, we utilize a CaCl2-extraction procedure to isolate non-structural proteins from Arabidopsis whole stems, followed by the in-solution and in-gel digestion methods coupled with Nano-LC-MS/MS, bioinformatics and literature analyses. This has led to the identification of 75 proteins identified using the in-solution method and 236 proteins identified by the in-gel method, among which about 10% of proteins predicted to be secreted. Together, eight cell wall proteins, namely AT1G75040, AT5G26000, AT3G57260, AT4G21650, AT3G52960, AT3G49120, AT5G49360, and AT3G14067, were identified by the in-solution method; among them, three were the GHs (AT5G26000, myrosinase 1, GH1; AT3G57260, β-1,3-glucanase 2, GH17; AT5G49360, bifunctional XYL 1/α-L-arabinofuranosidase, GH3). Moreover, four more GHs: AT4G30270 (xyloglucan endotransferase, GH16), AT1G68560 (bifunctional α-l-arabinofuranosidase/XYL, GH31), AT1G12240 (invertase, GH32) and AT2G28470 (β-galactosidase 8, GH35), were identified by the in-gel solution method only. Notably, more than half of above identified GHs are xylan- or hemicellulose-modifying enzymes, and will likely have an impact on cellulose accessibility, which is a critical factor for downstream enzymatic hydrolysis of plant tissues for biofuels production. The implications of these cell wall proteins identified at the late growth stage for the genetic engineering of bioenergy crops are discussed. PMID:26029221

  6. Strain distribution across the Greater Himalayan Sequence, Annapurna-Dhaulagiri, Nepal

    NASA Astrophysics Data System (ADS)

    Parsons, A. J.; Phillips, R. J.; Lloyd, G. E.; Searle, M. P.; Law, R. D.; Ferre, E. C.

    2012-12-01

    The Himalaya provides a unique natural laboratory to observe orogenic processes at a variety of temporal and spatial scales. The potential for these observations to serve as kinematic and geodynamic analogues for past orogens relies on a robust understanding of the evolution of the Himalayan mountain belt. Field structural data, supported by thermobaromety, geochronology and thermodynamic modelling, generally support a channel flow model in which a partially molten middle crust layer, the Greater Himalaya Sequence (GHS), was extruded to the south during Miocene time bounded by high-strain ductile shears above and below. This model suggests that the GHS, the metamorphic core of the orogen, represents an exhumed, rheologically weak, mid-crustal channel. Lateral flow of the channel was driven southwards by the lithostatic pressure gradient between the 5 km high Tibetan plateau and the < 1 km elevation and average crustal thickness of the Indian plate. The vertical distribution of strain across the GHS is one element of the channel flow hypothesis that is yet to be fully investigated. This project considers this issue by examining specifically, the vertical distribution and evolution of strain across the GHS and bounding units. A variety of techniques, that include SEM electron back scattered diffraction (EBSD) and anisotropy of magnetic susceptibility (AMS) will be used to analyse samples collected during recent field work in the Annapurna-Dhaulagiri Himal, central Nepal. These samples were collected from two transects along the Modi Khola valley and the Kali Gandaki valley. EBSD will be used to measure the lattice preferred orientation of individual mineral phases of these samples, providing a proxy for strain and valuable information on deformation mechanisms. Given specific magnetic carriers, AMS will be used to provide a proxy for finite strain in samples that are too heterogeneous for EBSD. Combined EBSD and AMS data will be augmented by additional strain and

  7. Identifying the ionically bound cell wall and intracellular glycoside hydrolases in late growth stage Arabidopsis stems: Implications for the genetic engineering of bioenergy crops

    DOE PAGES

    Wei, Hui; Brunecky, Roman; Donohoe, Bryon S.; ...

    2015-05-13

    Identifying the cell wall-ionically bound glycoside hydrolases (GHs) in Arabidopsis stems is important for understanding the regulation of cell wall integrity. For cell wall proteomics studies, the preparation of clean cell wall fractions is a challenge since cell walls constitute an open compartment, which is more likely to contain a mixture of intracellular and extracellular proteins due to cell leakage at the late growth stage. Here, for this study, we utilize a CaCl2-extraction procedure to isolate non-structural proteins from Arabidopsis whole stems, followed by the in-solution and in-gel digestion methods coupled with Nano-LC-MS/MS, bioinformatics and literature analyses. This has ledmore » to the identification of 75 proteins identified using the in-solution method and 236 proteins identified by the in-gel method, among which about 10% of proteins predicted to be secreted. Together, eight cell wall proteins, namely AT1G75040, AT5G26000, AT3G57260, AT4G21650, AT3G52960, AT3G49120, AT5G49360, and AT3G14067, were identified by the in-solution method; among them, three were the GHs (AT5G26000, myrosinase 1, GH1; AT3G57260, β-1,3-glucanase 2, GH17; AT5G49360, bifunctional XYL 1/α-L-arabinofuranosidase, GH3). Moreover, four more GHs: AT4G30270 (xyloglucan endotransferase, GH16), AT1G68560 (bifunctional α-l-arabinofuranosidase/XYL, GH31), AT1G12240 (invertase, GH32) and AT2G28470 (β-galactosidase 8, GH35), were identified by the in-gel solution method only. Notably, more than half of above identified GHs are xylan- or hemicellulose-modifying enzymes, and will likely have an impact on cellulose accessibility, which is a critical factor for downstream enzymatic hydrolysis of plant tissues for biofuels production. Finally, the implications of these cell wall proteins identified at the late growth stage for the genetic engineering of bioenergy crops are discussed.« less

  8. Identifying the ionically bound cell wall and intracellular glycoside hydrolases in late growth stage Arabidopsis stems: Implications for the genetic engineering of bioenergy crops

    SciTech Connect

    Wei, Hui; Brunecky, Roman; Donohoe, Bryon S.; Ding, Shi -You; Ciesielski, Peter N.; Yang, Shihui; Tucker, Melvin P.; Himmel, Michael E.

    2015-05-13

    Identifying the cell wall-ionically bound glycoside hydrolases (GHs) in Arabidopsis stems is important for understanding the regulation of cell wall integrity. For cell wall proteomics studies, the preparation of clean cell wall fractions is a challenge since cell walls constitute an open compartment, which is more likely to contain a mixture of intracellular and extracellular proteins due to cell leakage at the late growth stage. Here, for this study, we utilize a CaCl2-extraction procedure to isolate non-structural proteins from Arabidopsis whole stems, followed by the in-solution and in-gel digestion methods coupled with Nano-LC-MS/MS, bioinformatics and literature analyses. This has led to the identification of 75 proteins identified using the in-solution method and 236 proteins identified by the in-gel method, among which about 10% of proteins predicted to be secreted. Together, eight cell wall proteins, namely AT1G75040, AT5G26000, AT3G57260, AT4G21650, AT3G52960, AT3G49120, AT5G49360, and AT3G14067, were identified by the in-solution method; among them, three were the GHs (AT5G26000, myrosinase 1, GH1; AT3G57260, β-1,3-glucanase 2, GH17; AT5G49360, bifunctional XYL 1/α-L-arabinofuranosidase, GH3). Moreover, four more GHs: AT4G30270 (xyloglucan endotransferase, GH16), AT1G68560 (bifunctional α-l-arabinofuranosidase/XYL, GH31), AT1G12240 (invertase, GH32) and AT2G28470 (β-galactosidase 8, GH35), were identified by the in-gel solution method only. Notably, more than half of above identified GHs are xylan- or hemicellulose-modifying enzymes, and will likely have an impact on cellulose accessibility, which is a critical factor for downstream enzymatic hydrolysis of plant tissues for biofuels production. Finally, the implications of these cell wall proteins identified at the late growth stage for the genetic engineering of bioenergy crops are discussed.

  9. Measurement of Clathrate Hydrate Thermodynamic Stability in the Presence of Ammonia

    NASA Technical Reports Server (NTRS)

    Dunham, Marc

    2012-01-01

    There is a lack of data available for the stability of clathrate hydrates in the presence of ammonia for low-to-moderate pressures in the 0-10 MPa range. Providing such data will allow for a better understanding of natural mass transfer processes on celestial bodies like Titan and Enceladus, on which destabilization of clathrates may be responsible for replenishment of gases in the atmosphere. The experimental process utilizes a custom-built gas handling system (GHS) and a cryogenic calorimeter to allow for the efficient testing of samples under varying pressures and gas species.

  10. Thermal metamorphism of the Arunachal Himalaya, India: Raman thermometry and thermochronological constraints on the tectono-thermal evolution

    NASA Astrophysics Data System (ADS)

    Mathew, George; De Sarkar, Sharmistha; Pande, Kanchan; Dutta, Suryendu; Ali, Shakir; Rai, Apritam; Netrawali, Shilpa

    2013-05-01

    Determination of the peak thermal condition is vital in order to understand tectono-thermal evolution of the Himalayan belt. The Lesser Himalayan Sequence (LHS) in the Western Arunachal Pradesh, being rich in carbonaceous material (CM), facilitates the determination of peak metamorphic temperature based on Raman spectroscopy of carbonaceous material (RSCM). In this study, we have used RSCM method of Beyssac et al. (J Metamorph Geol 20:859-871, 2002a) and Rahl et al. (Earth Planet Sci Lett 240:339-354, 2005) to estimate the thermal history of LHS and Siwalik foreland from the western Arunachal Pradesh. The study indicates that the temperature of 700-800 °C in the Greater Himalayan Sequence (GHS) decreases to 650-700 °C in the main central thrust zone (MCTZ) and decreases further to <200 °C in the Mio-Pliocene sequence of Siwaliks. The work demonstrates greater reliability of Rahl et al.'s (Earth Planet Sci Lett 240:339-354, 2005) RSCM method for temperatures >600 and <340 °C. We show that the higher and lower zones of Bomdila Gneiss (BG) experienced temperature of ~600 °C and exhumed at different stages along the Bomdila Thrust (BT) and Upper Main Boundary Thrust (U.MBT). Pyrolysis analysis of the CM together with the Fission Track ages from upper Siwaliks corroborates the RSCM thermometry estimate of ~240 °C. The results indicate that the Permian sequence north of Lower MBT was deposited at greater depths (>12 km) than the upper Siwalik sediments to its south at depths <8 km before they were exhumed. The 40Ar/39Ar ages suggest that the upper zones of Se La evolved ~13-15 Ma. The middle zone exhumed at ~11 Ma and lower zone close to ~8 Ma indicating erosional unroofing of the MCT sheet. The footwall of MCTZ cooled between 6 and 8 Ma. Analyses of P-T path imply that LHS between MCT and U.MBT zone falls within the kyanite stability field with near isobaric condition. At higher structural level, the temperatures increase gradually with P-T conditions in the

  11. Physiological significance of ghrelin revealed by studies using genetically engineered mouse models with modifications in the ghrelin system.

    PubMed

    Ariyasu, Hiroyuki; Akamizu, Takashi

    2015-01-01

    Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R or ghrelin receptor), is a 28-amino acid acylated peptide mainly produced in the stomach. The pharmacological administration of ghrelin is known to exert diverse effects, such as stimulating GH secretion, promoting food intake, and increasing adiposity. In recent years, genetically engineered mouse models have provided important insights into the physiology of various hormones. In this review, we discuss current knowledge regarding the physiological significance of ghrelin on the basis of studies using genetically engineered mouse models with modifications in the ghrelin system.

  12. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans.

    PubMed

    Broglio, F; Arvat, E; Benso, A; Gottero, C; Muccioli, G; Papotti, M; van der Lely, A J; Deghenghi, R; Ghigo, E

    2001-10-01

    Ghrelin, a 28 amino acid gastric hormone is a natural ligand of the GH Secretagogue (GHS) receptor (GHS-R) and strongly stimulates GH secretion though, like synthetic GHS, it shows other endocrine and non-endocrine activities. Aim of the present study was to clarify whether ghrelin administration influences insulin and glucose levels in humans. To this goal, we compared the effects of ghrelin, hexarelin, a synthetic GHS, or placebo on insulin and glucose as well as on GH levels in 11 normal young volunteers (age [mean +/- SEM]: 28.5 +/- 3.1 yr; BMI: 22.2 +/- 0.9 Kg/m(2)). Ghrelin induced very marked increase in GH secretion (DeltaAUC(0-180): 5777.1 +/- 812.6 microg/l/h; p < 0.01) which was not modified by placebo. Placebo administration did not modify insulin and glucose levels. On the other hand, ghrelin administration induced a prompt increase in glucose levels (DeltaAUC(0-180): 1343.1 +/- 443.5 mg/dl/h; p < 0.01 vs. saline). Absolute glucose levels at +15' were already higher than those at baseline (93.9 +/- 7.1 mg/dl; p < 0.01) and persisted elevated up to 165' (90.3 +/- 5.8 mg/dl; p < 0.01 vs. 0'). Ghrelin administration was also followed by a decrease in serum insulin levels (DeltaAUC(0-180): -207.1 +/- 70.5 mU/l/h; p < 0.05 vs. saline). Absolute insulin levels were significantly reduced from 30' (11.4 +/- 0.9 mU/l, p < 0.1 vs. 0'), showed the nadir at +45' (10.0 +/- 0.6 mU/l, p < 0.01 vs. 0') and then persisted lower (p < 0.01) than baseline up to +105'. Hexarelin administration did not modify glucose and insulin levels despite its marked GH-releasing effect (DeltaAUC(0-180): 4156.8 +/- 1180.3 microg/l/h; p < 0.01 vs. saline) that was slightly lower (p < 0.05) than that of ghrelin. In conclusion, these findings show that, besides stimulating GH secretion, ghrelin is a gastric hormone possessing metabolic actions such as hyperglycemic effect and lowering effect on insulin secretion in humans, at least after acute administration.

  13. [Role of bones in the physiopathology of idiopathic hypercalciuria: effect of amino-bisphosphonate alendronate].

    PubMed

    Weisinger, J R; Alonzo, E; Machado, C; Carlini, R; Martinis, R; Paz-Martínez, V; Bellorín-Font, E

    1997-01-01

    Previous studies from our laboratory demonstrated that bone mineral content is affected in patients with idiopathic hypercalciuria and that there is a correlation between bone mineral loss and in-vitro cytokine production. At the same time we found that short term treatment with alendronate decreased urinary calcium in these subjects. In the present study we have examined the long-term effects of alendronate treatment (10 mg/day for one year) on urinary calcium, urinary hydroxyproline and bone mineral content in 18 idiopathic hypercalciuric and 8 normocalciuric stone formers. Clinical characteristics, as well as gender and age distribution were similar in both groups. Urinary calcium and hydroxyproline, were measured monthly. Calcium excretion decreased significantly at the end of the first month, and remained lower thereafter (277 +/- 28, before vs. 202 +/- 26 mg/g creatinine, after 12 months on alendronate, p < 0.01). Urinary hydroxyproline decreased significantly during the study (125.5 +/- 32.1 vs. 39.66 +/- 17.5 mg/g creatinine, p < 0.05). Serum calcium, glomerular filtration rate, and urinary sodium, did not change during the study. Lumbar spine bone density (trabecular bone) obtained with X ray absorptiometry revealed a significant increase from 1.162 +/- 0.231 to 1.197 +/- 0.248 g/cm2 (p < 0.01). These changes were associated with a significant decrease in IL-1 alpha mRNA transcription by unstimulated and lipopolysaccharide stimulated blood mononuclear cells, as tested by the reverse transcriptase polymerase chain reaction. No changes were observed in bone cortical sites (femoral neck). Normocalciuric subjects showed no significant changes in urinary calcium. In summary, the changes observed in urinary calcium excretion and different bone metabolic parameters, suggest a role of bone in the pathophysiology of idiopathic hypercalciuria.

  14. High urinary calcium excretion and genetic susceptibility to hypertension and kidney stone disease.

    PubMed

    Mente, Andrew; Honey, R John D' A; McLaughlin, John M; Bull, Shelley B; Logan, Alexander G

    2006-09-01

    Increased urinary calcium excretion commonly is found in patients with hypertension and kidney stone disease (KSD). This study investigated the aggregation of hypertension and KSD in families of patients with KSD and hypercalciuria and explored whether obesity, excessive weight gain, and diabetes, commonly related conditions, also aggregate in these families. Consecutive patients with KSD, aged 18 to 50 yr, were recruited from a population-based Kidney Stone Center, and a 24-h urine sample was collected. The first-degree relatives of eligible patients (n = 333) and their spouse were interviewed by telephone to collect demographic and health information. Familial aggregation was assessed using generalized estimating equations. Multivariate-adjusted odds ratios (OR) revealed significant associations between hypercalciuria in patients and hypertension (OR 2.9; 95% confidence interval 1.4 to 6.2) and KSD (OR 1.9; 95% confidence interval 1.03 to 3.5) in first-degree relatives, specifically in siblings. No significant associations were found in parents or spouses or in patients with hyperuricosuria. Similarly, no aggregation with other conditions was observed. In an independent study of siblings of hypercalciuric patients with KSD, the adjusted mean fasting urinary calcium/creatinine ratio was significantly higher in the hypertensive siblings compared with normotensive siblings (0.60 +/- 0.32 versus 0.46 +/- 0.28 mmol/mmol; P < 0.05), and both sibling groups had significantly higher values than the unselected study participants (P < 0.001). Urinary sodium/creatinine and uric acid/creatinine ratios were not different among the groups. Although an environmental effect cannot be excluded fully, our findings suggest that the disturbance in calcium metabolism in hypertension and KSD has a genetic basis.

  15. Epigenetic Regulation of MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium Handling

    PubMed Central

    Gong, Yongfeng; Himmerkus, Nina; Plain, Allein; Bleich, Markus

    2015-01-01

    The kidney has a major role in extracellular calcium homeostasis. Multiple genetic linkage and association studies identified three tight junction genes from the kidney—claudin-14, -16, and -19—as critical for calcium imbalance diseases. Despite the compelling biologic evidence that the claudin-14/16/19 proteins form a regulated paracellular pathway for calcium reabsorption, approaches to regulate this transport pathway are largely unavailable, hindering the development of therapies to correct calcium transport abnormalities. Here, we report that treatment with histone deacetylase (HDAC) inhibitors downregulates renal CLDN14 mRNA and dramatically reduces urinary calcium excretion in mice. Furthermore, treatment of mice with HDAC inhibitors stimulated the transcription of renal microRNA-9 (miR-9) and miR-374 genes, which have been shown to repress the expression of claudin-14, the negative regulator of the paracellular pathway. With renal clearance and tubule perfusion techniques, we showed that HDAC inhibitors transiently increase the paracellular cation conductance in the thick ascending limb. Genetic ablation of claudin-14 or the use of a loop diuretic in mice abrogated HDAC inhibitor-induced hypocalciuria. The genetic mutations in the calcium-sensing receptor from patients with autosomal dominant hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes, and treatment with an HDAC inhibitor rescued the phenotypes of cell and animal models of ADH. Furthermore, systemic treatment of mice with antagomiRs against these miRs relieved claudin-14 gene silencing and caused an ADH-like phenotype. Together, our findings provide proof of concept for a novel therapeutic principle on the basis of epigenetic regulation of renal miRs to treat hypercalciuric diseases. PMID:25071082

  16. Ghrelin, food intake, and botanical extracts: A Review

    PubMed Central

    Rezaie, Peyman; Mazidi, Mohsen; Nematy, Mohsen

    2015-01-01

    A kind of growth hormone secretagogue (GHS), ghrelin, was first isolated from the rat stomach and plays a major role in the activation of the growth hormone secretagogue receptor 1a (GHS-R1a) resulting the release of growth hormone (GH). The preproghrelin gene is placed on chromosome 3, at locus 3p25 –2 in humans and constitutes five exons and three introns. Ghrelin is most plentifully expressed in particular cells in the oxyntic glands of the gastric epithelium, initially named X/A-like cells. Almost 60-70% of circulating ghrelin is secreted by the stomach. Plasma ghrelin concentration alters throughout the day. Ghrelin has been suggested to act as a meal initiator because of its appetite-stimulating influences in free feeding rats in short period. In addition to ghrelin’s function as a meal motivator, it seems to contribute in long-term energy balance and nutritional status. In addition, many studies have been carried out in order to investigate the effects of natural and medicinal plants and botanical extracts on appetite, food intake, energy hemostasis, and the level of related hormones including ghrelin. Due to the importance of ghrelin in nutritional and medical sciences, this review was performed to understand new aspects of this hormone’s function. PMID:26445708

  17. SWeRF--A method for estimating the relevant fine particle fraction in bulk materials for classification and labelling purposes.

    PubMed

    Pensis, Ingeborg; Luetzenkirchen, Frank; Friede, Bernd

    2014-05-01

    In accordance with the European regulation for classification, labelling and packaging of substances and mixtures (CLP) as well as the criteria as set out in the Globally Harmonized System (GHS), fine fraction of crystalline silica (CS) has been classified as a specific target organ toxicity, the specific organ in this case being the lung. Generic cut-off values for products containing a fine fraction of CS trigger the need for a method for the quantification of the fine fraction of CS in bulk materials. This article describes the so-called SWeRF method, the size-weighted relevant fine fraction. The SWeRF method combines the particle size distribution of a powder with probability factors from the EN 481 standard and allows the relevant fine fraction of a material to be calculated. The SWeRF method has been validated with a number of industrial minerals. This will enable manufacturers and blenders to apply the CLP and GHS criteria for the classification of mineral products containing RCS a fine fraction of CS.

  18. Deformation temperatures and flow vorticities near the base of the Greater Himalayan Series, Sutlej Valley and Shimla Klippe, NW India

    NASA Astrophysics Data System (ADS)

    Law, R. D.; Stahr, D. W.; Francsis, M. K.; Ashley, K. T.; Grasemann, B.; Ahmad, T.

    2013-09-01

    We report new deformation temperature and flow vorticity data from the base of the Greater Himalayan Series (GHS) exposed in the Sutlej Valley and Shimla Klippe of NW India. We focus on three groups of transects across the hanging wall of the Main Central Thrust (MCT). In order of relative foreland - hinterland positions, they are the Shimla Klippe, Western and Eastern Sutlej transects. Deformation temperatures indicated by quartz c-axis fabric opening-angles increase both from foreland to hinterland at a given structural distance above the MCT and up structural section from the MCT within individual transects. Deformation temperatures in the immediate hanging wall to the MCT are estimated at ˜510-535, 535-550 and 610 °C on the Shimla, Western Sutlej and Eastern Sutlej transects, respectively. The steepest inferred field gradients in deformation temperatures are recorded adjacent to the MCT and progressively decrease up structural section following a power law relationship. Comparison with temperature estimates based on multi-mineral phase equilibria data suggests that penetrative shearing occurred at close to peak metamorphic conditions. Vorticity analyses indicate that shearing along the base of the GHS occurred under sub-simple shear conditions (Wm values of 0.9-1.0) with a minor component of pure shear.

  19. A Trapped Covalent Intermediate of a Glycoside Hydrolase on the Pathway to Transglycosylation. Insights from Experiments and Quantum Mechanics/Molecular Mechanics Simulations.

    PubMed

    Raich, Lluís; Borodkin, Vladimir; Fang, Wenxia; Castro-López, Jorge; van Aalten, Daan M F; Hurtado-Guerrero, Ramón; Rovira, Carme

    2016-03-16

    The conversion of glycoside hydrolases (GHs) into transglycosylases (TGs), i.e., from enzymes that hydrolyze carbohydrates to enzymes that synthesize them, represents a promising solution for the large-scale synthesis of complex carbohydrates for biotechnological purposes. However, the lack of knowledge about the molecular details of transglycosylation hampers the rational design of TGs. Here we present the first crystallographic structure of a natural glycosyl-enzyme intermediate (GEI) of Saccharomyces cerevisiae Gas2 in complex with an acceptor substrate and demonstrate, by means of quantum mechanics/molecular mechanics metadynamics simulations, that it is tuned for transglycosylation (ΔG(⧧) = 12 kcal/mol). The 2-OH···nucleophile interaction is found to be essential for catalysis: its removal raises the free energy barrier significantly (11 and 16 kcal/mol for glycosylation and transglycosylation, respectively) and alters the conformational itinerary of the substrate (from (4)C1 → [(4)E](⧧) → (1,4)B/(4)E to (4)C1 → [(4)H3](⧧) → (4)C1). Our results suggest that changes in the interactions involving the 2-position could have an impact on the transglycosylation activity of several GHs.

  20. Lean mean fat reducing "ghrelin" machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity.

    PubMed

    Schellekens, Harriët; Dinan, Timothy G; Cryan, John F

    2010-01-01

    Obesity has reached epidemic proportions not only in Western societies but also in the developing world. Current pharmacological treatments for obesity are either lacking in efficacy and/or are burdened with adverse side effects. Thus, novel strategies are required. A better understanding of the intricate molecular pathways controlling energy homeostasis may lead to novel therapeutic intervention. The circulating hormone, ghrelin represents a major target in the molecular signalling regulating food intake, appetite and energy expenditure and its circulating levels often display aberrant signalling in obesity. Ghrelin exerts its central orexigenic action mainly in the hypothalamus and in particular in the arcuate nucleus via activation of specific G-protein coupled receptors (GHS-R). In this review we describe current pharmacological models of how ghrelin regulates food intake and how manipulating ghrelin signalling may give novel insight into developing better and more selective anti-obesity drugs. Accumulating data suggests multiple ghrelin variants and additional receptors exist to play a role in energy metabolism and these may well play an important role in obesity. In addition, the recent findings of hypothalamic GHS-R crosstalk and heterodimerization may add to the understanding of the complexity of bodyweight regulation.

  1. Neutralizing circulating ghrelin by expressing a growth hormone secretagogue receptor-based protein protects against high-fat diet-induced obesity in mice.

    PubMed

    Gagnon, J; Zhu, L; Anini, Y; Wang, Q

    2015-09-01

    Ghrelin is a stomach-derived peptide hormone that stimulates appetite and promotes adiposity through binding to the growth hormone secretagogue receptor (GHS-R1a). Administration of ghrelin in rodents increases weight gain due to stimulating food intake and reducing fat utilization. Therefore, reducing circulating ghrelin levels holds the potential to reduce weight gain. We developed a GHS-R1a-fusion constructs of a decoy protein containing the ligand-binding domains of the ghrelin receptor. Intramuscular injection of the GHSR/Fc plasmid decreased circulating levels of acylated-ghrelin. When challenged with the high fat diet, treated mice displayed reduced weight gain compared with controls, which was associated with reduced fat accumulation in the peritoneum but not lean mass. Quantitative PCR with reverse transcription showed increased PPARγ and hormone sensitive lipase transcripts levels in adipose tissue of treated animals, illustrating a preference for increased fat utilization. Intra-peritoneal glucose tolerance and insulin tolerance tests showed improved glucose clearance and insulin sensitivity in GHSR/Fc treated animals. We suggest that in vivo expression of the GHSR-based fusion protein prevents diet-induced weight gain, altering adipose gene expression and improving glucose tolerance. These findings, while confirming the role of ghrelin in peripheral energy metabolism, suggest that a strategy involving neutralization of the circulation ghrelin by intramuscular injection of the GHSR1/Fc fusion construct may find clinical application in the treatment of obesity.

  2. Transitional change in rat fetal cell proliferation in response to ghrelin and des-acyl ghrelin during the last stage of pregnancy

    SciTech Connect

    Inoue, Yoshiyuki; Nakahara, Keiko; Kangawa, Kenji; Murakami, Noboru

    2010-03-12

    Expression of mRNA for the ghrelin receptor, GHS-R1a, was detected in various peripheral and central tissues of fetal rats, including skin, bone, heart, liver, gut, brain and spinal cord, on embryonic day (ED)15 and ED17. However, its expression in skin, bone, heart and liver, but not in gut, brain and spinal cord, became relatively weak on ED19 and disappeared after birth (ND2). Ghrelin and des-acyl ghrelin facilitated the proliferation of cultured fetal (ED17, 19), but not neonatal (ND2), skin cells. On the other hand, with regard to cells from the spinal cord and hypothalamus, the proliferative effect of ghrelin continued after birth, whereas the effect of des-acyl ghrelin on neurogenesis in these tissues was lost at the ED19 fetal and ND2 neonatal stages. Immunohistochemistry revealed that the cells in the hypothalamus induced to proliferate by ghrelin at the ND2 stage were positive for nestin and glial fibrillary acidic protein. These results suggest that in the period immediately prior to, and after birth, rat fetal cells showing proliferation in response to ghrelin and des-acyl ghrelin are at a transitional stage characterized by alteration of the expression of GHS-R1a and an undefined des-acyl ghrelin receptor, their responsiveness varying among different tissues.

  3. The utility of scores in the decision to salvage or amputation in severely injured limbs.

    PubMed

    Shanmuganathan, Rajasekaran

    2008-10-01

    The decision to amputate or salvage a severely injured limb can be very challenging to the trauma surgeon. A misjudgment will result in either an unnecessary amputation of a valuable limb or a secondary amputation after failed salvage. Numerous scores have been proposed to provide guidelines to the treating surgeon, the notable of which are Mangled extremity severity score (MESS); the predictive salvage index (PSI); the Limb Salvage Index (LSI); the Nerve Injury, Ischemia, Soft tissue injury, Skeletal injury, Shock and Age of patient (NISSSA) score; and the Hannover fracture scale-97 (HFS-97). These scores have all been designed to evaluate limbs with combined orthopaedic and vascular injuries and have a poor sensitivity and specificity in evaluating IIIB injuries. Recently the Ganga Hospital Score (GHS) has been proposed which is specifically designed to evaluate a IIIB injury. Another notable feature of GHS is that it offers guidelines in the choice of the appropriate reconstruction protocol. The basis of the commonly used scores with their utility have been discussed in this paper.

  4. Identification of ghrelin receptor blocker, D-[Lys3] GHRP-6 as a CXCR4 receptor antagonist.

    PubMed

    Patel, Kalpesh; Dixit, Vishwa Deep; Lee, Jun Ho; Kim, Jie Wan; Schaffer, Eric M; Nguyen, Dzung; Taub, Dennis D

    2012-01-01

    [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS) is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R) antagonist. Unexpectedly, we identified that DLS also has the ability to block CXCL12 binding and activity through CXCR4 on T cells and peripheral blood mononuclear cells (PBMCs). Moreover, as CXCR4 has been shown to act as a major co-receptor for HIV-1 entry into CD4 positive host cells, we have also found that DLS partially blocks CXCR4-mediated HIV-1 entry and propagation in activated human PBMCs. These data demonstrate that DLS is not the specific and selective antagonist as thought for GHS-R1a and appears to have additional effects on the CXCR4 chemokine receptor. Our findings also suggest that structural analogues that mimic DLS binding properties may also have properties of blocking HIV infectivity, CXCR4 dependent cancer cell migration and attenuating chemokine-mediated immune cell trafficking in inflammatory disorders.

  5. Ghrelin and nicotine stimulate equally the dopamine release in the rat amygdala.

    PubMed

    Palotai, Miklós; Bagosi, Zsolt; Jászberényi, Miklós; Csabafi, Krisztina; Dochnal, Roberta; Manczinger, Máté; Telegdy, Gyula; Szabó, Gyula

    2013-10-01

    The orexigenic peptide ghrelin plays a prominent role in the regulation of energy balance and in the mediation of reward processes and reinforcement for addictive drugs, such as nicotine. Nicotine is the principal psychoactive component in tobacco, which is responsible for addiction and relapse of smokers. Ghrelin and nicotine activates the mesolimbicocortical dopaminergic pathways via growth hormone secretagogue receptors (GHS-R1A) and nicotinic acetylcholine receptors (nAchR), respectively, resulting in the release of dopamine in the nucleus accumbens, the amygdala and the prefrontal cortex. In the present study an in vitro superfusion of rat amygdalar slices was performed in order to investigate the direct action of ghrelin and nicotine on the amygdalar dopamine release. Ghrelin increased significantly the dopamine release from the rat amygdala following electrical stimulation. This effect was inhibited by both the selective GHS-R1A antagonist GHRP-6 and the selective nAchR antagonist mecamylamine. Under the same conditions, nicotine also increased significantly the dopamine release from the rat amygdala. This effect was antagonized by mecamylamine, but not by GHRP-6. Co-administration of ghrelin and nicotine induced a similar increase of amygdalar dopamine release. This stimulatory effect was partially reversed by both GHRP-6 and mecamylamine. The present results demonstrate that both ghrelin and nicotine stimulates directly the dopamine release in the amygdala, an important dopaminergic target area of the mesolimbicocortical pathway.

  6. Effects of subacute hypothyroidism on metabolism and growth-related molecules.

    PubMed

    Chang, Yen-Jui; Hwu, Chii-Min; Yeh, Chii-Chang; Wang, Paulus S; Wang, Shyi-Wu

    2014-07-30

    Thyroid hormones are crucial hormones that primarily regulate the metabolism of entire body cells. In this study, Sprague-Dawley rats were grouped into sham thyroidectomy (Sham Tx), thyroidectomy (Tx), Tx with thyroxine replacement (Tx + T4), and PTU injection (PTU) groups. Metabolic parameters were measured by means of metabolic cages for 14 days. After 14 days, the rats were sacrificed while the levels of plasma or serum TSH and growth-related molecules, such as active and total ghrelin, GH, and IGF-1, were assayed. The results revealed that hypothyroid rats tended to eat less food and experienced substantial body weight gain, whereas the rats with T4 replacement tended to eat more food while continuing to lose weight. In hypothyroid rats, the growth-related molecules, such as active ghrelin and total ghrelin secretion, were enhanced, and the ghrelin receptors were also up-regulated. However, circulating GH levels were not elevated and IGF-1 secretion was inhibited in hypothyroid rats. In the Tx + T4 group, the changes of active ghrelin, total ghrelin, GHS-R expression, and IGF-1 were reversed, whereas the GH secretion was higher than that of the Sham Tx group and hypothyroid groups. This study resulted in the novel finding that the ghrelin/GHS-R axis and GH/IGF-1 axis are interrupted in hypothyroid rats.

  7. Potential of semiarid soil from Caatinga biome as a novel source for mining lignocellulose-degrading enzymes.

    PubMed

    Lacerda Júnior, Gileno V; Noronha, Melline F; de Sousa, Sanderson Tarciso P; Cabral, Lucélia; Domingos, Daniela F; Sáber, Mírian L; de Melo, Itamar S; Oliveira, Valéria M

    2017-02-01

    The litterfall is the major organic material deposited in soil of Brazilian Caatinga biome, thus providing the ideal conditions for plant biomass-degrading microorganisms to thrive. Herein, the phylogenetic composition and lignocellulose-degrading capacity have been explored for the first time from a fosmid library dataset of Caatinga soil by sequence-based screening. A complex bacterial community dominated by Proteobacteria and Actinobacteria was unraveled. SEED subsystems-based annotations revealed a broad range of genes assigned to carbohydrate and aromatic compounds metabolism, indicating microbial ability to utilize plant-derived material. CAZy-based annotation identified 7275 genes encoding 37 glycoside hydrolases (GHs) families related to hydrolysis of cellulose, hemicellulose, oligosaccharides and other lignin-modifying enzymes. Taxonomic affiliation of genes showed high genetic potential of the phylum Acidobacteria for hemicellulose degradation, whereas Actinobacteria members appear to play an important role in celullose hydrolysis. Additionally, comparative analyses revealed greater GHs profile similarity among soils as compared to the digestive tract of animals capable of digesting plant biomass, particularly in the hemicellulases content. Combined results suggest a complex synergistic interaction of community members required for biomass degradation into fermentable sugars. This large repertoire of lignocellulolytic enzymes opens perspectives for mining potential candidates of biochemical catalysts for biofuels production from renewable resources and other environmental applications.

  8. Statement by the Growth Hormone Research Society on the GH/IGF-I axis in extending health span.

    PubMed

    Thorner, Michael O

    2009-10-01

    Despite the fact that growth hormone (GH) has not been approved for antiaging purposes, its use for this indication is widespread and increasing. The Growth Hormone Research Society (GRS) convened an international workshop to critically review and debate the available evidence related to the use of GH in the older adults and the relationship between the GH/insulin-like growth factor I (IGF-I) axis and the aging process. This statement presents the conclusions reached and gives recommendations for future studies in this research field regarding the use of GH and growth hormone secretagogues (GHS) for promoting health span. The participants concluded that, until future clinical research in this area is conducted, in particular carefully designed, long-term studies, using validated outcome parameters, the clinical use of GH or GHS in older adults, alone or in combination with testosterone, cannot be recommended. In addition, future basic studies in model systems, to continue to unravel GH/IGF-I effects related to human life span and health span, were advocated.

  9. Rapidly building global health security capacity--Uganda demonstration project, 2013.

    PubMed

    Borchert, Jeff N; Tappero, Jordan W; Downing, Robert; Shoemaker, Trevor; Behumbiize, Prosper; Aceng, Jane; Makumbi, Issa; Dahlke, Melissa; Jarrar, Bassam; Lozano, Briana; Kasozi, Sam; Austin, Mark; Phillippe, Dru; Watson, Ian D; Evans, Tom J; Stotish, Timothy; Dowell, Scott F; Iademarco, Michael F; Ransom, Raymond; Balajee, Arunmozhi; Becknell, Kristi; Beauvais, Dennis; Wuhib, Tadesse

    2014-01-31

    Increasingly, the need to strengthen global capacity to prevent, detect, and respond to public health threats around the globe is being recognized. CDC, in partnership with the World Health Organization (WHO), has committed to building capacity by assisting member states with strengthening their national capacity for integrated disease surveillance and response as required by International Health Regulations (IHR). CDC and other U.S. agencies have reinforced their pledge through creation of global health security (GHS) demonstration projects. One such project was conducted during March-September 2013, when the Uganda Ministry of Health (MoH) and CDC implemented upgrades in three areas: 1) strengthening the public health laboratory system by increasing the capacity of diagnostic and specimen referral networks, 2) enhancing the existing communications and information systems for outbreak response, and 3) developing a public health emergency operations center (EOC) (Figure 1). The GHS demonstration project outcomes included development of an outbreak response module that allowed reporting of suspected cases of illness caused by priority pathogens via short messaging service (SMS; i.e., text messaging) to the Uganda District Health Information System (DHIS-2) and expansion of the biologic specimen transport and laboratory reporting system supported by the President's Emergency Plan for AIDS Relief (PEPFAR). Other enhancements included strengthening laboratory management, establishing and equipping the EOC, and evaluating these enhancements during an outbreak exercise. In 6 months, the project demonstrated that targeted enhancements resulted in substantial improvements to the ability of Uganda's public health system to detect and respond to health threats.

  10. Reduction in circulating ghrelin concentration after maturation does not affect food intake.

    PubMed

    Ariyasu, Hiroyuki; Yamada, Go; Iwakura, Hiroshi; Matsumura, Sigenobu; Inoue, Kazuo; Kangawa, Kenji; Nakao, Kazuwa; Akamizu, Takashi

    2014-01-01

    Ghrelin has a potent orexigenic effect and induces adiposity when administered exogenously. Since plasma ghrelin levels rise before meals, ghrelin was thought to play a crucial role in the regulation of appetite. In contrast, mice deficient in the production of ghrelin or the corresponding receptor, GHS-R, do not eat less, throwing the role of ghrelin in the regulation of energy homeostasis into question. Since these mice lack ghrelin or GHS-R from the time of conception, the possibility that compensatory mechanisms may have arisen during development cannot be ruled out. In this study, we used a transgenic mouse model that expresses human diphtheria toxin (DT) receptor cDNA under the control of the ghrelin promoter (GPDTR-Tg mice). As previously reported, an injection of DT into this mouse model ablates ghrelin-secreting cells in the stomach but not in the hypothalamus, resulting in a reduction in circulating ghrelin levels. We used this model system to evaluate the physiological roles of circulating ghrelin in the regulation of food intake. Meal patterns, diurnal and nocturnal meal sizes, and cumulative food intake of DT-treated GPDTR-Tg mice were not affected, although circulating ghrelin levels markedly decreased even after fasting. These mice also displayed normal responses to starvation; however, the use of fat increased and slower weight gain when maintained on a high fat diet was observed. Together, these data suggest that circulating ghrelin does not play a crucial role in feeding behavior, but rather is involved in maintaining body weight.

  11. A Novel Member of GH16 Family Derived from Sugarcane Soil Metagenome.

    PubMed

    Alvarez, Thabata Maria; Liberato, Marcelo Vizoná; Cairo, João Paulo L Franco; Paixão, Douglas A A; Campos, Bruna M; Ferreira, Marcel R; Almeida, Rodrigo F; Pereira, Isabela O; Bernardes, Amanda; Ematsu, Gabriela C G; Chinaglia, Mariana; Polikarpov, Igor; de Oliveira Neto, Mario; Squina, Fabio Marcio

    2015-09-01

    Glycoside hydrolases (GHs) are enzymes found in all living kingdoms that are involved in multiple physiological functions. Due to their multiple enzymatic activities, GHs are broadly applied in bioethanol, food, and paper industry. In order to increase the productivity of these industrial processes, a constant search for novel and efficient enzymes has been proved to be necessary. In this context, metagenomics is a powerful approach to achieve this demand. In the current study, we describe the discovery and characterization of a novel member of GH16 family derived from the sugarcane soil metagenome. The enzyme, named SCLam, has 286 amino acid residues and displays sequence homology and activity properties that resemble known laminarases. SCLam is active against barley beta-glucan, laminarin, and lichenan (72, 33, and 10 U mg(-1), respectively). The optimal reaction conditions were identified as 40 °C and pH 6.5. The low-resolution structure was determined using the small-angle X-ray scattering technique, revealing that SCLam is a monomer in solution with a radius of gyration equal to 19.6 Å. To the best of our knowledge, SCLam is the first nonspecific (1,3/1,3:1,4)-β-D-glucan endohydrolase (EC 3.2.1.6) recovered by metagenomic approach to be characterized.

  12. StratBAM: A Discrete-Event Simulation Model to Support Strategic Hospital Bed Capacity Decisions.

    PubMed

    Devapriya, Priyantha; Strömblad, Christopher T B; Bailey, Matthew D; Frazier, Seth; Bulger, John; Kemberling, Sharon T; Wood, Kenneth E

    2015-10-01

    The ability to accurately measure and assess current and potential health care system capacities is an issue of local and national significance. Recent joint statements by the Institute of Medicine and the Agency for Healthcare Research and Quality have emphasized the need to apply industrial and systems engineering principles to improving health care quality and patient safety outcomes. To address this need, a decision support tool was developed for planning and budgeting of current and future bed capacity, and evaluating potential process improvement efforts. The Strategic Bed Analysis Model (StratBAM) is a discrete-event simulation model created after a thorough analysis of patient flow and data from Geisinger Health System's (GHS) electronic health records. Key inputs include: timing, quantity and category of patient arrivals and discharges; unit-level length of care; patient paths; and projected patient volume and length of stay. Key outputs include: admission wait time by arrival source and receiving unit, and occupancy rates. Electronic health records were used to estimate parameters for probability distributions and to build empirical distributions for unit-level length of care and for patient paths. Validation of the simulation model against GHS operational data confirmed its ability to model real-world data consistently and accurately. StratBAM was successfully used to evaluate the system impact of forecasted patient volumes and length of stay in terms of patient wait times, occupancy rates, and cost. The model is generalizable and can be appropriately scaled for larger and smaller health care settings.

  13. Determination of growth hormone secretagogue pralmorelin (GHRP-2) and its metabolite in human urine by liquid chromatography/electrospray ionization tandem mass spectrometry.

    PubMed

    Okano, Masato; Sato, Mitsuhiko; Ikekita, Ayako; Kageyama, Shinji

    2010-07-30

    GHRP-2 (pralmorelin, D-Ala-D-(beta-naphthyl)-Ala-Ala-Trp-D-Phe-Lys-NH(2)), which belongs to a class of growth hormone secretagogue (GHS), is intravenously used to diagnose growth hormone (GH) deficiency. Because it may be misused in expectation of a growth-promoting effect by athletes, the illicit use of GHS by athletes has been prohibited by the World Anti-Doping Agency (WADA). Therefore, the mass spectrometric identification of urinary GHRP-2 and its metabolite D-Ala-D-(beta-naphthyl)-Ala-Ala-OH (AA-3) was studied using liquid chromatography/electrospray ionization tandem mass spectrometry for doping control purposes. The method consists of solid-phase extraction using stable-isotope-labeled GHRP-2 as an internal standard and subsequent ultra-performance liquid chromatography/tandem mass spectrometry, and the two target peptides were determined at urinary concentrations of 0.5-10 ng/mL. The recoveries ranged from 84 to 101%, and the assay precisions were calculated as 1.6-3.8% (intra-day) and 1.9-4.3% (inter-day). Intravenous administration of GHRP-2 in ten male volunteers was studied to demonstrate the applicability of the method. In all ten cases, unchanged GHRP-2 and its specific metabolite AA-3 were detected in urine.

  14. A cross-sectional study on association of work environment, coping style, and other risk factors with depression among caregivers in group homes in Japan.

    PubMed

    Suzumura, Miwa; Fushiki, Yasuhiro; Kobayashi, Kota; Oura, Asae; Suzumura, Shigeo; Yamashita, Masafumi; Mori, Mitsuru

    2013-01-01

    A cross-sectional study was conducted to explore the potential association between work environment and/or stress coping ability, and depressive status among caregivers working for "group homes (GHs)" in Japan. In January 2010, 438 out of 700 caregivers working at GHs in Sapporo City returned completed questionnaires to us. The questionnaires consisted of the Center of Epidemiological Scales-Depression, items about worker's attributions, Ozeki's coping scale, and so on. An analysis using a logistic regression model was used to find the associations adjusting for gender and age. Subjects who were 45 yr or older, had a spouse, had job training, a standard workload and scored high in emotion-oriented coping were significantly associated with a decreased risk of depression. Subjects who were less proud of their job, less willing to continue care for the frail elderly and had fewer acceptances by their supervisors or colleagues for consultation were significantly associated with an increased risk of depression. This study supports our hypothesis that there can be possible variables among individual factors, work environment and/or coping style for stress which may modulate a risk on the depressive status of caregivers.

  15. Hepatitis A outbreak among adults with developmental disabilities in group homes--Michigan, 2013.

    PubMed

    Bohm, Susan R; Berger, Keira Wickliffe; Hackert, Pamela B; Renas, Richard; Brunette, Suzanne; Parker, Nicole; Padro, Carolyn; Hocking, Anne; Hedemark, Mary; Edwards, Renai; Bush, Russell L; Khudyakov, Yury; Nelson, Noele P; Teshale, Eyasu H

    2015-02-20

    Hepatitis A virus (HAV) infections among persons with developmental disabilities living in institutions were common in the past, but with improvements in care and fewer persons institutionalized, the number of HAV infections has declined in these institutions. However, residents in institutions are still vulnerable if they have not been vaccinated. On April 24, 2013, a resident of a group home (GH) for adults with disabilities in southeast Michigan (GH-A) was diagnosed with hepatitis A and died 2 days later of fulminant liver failure. Four weeks later, a second GH-A resident was diagnosed with hepatitis A. None of the GH-A residents or staff had been vaccinated against hepatitis A. Over the next 3 months, six more cases of hepatitis A were diagnosed in residents in four other Michigan GHs. Three local health departments were involved in case investigation and management, including administration of postexposure prophylaxis (PEP). Serum specimens from seven cases were found to have an identical strain of HAV genotype 1A. This report describes the outbreak investigation, the challenges of timely delivery of PEP for hepatitis A, and the need for preexposure vaccination against hepatitis A for adults living or working in GHs for the disabled.

  16. Molecular Basis of Arabinobio-hydrolase Activity in Phytopathogenic Fungi

    PubMed Central

    Carapito, Raphaël; Imberty, Anne; Jeltsch, Jean-Marc; Byrns, Simon C.; Tam, Pui-Hang; Lowary, Todd L.; Varrot, Annabelle; Phalip, Vincent

    2009-01-01

    The phytopathogenic fungus Fusarium graminearum secretes a very diverse pool of glycoside hydrolases (GHs) aimed at degrading plant cell walls. α-l-Arabinanases are essential GHs participating in the complete hydrolysis of hemicellulose, a natural resource for various industrial processes, such as bioethanol or pharmaceuticals production. Arb93A, the exo-1,5-α-l-arabinanase of F. graminearum encoded by the gene fg03054.1, belongs to the GH93 family, for which no structural data exists. The enzyme is highly active (1065 units/mg) and displays a strict substrate specificity for linear α-1,5-l-arabinan. Biochemical assays and NMR experiments demonstrated that the enzyme releases α-1,5-l-arabinobiose from the nonreducing end of the polysaccharide. We determined the crystal structure of the native enzyme and its complex with α-1,5-l-arabinobiose, a degradation product of α-Me-1,5-l-arabinotetraose, at 1.85 and 2.05Å resolution, respectively. Arb93A is a monomeric enzyme, which presents the six-bladed β-propeller fold characteristic of sialidases of clan GHE. The configuration of the bound arabinobiose is consistent with the retaining mechanism proposed for the GH93 family. Catalytic residues were proposed from the structural analysis, and site-directed mutagenesis was used to validate their role. They are significantly different from those observed for GHE sialidases. PMID:19269961

  17. Evidence that the growth hormone receptor mediates differentiation and development of the mammary gland.

    PubMed

    Feldman, M; Ruan, W; Cunningham, B C; Wells, J A; Kleinberg, D L

    1993-10-01

    We have shown that nonlactogenic rat (r) GH is far more potent than rPRL in inducing rat mammary development. To determine the relative roles of GH and PRL in mammary development and their mechanisms of action, we have compared the abilities of a group of native and mutant GHs, PRLs, and placental lactogens (PLs) to induce mammary development, bind to GH receptors, and activate lactogenic receptors. Mammary development was assessed histologically by counting terminal end buds and alveolar structures in glands from sexually immature, hypophysectomized, castrated, estradiol-treated rats. Hormones were implanted, in Elvax pellets, into the lumbar mammary gland. Significant increases in terminal end buds (P < 0.03) over internal control values were obtained with rGH, recombinant human GH (rhGH), rbGH, and one of two mutant rhGHs. These four hormones were also found to bind to GH receptors with high affinity. In contrast, little development occurred with hPRL, rPRL, rhPL, ovine PRL, mutant forms of rhPRL and rhPL, and a mutant of rhGH altered to reduce binding to GH and PRL receptors. All of these substances are more than 50-fold reduced in binding to the GH receptor, yet can bind and activate lactogenic receptors. Thus, only those natural or mutant pituitary or placental hormones with high binding affinity to GH receptors induce mammary development, suggesting that GH receptors play a central role in this process.

  18. SWeRF—A Method for Estimating the Relevant Fine Particle Fraction in Bulk Materials for Classification and Labelling Purposes

    PubMed Central

    2014-01-01

    In accordance with the European regulation for classification, labelling and packaging of substances and mixtures (CLP) as well as the criteria as set out in the Globally Harmonized System (GHS), fine fraction of crystalline silica (CS) has been classified as a specific target organ toxicity, the specific organ in this case being the lung. Generic cut-off values for products containing a fine fraction of CS trigger the need for a method for the quantification of the fine fraction of CS in bulk materials. This article describes the so-called SWeRF method, the size-weighted relevant fine fraction. The SWeRF method combines the particle size distribution of a powder with probability factors from the EN 481 standard and allows the relevant fine fraction of a material to be calculated. The SWeRF method has been validated with a number of industrial minerals. This will enable manufacturers and blenders to apply the CLP and GHS criteria for the classification of mineral products containing RCS a fine fraction of CS. PMID:24389081

  19. Glycoside hydrolase processivity is directly related to oligosaccharide binding free energy.

    PubMed

    Payne, Christina M; Jiang, Wei; Shirts, Michael R; Himmel, Michael E; Crowley, Michael F; Beckham, Gregg T

    2013-12-18

    Many glycoside hydrolase (GH) enzymes act via a processive mechanism whereby an individual carbohydrate polymer chain is decrystallized and hydrolyzed along the chain without substrate dissociation. Despite considerable structural and biochemical studies, a molecular-level theory of processivity that relates directly to structural features of GH enzymes does not exist. Here, we hypothesize that the degree of processivity is directly linked to the ability of an enzyme to decrystallize a polymer chain from a crystal, quantified by the binding free energy of the enzyme to the cello-oligosaccharide. We develop a simple mathematical relationship formalizing this hypothesis to quantitatively relate the binding free energy to experimentally measurable kinetic parameters. We then calculate the absolute ligand binding free energy of cellulose chains to the biologically and industrially important GH Family 7 processive cellulases with free energy perturbation/replica-exchange molecular dynamics. Taken with previous observations, our results suggest that degree of processivity is directly correlated to the binding free energy of cello-oligosaccharide ligands to GH7s. The observed binding free energies also suggest candidate polymer morphologies susceptible to enzyme action when compared to the work required to decrystallize cellulose chains. We posit that the ligand binding free energy is a key parameter in comparing the activity and function of GHs and may offer a molecular-level basis toward a general theory of carbohydrate processivity in GHs and other enzymes able to process linear carbohydrate polymers, such as cellulose and chitin synthases.

  20. Characterization of new stable ghrelin analogs with prolonged orexigenic potency.

    PubMed

    Maletínská, Lenka; Pýchová, Miroslava; Holubová, Martina; Blechová, Miroslava; Demianová, Zuzana; Elbert, Tomáš; Železná, Blanka

    2012-03-01

    Ghrelin, the only known peripherally produced and centrally acting peptide that stimulates food intake, is synthesized primarily in the stomach and acts through the growth hormone secretagogue receptor (GHS-R1a). In addition to its orexigenic effect, ghrelin stimulates the release of growth hormone (GH). In this study, we investigated the biological properties of full-length and shortened ghrelin analogs in which octanoylated Ser(3) is replaced with an octanoic acid moiety coupled to diaminopropionic acid (Dpr). Ghrelin analogs stabilized with Dpr(N-octanoyl) in position 3 and noncoded amino acids in position 1 (sarcosine) and/or position 4 (naphthylalanine or cyclohexylalanine) were found to possess affinities similar to those of ghrelin for cell membranes with transfected GHS-R1a. In vivo, the prolonged orexigenic effects of analogs containing Dpr(N-octanoyl)(3) compared with that of ghrelin in adult mice and a similar impact on GH secretion in young mice were found. Full-length [Dpr(N-octanoyl)(3)]ghrelin and its analogs with a noncoded amino acid in position 1 and/or 4 showed significantly prolonged stability in blood plasma compared with that of ghrelin. Ghrelin analogs with a prolonged orexigenic effect are potential treatments for GH deficiency or cachexia that accompanies chronic diseases. Desoctanoylated ghrelin analogs and N-terminal penta- and octapeptides of ghrelin did not show any biological activity.

  1. Structural insights into the early stages of exhumation along an orogen-scale detachment: The South Tibetan Detachment System, Dzakaa Chu section, Eastern Himalaya

    NASA Astrophysics Data System (ADS)

    Cottle, John M.; Jessup, Micah J.; Newell, Dennis L.; Searle, Michael P.; Law, Richard D.; Horstwood, Matthew S. A.

    2007-11-01

    Structural transects through the South Tibetan Detachment system (STDS) in the Dzakaa Chu valley, Tibet reveal a ˜1000-m thick, low-angle (<35°) zone of distributed ductile shear that displaces Paleozoic sediments over amphibolite facies gneisses, calc-mylonites and leucogranites of the Greater Himalayan Series (GHS). Within the shear zone, grain-size reduction with dynamic recrystallisation of quartz and growth of secondary phyllosilicates accommodated ductile deformation at elevated temperatures. Small-scale brittle normal faults and extensional shear veins overprint ductile features recording deformation at lower temperatures. Our structural data indicate that the Dzakaa Chu STDS records a progression from ductile- to brittle-deformation without development of a discrete detachment fault(s) that is common to many STDS sections. U(-Th)-Pb dating of post-kinematic leucogranites suggest that, in the lower part of the shear zone, mylonitic fabric development occurred prior to ˜20 Ma. By integrating structural and geochronological evidences we propose that the Dzakaa Chu STDS represents a deeper structural position than elsewhere in the Himalaya and provides important insight into the early ductile exhumation of the GHS that was dominated by movement along a 1-km wide shear zone without discrete brittle detachments. These findings are an important step towards understanding the development of low-angle detachment fault systems active during continental collision.

  2. Protective but Not Anticonvulsant Effects of Ghrelin and JMV-1843 in the Pilocarpine Model of Status epilepticus

    PubMed Central

    Lucchi, Chiara; Curia, Giulia; Vinet, Jonathan; Gualtieri, Fabio; Bresciani, Elena; Locatelli, Vittorio; Torsello, Antonio; Biagini, Giuseppe

    2013-01-01

    In models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth hormone secretagogue-receptor 1a (GHS-R1a). This activity may be explained by anticonvulsant properties that, however, are controversial. We further investigated neuroprotection and the effects on seizures by comparing ghrelin with a more effective GHS-R1a agonist, JMV-1843. Rats were treated either with ghrelin, JMV-1843 or saline 10 min before pilocarpine, which was used to induce status epilepticus. Status epilepticus, developed in all rats, was attenuated by diazepam. No differences were observed among the various groups in the characteristics of pilocarpine-induced seizures. In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.45±0.07 mm2 in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression. Both ghrelin (P<0.05) and JMV-1843 (P<0.01) were able to reduce the area of loss in glial fibrillary acidic protein immunostaining. In addition, JMV-1843 counteracted (P<0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats. JMV-1843 was able to ameliorate neuronal survival in the hilus of dentate gyrus and medial entorhinal cortex layer III (P<0.05 vs saline and ghrelin groups). These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus. PMID:24015271

  3. Suitability of histopathology as an additional endpoint to the Isolated Chicken Eye Test for classification of non-extreme pH detergent and cleaning products.

    PubMed

    Cazelle, Elodie; Eskes, Chantra; Hermann, Martina; Jones, Penny; McNamee, Pauline; Prinsen, Menk; Taylor, Hannah; Wijnands, Marcel V W

    2014-06-01

    A.I.S.E. investigated the suitability of histopathological evaluations as an additional endpoint to the regulatory adopted ICE in vitro test method (OECD TG 438) to identify non-extreme pH detergent and cleaning products that require classification as EU CLP/UN GHS Category 1 (serious eye damage). To this aim, a total of 30 non-extreme pH products covering the range of in vivo classifications for eye irritation, and representing various product categories were tested. Epithelium vacuolation (mid and lower layers) and erosion (at least moderate) were found to be the most relevant histopathological effects induced by products classified in vivo as Category 1. Histopathology criteria specifically developed for non-extreme pH detergent and cleaning products were shown to correctly identify materials classified as Category 1 based on in vivo persistent effects, and to significantly increase the overall sensitivity of the standard ICE prediction model for Category 1 identification (to 75%) whilst maintaining a good concordance (73%). In contrast, use of EU CLP additivity approach for classification of mixtures was considerably less predictive, with a concordance of only 27%, and 100% over-predictions of non-Category 1 products. As such, use of histopathology as an addition to the ICE test method was found suitable to identify EU CLP/UN GHS Category 1 non-extreme pH detergent and cleaning products and to allow a better discrimination from Category 2 products.

  4. Carbohydrate-binding module assisting glycosynthase-catalysed polymerizations.

    PubMed

    Codera, Victoria; Gilbert, Harry J; Faijes, Magda; Planas, Antoni

    2015-08-15

    Carbohydrate-binding modules (CBMs) are found within multi-modular polysaccharide degrading enzymes [glycoside hydrolases (GHs)]. CBMs play a critical role in the recognition of plant cell-wall polysaccharides and enhance the hydrolase activity of their cognate catalytic domains by increasing enzyme substrate proximity. Mimicking their role in Nature, we, in the present study, propose that CBMs may assist in vitro glycosynthase-catalysed polymerization reactions to produce artificial polysaccharides. Glycosynthases are GHs that have been engineered to catalyse glycoside bond formation for the synthesis of oligosaccharides, glycoconjugates and glycans. The degree of polymerization (DP) of the glycans generated is limited by the solubility of the polymeric product. In the present study, we have targeted the synthesis of artificial 1,3-1,4-β-glucans with a regular sequence using the glycosynthase E(134)S derived from a Bacillus licheniformis lichenase. We show that the addition of CBM11, which binds mixed-linked β-glucans, either as an isolated protein or fused to the glycosynthase E(134)S, has an effect on the DP of the polysaccharide products that is dependent on the rate of polymerization. The mechanism by which CBM influences the DP of the synthesized glycans is discussed.

  5. 'Translational formative evaluation': critical in up-scaling public health programmes.

    PubMed

    O'Hara, Blythe J; Phongsavan, Philayrath; King, Lesley; Develin, Elizabeth; Milat, Andrew J; Eggins, Dianne; King, Elizabeth; Smith, Joanne; Bauman, Adrian E

    2014-03-01

    The process of generating evidence-based public health interventions is understood to include steps that define the issue, generate and test solutions in controlled settings, replicate and then disseminate more widely. However, to date models have not considered the types and scale of formative evaluation tasks that are needed to up-scale interventions, from efficacy to population-wide dissemination in the real world. In this paper, we propose that an additional stage of 'translational formative evaluation' is necessary for the translation of effectiveness evidence into wide-scale public health practice. We illustrate the utility of translational formative evaluation, through a case study of the Get Healthy Information and Coaching Service(®) (GHS), a population-based telephone service designed to assist adults change lifestyle-related behaviours. The additional translational formative evaluation steps comprised synthesis of efficacy studies, qualitative research with the wider target audience, environmental analysis and stakeholder consultation. They produced precise recommendations to refine GHS design and implementation. Translational formative evaluation is a necessary intermediate step, following efficacy studies and a precursor to population-wide implementation of public health programmes.

  6. Ghrelin Receptor Regulates Appetite and Satiety during Aging in Mice by Regulating Meal Frequency and Portion Size but Not Total Food Intake1234

    PubMed Central

    Lin, Ligen; Nuotio-Antar, Alli M.; Ma, Xiaojun; Liu, Feng; Fiorotto, Marta L.; Sun, Yuxiang

    2014-01-01

    Aging is often associated with overweight and obesity. There exists a long-standing debate about whether meal pattern also contributes to the development of obesity. The orexigenic hormone ghrelin regulates appetite and satiety by activating its receptor, growth hormone secretagogue receptor (GHS-R). In mice, circulating ghrelin concentrations and brain GHS-R expression were shown to increase with aging. To assess whether GHS-R regulates feeding pattern during aging, we studied meal patterns for the following cohorts of male mice fed a normal unpurified diet: 1) 3–4 mo, young wild-type (WT) mice; 2) 3–4 mo, young Ghsr-null (Ghsr−/−) mice; 3) 12–14 mo, middle-aged WT (WT-M) mice; 4) 12–14 mo, middle-aged Ghsr−/− (Ghsr−/−-M) mice; 5) 24–26 mo, old WT (WT-O) mice; and 6) 24–26 mo, old Ghsr−/− (Ghsr−/−-O) mice. Although the total daily food intake of Ghsr−/− mice was similar to that of WT controls, Ghsr−/−-M and Ghsr−/−-O mice had 9% (P = 0.07) and 16% (P < 0.05) less body weight compared with WT-M and WT-O mice, respectively, primarily due to reduced fat mass (P < 0.05, WT-M vs. Ghsr−/−-M and WT-O vs. Ghsr−/−-O). Intriguingly, Ghsr−/−-M mice ate larger meals (on average, Ghsr−/−-M mice ate 0.117 g/meal and WT-M mice ate 0.080 g/meal; P < 0.01) and took a longer time to eat (Ghsr−/−-M, 196.0 s and WT-M, 128.9 s; P < 0.01), but ate less frequently (Ghsr−/−-M, 31.0 times/d and WT-M, 42.3 times/d; P < 0.05) than WT-M controls. In addition, we found that expression of hypothalamic orexigenic peptides, neuropeptide Y (NPY) and agouti-related peptide (AgRP), was relatively lower in aged WT mice (P = 0.09 for NPY and P = 0.06 for AgRP), but anorexic peptide pro-opiomelanocortin (POMC) expression remained unchanged between the WT age groups. Interestingly, old Ghsr−/− mice had greater hypothalamic NPY expression (102% higher; P < 0.05) and AgRP expression (P = 0.07) but significantly lower POMC expression

  7. Geochronogy of leucogranites in Yadong region: constraints on the age of the South Tibetan Detachment System in central-eastern Himalaya

    NASA Astrophysics Data System (ADS)

    Liu, Zhi-Chao; Wu, Fu-Yuan; Ji, Wei-Qiang; Wang, Jian-Gang; Liu, Xiao-Chi

    2016-04-01

    The South Tibetan Detachment System (STDS) is a series of low-angle normal faults with an extension of more than 2000 km along strike of the Himalaya orogen (Burchfiel et al., 1992). It separates the high-grade rocks of the Greater Himalaya Sequence (GHS) from the generally low-grade metasedimentary rocks of Tethyan Himalaya Sequence (THS) above. Knowing the timing of deformations related to the STDS is critical to understanding the exhumation history of the Himalaya. In central-eastern Himalaya, the STDS is disrupted by a major northeast-trending fault zone that was referred as Yadong Cross Structure (YCS). Exposures of the STDS either side of the YCS have been well determined, and the cessation timing of shearing have been estimated prior to 22~16 Ma for the western section and younger than 12 Ma for the eastern section (see the review in Leloup et al., 2010). It suggests that the YCS is key region that corresponds to a major timing discontinuity. However, the exposure of STDS in Yadong region and its activity timing has not been well constrained. Field mapping of the Yadong region reveals that a klippen of Cambrian biotite schist, chlorite schist, calcischists and quartzite, and Ordovician limestones of the THS units was resting on garnet-sillimanite-plagioclase gneisses, augen granitic gneisses and migmatites of the GHS basement (China University of Geosciences, 2005, unpublished). Structural relationships indicate that the contact is a low-angle normal fault, which was termed as Yadong shear zone (Xu et al., 2013). We correlate the Yadong shear zone to the STDS following the broader convention that STDS is defined as the contact between the THS and GHS. There are two leucogranite plutons within the shear zone, the Dingga pluton to the north and the Gaowu pluton to the south. They intruded into both GHS and THS, with the main bodies are undeformed and isotropic. Furthermore, there are numbers of undeformed dykes crosscut the foliations of the country rocks

  8. Effects of microgravity on renal stone risk assessment

    NASA Technical Reports Server (NTRS)

    Pietrzyk, R. A.; Pak, C. Y. C.; Cintron, N. M.; Whitson, P. A.

    1992-01-01

    Physiologic changes induced during human exposure to the microgravity environment of space may contribute to an increased potential for renal stone formation. Renal stone risk factors obtained 10 days before flight and immediately after return to earth indicated that calcium oxalate and uric acid stone-forming potential was increased after space flights of 4-10 days. These data describe the need for examining renal stone risk during in-flight phases of space missions. Because of limited availability of space and refrigerated storage on spacecraft, effective methods must be developed for collecting urine samples in-flight and for preserving (or storing) them at temperatures and under conditions commensurate with mission constraints.

  9. The pattern of urinary stone disease in Leeds and in the United Kingdom in relation to animal protein intake during the period 1960-1980.

    PubMed

    Robertson, W G; Peacock, M

    1982-01-01

    Studies on the occurrence of urinary stone disease in Leeds between 1960 and 1980 show that there was an increase in the number of stones formed during the period 1960-1970, a fall between 1972 and a subsequent rise between 1977 and 1980. The fluctuations in stone incidence were accounted for almost entirely by changes in the number of 'pure' calcium oxalate stones and, to a lesser extent, the number of uric acid stones produced. The incidence patterns of these types of stone closely reflected changes in the consumption of animal protein in the population as a whole during the same period. There were no parallel changes either in the number of stones consisting of a mixture of calcium oxalate and calcium phosphate or in the number of infection stones.

  10. Experimental oxalate urolith formation in rats.

    PubMed

    McIntosh, G H; Belling, G B; Bulman, F H

    1979-06-01

    Urinary calculi composed of calcium oxalate were produced in male hooded Wistar rats fed a vitamin B6 deficient diet over 16 weeks. This basic diet was modified by doubling the phosphate content or loading with vitamin C or D3 in three treatment groups. The number of rats developing oxalate stones was not altered by the addition of vitamin D3 or phosphate, but there was a significant increase in total weight of stone formed and histological evidence of extensive renal damage in rats on the high vitamin D3 diet. The addition of vitamin C to the vitamin B6 deficient rats resulted in a reduction in the number of rats with uroliths and a fall in urinary oxalate excretion, while similarly loaded vitamin B6 supplemented controls were free of oxalate calculi. It is concluded that the oxalate urolithiasis induced by vitamin B6 deficiency was exacerbated by added vitamin D3 and reduced by vitamin C.

  11. [Acute pancreatitis after endoscopic evacuation of the gall stone, presenting as duodenal perforation: a case report].

    PubMed

    Zyluk, Andrzej; Jagielski, Wojciech

    2015-01-01

    We present the case of a 25-year-old patient who had sphincterotomy performed for the retrieval of gall stones form the common bile duct, and in whom, immediately after the procedure, signs and symptoms of the retroperitoneal, iatrogenic perforation of the duodenum had developed. Additionally, the patient showed clinical and biochemical symptoms of acute pancreatitis. The patient was operated on, and, intraoperatively, the duodenal perforation was not found, but excessive inflammatory infiltration of the retroperitoneal space, without bile leakage, and typical features for acute pancreatitis. The operation was confined to the duodenal and retroperitoneal space exposure, drainage and jejunostomy for nourishment. The postoperative course was uneventful, acute pancreatitis did not develop into the necrotising form, and the patient eventually recovered.

  12. Research Of The Influence Of Reftinskii SDPP’S Ash On The Processes Of Cement Stone’S Structure Forming

    NASA Astrophysics Data System (ADS)

    Zimakova, G. A.; Solonina, V. A.; Zelig, M. P.

    2017-01-01

    The article describes the experimental research of cement stone. Cement stone forming involves highly dispersive mineral additive - ground ash. It is stated that the substitution of some part of cement with activated ash leaves cement strength high. This is possible due to the activity of ash in structure forming processes. Activation of ash provides the increase in its puzzolanic activity, complete hydration processes. it is stated that ash grinding leads to a selective crystallization hydrated neoformations. Their morthology is different on outer and inner surfaces of ash spheres. The usage of ash can provide cement economy on condition that rheological characteristics of concrete stay constant. Besides, the usage of ash will improve physical and mechanic characteristics of cement stone and concrete.

  13. Kidney stone risk following Roux-en-Y gastric bypass surgery

    PubMed Central

    Gonzalez, Ricardo D.

    2014-01-01

    Since the first report in 2005, Roux-en-Y gastric bypass (RYGB) surgery has been linked to a variety of metabolic changes that alter kidney stone risk. The studies with the highest level of evidence, performed in non-stone forming patients before and after RYGB, cite a number of kidney stone risk factors, including a 25% increase in urinary oxalate, a 30% decrease in urinary citrate, and reduction in urine volume by half a liter. In addition to these, recent clinical and experimental studies have contributed to our understanding of the pathophysiology of stone disease in this unique population. This review summarizes the current RYGB urinary chemistry profiles and epidemiological studies, outlines known and theoretical mechanisms of hyperoxaluria and hypocitrituria, and provides some standard recommendations for reducing stone risk in RYGB stone formers as well as some novel ones, including correction of metabolic acidosis and use of probiotics. PMID:25473624

  14. A simple method for quantitating the propensity for calcium oxalate crystallization in urine

    NASA Technical Reports Server (NTRS)

    Wabner, C. L.; Pak, C. Y.

    1991-01-01

    To assess the propensity for spontaneous crystallization of calcium oxalate in urine, the permissible increment in oxalate is calculated. The previous method required visual observation of crystallization with the addition of oxalate, this warranted the need for a large volume of urine and a sacrifice in accuracy in defining differences between small incremental changes of added oxalate. Therefore, this method has been miniaturized and spontaneous crystallization is detected from the depletion of radioactive oxalate. The new "micro" method demonstrated a marked decrease (p < 0.001) in the permissible increment in oxalate in urine of stone formers versus normal subjects. Moreover, crystallization inhibitors added to urine, in vitro (heparin or diphosphonate) or in vivo (potassium citrate administration), substantially increased the permissible increment in oxalate. Thus, the "micro" method has proven reliable and accurate in discriminating stone forming from control urine and in distinguishing changes of inhibitory activity.

  15. [Detection of urinary organic acids by gradual titration of pH 2,0-7,4. Significance for the assessment of the litho-protective characteristic of the examined urine].

    PubMed

    Leskovar, P; Hartung, R; Hropot, M; Huber, H; Friedl, H; Wellnhofer, E; Steffek, D; Schöninger, R

    1981-08-01

    The role of organic acids in urine is not sufficiently known until today. From our detailed in vitro studies it can be concluded that some of them are highly efficacious in the inhibition of Ca-oxalate and Ca-phosphate crystal growth. Moreover, some of them showed, as acids and as salts, a strong lytic effect on stone-forming crystals and native stone-material. By the oral application to rats, concentrations preventing any precipitation out of meta- and instable Ca-oxalate solutions could be achieved. The renal excretion was controlled by the stepwise titration of preacidified urinary samples from pH 2.0 to 7.4 and the lithoprotective character of urine estimated by the Ca2+-binding capacity.

  16. The potential role of salt abuse on the risk for kidney stone formation

    NASA Technical Reports Server (NTRS)

    Sakhaee, K.; Harvey, J. A.; Padalino, P. K.; Whitson, P.; Pak, C. Y.

    1993-01-01

    The kidney stone-forming risk of a high sodium diet was evaluated by assessing the effect of such a diet on the crystallization of stone-forming salts in urine. Fourteen normal subjects participated in 2 phases of study of 10 days duration each, comprising a low sodium phase (basal metabolic diet containing 50 mmol. sodium per day) and a high sodium phase (basal diet plus 250 mmol. sodium chloride per day). The high sodium intake significantly increased urinary sodium (34 +/- 12 to 267 +/- 56 mmol. per day), calcium (2.73 +/- 1.03 to 3.93 +/- 1.51 mmol. per day) and pH (5.79 +/- 0.44 to 6.15 +/- 0.25), and significantly decreased urinary citrate (3.14 +/- 1.19 to 2.52 +/- 0.83 mmol. per day). Arterialized venous blood bicarbonate and total serum carbon dioxide concentrations decreased significantly during the high sodium diet, whereas serum chloride concentration increased. However, no change in arterialized venous pH was detected. Thus, a high sodium intake not only increased calcium excretion, but also increased urinary pH and decreased citrate excretion. The latter effects are probably due to sodium-induced bicarbonaturia and a significant decrease in serum bicarbonate concentration, respectively. Commensurate with these changes, the urinary saturation of calcium phosphate (brushite) and monosodium urate increased, and the inhibitor activity against calcium oxalate crystallization (formation product) decreased. The net effect of a high sodium diet was an increased propensity for the crystallization of calcium salts in urine.

  17. Insights on the pathology of kidney stone formation.

    PubMed

    Evan, Andrew P; Coe, Fredric L; Lingeman, James E; Worcester, Elaine

    2005-11-01

    The purpose of these studies was to test the hypothesis that Randall's plaque develops in unique anatomical sites of the kidney and that its formation is conditioned by specific stone-forming pathophysiologies. To test this hypothesis, we performed intraoperative mapping studies with biopsies of papilla from the kidneys of 15 idiopathic calcium oxalate (CaOx) stone formers, four intestinal bypass for obesity patients and ten brushite stone formers, and obtained papillary specimens from four non-stone formers after nephrectomy. Both light and electron microscopic examination of tissue changes along with infrared and electron diffraction analyses of mineral composition were performed. Distinct patterns of mineral deposition and papillary pathology were discovered in each of the three different stone forming groups. CaOx stone formers had predictable sites of interstitial apatite crystals beginning at the thin loops of Henle and spreading to the urothelium. These plaque areas are termed Randall's plaque and are thought to serve as sites for stone attachment. The papilla and medullary tubules appeared normal. The intestinal bypass patients only had intraluminal sites of crystalline material in the medullary collecting ducts. The brushite stone formers had the most severe form of cortical and medullary changes with sites of Randall's plaque, and yellowish intraluminal deposits in medullary collecting ducts. All deposits were determined to be apatite. The metabolic and surgical pathologic finding in three distinct groups of stone formers clearly shows that "the histology of the renal papilla from a stone former is particular to the clinical setting". It is observations like these that we believe will provide the insights to allow the stone community to generate better clinical treatments for kidney stone disease, as we understand the pathogenesis of stone formation for each type of stone former.

  18. Stone former urine proteome demonstrates a cationic shift in protein distribution compared to normal.

    PubMed

    Kolbach-Mandel, Ann M; Mandel, Neil S; Hoffmann, Brian R; Kleinman, Jack G; Wesson, Jeffrey A

    2017-03-17

    Many urine proteins are found in calcium oxalate stones, yet decades of research have failed to define the role of urine proteins in stone formation. This urine proteomic study compares the relative amounts of abundant urine proteins between idiopathic calcium oxalate stone forming and non-stone forming (normal) cohorts to identify differences that might correlate with disease. Random mid-morning urine samples were collected following informed consent from 25 stone formers and 14 normal individuals. Proteins were isolated from urine using ultrafiltration. Urine proteomes for each sample were characterized using label-free spectral counting mass spectrometry, so that urine protein relative abundances could be compared between the two populations. A total of 407 unique proteins were identified with the 38 predominant proteins accounting for >82% of all sample spectral counts. The most highly abundant proteins were equivalent in stone formers and normals, though significant differences were observed in a few moderate abundance proteins (immunoglobulins, transferrin, and epidermal growth factor), accounting for 13 and 10% of the spectral counts, respectively. These proteins contributed to a cationic shift in protein distribution in stone formers compared to normals (22% vs. 18%, p = 0.04). Our data showing only small differences in moderate abundance proteins suggest that no single protein controls stone formation. Observed increases in immunoglobulins and transferrin suggest increased inflammatory activity in stone formers, but cannot distinguish cause from effect in stone formation. The observed cationic shift in protein distribution would diminish protein charge stabilization, which could lead to protein aggregation and increased risk for crystal aggregation.

  19. [Epidemiology of nephrolithiasis in France].

    PubMed

    Daudon, M

    2005-12-01

    Nephrolithiasis is a frequent disease that affects about 10% of people in western countries. The prevalence of calcium oxalate stones has been constantly increasing during the past fifty years in France as well as in other industrialized countries. Stone composition varies depending to gender and age of patients and also underlines the role of other risk factors and associated pathologies such as body mass index and diabetes mellitus. The decrease in struvite frequency in female patients is the result of a significantly improved diagnostic and treatment of urinary tract infections by urea-splitting bacteria. In contrast, the increasing occurrence of weddellite calculi in stone forming women aged more than 50 years could be the consequence of post-menopausal therapy. A high prevalence of uric acid was found in overweight and obese stone formers and in diabetic ones as well. Another important finding was the increased occurrence with time of calcium oxalate stones formed from papillary Randall's plaques, especially in young patients. Nutritional risk factors for stone disease are well known: they include excessive consumption of animal proteins, sodium chloride and rapidly absorbed glucides, and insufficient dietary intake of fruits and potassium-rich vegetables, which provide an alkaline load. As a consequence, an excessive production of hydrogen ions may induce several urinary disorders including low urine pH, high urine calcium and uric acid excretion and low urine citrate excretion. Excess in calorie intake, high chocolate consumption inducing hyperoxaluria and low water intake are other factors, which favour excessive urine concentration of solutes. Restoring the dietary balance is the first advice to prevent stone recurrence. However, the striking increase of some types of calculi, such as calcium oxalate stones developed from Randall's plaque, should alert to peculiar lithogenetic risk factors and suggests that specific advices should be given to prevent stone

  20. Alkali absorption and citrate excretion in calcium nephrolithiasis

    NASA Technical Reports Server (NTRS)

    Sakhaee, K.; Williams, R. H.; Oh, M. S.; Padalino, P.; Adams-Huet, B.; Whitson, P.; Pak, C. Y.

    1993-01-01

    The role of net gastrointestinal (GI) alkali absorption in the development of hypocitraturia was investigated. The net GI absorption of alkali was estimated from the difference between simple urinary cations (Ca, Mg, Na, and K) and anions (Cl and P). In 131 normal subjects, the 24 h urinary citrate was positively correlated with the net GI absorption of alkali (r = 0.49, p < 0.001). In 11 patients with distal renal tubular acidosis (RTA), urinary citrate excretion was subnormal relative to net GI alkali absorption, with data from most patients residing outside the 95% confidence ellipse described for normal subjects. However, the normal relationship between urinary citrate and net absorbed alkali was maintained in 11 patients with chronic diarrheal syndrome (CDS) and in 124 stone-forming patients devoid of RTA or CDS, half of whom had "idiopathic" hypocitraturia. The 18 stone-forming patients without RTA or CDS received potassium citrate (30-60 mEq/day). Both urinary citrate and net GI alkali absorption increased, yielding a significantly positive correlation (r = 0.62, p < 0.0001), with the slope indistinguishable from that of normal subjects. Thus, urinary citrate was normally dependent on the net GI absorption of alkali. This dependence was less marked in RTA, confirming the renal origin of hypocitraturia. However, the normal dependence was maintained in CDS and in idiopathic hypocitraturia, suggesting that reduced citrate excretion was largely dietary in origin as a result of low net alkali absorption (from a probable relative deficiency of vegetables and fruits or a relative excess of animal proteins).

  1. In-house validation of the EpiOcular(TM) eye irritation test and its combination with the bovine corneal opacity and permeability test for the assessment of ocular irritation.

    PubMed

    Kolle, Susanne N; Kandárová, Helena; Wareing, Britta; van Ravenzwaay, Bennard; Landsiedel, Robert

    2011-09-01

    In 2009, the Bovine Corneal Opacity and Permeability (BCOP) test was accepted by the regulatory bodies for the identification of corrosive and severe ocular irritants (Global Harmonised System [GHS] Category 1). However, no in vitro test is currently accepted for the differentiation of ocular irritants (GHS Category 2) and non-irritants (GHS No Category). Human reconstructed tissue models have been suggested for incorporation into a tiered testing strategy to ultimately replace the Draize rabbit eye irritation test (OECD TG 405). The purpose of this study was to evaluate whether the EpiOcular(TM) reconstructed cornea-like tissue model and the COLIPA pre-validated EpiOcular Eye Irritation Test (EpiOcular-EIT) could be used as suitable components of this testing strategy. The in-house validation of the EpiOcular-EIT was performed by using 60 test substances, including a broad variety of chemicals and formulations for which in vivo data (from the Draize rabbit eye irritation test) were available. The test substances fell into the following categories: 18 severe irritants/corrosives (Category 1), 21 irritants (Category 2), and 21 non-irritants (No Category). Test substances that decreased tissue viability to ≤ 60% (compared to the negative control tissue) were considered to be eye irritants (Category 1/2). Test substances resulting in tissue viability of > 60% were considered to be non-irritants (No Category). For the assessed dataset and the classification cut-off of 60% viability, the EpiOcular-EIT provided 98% and 84% sensitivity, 64% and 90% specificity, and 85% and 86% overall accuracy for the literature reference and BASF proprietary substances, respectively. Applying a 50% tissue viability cut-off to distinguish between irritants and non-irritants resulted in 93% and 82% sensitivity, 68% and 100% specificity, and 84% and 88% accuracy for the literature reference and BASF proprietary substances, respectively. Further, in the EpiOcular-EIT (60% cut-off), 100% of

  2. P-T-t-d History of the Greater Himalaya Sequence metapelites in the Zanskar Shear Zone, NW India

    NASA Astrophysics Data System (ADS)

    Beck, E.; Leech, M. L.; Basta, S.

    2013-12-01

    Greater Himalaya Sequence (GHS) metapelites deformed in the Zanskar Shear Zone (ZSZ) record geochemical and structural evidence of a complex history. This study applies a multi-component approach to understanding the metamorphic and deformational evolution of the high-grade metapelites in western Himalaya. Samples collected from NE to SW from the ZSZ, along Malung Takpo, record increasing metamorphic grade and decreasing mylonitization with increased distance from the shear zone. Microscopic evidence for variable degrees of deformation includes: change in crystal size, foliation development, pressure shadows, and kink bands. The dominant mineralogy is Qz+Kfs+Pl+Bt+Ms+Grt+Ky×Sil×St+opaques. Advanced isochemical phase diagrams (pseudosections) are calculated in Perple_X using whole-rock geochemical (XRF) data for six samples. The pseudosection conditions range 3-15 kbar and 300-800°C and use the solution models Bio(TCC), Chl(HP), St(HP), hCrd, feldspar, Mica(CHA), and Gt(HP) with modifications made to increase the models' accuracy. The generated phase equilibria diagrams, in conjunction with observed mineral growth relationships, are used to determine the P-T paths and illustrate peak and retrograde metamorphic events. Three dating techniques [U-Pb, 40Ar/39Ar, and (U-Th)/He] are incorporated to constrain timing along the P-T paths. U-Pb SHRIMP dating of monazite constrains the timing of regional metamorphism to ~27 Ma. 40Ar/39Ar dating of muscovite and biotite yields ages of ~20-19 Ma and 15 Ma, respectively, for cooling and exhumation through the middle crust. Dates acquired from (U-Th)/He analyses of monazite and zircon will indicate the timing of the end of movement along the ZSZ. Electron backscatter diffraction (EBSD) maps crystallographic orientation of minerals and is used to determine their responses to deformation. Crystallographic responses in quartz and feldspar are used to constrain the conditions during deformation. This will be supplemented by

  3. D-Lys(3)-GHRP-6 antagonizes the effect of unacylated but not of acylated ghrelin on the growth of HECa10 murine endothelial cells.

    PubMed

    Polowinczak-Przybylek, Joanna; Siejka, Agnieszka; Melen-Mucha, Gabriela

    2012-12-01

    Recent studies demonstrate that ghrelin can be an endogenous regulator of angiogenesis. We studied direct effects of human acylated (hAG) and unacylated (hUAG) ghrelin, as well as of rat acylated ghrelin (rAG) on the growth of HECa10 murine endothelial cells. Ghrelin was applied separately or together with D-Lys(3)-GHRP-6, which is commonly used as an antagonist of ghrelin receptor type 1a - GHS-R1a. The growth of HECa10 cells was assessed with Mosmann and in selected study conditions also with BrdU and TUNEL methods. Both hAG and hUAG (10(-5) M to 10(-12) M) inhibited the growth of HECa10 cells in 24h and 72 h cultures. Similarly, rAG decreased the growth of the cells after 24h (10(-7) M and 10(-11) M), and after 72 h (10(-7) M, 10(-8) M and 10(-11) M). Unexpectedly, D-Lys(3)-GHRP-6 itself also inhibited the growth of these cells at 10(-4) to 10(-6) M in 24h, 48 h (dose-response effect) and 72 h cultures. D-Lys(3)-GHRP-6 did not modify the inhibitory effect of rAG. However, D-Lys(3)-GHRP-6 at the concentration of 10(-4) M diminished, abolished or even reversed the inhibitory effect of hUAG in 72 h culture and this was dependent on ghrelin concentrations. These data indicate that both AG and UAG have antiangiogenic properties at least at the level of endothelial growth, through decreased metabolic activity of the cells or stimulation of apoptosis. D-Lys(3)-GHRP-6 (inhibitor of GHS-R1a) seems not to be an appropriate antagonist in this experimental condition. Similar effects of these substances on HECa10 cells suggest that they are not mediated by GHS-R1a.

  4. Cosmetics Europe compilation of historical serious eye damage/eye irritation in vivo data analysed by drivers of classification to support the selection of chemicals for development and evaluation of alternative methods/strategies: the Draize eye test Reference Database (DRD).

    PubMed

    Barroso, João; Pfannenbecker, Uwe; Adriaens, Els; Alépée, Nathalie; Cluzel, Magalie; De Smedt, Ann; Hibatallah, Jalila; Klaric, Martina; Mewes, Karsten R; Millet, Marion; Templier, Marie; McNamee, Pauline

    2017-02-01

    A thorough understanding of which of the effects assessed in the in vivo Draize eye test are responsible for driving UN GHS/EU CLP classification is critical for an adequate selection of chemicals to be used in the development and/or evaluation of alternative methods/strategies and for properly assessing their predictive capacity and limitations. For this reason, Cosmetics Europe has compiled a database of Draize data (Draize eye test Reference Database, DRD) from external lists that were created to support past validation activities. This database contains 681 independent in vivo studies on 634 individual chemicals representing a wide range of chemical classes. A description of all the ocular effects observed in vivo, i.e. degree of severity and persistence of corneal opacity (CO), iritis, and/or conjunctiva effects, was added for each individual study in the database, and the studies were categorised according to their UN GHS/EU CLP classification and the main effect driving the classification. An evaluation of the various in vivo drivers of classification compiled in the database was performed to establish which of these are most important from a regulatory point of view. These analyses established that the most important drivers for Cat 1 Classification are (1) CO mean ≥ 3 (days 1-3) (severity) and (2) CO persistence on day 21 in the absence of severity, and those for Cat 2 classification are (3) CO mean ≥ 1 and (4) conjunctival redness mean ≥ 2. Moreover, it is shown that all classifiable effects (including persistence and CO = 4) should be present in ≥60 % of the animals to drive a classification. As a consequence, our analyses suggest the need for a critical revision of the UN GHS/EU CLP decision criteria for the Cat 1 classification of chemicals. Finally, a number of key criteria are identified that should be taken into consideration when selecting reference chemicals for the development, evaluation and/or validation of alternative methods and

  5. Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model

    PubMed Central

    Sawada, Yumi; Hashimoto, Hirofumi; Yoshimura, Mitsuhiro; Ohbuchi, Katsuya; Sudo, Yuka; Suzuki, Masami; Miyano, Kanako; Shiraishi, Seiji; Higami, Yoshikazu; Yanagihara, Kazuyoshi; Hattori, Tomohisa; Kase, Yoshio; Ueta, Yoichi; Uezono, Yasuhito

    2017-01-01

    Cancer cachexia (CC) is a multifactorial disease characterized by decreased food intake and loss of body weight due to reduced musculature with or without loss of fat mass. Patients with gastric cancer have a high incidence of cachexia. We previously established a novel CC rat model induced by human gastric cancer-derived 85As2 cells in order to examine the pathophysiology of CC and identify potential therapeutics. In patients with CC, anorexia is often observed, despite elevation of ghrelin, suggesting that ghrelin resistance may develop in these patients. In this study, we aimed to clarify the occurrence of ghrelin resistance in CC rats accompanied by anorexia and we investigated whether rikkunshito (RKT), a traditional Japanese Kampo medicine that potentiates ghrelin signaling, ameliorated CC-related anorexia through alleviation of ghrelin resistance. 85As2-tumor-bearing rats developed severe CC symptoms, including anorexia and loss of body weight/musculature, with the latter symptoms being greater in cachectic rats than in non-tumor-bearing or pair-fed rats. CC rats showed poor responses to intraperitoneal injection of ghrelin. In CC rats, plasma ghrelin levels were elevated and hypothalamic anorexigenic peptide mRNA levels were decreased, whereas hypothalamic growth hormone secretagogue receptor (GHS-R) mRNA was not affected. In vitro, RKT directly enhanced ghrelin-induced GHS-R activation. RKT administrated orally for 7 days partly alleviated the poor response to ghrelin and ameliorated anorexia without affecting the elevation of plasma ghrelin levels in CC rats. The expression of hypothalamic orexigenic neuropeptide Y mRNA but not hypothalamic GHS-R mRNA was increased by RKT. Thus, the 85As2 cell-induced CC rat model developed ghrelin resistance, possibly contributing to anorexia and body weight loss. The mechanism through which RKT ameliorated anorexia in the CC rat model may involve alleviation of ghrelin resistance by enhancement of ghrelin signaling

  6. Ghrelin decreases food intake in juvenile rainbow trout (Oncorhynchus mykiss) through the central anorexigenic corticotropin-releasing factor system.

    PubMed

    Jönsson, Elisabeth; Kaiya, Hiroyuki; Björnsson, Björn Thrandur

    2010-03-01

    Ghrelin stimulates pituitary growth hormone (GH) release, and has a key role in the regulation of food intake and adiposity in vertebrates. To investigate the central effect of native rainbow trout ghrelin (rtghrelin) on food intake in rainbow trout, as well as its possible mode of action, four groups of fish received a single injection into the third brain ventricle (i.c.v. injection): (1) control group (physiological saline) (2) ghrelin-treated group (2.0 ng rtghrelin g bwt(-1)), (3) group given the corticotropin-releasing hormone receptor antagonist alpha-helical CRF 9-41 (ahCRF) (4.0 ng g bwt(-1)) and (4) group receiving the same dose of both ghrelin and ahCRF. Food intake was assessed 1h after treatment. In addition, the presence of the GHS-R (the ghrelin receptor) in the rainbow trout CNS was examined with Western blot. To investigate peripheral effects of ghrelin, rainbow trout received an intraperitoneal cholesterol-based implant with or without rtghrelin, and daily food intake was measured during 14 days. Weight and length were measured at the start and termination of the experiment and specific growth rates were calculated. Mesenteric fat stores, muscle and liver lipid content were analysed after the treatment period. Central ghrelin injections decreased food intake compared with controls, and treatment with ahCRF abolished the ghrelin-effect. Western blot analysis of the GHS-R revealed a single band at around 60 kDa in pituitary, hypothalamus, brain and stomach. Long-term peripheral ghrelin treatment decreased daily food intake compared with controls. This was reflected in a ghrelin-induced decrease in weight growth rate (p<0.06). There was no effect of ghrelin on plasma GH levels or tissue fat stores. The conclusion from this study is that the GHS-R is indicated in the CNS in rainbow trout and that ghrelin may act there as an anorexigenic hormone, through a CRF-mediated pathway. Elevated peripheral ghrelin levels also seem to lead to decreased feed

  7. Cell Surface Glycoside Hydrolases of Streptococcus gordonii Promote Growth in Saliva

    PubMed Central

    Zhou, Yuan; Zhang, Luxia; Shah, Nehal; Palmer, Robert J.; Cisar, John O.

    2016-01-01

    ABSTRACT The growth of the oral commensal Streptococcus gordonii in saliva may depend on a number of glycoside hydrolases (GHs), including three cell wall-anchored proteins that are homologs of pneumococcal β-galactosidase (BgaA), β-N-acetylglucosaminidase (StrH), and endo-β-N-acetylglucosaminidase D (EndoD). In the present study, we introduced unmarked in-frame deletions into the corresponding genes of S. gordonii DL1, verified the presence (or absence) of the encoded proteins on the resulting mutant strains, and compared these strains with wild-type strain DL1 for growth and glycan foraging in saliva. The overnight growth of wild-type DL1 was reduced 3- to 10-fold by the deletion of any one or two genes and approximately 20-fold by the deletion of all three genes. The only notable change in the salivary proteome associated with this reduction of growth was a downward shift in the apparent molecular masses of basic proline-rich glycoproteins (PRG), which was accompanied by the loss of lectin binding sites for galactose-specific Erythrina cristagalli agglutinin (ECA) and mannose-specific Galanthus nivalis agglutinin (GNA). The binding of ECA to PRG was also abolished in saliva cultures of mutants that expressed cell surface BgaA alone or together with either StrH or EndoD. However, the subsequent loss of GNA binding was seen only in saliva cocultures of different mutants that together expressed all three cell surface GHs. The findings indicate that the growth of S. gordonii DL1 in saliva depends to a significant extent on the sequential actions of first BgaA and then StrH and EndoD on N-linked glycans of PRG. IMPORTANCE The ability of oral bacteria to grow on salivary glycoproteins is critical for dental plaque biofilm development. Little is known, however, about how specific salivary components are attacked and utilized by different members of the biofilm community, such as Streptococcus gordonii. Streptococcus gordonii DL1 has three cell wall

  8. Growth Hormone Deficiency Is Associated with Worse Cardiac Function, Physical Performance, and Outcome in Chronic Heart Failure: Insights from the T.O.S.CA. GHD Study

    PubMed Central

    Giallauria, Francesco; Bossone, Eduardo; Isgaard, Jörgen; Marra, Alberto M.; Bobbio, Emanuele; Vriz, Olga; Åberg, David N.; Masarone, Daniele; De Paulis, Amato; Saldamarco, Lavinia; Vigorito, Carlo; Formisano, Pietro; Niola, Massimo; Perticone, Francesco; Bonaduce, Domenico; Saccà, Luigi; Colao, Annamaria; Cittadini, Antonio

    2017-01-01

    Background Although mounting evidence supports the concept that growth hormone (GH) deficiency (GHD) affects cardiovascular function, no study has systematically investigated its prevalence and role in a large cohort of chronic heart failure (CHF) patients. Aim of this study is to assess the prevalence of GHD in mild-to-moderate CHF and to explore clinical and functional correlates of GHD. Methods One-hundred thirty CHF patients underwent GH provocative test with GHRH+arginine and accordingly categorized into GH-deficiency (GHD, n = 88, age = 61.6±1.1 years, 68% men) and GH-sufficiency (GHS, n = 42, age = 63.6±1.5 years, 81% men) cohorts. Both groups received comprehensive cardiovascular examination and underwent Doppler echocardiography, cardiopulmonary exercise testing, and biochemical and hormonal assay. Results GHD was detected in roughly 30% of CHF patients. Compared to GHD, GHS patients showed smaller end-diastolic and end-systolic LV volumes (-28%, p = .008 and -24%, p = .015, respectively), lower LV end-systolic wall stress (-21%, p = .03), higher RV performance (+18% in RV area change, p = .03), lower estimated systolic pulmonary artery pressure (-11%, p = .04), higher peak VO2 (+20%, p = .001) and increased ventilatory efficiency (-12% in VE/VCO2 slope, p = .002). After adjusting for clinical covariates (age, gender, and tertiles of LV ejection fraction, IGF-1, peak VO2, VE/VCO2 slope, and NT-proBNP), logistic multivariate analysis showed that peak VO2 (β = -1.92, SE = 1.67, p = .03), VE/VCO2 slope (β = 2.23, SE = 1.20, p = .02) and NT-proBNP (β = 2.48, SE = 1.02, p = .016), were significantly associated with GHD status. Finally, compared to GHS, GHD cohort showed higher all-cause mortality at median follow-up of 3.5 years (40% vs. 25%, p < .001, respectively), independent of age, sex, NT-proBNP, peak VO2 and LVEF. Conclusions GH deficiency identifies a subgroup of CHF patients characterized by impaired functional capacity, LV remodeling and elevated

  9. Did the Karakoram fault interrupt mid-crustal channel flow in the western Himalaya?

    NASA Astrophysics Data System (ADS)

    Leech, M. L.

    2007-12-01

    There is a marked change in the volume and age of granitoids from west to east across the Himalaya; that change occurs at the southeastern termination of the Karakoram fault where it merges with the Indus-Yarlung suture zone, near the Gurla Mandhata gneiss dome. These granitoids are derived from a ductile mid-crustal channel formed when anatectic melts from the mid-crust beneath the Tibetan plateau were driven south by erosion at the Himalayan topographic front. The "channel flow" model predicts upwellings of these granites within the Tethyan Himalaya Sequence as part of a chain of gneiss domes and exposure of the channel at its southern termination in the Greater Himalaya Sequence (GHS) as evidenced by widespread migmatites and leucogranite bodies at the top of the GHS in the footwall of the South Tibetan Detachment. Leo Pargil is the westernmost gneiss dome in a chain of domes formed within the Tethyan Himalaya Sequence that extends eastward 1600 km through the North Himalayan gneiss domes (that includes the better known Kangmar dome). New U-Pb SHRIMP dating of zircons show leucogranite bodies from the Leo Pargil gneiss dome are Early Miocene (22-20 Ma) corresponding to some of the older granites dated from across the Himalaya. Transects through the GHS along the Beas and Sutlej River valleys in the western Himalaya near Leo Pargil reveal rare to minimal amounts of migmatites and leucogranite, whereas there are abundant migmatites and large leucogranite bodies in a transect along the Friendship Highway from Lhasa to Kathmandu in the area of the North Himalayan gneiss domes. The timing of the initiation of slip on the Karakoram fault is dated from syn- kinematic rocks in the shear zone at Tangste/Pangong Tso at c. 25-21 Ma. If the Karakoram fault acted as a barrier the flow of granitoid melts in a mid-crustal channel, one would expect more abundant and younger granites east of the Karakoram fault as the channel continued to flow south after c. 20 Ma; the youngest

  10. Ages, Trace-Element and Hf Isotopic Compositions of the Detrital Zircons from the Metamorphic Basements in the Eastern Himalayan Syntaxis: Implications for Tectonics and Paleogeography

    NASA Astrophysics Data System (ADS)

    Guo, L.; Zhang, H. F.; Harris, N.

    2014-12-01

    The origin of the Greater Himalayan Sequence (GHS) of the Himalaya and the paleogeographic position of the Lhasa terrane within Gondwanaland remain controversial. In the Eastern Himalayan syntaxis, the metamorphic basements of the northern Indian plate (Namche Barwa Group) and the South Lhasa terrane (Nyingchi Complex) can be studied to explore these issues. The youngest ages of detrital zircons in the metasedimentary rocks from the Pai Formation of the Namche Barwa Group (NBG) and the Nyingchi Complex suggest their maximum depositional ages are no older than 942 Ma and 1006 Ma, respectively. A granitic gneiss intruding the Pai Formation and a metarhyolite overlying the Nyingchi Complex have protolith ages of 477 ± 3 Ma and 507 ± 4 Ma, respectively, providing upper age limits for their deposition. The detrital zircons in the Pai Formation and Nyingchi Complex define four major age peaks at ~1170 Ma, ~1350 Ma, ~1565 Ma, and ~1750 Ma. Both the ~1170 Ma and ~1350 Ma zircons have large variation of eHf(t) values (-19.4 to +5.6); most ~1565 Ma zircons have positive eHf(t) values (+1.2 - +9.0), and most ~1750 Ma zircons have negative eHf(t) values (-7.1 to -1.9), which are consistent with those of the Mesoproterozoic orthogneiss in the Duoxiongla migmatite of NBG. The trace-element signatures of ~1.5-1.3 Ga detrital zircons indicate they were derived from sources characterized by bimodal magmatism. The potential sources for the metasediments in the Pai Formation and Nyingchi Complex include the Rayner-Eastern Ghats Orogen and its contact zone with the Archaean Indian cratons, the Central Indian Tectonic Zone, the northeastern India craton and Dharwar craton, South Lhasa terrane and probably Eastern Antarctic. Comparisons of detrital zircon age spectra of the coeval metasedimentary rocks from the Nyingchi Complex, the Pai Formation, the GHS and upper Lesser Himalayan Sequence in Arunachal Himalayan, and the Indian cratonic successions suggest that: (1) the NBG is the

  11. LAHS: A novel harmony search algorithm based on learning automata

    NASA Astrophysics Data System (ADS)

    Enayatifar, Rasul; Yousefi, Moslem; Abdullah, Abdul Hanan; Darus, Amer Nordin

    2013-12-01

    This study presents a learning automata-based harmony search (LAHS) for unconstrained optimization of continuous problems. The harmony search (HS) algorithm performance strongly depends on the fine tuning of its parameters, including the harmony consideration rate (HMCR), pitch adjustment rate (PAR) and bandwidth (bw). Inspired by the spur-in-time responses in the musical improvisation process, learning capabilities are employed in the HS to select these parameters based on spontaneous reactions. An extensive numerical investigation is conducted on several well-known test functions, and the results are compared with the HS algorithm and its prominent variants, including the improved harmony search (IHS), global-best harmony search (GHS) and self-adaptive global-best harmony search (SGHS). The numerical results indicate that the LAHS is more efficient in finding optimum solutions and outperforms the existing HS algorithm variants.

  12. Structural Snapshots for Mechanism‐Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars

    PubMed Central

    Adamson, Christopher; Pengelly, Robert J.; Shamsi Kazem Abadi, Saeideh; Chakladar, Saswati; Draper, Jason

    2016-01-01

    Abstract Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism‐based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism‐based GH inactivator, the results of which show that the two Michaelis complexes are in 2H3 conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened 2H3 half‐chair). We conclude that these inactivator reactions mainly involve motion of the pseudo‐anomeric carbon atom, knowledge that should stimulate the design of new transition‐state analogues for use as chemical biology tools. PMID:27783466

  13. A sub-proteome of Arabidopsis thaliana mature stems trapped on Concanavalin A is enriched in cell wall glycoside hydrolases

    PubMed Central

    Minic, Zoran; Jamet, Elisabeth; Négroni, Luc; Arsene Der Garabedian, P.; Zivy, Michel; Jouanin, Lise

    2007-01-01

    N-glycosylated proteins were isolated from Arabidopsis thaliana mature stems using affinity chromatography on Concanavalin A Sepharose, separated by 2D-electrophoresis and identified using nanoHPLC-MS/MS and MALDI-TOF MS. 102 glycoproteins were identified. 94% of these proteins were predicted by bioinformatics to be targeted to the secretory pathway and 87% of them were predicted to be localized in the cell wall or at the plasma membrane. 30% of these proteins belong to glycoside hydrolases (GHs) families with some of them possibly involved in the hydrolysis of cell wall polysaccharides. The second major class of identified proteins comprises aspartyl and serine proteases. Other proteins are predicted to be oxido-reductases, contain interacting domains, are potentially involved in signalling or have an unknown function. This is to our knowledge the first survey of plant cell wall N-glycosylated proteins. PMID:17526915

  14. Structure-activity analysis of the growth hormone secretagogue GHRP-6 by alpha- and beta-amino gamma-lactam positional scanning.

    PubMed

    Boutard, Nicolas; Jamieson, Andrew G; Ong, Huy; Lubell, William D

    2010-01-01

    Incorporation of amino lactams into biologically active peptides restricts conformational mobility and may enhance selectivity and increase potency. alpha- and beta-amino gamma-lactams (Agl and Bgl), in both S and R configurations, were introduced into the growth hormone secretagogue GHRP-6 using a Fmoc-compatible solid-phase protocol relying on N-alkylation with five- and six-membered cyclic sulfamidates, followed by lactam annulation under microwave heating. Using this protocol in conjunction with IRORI Kan techniques furnished eleven new GHRP-6 analogs, and their binding affinity IC50 values on both the growth hormone secretagogue receptor 1a (GHS-R1a) and CD36 receptors are herein reported. The results indicate that selectivity towards one receptor or the other can be modulated by lactam substitution, typically at the Ala3 and the D-Phe5 positions.

  15. Effects of Green House nursing homes on residents' families.

    PubMed

    Lum, Terry Y; Kane, Rosalie A; Cutler, Lois J; Yu, Tzy-Chyi

    2008-01-01

    A longitudinal quasi-experimental study with two comparison groups was conducted to test the effects of a Green House (GH) nursing home program on residents' family members. The GHs are individual residences, each serving 10 elders, where certified nursing assistant (CNA)-level resident assistants form primary relationships with residents and family, family is encouraged to visits, and professionals adapted their roles to support the model. GH family were somewhat less involved in providing assistance to their residents although family contact did not differ among the settings at any time period. GH family were more satisfied with their resident's care and with their own experience as family members, and had no greater family burden. Issues in studying family outcomes are discussed as well as implications for roles of various personnel, including social service and activities staff in a GH model.

  16. Role of the ghrelin/obestatin balance in the regulation of neuroendocrine circuits controlling body composition and energy homeostasis.

    PubMed

    Epelbaum, Jacques; Bedjaoui, Nawel; Dardennes, Roland; Feng, Dan Dan; Gardette, Robert; Grouselle, Dominique; Loudes, Catherine; Simon, Axelle; Tolle, Virginie; Yang, Seung Kwon; Zizzari, Philippe

    2010-01-27

    Ghrelin and obestatin are two peptides isolated from the gastrointestinal tract and encoded by the same preproghrelin gene. They convey to the central nervous system informations concerning the nutritional status and/or the energy stores. Ghrelin, mostly acting through the GH secretagogue receptor GHS-R, is a potent GH secretagogue, an orexigenic peptide and a long-term regulator of energy homeostasis. Obestatin was initially described for its anorexigenic effects and its binding to the G protein-coupled receptor 39 (GPR39). However, the role of obestatin is still controversial and the nature of the obestatin receptor remains an open question. This review is focussed on the possible implication of the ghrelin/obestatin system in psychiatric diseases with particular emphasis on eating disorders.

  17. “Newton’s cradle” proton relay with amide–imidic acid tautomerization in inverting cellulase visualized by neutron crystallography

    PubMed Central

    Nakamura, Akihiko; Ishida, Takuya; Kusaka, Katsuhiro; Yamada, Taro; Fushinobu, Shinya; Tanaka, Ichiro; Kaneko, Satoshi; Ohta, Kazunori; Tanaka, Hiroaki; Inaka, Koji; Higuchi, Yoshiki; Niimura, Nobuo; Samejima, Masahiro; Igarashi, Kiyohiko

    2015-01-01

    Hydrolysis of carbohydrates is a major bioreaction in nature, catalyzed by glycoside hydrolases (GHs). We used neutron diffraction and high-resolution x-ray diffraction analyses to investigate the hydrogen bond network in inverting cellulase PcCel45A, which is an endoglucanase belonging to subfamily C of GH family 45, isolated from the basidiomycete Phanerochaete chrysosporium. Examination of the enzyme and enzyme-ligand structures indicates a key role of multiple tautomerizations of asparagine residues and peptide bonds, which are finally connected to the other catalytic residue via typical side-chain hydrogen bonds, in forming the “Newton’s cradle”–like proton relay pathway of the catalytic cycle. Amide–imidic acid tautomerization of asparagine has not been taken into account in recent molecular dynamics simulations of not only cellulases but also general enzyme catalysis, and it may be necessary to reconsider our interpretation of many enzymatic reactions. PMID:26601228

  18. Measurement-induced-nonlocality for Dirac particles in Garfinkle-Horowitz-Strominger dilation space-time

    NASA Astrophysics Data System (ADS)

    He, Juan; Xu, Shuai; Ye, Liu

    2016-05-01

    We investigate the quantum correlation via measurement-induced-nonlocality (MIN) for Dirac particles in Garfinkle-Horowitz-Strominger (GHS) dilation space-time. It is shown that the physical accessible quantum correlation decreases as the dilation parameter increases monotonically. Unlike the case of scalar fields, the physical accessible correlation is not zero when the Hawking temperature is infinite owing to the Pauli exclusion principle and the differences between Fermi-Dirac and Bose-Einstein statistics. Meanwhile, the boundary of MIN related to Bell-violation is derived, which indicates that MIN is more general than quantum nonlocality captured by the violation of Bell-inequality. As a by-product, a tenable quantitative relation about MIN redistribution is obtained whatever the dilation parameter is. In addition, it is worth emphasizing that the underlying reason why the physical accessible correlation and mutual information decrease is that they are redistributed to the physical inaccessible regions.

  19. Testing the channel flow model in the eastern Himalaya, eastern Bhutan: insights from preliminary thermobarometric data

    NASA Astrophysics Data System (ADS)

    Agustsson, K. S.; Gordon, S. M.; Long, S. P.; Seward, G. G.; Zeiger, K. J.; Penfold, M. L.

    2013-12-01

    The study of modern continent-continent collision provides insight into the links between the upper and lower crust, including the processes involved in the deep burial and exhumation of crustal rocks. Rocks of the Greater Himalayan Sequence (GHS), which were buried to mid- to lower-crustal levels, are exposed throughout the Himalayan orogenic belt, between the top-to-the-south Main Central Thrust and the top-to-the-north South Tibetan Detachment. The GHS consists of orthogneiss, metasedimentary rocks, and large-scale (>100 km2) leucogranite bodies. Within the Bhutan Himalaya, the top-to-the south Kakhtang Thrust (KT) separates the GHS into upper (GHSu) and lower (GHSl) structural levels. Previous studies have mapped the location of the KT by the crossing of the second sillimanite isograd and by a significant increase in the volume of crystallized melt. Previous work in Bhutan has mainly focused on the GHSl, whereas the extrusion of the higher-temperature GHSu has not been well studied, and there is little quantitative data describing the P-T history of these rocks. In order to test between different end-member models for the exhumation of the GHSu, including channel flow and critical taper, new thermobarometry data was collected from a transect of samples across the KT. The channel-flow model predicts that the GHSu would have achieved peak upper-amphibolite facies P-T conditions followed by retrograde, near-isothermal decompression. In contrast, the critical-taper model predicts near-isobaric cooling of the GHSu. The electron microprobe at UC-Santa Barbara was used to measure the composition of and test for zoning within garnet, plagioclase, and biotite. Garnets in all four samples are typically subhedral to euhedral and show relatively weak zonation and flat Mg, Fe, and Ca profiles. A few garnets do exhibit bell-shaped Mn and Ca profiles. In addition, a ca. 100 μm rim high in Mg, Ca and Mn but low in Fe is present on all garnets and is indicative of diffusional

  20. Ghrelin: a multifunctional hormone in non-mammalian vertebrates.

    PubMed

    Kaiya, Hiroyuki; Miyazato, Mikiya; Kangawa, Kenji; Peter, Richard E; Unniappan, Suraj

    2008-02-01

    In mammals, ghrelin is a non-amidated peptide hormone, existing in both acylated and non-acylated forms, produced mainly from the X/A or ghrelin cells present in the mucosal layer of the stomach. Ghrelin is a natural ligand of the growth hormone (GH) secretagogue-receptor (GHS-R), and functions primarily as a GH-releasing hormone and an orexigen, as well as having several other biological actions. Among non-mammalian vertebrates, amino acid sequence of ghrelin has been reported in two species of cartilaginous fish, seven species of teleosts, two species of amphibians, one species of reptile and six species of birds. The structure and functions of ghrelin are highly conserved among vertebrates. This review presents a concise overview of ghrelin biology in non-mammalian vertebrates.

  1. Therapeutic applications of ghrelin to cachexia utilizing its appetite-stimulating effect.

    PubMed

    Akamizu, Takashi; Kangawa, Kenji

    2011-11-01

    Ghrelin, which is a natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), stimulates food intake in both animals and humans. Ghrelin is the only circulating hormone known to stimulate appetite in humans. Ghrelin also stimulates GH secretion and inhibits the production of anorectic proinflammatory cytokines. As GH is an anabolic hormone, protein stores are spared at the expense of fat during conditions of caloric restriction. Thus, ghrelin exhibits anti-cachectic actions via both GH-dependent and -independent mechanisms. Several studies are evaluating the efficacy of ghrelin in the treatment of cachexia caused by a variety of diseases, including congestive heart failure, chronic obstructive pulmonary disease, cancer, and end-stage renal disease. These studies will hopefully lead to the development of novel therapeutic applications for ghrelin in the future. This review summarizes the recent advances in this area of research.

  2. Detection of the greenhouse gas signal from space - A progress report

    NASA Technical Reports Server (NTRS)

    Barnett, T. P.; Haskins, R.; Chahine, M.

    1991-01-01

    The spatial distribution of the expected changes in the atmospheric water vapor content and cloud cover, as predicted by the transient greenhouse gas (GHG) simulation of Hansen et al. (1988), are examined to determine whether the signals would be large enough and unique enough to be useful in a GHG detection study. The nature of the predicted GHG signal was first examined using the transient CO2 run from the GISS ocean/atmosphere general circulation model. Next, the remotely sensed irradiance characteristics data (as the measure of water vapor content) supplied by the HIRS/MSU sensors for the area of the equatorial cold tongue region (the region in which there are no measurement stations). It is shown that HIRS/MSU signals can provide data necessary for detecting GHS signals in atmospheric moisture for regions where ground observations are not possible.

  3. Advances in metals classification under the United Nations globally harmonized system of classification and labeling.

    PubMed

    Skeaff, James; Adams, William J; Rodriguez, Patricio; Brouwers, Tony; Waeterschoot, Hugo

    2011-10-01

    This article shows how regulatory obligations mandated for metal substances can be met with a laboratory-based transformation/dissolution (T/D) method for deriving relevant hazard classification outcomes, which can then be linked to attendant environmental protection management decisions. We report the results of a ring-test at 3 laboratories conducted to determine the interlaboratory precision of the United Nations T/D Protocol (T/DP) in generating data for classifying 4 metal-bearing substances for acute and chronic toxicity under the United Nations Globally Harmonized System of Classification and Labelling (GHS) criteria with respect to the aquatic environment. The test substances were Ni metal powder, cuprous oxide (Cu(2) O) powder, tricobalt tetroxide (Co(3) O(4) ) powder, and cuttings of a NILO K Ni-Co-Fe alloy. Following GHS Annex 10 guidelines, we tested 3 loadings (1, 10, and 100 mg/L) of each substance at pH 6 and 8 for 7 or 28 d to yield T/D data for acute and chronic classification, respectively. We compared the T/DP results (dissolved metal in aqueous media) against acute and chronic ecotoxicity reference values (ERVs) for each substance to assess GHS classification outcomes. For dissolved metal ions, the respective acute and chronic ERVs established at the time of the T/D testing were: 29 and 8 µg/L for Cu; 185 and 1.5 µg/L for Co; and 13.3 and 1.0 mg/L for Fe. The acute ERVs for Ni were pH-dependent: 120 and 68 µg/L at pH 6 and 8, respectively, whereas the chronic ERV for Ni was 2.4 µg/L. The acute classification outcomes were consistent among 3 laboratories: cuprous oxide, Acute 1; Ni metal powder, Acute 3; Co(3) O(4) and the NILO K alloy, no classification. We obtained similar consistent results in chronic classifications: Cu(2) O, Ni metal powder, and Co(3) O(4) , Chronic 4; and the NILO K alloy, no classification. However, we observed equivocal results only in 2 of a possible 48 cases where the coefficient of variation of final T

  4. "Newton's cradle" proton relay with amide-imidic acid tautomerization in inverting cellulase visualized by neutron crystallography.

    PubMed

    Nakamura, Akihiko; Ishida, Takuya; Kusaka, Katsuhiro; Yamada, Taro; Fushinobu, Shinya; Tanaka, Ichiro; Kaneko, Satoshi; Ohta, Kazunori; Tanaka, Hiroaki; Inaka, Koji; Higuchi, Yoshiki; Niimura, Nobuo; Samejima, Masahiro; Igarashi, Kiyohiko

    2015-08-01

    Hydrolysis of carbohydrates is a major bioreaction in nature, catalyzed by glycoside hydrolases (GHs). We used neutron diffraction and high-resolution x-ray diffraction analyses to investigate the hydrogen bond network in inverting cellulase PcCel45A, which is an endoglucanase belonging to subfamily C of GH family 45, isolated from the basidiomycete Phanerochaete chrysosporium. Examination of the enzyme and enzyme-ligand structures indicates a key role of multiple tautomerizations of asparagine residues and peptide bonds, which are finally connected to the other catalytic residue via typical side-chain hydrogen bonds, in forming the "Newton's cradle"-like proton relay pathway of the catalytic cycle. Amide-imidic acid tautomerization of asparagine has not been taken into account in recent molecular dynamics simulations of not only cellulases but also general enzyme catalysis, and it may be necessary to reconsider our interpretation of many enzymatic reactions.

  5. Status of governmental oral health care delivery system in Haryana, India

    PubMed Central

    Vashist, Ashish; Parhar, Swati; Gambhir, Ramandeep Singh; Sohi, Ramandeep Kaur; Talwar, Puneet Singh

    2016-01-01

    Background: Health system should be organized to meet the needs of entire population of the nation. This means that the state has the direct responsibility for the health of its population and improving the quality of life through research, education, and provision of health services. The present study was conducted to evaluate the government oral health care delivery system in Haryana, India. Materials and Methods: The present cross-sectional study was conducted among 135 dental care units (DCUs) of various primary health centers (PHCs), community health centers (CHCs), and general hospitals (GHs) existing in the state by employing a cluster random sampling technique. Data regarding the provision of water and electricity supply, dental man power and their qualification, number and type of instruments in the dental operatory unit, etc., were collected on a structured format. Statistical analysis was done using number and percentages (SPSS package version 16). Results: Alternative source of electricity (generator) existed in only a few of health centers. About 93.4% (155) of the staff were graduates (BDS) and 6.6% (11) were postgraduates (MDS). Ultrasonic scaler was available at dental units of 83.1% (64) of PHCs, 73.1% (19) of CHCs, and 93.8% (30) of GHs. Patient drapes were provided in 48.1% (65) of the DCUs, doctor's aprons were provided in 74.1% (100) of the places. Conclusion: There is a shortfall in infrastructure and significant problem with the adequacy of working facilities. A great deal of effort is required to harmonize the oral health care delivery system. PMID:28217581

  6. Localizing gene regulation reveals a staggered wood decay mechanism for the brown rot fungus Postia placenta

    PubMed Central

    Zhang, Jiwei; Presley, Gerald N.; Ryu, Jae-San; Menke, Jon R.; Figueroa, Melania; Orr, Galya; Schilling, Jonathan S.

    2016-01-01

    Wood-degrading brown rot fungi are essential recyclers of plant biomass in forest ecosystems. Their efficient cellulolytic systems, which have potential biotechnological applications, apparently depend on a combination of two mechanisms: lignocellulose oxidation (LOX) by reactive oxygen species (ROS) and polysaccharide hydrolysis by a limited set of glycoside hydrolases (GHs). Given that ROS are strongly oxidizing and nonselective, these two steps are likely segregated. A common hypothesis has been that brown rot fungi use a concentration gradient of chelated metal ions to confine ROS generation inside wood cell walls before enzymes can infiltrate. We examined an alternative: that LOX components involved in ROS production are differentially expressed by brown rot fungi ahead of GH components. We used spatial mapping to resolve a temporal sequence in Postia placenta, sectioning thin wood wafers colonized directionally. Among sections, we measured gene expression by whole-transcriptome shotgun sequencing (RNA-seq) and assayed relevant enzyme activities. We found a marked pattern of LOX up-regulation in a narrow (5-mm, 48-h) zone at the hyphal front, which included many genes likely involved in ROS generation. Up-regulation of GH5 endoglucanases and many other GHs clearly occurred later, behind the hyphal front, with the notable exceptions of two likely expansins and a GH28 pectinase. Our results support a staggered mechanism for brown rot that is controlled by differential expression rather than microenvironmental gradients. This mechanism likely results in an oxidative pretreatment of lignocellulose, possibly facilitated by expansin- and pectinase-assisted cell wall swelling, before cellulases and hemicellulases are deployed for polysaccharide depolymerization. PMID:27621450

  7. The N-Glycan Cluster from Xanthomonas campestris pv. campestris

    PubMed Central

    Dupoiron, Stéphanie; Zischek, Claudine; Ligat, Laetitia; Carbonne, Julien; Boulanger, Alice; Dugé de Bernonville, Thomas; Lautier, Martine; Rival, Pauline; Arlat, Matthieu; Jamet, Elisabeth; Lauber, Emmanuelle; Albenne, Cécile

    2015-01-01

    N-Glycans are widely distributed in living organisms but represent only a small fraction of the carbohydrates found in plants. This probably explains why they have not previously been considered as substrates exploited by phytopathogenic bacteria during plant infection. Xanthomonas campestris pv. campestris, the causal agent of black rot disease of Brassica plants, possesses a specific system for GlcNAc utilization expressed during host plant infection. This system encompasses a cluster of eight genes (nixE to nixL) encoding glycoside hydrolases (GHs). In this paper, we have characterized the enzymatic activities of these GHs and demonstrated their involvement in sequential degradation of a plant N-glycan using a N-glycopeptide containing two GlcNAcs, three mannoses, one fucose, and one xylose (N2M3FX) as a substrate. The removal of the α-1,3-mannose by the α-mannosidase NixK (GH92) is a prerequisite for the subsequent action of the β-xylosidase NixI (GH3), which is involved in the cleavage of the β-1,2-xylose, followed by the α-mannosidase NixJ (GH125), which removes the α-1,6-mannose. These data, combined to the subcellular localization of the enzymes, allowed us to propose a model of N-glycopeptide processing by X. campestris pv. campestris. This study constitutes the first evidence suggesting N-glycan degradation by a plant pathogen, a feature shared with human pathogenic bacteria. Plant N-glycans should therefore be included in the repertoire of molecules putatively metabolized by phytopathogenic bacteria during their life cycle. PMID:25586188

  8. Hormone fatty acid modifications: gram negative bacteria and vertebrates demonstrate common structure and function.

    PubMed

    Tizzano, Marco; Sbarbati, Andrea

    2006-01-01

    Bacteria are known to regulate diverse physiological processes through a mechanism called quorum sensing (QS). Prokaryotes communicate by extracellular signalling compounds, i.e. autoinducers (acyl homoserine lactone, AHL of Gram negative bacteria) or pheromones (post-translationally modified peptides of Gram positive bacteria), which activate genetic pathways when they reach a sufficient concentration (QS). A large number of Gram-negative quorum-sensing systems studied so far utilize N-acyl homoserine lactones as signal molecules. In vertebrates small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. GH release is stimulated by hypothalamic GH-releasing hormone (GHRH) and ghrelin (endogenous ligand of the GHS-receptor, GHS-R). Ghrelin is a 28-amino acid peptide, in which the serine-3 (Ser3) is n-octanoylated, and this modification is essential for ghrelin's activity. Ghrelin is the first known case of a peptide hormone modified by a fatty acid. The major active form of ghrelin is a 28-amino acid peptide with octanoylated Ser3; one of the more represented bacterial autoinducers is the N-Octanoyl-DL-homoserine lactone (C8-HL) molecule. The authors hypothesize that Gram-negative bacteria and vertebrates have a functional similarity in the search of food and an important structural homology of AHL and ghrelin for the highly conserved Serine-acylated motive in both molecules. Our suggestions could help one to understand the convergent origin and the biologic meaning of the Serine-acylated group in these organisms, a biologic meaning very important due to the high conservation in two kingdoms which are so different.

  9. Reliability and Validity of Amharic Version of EORTC QLQ-C 30 Questionnaire among Gynecological Cancer Patients in Ethiopia

    PubMed Central

    Ayana, Birhanu Abera; Negash, Shiferaw; Yusuf, Lukman; Tigeneh, Wendemagegnhu

    2016-01-01

    Background Cancer is a growing public health problem worldwide. The focus of cancer treatment, in addition to curation, is improving the quality of life (QOL). This study aimed to assess the reliability and validity of Amharic version of European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) among gynecological cancer patients in Ethiopia. Methods A facility-based cross-sectional study was conducted using the Amharic version of EORTC QLQ-C30 on 153 gynecological cancer patients in Tikur Anbassa Specialized Hospital (TASH), Addis Ababa, Ethiopia. Descriptive statistics, correlation analysis and multivariable linear regression were employed in statistical analysis. Results The Amharic version of EORTC QLQ-C30 had a Cronbach’s α value of 0.81. The internal consistency for each domain of EORTC QLQ-C30 was also acceptable (Cronbach’s α >0.7) except for cognitive function domain (Cronbach’s α = 0.29). Stepwise multivariable linear regression analysis showed that emotional functioning (p<0.001), fatigue (p<0.001) and social functioning (p = 0.004) were the determinative scales of EORTC QLQ-C30 on global health status (GHS). The clinical validity test (Known group validity) showed that there were significant differences in score for twelve out of 15 domains, between surgery and radiation scheduled patients. All items of emotional function, role function, fatigue, and GHS meet the discriminate validity criterion. Conclusion The Amharic version of EORTC QLQ-C30 found to be reliable and had an acceptable validity to assess the QOL for gynecological cancer patients. We recommend further work on the validity and responsiveness of the EORTC QLQ-C30 with stronger design. PMID:27304066

  10. Pressure-temperature-time-deformation path of kyanite-bearing migmatitic paragneiss in the Kali Gandaki valley (Central Nepal): Investigation of Late Eocene-Early Oligocene melting processes

    NASA Astrophysics Data System (ADS)

    Iaccarino, Salvatore; Montomoli, Chiara; Carosi, Rodolfo; Massonne, Hans-Joachim; Langone, Antonio; Visonà, Dario

    2015-08-01

    Kyanite-bearing migmatitic paragneiss of the lower Greater Himalayan Sequence (GHS) in the Kali Gandaki transect (Central Himalaya) was investigated. In spite of the intense shearing, it was still possible to obtain many fundamental information for understanding the processes active during orogenesis. Using a multidisciplinary approach, including careful meso- and microstructural observations, pseudosection modelling (with PERPLE_X), trace element thermobarometry and in situ monazite U-Th-Pb geochronology, we constrained the pressure-temperature-time-deformation path of the studied rock, located in a structural key position. The migmatitic gneiss has experienced protracted prograde metamorphism after the India-Asia collision (50-55 Ma) from ~ 43 Ma to 28 Ma. During the late phase (36-28 Ma) of this metamorphism, the gneiss underwent high-pressure melting at "near peak" conditions (710-720 °C/1.0-1.1 GPa) leading to kyanite-bearing leucosome formation. In the time span of 25-18 Ma, the rock experienced decompression and cooling associated with pervasive shearing reaching P-T conditions of 650-670 °C and 0.7-0.8 GPa, near the sillimanite-kyanite transition. This time span is somewhat older than previously reported for this event in the study area. During this stage, additional, but very little melt was produced. Taking the migmatitic gneiss as representative of the GHS, these data demonstrate that this unit underwent crustal melting at about 1 GPa in the Eocene-Early Oligocene, well before the widely accepted Miocene decompressional melting related to its extrusion. In general, kyanite-bearing migmatite, as reported here, could be linked to the production of the high-Ca granitic melts found along the Himalayan belt.

  11. Fertility, birth timing and marital breakdown: a reinterpretation of the evidence.

    PubMed

    Murphy, M J

    1984-10-01

    The conventional view that childlessness was associated with higher than average risk of marital breakdown was questioned on the basis of analysis of divorce records. The General Household Survey (GHS) is a large scale multipurpose continuous household survey in Great Britain. Since 1979, it has contained an expanded family information section addressed to women under 50 which, for ever-married women, collects information about numbers and dates of marriages, births (both inside and outside marriage) and, in the case of marriages which have ended, the reason for ending (death, divorce or separation), the date when cohabitation ceased and the date of absolute decree if available. In 1980, there were 5017 ever-married women aged 16-49 for whom marriage and fertility histories were obtained. Some results are shown for the interval between separation and divorce based on life table methods for women aged 50 and under. The marriage duration data suggest that, apart from very short and very long durations, the proportion of separation not followed by divorce by 10 years is reasonably constant, about 13%. The median interval is around 2.5 years, with short and long duration marriages having above-average intervals, partly due to restictions on divorce in the early years of marriage. The proportion of marriages breaking down at various marriage durations by the fertility status at the start of the year in question is shown. The proportion is calculated as the number of marriages which were intact at various specified marriage durations, but which had broken down in 1, 5 or 10 years and which could have experienced the full period in the absence of breakdown. At short durations, early childbearing (including premarital births) is associated with higher than average probabilities of breakdown. The impression given by these results is different from other studies. Retrospective multipurpose surveys such as the GHS appear to have many advantages over administrative records.

  12. Ghrelin signaling in heart remodeling of adult obese mice.

    PubMed

    Lacerda-Miranda, Glauciane; Soares, Vivian M; Vieira, Anatalia K G; Lessa, Juliana G; Rodrigues-Cunha, Alessandra C S; Cortez, Erika; Garcia-Souza, Erica P; Moura, Anibal S

    2012-05-01

    Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), has been suggested to be associated to obesity, insulin secretion, cardiovascular growth and homeostasis. GHS-R has been found in most of the tissues, and among the hormone action it is included the regulation of heart energy metabolism. Therefore, hypernutrition during early life leads to obesity, induces cardiac hypertrophy, compromises myocardial function, inducing heart failure in adulthood. We examined ghrelin signaling process in cardiac remodeling in these obese adult mice. The cardiomyocytes (cmy) of left ventricle were analyzed by light microscopy and stereology, content and phosphorilation of cardiac proteins: ghrelin receptor (growth hormone secretagogue receptor 1a, GHSR-1a), protein kinase B (AKT and pAKT), phosphatidil inositol 3 kinase (PI3K), AMP-activated protein kinase (AMPK and pAMPK) and actin were achieved by Western blotting. GHSR-1a gene expression was analyzed by Real Time-PCR. We observed hyperglycemia and higher liver and visceral fat weight in obese when compared to control group. Obese mice presented a marked increase in heart weight/tibia length, indicating an enlarged heart size or a remodeling process. Obese mice had increased GHSR-1a content and expression in the heart associated to PI3K content and increased AKT content and phosphorylation. In contrast, AMPK content and phosphorylation in heart was not different between experimental groups. Ghrelin plasma levels in obese group were decreased when compared to control group. Our data suggest that remodeled myocardial in adult obese mice overnourished in early life are associated with higher phosphorylation of GHSR-1a, PI3K and AKT but not with AMPK.

  13. Potassium Current Is Not Affected by Long-Term Exposure to Ghrelin or GHRP-6 in Somatotropes GC Cells.

    PubMed

    Domínguez Mancera, Belisario; Monjaraz Guzman, Eduardo; Flores-Hernández, Jorge L V; Barrientos Morales, Manuel; Martínez Hernandez, José M; Hernández Beltran, Antonio; Cervantes Acosta, Patricia

    2013-01-01

    Ghrelin is a growth hormone (GH) secretagogue (GHS) and GHRP-6 is a synthetic peptide analogue; both act through the GHS receptor. GH secretion depends directly on the intracellular concentration of Ca(2+); this is determined from the intracellular reserves and by the entrance of Ca(2+) through the voltage-dependent calcium channels, which are activated by the membrane depolarization. Membrane potential is mainly determined by K(+) channels. In the present work, we investigated the effect of ghrelin (10 nM) or GHRP-6 (100 nM) for 96 h on functional expression of voltage-dependent K(+) channels in rat somatotropes: GC cell line. Physiological patch-clamp whole-cell recording was used to register the K(+) currents. With Cd(2+) (1 mM) and tetrodotoxin (1  μ m) in the bath solution recording, three types of currents were characterized on the basis of their biophysical and pharmacological properties. GC cells showed a K(+) current with a transitory component (I A) sensitive to 4-aminopyridine, which represents ~40% of the total outgoing current; a sustained component named delayed rectifier (I K), sensitive to tetraethylammonium; and a third type of K(+) current was recorded at potentials more negative than -80 mV, permitting the entrance of K(+) named inward rectifier (KIR). Chronic treatment with ghrelin or GHRP-6 did not modify the functional expression of K(+) channels, without significant changes (P < 0.05) in the amplitudes of the three currents observed; in addition, there were no modifications in their biophysical properties and kinetic activation or inactivation.

  14. Characterization of Potential Polysaccharide Utilization Systems in the Marine Bacteroidetes Gramella Flava JLT2011 Using a Multi-Omics Approach

    PubMed Central

    Tang, Kai; Lin, Yingfan; Han, Yu; Jiao, Nianzhi

    2017-01-01

    Members of phylum Bacteroidetes are distributed across diverse marine niches and Flavobacteria is often the predominant bacterial class decomposing algae-derived polysaccharides. Here, we report the complete genome of Gramella flava JLT2011 (Flavobacteria) isolated from surface water of the southeastern Pacific. A remarkable genomic feature is that the number of glycoside hydrolase (GH) genes in the genome of G. flava JLT2011 is more than 2-fold higher than that of other Gramella species. The functional profiles of the GHs suggest extensive variation in Gramella species. Growth experiments revealed that G. flava JLT2011 has the ability to utilize a wide range of polysaccharides for growth such as xylan and homogalacturonan in pectin. Nearly half of all GH genes were located on the multi-gene polysaccharide utilization loci (PUL) or PUL-like systems in G. flava JLT2011. This species was also found to harbor the two xylan PULs and a pectin PUL, respectively. Gene expression data indicated that more GHs and sugar-specific outer-membrane susC-susD systems were found in the presence of xylan than in the presence of pectin, suggesting a different strategy for heteropolymeric xylan and homoglacturonan utilization. Multi-omics data (transcriptomics, proteomics, and metabolomics) indicated that xylan PULs and pectin PUL are respectively involved in the catabolism of their corresponding polysaccharides. This work presents a comparison of polysaccharide decomposition within a genus and expands current knowledge on the diversity and function of PULs in marine Bacteroidetes, thereby deepening our understanding of their ecological role in polysaccharide remineralization in the marine system. PMID:28261179

  15. Role of appetite-regulating peptides in the pathophysiology of addiction: implications for pharmacotherapy.

    PubMed

    Engel, Jörgen A; Jerlhag, Elisabet

    2014-10-01

    Food intake and appetite are regulated by various circulating hormones including ghrelin and glucagon-like-peptide 1 (GLP-1). Ghrelin, mainly released from the stomach, increases food intake, induces appetite, enhances adiposity as well as releases growth hormone. Hypothalamic "ghrelin receptors" (GHS-R1A) have a critical role in food intake regulation, but GHS-R1A are also expressed in reward related areas. GLP-1 is produced in the intestinal mucosa as well as in the hindbrain in response to nutrient ingestion. This gut-brain hormone reduces food intake as well as regulates glucose homeostasis, foremost via GLP-1 receptors in hypothalamus and brain stem. However, GLP-1 receptors are expressed in areas intimately associated with reward regulation. Given that regulation of food and drug intake share common neurobiological substrates, the possibility that ghrelin and GLP-1 play an important role in reward regulation should be considered. Indeed, this leading article describes that the orexigenic peptide ghrelin activates the cholinergic-dopaminergic reward link, an important part of the reward systems in the brain associated with reinforcement and thereby increases the incentive salience for motivated behaviors via this system. We also review the role of ghrelin signaling for reward induced by alcohol and addictive drugs from a preclinical, clinical and human genetic perspective. In addition, the recent findings showing that GLP-1 controls reward induced by alcohol, amphetamine, cocaine and nicotine in rodents are overviewed herein. Finally, the role of several other appetite regulatory hormones for reward and addiction is briefly discussed. Collectively, these data suggest that ghrelin and GLP-1 receptors may be novel targets for development of pharmacological treatments of alcohol and drug dependence.

  16. Comparative analysis of fungal genomes reveals different plant cell wall degrading capacity in fungi

    PubMed Central

    2013-01-01

    Background Fungi produce a variety of carbohydrate activity enzymes (CAZymes) for the degradation of plant polysaccharide materials to facilitate infection and/or gain nutrition. Identifying and comparing CAZymes from fungi with different nutritional modes or infection mechanisms may provide information for better understanding of their life styles and infection models. To date, over hundreds of fungal genomes are publicly available. However, a systematic comparative analysis of fungal CAZymes across the entire fungal kingdom has not been reported. Results In this study, we systemically identified glycoside hydrolases (GHs), polysaccharide lyases (PLs), carbohydrate esterases (CEs), and glycosyltransferases (GTs) as well as carbohydrate-binding modules (CBMs) in the predicted proteomes of 103 representative fungi from Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota. Comparative analysis of these CAZymes that play major roles in plant polysaccharide degradation revealed that fungi exhibit tremendous diversity in the number and variety of CAZymes. Among them, some families of GHs and CEs are the most prevalent CAZymes that are distributed in all of the fungi analyzed. Importantly, cellulases of some GH families are present in fungi that are not known to have cellulose-degrading ability. In addition, our results also showed that in general, plant pathogenic fungi have the highest number of CAZymes. Biotrophic fungi tend to have fewer CAZymes than necrotrophic and hemibiotrophic fungi. Pathogens of dicots often contain more pectinases than fungi infecting monocots. Interestingly, besides yeasts, many saprophytic fungi that are highly active in degrading plant biomass contain fewer CAZymes than plant pathogenic fungi. Furthermore, analysis of the gene expression profile of the wheat scab fungus Fusarium graminearum revealed that most of the CAZyme genes related to cell wall degradation were up-regulated during plant infection. Phylogenetic analysis also

  17. Localizing gene regulation reveals a staggered wood decay mechanism for the brown rot fungus Postia placenta.

    PubMed

    Zhang, Jiwei; Presley, Gerald N; Hammel, Kenneth E; Ryu, Jae-San; Menke, Jon R; Figueroa, Melania; Hu, Dehong; Orr, Galya; Schilling, Jonathan S

    2016-09-27

    Wood-degrading brown rot fungi are essential recyclers of plant biomass in forest ecosystems. Their efficient cellulolytic systems, which have potential biotechnological applications, apparently depend on a combination of two mechanisms: lignocellulose oxidation (LOX) by reactive oxygen species (ROS) and polysaccharide hydrolysis by a limited set of glycoside hydrolases (GHs). Given that ROS are strongly oxidizing and nonselective, these two steps are likely segregated. A common hypothesis has been that brown rot fungi use a concentration gradient of chelated metal ions to confine ROS generation inside wood cell walls before enzymes can infiltrate. We examined an alternative: that LOX components involved in ROS production are differentially expressed by brown rot fungi ahead of GH components. We used spatial mapping to resolve a temporal sequence in Postia placenta, sectioning thin wood wafers colonized directionally. Among sections, we measured gene expression by whole-transcriptome shotgun sequencing (RNA-seq) and assayed relevant enzyme activities. We found a marked pattern of LOX up-regulation in a narrow (5-mm, 48-h) zone at the hyphal front, which included many genes likely involved in ROS generation. Up-regulation of GH5 endoglucanases and many other GHs clearly occurred later, behind the hyphal front, with the notable exceptions of two likely expansins and a GH28 pectinase. Our results support a staggered mechanism for brown rot that is controlled by differential expression rather than microenvironmental gradients. This mechanism likely results in an oxidative pretreatment of lignocellulose, possibly facilitated by expansin- and pectinase-assisted cell wall swelling, before cellulases and hemicellulases are deployed for polysaccharide depolymerization.

  18. Suggestive evidence of a multi-cytokine resistin pathway in humans and its role on cardiovascular events in high-risk individuals

    PubMed Central

    Menzaghi, Claudia; Marucci, Antonella; Antonucci, Alessandra; De Bonis, Concetta; Ortega Moreno, Lorena; Salvemini, Lucia; Copetti, Massimiliano; Trischitta, Vincenzo; Di Paola, Rosa

    2017-01-01

    In cells and tissues resistin affects IL-1β, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine “resistin pathway”. We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMAIR, triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)-prospective design (follow-up 5.4 ± 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p < 0.001), but IL-12B. Consistently, serum resistin was correlated with all serum cytokines (all p < 0.001), but IL-12. Expression (eRPS) and serum (sRPS) resistin pathway scores (excluding IL-12) were each other correlated (p < 0.001) and both associated with cardiovascular risk factors (all p < 0.01). In GHS, sRPS was independently associated with MACE (HR = 1.44, 95% CI = 1.10–1.90). Our data indicate the existence of a resistin pathway, which is associated with cardiovascular risk factors and which strongly and independently predicts MACE. PMID:28290549

  19. Functional genes and thermophilic microorganisms responsible for arsenite oxidation from the shallow sediment of an untraversed hot spring outlet.

    PubMed

    Yang, Ye; Mu, Yao; Zeng, Xian-Chun; Wu, Weiwei; Yuan, Jie; Liu, Yichen; Guoji, E; Luo, Feng; Chen, Xiaoming; Li, Hao; Wang, Jianing

    2017-03-01

    Hot Springs have unique geochemical features. Microorganisms-mediated arsenite oxidation is one of the major biogeochemical processes occurred in some hot springs. This study aimed to understand the diversities of genes and microorganisms involved in arsenite oxidation from the outlet of an untraversed hot spring located at an altitude of 4226 m. Microcosm assay indicated that the microbial community from the hot spring was able to efficiently oxidize As(III) using glucose, lactic acid, yeast extract or sodium bicarbonate as the sole carbon source. The microbial community contained 7 phyla of microorganisms, of which Proteobacteria and Firmicutes are largely dominant; this composition is unique and differs significantly from those of other described hot springs. Twenty one novel arsenite oxidase genes were identified from the samples, which are affiliated with the arsenite oxidase families of α-Proteobacteria, β-Proteobacteria or Archaea; this highlights the high diversity of the arsenite-oxidizing microorganisms from the hot spring. A cultivable arsenite-oxidizer Chelatococcu sp. GHS311 was also isolated from the sample using enrichment technique. It can completely convert 75.0 mg/L As(III) into As(V) in 18 days at 45 °C. The arsenite oxidase of GHS311 shares the maximal sequence identity (84.7%) to that of Hydrogenophaga sp. CL3, a non-thermotolerant bacterium. At the temperature lower than 30 °C or higher than 65 °C, the growth of this strain was completely inhibited. These data help us to better understand the diversity and functional features of the thermophilic arsenite-oxidizing microorganisms from hot springs.

  20. Development Characteristics of PMMA in alternative alcohol:water mixtures

    NASA Astrophysics Data System (ADS)

    Ocola, Leonidas E.

    2015-03-01

    The most widely used resist in electron beam lithography is polymethylmethacrylate (PMMA). The standard developers used are solution mixtures of isopropanol (IPA) and methyl isobutyl ketone (MIBK) in a ratio of 3:1 and mixtures of IPA and water (H2O) in a ratio of 7:3. The Globally Harmonized System (GHS) classification entry for IPA includes: Specific target organ toxicity - single exposure (Category 3). MIBK is much more hazardous than IPA. The only GHS classification entry for Ethanol is: Flammable liquids (Category 2), i.e. more environmentally safe. Using Ethanol/H2O as a developer will therefore enable lower hazardous waste disposal costs to cleanrooms. We find Ethanol/H2O at 85% volume (2:1 molar) exhibits excellent lithography results as good as with IPA/H2O, and better contrast and sensitivity than IPA/H2O and MIBK/IPA developers. Lithographic data shows trends similar to published cosolvency data, but differ too much to be explained by it. In addition, unusual development at 50% volume concentrations for both IPA and Ethanol in H2O show dramatic pothole formation instead of uniform thickness loss found in standard contrast curve exposures. We believe local pockets of concentrated alcohol water molar mixtures are responsible for such behavior. This work was supported by the Department of Energy under Contract No. DE-AC02-06CH11357. Use of the Center for Nanoscale Materials was supported by the U. S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.

  1. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF‐1

    PubMed Central

    Dobie, Ross; Ahmed, Syed F.; Staines, Katherine A.; Pass, Chloe; Jasim, Seema; MacRae, Vicky E.

    2015-01-01

    Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like‐growth factor‐1 (IGF‐1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling‐2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF‐1 levels. Wild‐type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P < 0.01). In the absence of SOCS2, GH treatment enhanced metatarsal linear growth over a 12 day period. Despite this increase, IGF‐1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF‐1 levels were unchanged in GH‐challenged postnatal Socs2‐/‐ conditioned medium despite metatarsals showing enhanced linear growth. Growth‐plate Igf1 mRNA levels were not elevated in juvenile Socs2‐/‐ mice. GH did however elevate IGF‐binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2‐/‐ metatarsals. GH did not enhance the growth of Socs2‐/‐ metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF‐2 may be responsible as IGF‐2 promoted metatarsal growth and Igf2 expression was elevated in Socs2‐/‐ (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2‐/‐ mice, promoting growth via a mechanism that is independent of IGF‐1. J. Cell. Physiol. 9999: 2796–2806, 2015. © 2015 Wiley Periodicals, Inc. PMID:25833299

  2. Sulfated gastrin stimulates ghrelin and growth hormone release but inhibits insulin secretion in cattle.

    PubMed

    Zhao, Hongqiong; Yannaing, Swe; Thanthan, Sint; Kuwayama, Hideto

    2011-11-01

    This study was designed to determine the effects of gastrin on the circulating levels of ghrelin, growth hormone (GH), insulin, glucagon and glucose in ruminants. Two experiments were done in eight Holstein steers. Animals were randomly assigned to receive intravenous bolus injections: (1) 0.1% bovine serum albumin in saline as vehicle, 0.8, 4.0 and 20.0 μg/kg body weight (BW) of bovine sulfated gastrin-34; (2) vehicle, 0.53 μg/kg BW of bovine sulfated gastrin-17 alone or combined with 20.0 μg/kg BW of [D-Lys(3)]-GHRP-6, the selective antagonist of GHS-R1a. Blood samples were collected from -10 to 150 min relative to injection time. Concentrations of acyl and total ghrelin in response to gastrin-34 injection were significantly increased in a dose-dependent manner. Concentrations of GH were also markedly elevated by gastrin-34 injection; however, the effect of 20.0 μg/kg was weaker than that of 4.0 μg/kg. The three doses of gastrin-34 equally decreased insulin levels within 15 min and maintained the level until the time of last sampling. Gastrin-34 had no effect (P > 0.05) on the levels of glucagon and glucose. Levels of acyl ghrelin increased after administration of gastrin-17 alone or combined with [D-Lys(3)]-GHRP-6; however, [D-Lys(3)]-GHRP-6 did not block the elevation of GH by gastrin-17. The present results indicate that sulfated gastrin stimulates both ghrelin and GH release, but the GHS-R1a may not contribute to the release of GH by gastrin. Moreover, sulfated gastrin seems to indirectly maintain the homeostasis of blood glucose through the down-regulation of insulin in ruminants.

  3. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF-1.

    PubMed

    Dobie, Ross; Ahmed, Syed F; Staines, Katherine A; Pass, Chloe; Jasim, Seema; MacRae, Vicky E; Farquharson, Colin

    2015-11-01

    Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like-growth factor-1 (IGF-1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling-2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF-1 levels. Wild-type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P < 0.01). In the absence of SOCS2, GH treatment enhanced metatarsal linear growth over a 12 day period. Despite this increase, IGF-1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF-1 levels were unchanged in GH-challenged postnatal Socs2(-/-) conditioned medium despite metatarsals showing enhanced linear growth. Growth-plate Igf1 mRNA levels were not elevated in juvenile Socs2(-/-) mice. GH did however elevate IGF-binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2(-/-) metatarsals. GH did not enhance the growth of Socs2(-/-) metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF-2 may be responsible as IGF-2 promoted metatarsal growth and Igf2 expression was elevated in Socs2(-/-) (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2(-/-) mice, promoting growth via a mechanism that is independent of IGF-1.

  4. Eye Irritation Test (EIT) for Hazard Identification of Eye Irritating Chemicals using Reconstructed Human Cornea-like Epithelial (RhCE) Tissue Model

    PubMed Central

    Kaluzhny, Yulia; Kandárová, Helena; d’Argembeau-Thornton, Laurence; Kearney, Paul; Klausner, Mitchell

    2015-01-01

    To comply with the Seventh Amendment to the EU Cosmetics Directive and EU REACH legislation, validated non-animal alternative methods for reliable and accurate assessment of ocular toxicity in man are needed. To address this need, we have developed an eye irritation test (EIT) which utilizes a three dimensional reconstructed human cornea-like epithelial (RhCE) tissue model that is based on normal human cells. The EIT is able to separate ocular irritants and corrosives (GHS Categories 1 and 2 combined) and those that do not require labeling (GHS No Category). The test utilizes two separate protocols, one designed for liquid chemicals and a second, similar protocol for solid test articles. The EIT prediction model uses a single exposure period (30 min for liquids, 6 hr for solids) and a single tissue viability cut-off (60.0% as determined by the MTT assay). Based on the results for 83 chemicals (44 liquids and 39 solids) EIT achieved 95.5/68.2/ and 81.8% sensitivity/specificity and accuracy (SS&A) for liquids, 100.0/68.4/ and 84.6% SS&A for solids, and 97.6/68.3/ and 83.1% for overall SS&A. The EIT will contribute significantly to classifying the ocular irritation potential of a wide range of liquid and solid chemicals without the use of animals to meet regulatory testing requirements. The EpiOcular EIT method was implemented in 2015 into the OECD Test Guidelines as TG 492. PMID:26325674

  5. Nonionic homopolymeric amphipols: application to membrane protein folding, cell-free synthesis, and solution nuclear magnetic resonance.

    PubMed

    Bazzacco, Paola; Billon-Denis, Emmanuelle; Sharma, K Shivaji; Catoire, Laurent J; Mary, Sophie; Le Bon, Christel; Point, Elodie; Banères, Jean-Louis; Durand, Grégory; Zito, Francesca; Pucci, Bernard; Popot, Jean-Luc

    2012-02-21

    Nonionic amphipols (NAPols) synthesized by homotelomerization of an amphiphatic monomer are able to keep membrane proteins (MPs) stable and functional in the absence of detergent. Some of their biochemical and biophysical properties and applications have been examined, with particular attention being paid to their complementarity with the classical polyacrylate-based amphipol A8-35. Bacteriorhodopsin (BR) from Halobacterium salinarum and the cytochrome b(6)f complex from Chlamydomonas reinhardtii were found to be in their native state and highly stable following complexation with NAPols. NAPol-trapped BR was shown to undergo its complete photocycle. Because of the pH insensitivity of NAPols, solution nuclear magnetic resonance (NMR) two-dimensional (1)H-(15)N heteronuclear single-quantum coherence spectra of NAPol-trapped outer MP X from Escherichia coli (OmpX) could be recorded at pH 6.8. They present a resolution similar to that of the spectra of OmpX/A8-35 complexes recorded at pH 8.0 and give access to signals from solvent-exposed rapidy exchanging amide protons. Like A8-35, NAPols can be used to fold MPs to their native state as demonstrated here with BR and with the ghrelin G protein-coupled receptor GHS-R1a, thus extending the range of accessible folding conditions. Following NAPol-assisted folding, GHS-R1a bound four of its specific ligands, recruited arrestin-2, and activated binding of GTPγS by the G(αq) protein. Finally, cell-free synthesis of MPs, which is inhibited by A8-35 and sulfonated amphipols, was found to be very efficient in the presence of NAPols. These results open broad new perspectives on the use of amphipols for MP studies.

  6. Hepatic receptors for homologous growth hormone in the eel

    SciTech Connect

    Hirano, T. )

    1991-03-01

    The specific binding of 125I-labeled eel growth hormone (eGH) to liver membranes of the eel was examined. The specific binding to the 10,000g pellet was greater than that to the 600g pellet. The specific binding was linear up to about 100 mg fresh tissue, and was saturable with increasing amounts of membrane. The specific binding was pH-, temperature-, and time-dependent, with the optimum pH at 7.4, and greater specific binding was obtained at 15 and 25 degrees than at 35 degrees. Scatchard analysis of liver binding gave an association constant of 1.1 x 10(9) M-1 and a capacity of 105 fmol/mg protein. The receptor preparation was highly specific for GHs. Natural and recombinant eel GHs as well as recombinant salmon GH competed equally with 125I-eGH for the receptor sites of the 10,000g liver membrane. Ovine GH was more potent in displacing the labeled eGH than the homologous eel hormone. Tilapia GH and ovine prolactin (PRL) were needed in greater amounts (40 times) than eGH to displace the labeled eGH. Salmon and tilapia PRLs were still less potent (500 times) than eGH. There was no displacement with eel PRL. No significant change in the specific binding was seen 1 week after hypophysectomy, whereas injection of eGH into the hypophysectomized eel caused a significant reduction after 24 hr. The binding to the membrane fractions from gills, kidney, muscle, intestine, and brain was low and exclusively nonspecific, indicating the presence of specific GH receptors predominantly in the liver.

  7. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats.

    PubMed

    Kamegai, J; Tamura, H; Shimizu, T; Ishii, S; Sugihara, H; Wakabayashi, I

    2001-11-01

    Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), was originally purified from the rat stomach. Like the synthetic growth hormone secretagogues (GHSs), ghrelin specifically releases growth hormone (GH) after intravenous administration. Also consistent with the central actions of GHSs, ghrelin-immunoreactive cells were shown to be located in the hypothalamic arcuate nucleus as well as the stomach. Recently, we showed that a single central administration of ghrelin increased food intake and hypothalamic agouti-related protein (AGRP) gene expression in rodents, and the orexigenic effect of this peptide seems to be independent of its GH-releasing activity. However, the effect of chronic infusion of ghrelin on food consumption and body weight and their possible mechanisms have not been elucidated. In this study, we determined the effects of chronic intracerebroventricular treatment with ghrelin on metabolic factors and on neuropeptide genes that are expressed in hypothalamic neurons that have been previously shown to express the GHS-R and to regulate food consumption. Chronic central administration of rat ghrelin (1 microg/rat every 12 h for 72 h) significantly increased food intake and body weight. However, it did not affect plasma insulin, glucose, leptin, or GH concentrations. We also found that chronic central administration of ghrelin increased both neuropeptide Y (NPY) mRNA levels (151.0 +/- 10.1% of saline-treated controls; P < 0.05) and AGRP mRNA levels (160.0 +/- 22.5% of saline-treated controls; P < 0.05) in the arcuate nucleus. Thus, the primary hypothalamic targets of ghrelin are NPY/AGRP-containing neurons, and ghrelin is a newly discovered orexigenic peptide in the brain and stomach.

  8. Endocrine and orexigenic actions of growth hormone secretagogues in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Shepherd, Brian S; Johnson, Jaime K; Silverstein, Jeffrey T; Parhar, Ishwar S; Vijayan, Mathilakath M; McGuire, Alison; Weber, Gregory M

    2007-03-01

    The effects of growth hormone secretagogues (GHSs) on the teleost somatotropic axis are poorly understood, particularly with respect to insulin-like growth factor-I (IGF-I) and the IGF-binding proteins (IGFBPs). To assess the endocrine and orexigenic responses of rainbow trout (Oncorhynchus mykiss) to GHS treatment, animals were injected with human GHRH(1-29)-amide, KP-102 or rat ghrelin at 0, 1 or 10 pmol/g body mass. Feed intake was tested at 2 and 5 h post-injection and plasma levels of growth hormone (GH), IGF-I and the IGFBPs were determined at 3, 6 and 12 h post-injection. Feed intake was significantly elevated by all of the GHSs tested at both post-injection time points. All GHSs elevated plasma GH levels in a time-dependent manner. Plasma IGF-I levels were elevated by all GHSs at 3 h post-injection, whereas those animals treated with KP-102 and ghrelin exhibited depressions at 6 h. Four IGFBPs were identified in the plasma by western blotting. Levels of the 20 kDa IGFBP decreased over the sampling time. Levels of the 32 kDa IGFBP were significantly depressed by all GHSs tested. Levels of the 42 kDa IGFBP were significantly elevated by all GHSs tested. Plasma levels of the 50 kDa IGFBP was decreased in some treatment groups at 3 h, but elevated by 6 h in the ghrelin-treated groups and elevated in all treatment groups by 12 h post-injection. The endocrine and orexigenic responses demonstrate that GHSs influence the teleost neuroendocrine system beyond short-term actions (<3 h post-injection) on GH release and the responses of the IGFBPs to GHS treatment support this notion and clarify their identification as functional homologues to mammalian IGFBPs.

  9. Age-dependent reduction of ghrelin- and motilin-induced contractile activity in the chicken gastrointestinal tract.

    PubMed

    Kitazawa, Takio; Yoshida, Akiko; Tamano, Takuya; Teraoka, Hiroki; Kaiya, Hiroyuki

    2013-05-01

    Ghrelin is an endogenous ligand for growth hormone secretagogue-receptor 1a (GHS-R1a) and stimulates gastrointestinal (GI) motility in the chicken. Since ghrelin stimulates GH release, which regulates growth, it might be interesting to compare ghrelin-induced responses in GI tract of different-aged chickens. Motilin is a ghrelin-related gut peptide that induces strong contraction in the small intestine. Aim of this study was to clarify age-dependent changes in ghrelin- and motilin-induced contractions of the chicken GI tract and expression of their receptor mRNAs. Chicken ghrelin caused contraction of the crop and proventriculus. Ghrelin-induced contraction in the proventriculus decreased gradually up to 100 days after hatching, but the responses to ghrelin in the crop were the same during the growth period. GHS-R1a mRNA expression in the crop tended to increase, but that in the proventriculus decreased depending on the age. Chicken motilin caused contraction of the chicken GI tract. Atropine decreased the responses to motilin in the proventriculus but not in the ileum. Motilin-induced contraction in the proventriculus but not that in the ileum decreased depending on post-hatching days. On the other hand, motilin receptor mRNA expression in every region of the GI tract decreased with age, but the decrease was more marked in the proventriculus than in the ileum. In conclusion, ghrelin- and motilin-induced GI contractions selectively decreased in the chicken proventriculus depending on post-hatching days, probably due to the age-related decrease in respective receptors expression. The results suggest an age-related contribution of ghrelin and motilin to the regulation of chicken GI motility.

  10. Integrating optical fabrication and metrology into the optical design process

    NASA Astrophysics Data System (ADS)

    Harvey, James E.

    2014-12-01

    Image degradation due to scattered radiation from residual optical fabrication errors is a serious problem in many short wavelength (X-ray/EUV) imaging systems. Most commercially-available image analysis codes (ZEMAX, Code V, ASAP, FRED, etc.) currently require the scatter behavior (BSDF data) to be provided as input in order to calculate the image quality of such systems. This BSDF data is difficult to measure and rarely available for the operational wavelengths of interest. Since the smooth-surface approximation is often not satisfied at these short wavelengths, the classical Rayleigh-Rice expression that indicates the BRDF is directly proportional to the surface PSD cannot be used to calculate BRDFs from surface metrology data for even slightly rough surfaces. However, an FFTLog numerical Hankel transform algorithm enables the practical use of the computationally intensive Generalized Harvey-Shack (GHS) surface scatter theory [1] to calculate BRDFs from surface PSDs for increasingly short wavelengths that violate the smooth surface approximation implicit in the Rayleigh-Rice surface scatter theory [2-3]. The recent numerical validation [4] of the GHS theory (a generalized linear systems formulation of surface scatter theory), and an analysis of image degradation due to surface scatter in the presence of aberrations [5] has provided credence to the development of a systems engineering analysis of image quality as degraded not only by diffraction effects and geometrical aberrations, but to scattering effects due to residual optical fabrication errors as well. These advances, combined with the continuing increase in computer speed, leave us poised to fully integrate optical metrology and fabrication into the optical design process.

  11. Threshold of toxicological concern values for non-genotoxic effects in industrial chemicals: re-evaluation of the Cramer classification.

    PubMed

    Kalkhof, H; Herzler, M; Stahlmann, R; Gundert-Remy, U

    2012-01-01

    The TTC concept employs available data from animal testing to derive a distribution of NOAELs. Taking a probabilistic view, the 5th percentile of the distribution is taken as a threshold value for toxicity. In this paper, we use 824 NOAELs from repeated dose toxicity studies of industrial chemicals to re-evaluate the currently employed TTC values, which have been derived for substances grouped according to the Cramer scheme (Cramer et al. in Food Cosm Toxicol 16:255-276, 1978) by Munro et al. (Food Chem Toxicol 34:829-867, 1996) and refined by Kroes and Kozianowski (Toxicol Lett 127:43-46, 2002), Kroes et al. 2000. In our data set, consisting of 756 NOAELs from 28-day repeated dose testing and 57 NOAELs from 90-days repeated dose testing, the experimental NOAEL had to be extrapolated to chronic TTC using regulatory accepted extrapolation factors. The TTC values derived from our data set were higher than the currently used TTC values confirming the safety of the latter. We analysed the prediction of the Cramer classification by comparing the classification by this tool with the guidance values for classification according to the Globally Harmonised System of classification and labelling of the United Nations (GHS). Nearly 90% of the chemicals were in Cramer class 3 and assumed as highly toxic compared to 22% according to the GHS. The Cramer classification does underestimate the toxicity of chemicals only in 4.6% of the cases. Hence, from a regulatory perspective, the Cramer classification scheme might be applied as it overestimates hazard of a chemical.

  12. The N-Glycan cluster from Xanthomonas campestris pv. campestris: a toolbox for sequential plant N-glycan processing.

    PubMed

    Dupoiron, Stéphanie; Zischek, Claudine; Ligat, Laetitia; Carbonne, Julien; Boulanger, Alice; Dugé de Bernonville, Thomas; Lautier, Martine; Rival, Pauline; Arlat, Matthieu; Jamet, Elisabeth; Lauber, Emmanuelle; Albenne, Cécile

    2015-03-06

    N-Glycans are widely distributed in living organisms but represent only a small fraction of the carbohydrates found in plants. This probably explains why they have not previously been considered as substrates exploited by phytopathogenic bacteria during plant infection. Xanthomonas campestris pv. campestris, the causal agent of black rot disease of Brassica plants, possesses a specific system for GlcNAc utilization expressed during host plant infection. This system encompasses a cluster of eight genes (nixE to nixL) encoding glycoside hydrolases (GHs). In this paper, we have characterized the enzymatic activities of these GHs and demonstrated their involvement in sequential degradation of a plant N-glycan using a N-glycopeptide containing two GlcNAcs, three mannoses, one fucose, and one xylose (N2M3FX) as a substrate. The removal of the α-1,3-mannose by the α-mannosidase NixK (GH92) is a prerequisite for the subsequent action of the β-xylosidase NixI (GH3), which is involved in the cleavage of the β-1,2-xylose, followed by the α-mannosidase NixJ (GH125), which removes the α-1,6-mannose. These data, combined to the subcellular localization of the enzymes, allowed us to propose a model of N-glycopeptide processing by X. campestris pv. campestris. This study constitutes the first evidence suggesting N-glycan degradation by a plant pathogen, a feature shared with human pathogenic bacteria. Plant N-glycans should therefore be included in the repertoire of molecules putatively metabolized by phytopathogenic bacteria during their life cycle.

  13. Ghrelin Modulates the fMRI BOLD Response of Homeostatic and Hedonic Brain Centers Regulating Energy Balance in the Rat

    PubMed Central

    Deli, Levente; Gajári, Dávid; Dávid, Szabolcs; Pozsgay, Zsófia; Hegedűs, Nikolett; Tihanyi, Károly; Liposits, Zsolt

    2014-01-01

    The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1A) are pivotal regulators of hypothalamic feeding centers and reward processing neuronal circuits of the brain. These systems operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter messages and metabolic signals. Functional magnetic resonance imaging was employed in the current study to map BOLD responses to ghrelin in different brain regions with special reference on homeostatic and hedonic regulatory centers of energy balance. Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied. Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response in all studied regions of interest (ROI) within the limbic system. This effect was antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin effects in the presence or absence of JMV2959 in individual ROIs revealed significant changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost identical to those observed in males. Ovariectomy and chronic estradiol replacement had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by rimonabant significantly attenuated the response of the nucleus accumbens and septum. In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling energy balance in both sexes. The endocannabinoid signaling system contributes to the manifestation of ghrelin's BOLD effect in a region specific manner. In females, the estradiol milieu does

  14. Diet and renal stone formation.

    PubMed

    Trinchieri, A

    2013-02-01

    The relationship between diet and the formation of renal stones is demonstrated, but restrictive diets do not take into account the complexity of metabolism and the complex mechanisms that regulate the saturation and crystallization processes in the urine. The restriction of dietary calcium can reduce the urinary excretion of calcium but severe dietary restriction of calcium causes hyperoxaluria and a progressive loss of bone mineral component. Furthermore urinary calcium excretion is influenced by other nutrients than calcium as sodium, potassium, protein and refined carbohydrates. Up to 40% of the daily excretion of oxalate in the urine is from dietary source, but oxalate absorption in the intestine depends linearly on the concomitant dietary intake of calcium and is influenced by the bacterial degradation by several bacterial species of intestinal flora. A more rational approach should be based on the cumulative effects of foods and different dietary patterns on urinary saturation rather than on the effect of single nutrients. A diet based on a adequate intake of calcium (1000-1200 mg per day) and containment of animal protein and salt can decrease significantly urinary supersaturation for calcium oxalate and reduce the relative risk of stone recurrence in hypercalciuric renal stone formers. The DASH-style diet that is high in fruits and vegetables, moderate in low-fat dairy products and low in animal proteins and salt is associated with a lower relative supersaturation for calcium oxalate and a marked decrease in risk of incident stone formation. All the diets above mentioned have as a common characteristic the reduction of the potential acid load of the diet that can be correlated with a higher risk of recurrent nephrolithiasis, because the acid load of diet is inversely related to urinary citrate excretion. The restriction of protein and salt with an adequate calcium intake seem to be advisable but should be implemented with the advice to increase the intake

  15. Renal Stone Risk During Space Flight

    NASA Technical Reports Server (NTRS)

    Whitson, Peggy A.; Pietrzyk, Robert A.; Sams, Clarence F.; Pak, Charles Y. C.; Jones, Jeffrey A.

    1999-01-01

    Space flight produces a number of metabolic and physiological changes in the crewmembers exposed to microgravity. Following launch, body fluid volumes, electrolyte levels, and bone and muscle undergo changes as the human body adapts to the weightless environment. Changes in the urinary chemical composition may lead to the potentially serious consequences of renal stone formation. Previous data collected immediately after space flight indicate changes in the urine chemistry favoring an increased risk of calcium oxalate and uric acid stone formation (n = 323). During short term Shuttle space flights, the changes observed include increased urinary calcium and decreased urine volume, pH and citrate resulting in a greater risk for calcium oxalate and brushite stone formation (n = 6). Results from long duration Shuttle/Mir missions (n = 9) followed a similar trend and demonstrated decreased fluid intake and urine volume and increased urinary calcium resulting in a urinary environment saturated with the calcium stone-forming salts. The increased risk occurs rapidly upon exposure to microgravity, continues throughout the space flight and following landing. Dietary factors, especially fluid intake, or pharmacologic intervention can significantly influence the urinary chemical composition. Increasing fluid intake to produce a daily urine output of 2 liters/day may allow the excess salts in the urine to remain in solution, crystals formation will not occur and a renal stone will not develop. Results from long duration crewmembers (n = 2) who had urine volumes greater than 2.5 L/day minimized their risk of renal stone formation. Also, comparisons of stone-forming risk in short duration crewmembers clearly identified greater risk in those who produced less than 2 liters of urine/day. However, hydration and increased urine output does not correct the underlying calcium excretion due to bone loss and only treats the symptoms and not the cause of the increased urinary salts

  16. Effects of mineral composition of drinking water on risk for stone formation and bone metabolism in idiopathic calcium nephrolithiasis.

    PubMed

    Marangella, M; Vitale, C; Petrarulo, M; Rovera, L; Dutto, F

    1996-09-01

    1. To assess whether the mineral content of drinking water influences both risk of stone formation and bone metabolism in idiopathic calcium nephrolithiasis, 21 patients were switched from their usual home diets to a 10 mmol calcium, low-oxalate, protein-controlled diet, supplemented with 21 of three different types of mineral water. Drinking water added 1, 6 and 20 mmol of calcium and 0.5, 10 and 50 mmol of bicarbonate respectively to the controlled diet. 2. The three controlled study periods lasted 1 month each and were separated by a 20 day washout interval. Blood and urine chemistries, including intact parathyroid hormone, calcitriol and two markers of bone resorption, were performed at the end of each study period. The stone-forming risk was assessed by calculating urine saturation with calcium oxalate (beta CaOx), calcium phosphate (beta bsh) and uric acid (beta UA). 3. The addition of any mineral water produced the expected increase in urine output and was associated with similar decreases in beta CaOx and beta UA, whereas beta bsh varied marginally. These equal decreases in beta CaOx, however, resulted from peculiar changes in calcium, oxalate and citrate excretion during each study period. The increase in overall calcium intake due to different drinking water induced modest increases in calcium excretion, whereas oxalate excretion tended to decrease. The changes in oxalate excretion during any one study period compared with another were significantly related to those in calcium intake. Citrate excretion was significantly higher with the high-calcium, alkaline water. 4. Parathyroid hormone, calcitriol and markers of bone resorption increased when patients were changed from the high-calcium, alkaline to the low-calcium drinking water. 5. We suggest that overall calcium intake may be tailored by supplying calcium in drinking water. Adverse effects on bone turnover with low-calcium diets can be prevented by giving high-calcium, alkaline drinking water, and the

  17. Linking microstructures, petrology and in situ U-(Th)-Pb geochronology to constrain P-T-t-D evolution of the Greather Himalyan Sequences in Western Nepal (Central Himalaya)

    NASA Astrophysics Data System (ADS)

    Iaccarino, Salvatore; Montomoli, Chiara; Carosi, Rodolfo; Langone, Antonio

    2013-04-01

    Last advances in forward modelling of metamorphic rocks and into the understanding of accessories minerals behaviour, suitable for geochronology (e.g. zircon and monazite), during metamorphism, bring new insights for understanding the evolution of metamorphic tectonites during orogenic cycles (Williams and Jercinovic, 2012 and reference therein). One of the best exposure of high- to medium grade- metamorphic rocks, is represented by the Greater Himalayan Sequence (GHS) in the Himalayan Belt, one of the most classic example of collisional orogen. Recent field work in Mugu Karnali valley, Western Nepal (Central Himalaya), identified a compressional top to the South ductile shear zone within the core of the GHS, named Magri Shear Zone (MSZ), developed in a high temperature regime as testified by quartz microstructures and syn-kinematic growth of sillimanite. In order to infer the tectono-metamorphic meaning of MSZ, a microstructural study coupled with pseudosection modelling and in situ U-(Th)-Pb monazite geochronology was performed on selected samples from different structural positions. Footwall sample constituted by (Grt + St ± Ky) micaschist shows a prograde garnet growth (cores to inner rims zoning), from ~500°C, ~0.60GPa (close to garnet-in curve) to ~580°C, ~1.2 GPa temporal constrained between 21-18 Ma, by medium Y cores to very low Y mantles monazite micro-chemical/ages domain . In this sample garnet was still growing during decompression and heating at ~640°C, ~0.75 GPa (rims), and later starts to be consumed, in conjunction with staurolite growth at 15-13 Ma, as revealed by high Y rims monazite micro-chemical/ages domain. Hanging-wall mylonitic samples have a porphyroclastic texture, with garnet preserve little memory of prograde path. Garnet near rim isoplets and matrix minerals intersect at ~700°C and ~0.70 GPa. A previous higher P stage, at ~1.10 GPa ~600°C, is testified by cores of larger white mica porhyroclasts. Prograde zoned allanite (Janots

  18. On the Strength and Validity of Hazard Banding

    PubMed Central

    Scheffers, Theo; Doornaert, Blandine; Berne, Nathalie; van Breukelen, Gerard; Leplay, Antoine; van Miert, Erik

    2016-01-01

    Hazard Banding (HB) is a process of allocating chemical substances in bands of increasing health hazard based on their hazard classifications. Recent Control Banding (CB) tools use the classifications of the United Nations Global Harmonized System (UN GHS) or the European Union Classifications, Labelling and Packaging (EU CLP) which are grouped over 5 HBs. The use of CB is growing worldwide for the risk control of substances without an Occupational Exposure Limit Value (OELV). Well-known CB-tools like HSE-COSHH Essentials, BAuA-Einfaches Maßnahmenkonzept Gefahrstoffe (EMKG), and DGUV-IFA-Spaltenmodell (IFA) use however different GHS/CLP groupings which may lead to dissimilar HBs and control regimes for individual substances. And as the choice for a CB tool seems to be determined by geography and/or local status these differences may hamper a global, aligned HSE approach. Therefore, the HB-engines of the three public CBs and an in-company (Solvay) CB called ‘Occupational Exposure Banding’ (S-OEB) were compared mutually and ranked in their relation with the OELV as the ‘de facto’ standard. This was investigated graphically and using a 5 strength indicator, statistical method. A data set of 229 substances with high-quality GHS/CLP classifications and OELVs was used. HB concentration ranges, as linked to S-OEB and COSHH, were validated against the corresponding OELV distributions. The four HB-engines allocate between 23 and 64% of the 229 substances in the same bands. The remaining substances differ at least one band, with IFA placing more substances in a higher hazard band, EMKG doing the opposite and COSHH and S-OEB in between. The overall strength scores of S-OEB, IFA, and EMGK HB-engines are higher than COSHH, with S-OEB having the highest overall strength score. The lower ends of the concentration ranges defined for the 3 ‘highest’ hazard bands of S-OEB were in good agreement with the 10th percentiles of the corresponding OELV distributions obtained

  19. Human Growth Hormone: 45-kDa Isoform with Extraordinarily Stable Interchain Disulfide Links has Attenuated Receptor-Binding and Cell-Proliferative Activities

    PubMed Central

    Bustamante, Juan J.; Grigorian, Alexei L.; Muñoz, Jesus; Aguilar, Roberto M.; Treviño, Lisa R.; Martinez, Andrew O.; Haro, Luis S.

    2010-01-01

    Background Human growth hormone (hGH) is a complex mixture of molecular isoforms. Gaps in our knowledge exist regarding the structures and biological significances of the uncharacterized hGH molecular variants. Mercaptoethanol-resistant 45-kDa human growth hormone (MER-45kDa hGH) is an extraordinarily stable disulfide-linked hGH homodimer whose biological significance is unknown. Objectives To elucidate the pharmacokinetic abilities of dimeric MER-45-kDa hGH to bind to GH and prolactin (PRL) receptors and to elucidate its abilities to stimulate cell-proliferation in lactogen-induced and somatogen-induced in vitro cell proliferation bioassays. Design The binding of MER-45-kDa hGH to GH and PRL receptors was tested in radioreceptorassays (RRAs). Competitive displacements of [125I]-bovine GH from bovine liver membranes, [125I]-ovine PRL from lactating rabbit mammary gland membranes and [125I]-hGH from human IM-9 lymphocytes by unlabelled GHs, PRLs or dimeric MER-45-kDa hGH were evaluated. The abilities of dimeric MER-45-kDa hGH to stimulate proliferation of lactogen-responsive Nb2 lymphoma cells and to stimulate proliferation of somatogen-responsive T47-D human breast cancer cells was assessed by incubation of cells with GHs or PRLs and subsequently measuring growth using the MTS cell proliferation assay. Results Dimeric MER-45-kDa hGH, compared to monomeric hGH, had reduced binding affinities to both GH and prolactin receptors. In a bovine liver GH radioreceptorassay its ED50 (197.5 pM) was 40.8% that of monomeric hGH. In a human IM-9 lymphocyte hGH RRA its ED50 (2.96 nM) was 26.2% that of monomeric hGH. In a lactating rabbit mammary gland prolactin RRA its ED50 (3.56 nM) was 16.8% that of a monomeric hGH. Dimeric MER-45-kDa hGH, compared to monomeric hGH, had a diminished capacity to stimulate proliferation of cells in vitro. In a dose-response relationship assessing proliferation of Nb2 lymphoma cells its ED50 (191 pM) was 18.0% that of monomeric hGH. While

  20. On the Strength and Validity of Hazard Banding.

    PubMed

    Scheffers, Theo; Doornaert, Blandine; Berne, Nathalie; van Breukelen, Gerard; Leplay, Antoine; van Miert, Erik

    2016-11-01

    Hazard Banding (HB) is a process of allocating chemical substances in bands of increasing health hazard based on their hazard classifications. Recent Control Banding (CB) tools use the classifications of the United Nations Global Harmonized System (UN GHS) or the European Union Classifications, Labelling and Packaging (EU CLP) which are grouped over 5 HBs. The use of CB is growing worldwide for the risk control of substances without an Occupational Exposure Limit Value (OELV). Well-known CB-tools like HSE-COSHH Essentials, BAuA-Einfaches Maßnahmenkonzept Gefahrstoffe (EMKG), and DGUV-IFA-Spaltenmodell (IFA) use however different GHS/CLP groupings which may lead to dissimilar HBs and control regimes for individual substances. And as the choice for a CB tool seems to be determined by geography and/or local status these differences may hamper a global, aligned HSE approach. Therefore, the HB-engines of the three public CBs and an in-company (Solvay) CB called 'Occupational Exposure Banding' (S-OEB) were compared mutually and ranked in their relation with the OELV as the 'de facto' standard. This was investigated graphically and using a 5 strength indicator, statistical method. A data set of 229 substances with high-quality GHS/CLP classifications and OELVs was used. HB concentration ranges, as linked to S-OEB and COSHH, were validated against the corresponding OELV distributions. The four HB-engines allocate between 23 and 64% of the 229 substances in the same bands. The remaining substances differ at least one band, with IFA placing more substances in a higher hazard band, EMKG doing the opposite and COSHH and S-OEB in between. The overall strength scores of S-OEB, IFA, and EMGK HB-engines are higher than COSHH, with S-OEB having the highest overall strength score. The lower ends of the concentration ranges defined for the 3 'highest' hazard bands of S-OEB were in good agreement with the 10(th) percentiles of the corresponding OELV distributions obtained from the

  1. Citrate and renal calculi: an update

    NASA Technical Reports Server (NTRS)

    Pak, C. Y.

    1994-01-01

    Citrate is an inhibitor of the crystallization of stone-forming calcium salts. Hypocitraturia, frequently encountered in patients with nephrolithiasis, is therefore an important risk factor for stone formation. Potassium citrate provides physiological and physicochemical correction and inhibits new stone formation, not only in hypocitraturic calcium nephrolithiasis but also in uric acid nephrolithiasis. Inhibition of stone recurrence has now been validated by a randomized trial. Ongoing research has disclosed additional causes of hypocitraturia (sodium excess, low intestinal alkali absorption, but not primary citrate malabsorption). Moreover, new insights on potassium citrate action have been shown, notably that some of absorbed citrate escapes oxidation and contributes to the citraturic response, that ingestion with a meal does not sacrifice physiological or physicochemical action, that orange juice mimics but does not completely duplicate its actions, that potassium citrate may have a beneficial bone-sparing effect, that it may reduce stone fragments following ESWL, and that danger of aluminum toxicity is not great in subjects with functioning kidneys. Finally, the research on potassium citrate has led to two promising products, calcium citrate as an optimum calcium supplement and potassium-magnesium citrate which may be superior to potassium citrate in the management of stone disease.

  2. Elemental Content of Calcium Oxalate Stones from a Canine Model of Urinary Stone Disease

    PubMed Central

    Killilea, David W.; Westropp, Jodi L.; Shiraki, Ryoji; Mellema, Matthew; Larsen, Jennifer; Kahn, Arnold J.; Kapahi, Pankaj; Chi, Thomas; Stoller, Marshall L.

    2015-01-01

    One of the most common types of urinary stones formed in humans and some other mammals is composed of calcium oxalate in ordered hydrated crystals. Many studies have reported a range of metals other than calcium in human stones, but few have looked at stones from animal models such as the dog. Therefore, we determined the elemental profile of canine calcium oxalate urinary stones and compared it to reported values from human stones. The content of 19 elements spanning 7-orders of magnitude was quantified in calcium oxalate stones from 53 dogs. The elemental profile of the canine stones was highly overlapping with human stones, indicating similar inorganic composition. Correlation and cluster analysis was then performed on the elemental profile from canine stones to evaluate associations between the elements and test for potential subgrouping based on elemental content. No correlations were observed with the most abundant metal calcium. However, magnesium and sulfur content correlated with the mineral hydration form, while phosphorous and zinc content correlated with the neuter status of the dog. Inter-elemental correlation analysis indicated strong associations between barium, phosphorous, and zinc content. Additionally, cluster analysis revealed subgroups within the stones that were also based primarily on barium, phosphorous, and zinc. These data support the use of the dog as a model to study the effects of trace metal homeostasis in urinary stone disease. PMID:26066810

  3. JESS: What Can It Teach Us?

    NASA Astrophysics Data System (ADS)

    Rodgers, Allen L.; Allie-Hamdulay, Shameez; Jackson, Graham E.

    2007-04-01

    Knowledge of the chemical complexes (speciation) in urine can be extremely important in evaluating the risk of crystallization of stone forming salts. In order to determine the speciation, a database of thermodynamic constants for the wide variety of complexes that might form from the known components in urine, is required. JESS (Joint Expert Speciation System) is a software package that has such a database. In the present study, some of its applications in urolithiasis research were explored. To illustrate the effect of therapeutic complexing agents on the risk of calcium oxalate and calcium phosphate (brushite) stone formation, tetracycline was introduced into the urine model. Speciation calculations showed that the risk decreased with increasing tetracycline concentration and increasing pH. In a second application, the saturation index (equivalent to the relative supersaturation) of calcium oxalate and brushite were independently calculated while precipitation of these salts was modeled. This revealed that in mixed calcium oxalate-brushite stones, the former salt is more likely to be the nucleus than the latter. It is suggested that JESS is a powerful tool for obtaining deep insights into the sophisticated crystallization processes which govern stone pathogenesis.

  4. Effect of drinking parsley leaf tea on urinary composition and urinary stones' risk factors.

    PubMed

    Alyami, Fahad A; Rabah, Danny M

    2011-05-01

    To investigate the effect of parsley leaf tea on urine composition and the inhibitors of urinary tract stones formation, we studied 20 healthy volunteers who were divided into two groups: the first group of 10 subjects drank daily 1,200 mL of parsley leaf tea for 2 weeks, while the second group drank at least 1,200 mL daily of bottled water for the same period. This was followed by a 2-week "washout" period before the two groups were crossed over for another 2 weeks. During the experimental phase, 24-h urine samples were collected at baseline, on day 14, and at the end of the 6-week period and different urinary parameters were measured and analyzed statistically. We found no significant difference in the urine volume, pH, sodium, potassium, chloride, urea, creatinine, phosphorus, magnesium, uric acid, cystine, or citric acid. Further research is needed to evaluate the effects of parsley leaf tea on urinary parameters in healthy and stone-forming patients.

  5. Artificial tektites: an experimental technique for capturing the shapes of spinning drops

    NASA Astrophysics Data System (ADS)

    Baldwin, Kyle A.; Butler, Samuel L.; Hill, Richard J. A.

    2015-01-01

    Determining the shapes of a rotating liquid droplet bound by surface tension is an archetypal problem in the study of the equilibrium shapes of a spinning and charged droplet, a problem that unites models of the stability of the atomic nucleus with the shapes of astronomical-scale, gravitationally-bound masses. The shapes of highly deformed droplets and their stability must be calculated numerically. Although the accuracy of such models has increased with the use of progressively more sophisticated computational techniques and increases in computing power, direct experimental verification is still lacking. Here we present an experimental technique for making wax models of these shapes using diamagnetic levitation. The wax models resemble splash-form tektites, glassy stones formed from molten rock ejected from asteroid impacts. Many tektites have elongated or `dumb-bell' shapes due to their rotation mid-flight before solidification, just as we observe here. Measurements of the dimensions of our wax `artificial tektites' show good agreement with equilibrium shapes calculated by our numerical model, and with previous models. These wax models provide the first direct experimental validation for numerical models of the equilibrium shapes of spinning droplets, of importance to fundamental physics and also to studies of tektite formation.

  6. Effect of Aerva lanata on calcium oxalate urolithiasis in rats.

    PubMed

    Soundararajan, P; Mahesh, R; Ramesh, T; Begum, V Hazeena

    2006-12-01

    Calcium oxalate (CaOx) stone was induced in rats using 0.75% of ethylene glycol in drinking water for 28 days. Ethylene glycol treated rats showed significant increase in the activities of oxalate synthesizing enzymes such as glycolic acid oxidase (GAO) in liver and lactate dehydrogenase (LDH) in liver and kidney. CaOx crystal deposition, as indicated by increased excretion of stone-forming constituents in urine, such as calcium, oxalate, uric acid, phosphorus and protein and decreased concentration of inhibitors, such as citrate and magnesium was observed in ethylene glycol induced urolithic rats. Histopathological studies also confirmed the deposition of CaOx crystals. Administration of Aerva lanata aqueous suspension (2g/kg body wt/dose/day for 28 days) to CaOx urolithic rats had reduced the oxalate synthesizing enzymes, diminished the markers of crystal deposition in the kidney. The results of the present study confirmed that A. lanata can be used as an curative agent for urolithiasis.

  7. Uric Acid Nephrolithiasis: A Systemic Metabolic Disorder

    PubMed Central

    Moe, Orson W.

    2014-01-01

    Uric acid nephrolithiasis is characteristically a manifestation of a systemic metabolic disorder. It has a prevalence of about 10% among all stone formers, the third most common type of kidney stone in the industrialized world. Uric acid stones form primarily due to an unduly acid urine; less deciding factors are hyperuricosuria and a low urine volume. The vast majority of uric acid stone formers have the metabolic syndrome, and not infrequently, clinical gout is present as well. A universal finding is a low baseline urine pH plus insufficient production of urinary ammonium buffer. Persons with gastrointestinal disorders, in particular chronic diarrhea or ostomies, and patients with malignancies with a large tumor mass and high cell turnover comprise a less common but nevertheless important subset. Pure uric acid stones are radiolucent but well visualized on renal ultrasound. A 24 h urine collection for stone risk analysis provides essential insight into the pathophysiology of stone formation and may guide therapy. Management includes a liberal fluid intake and dietary modification. Potassium citrate to alkalinize the urine to a goal pH between 6 and 6.5 is essential, as undissociated uric acid deprotonates into its much more soluble urate form. PMID:25045326

  8. Sedimentary rocks in our mouth: dental pulp stones made by nanobacteria

    NASA Astrophysics Data System (ADS)

    Ciftcioglu, Neva; Ciftcioglu, Vefa; Vali, Hojatollah; Turcott, Eduardo; Kajander, E. Olavi

    1998-07-01

    The mechanisms of dental pulp stone formation are still largely unknown. Pulp stones are mainly composed of carbonate apatite. Only few experimental reports have elucidated the potential of some selected bacteria to produce apatite under in vitro conditions using special calcification media. The tested stone forming bacteria were, in fact, often better known for their cariogenic potential. Our preliminary work with 18 dental pulp stones from Turkey, selected only by severity of the stone formation, indicated the presence of nanobacterial antigens in the demineralized stones. Furthermore, high incidence of kidney stones and gall stones in the patient group and in their parents was found. This raises the implication that nanobacteria may enter the body also via oral route, in addition to the parenteral and transplacental routes. The role of nanobacteria in dental pulp stone formation was further studied by following nanobacterial colonization and mineral formation on human tooth in vitro. Two molar teeth, one having pulp stone and one without, were vertically cut into two pieces, sterilized by autoclaving and incubated with or without nanobacteria in DMEM. Electron microscopic observations indicate that nanobacteria can cause apatite stone formation on tooth surface. The sever from of dental pulp stone formation might be associated with nanobacteria. This form of dental disease results in loss of teeth due to osteolytic processes. This addresses the necessity for a study on unconventional mineral-forming bacteria as a cause for human diseases.

  9. Modification by food of the calcium absorbability and physicochemical effects of calcium citrate

    NASA Technical Reports Server (NTRS)

    Wabner, C. L.; Pak, C. Y.

    1992-01-01

    The food-calcium (Ca) interaction was examined in 12 healthy women (mean age 38 years) maintained on a constant metabolic diet. They underwent three phases of study, comprised of control (no Ca), Ca citrate (1 g Ca/day) during meals, and Ca citrate separately from meals. Each phase was 7 days in length and two 24-hour urine samples were collected on days 6 and 7. The rise from the control phase in urinary Ca was slightly more prominent when Ca citrate was given with meals than without (68 and 62%, respectively). The fall in urinary phosphorus was equivalent at about 25% between Ca citrate phases. The rise in urinary citrate and pH and the decline in urinary ammonium were more prominent when Ca citrate was given with meals; however, the changes were small or nonsignificant. The urinary saturation of Ca oxalate, brushite or monosodium urate did not differ between the two Ca citrate phases. There was a nonsignificant rise in serum iron during Ca citrate phases. The results suggest that: 1) dissolution and absorption of Ca citrate might be slightly greater when given with food than without; 2) that the ability of Ca citrate to attenuate crystallization of stone-forming Ca salts in urine is not modified by food; and 3) that Ca citrate may not impair iron absorption from food.

  10. The influence of bacteria on struvite crystal habit and its importance in urinary stone formation

    NASA Astrophysics Data System (ADS)

    Clapham, L.; McLean, R. J. C.; Nickel, J. C.; Downey, J.; Costerton, J. W.

    1990-07-01

    Infection-induced urinary stones form as a result of a urinary tract infection by urease-producing bacteria. These stones are not totally crystalline in nature but rather consist of an agglomeration of bacteria, organic matrix, and crystal of struvite (MgNH 4PO 4· 6H 2O). Crystal formation is related to the ability of the bacteria to effect an increase in the urine pH. Another equally important bacterial role lies in their formation of a 'biofilm' which later becomes the organic matrix constituent of the stone. Results of the present in vitro study indicate that crystals are formed more readily if produced within the bacterial biofilm than in the surrounding urine. It is proposed that supersaturation, due in part to a bacterial-induced pH increase and in part to the metal binding tendency of the biofilm, leads to crystal formation via a gel growth mechanism within the biofilm itself. In time further bacterial cell division, microcolony.

  11. The risk of renal stone formation during and after long duration space flight

    NASA Technical Reports Server (NTRS)

    Whitson, P. A.; Pietrzyk, R. A.; Morukov, B. V.; Sams, C. F.

    2001-01-01

    BACKGROUND: The formation of a renal stone during space flight may have serious negative effects on the health of the crewmember and the success of the mission. Urinary biochemical factors and the influence of dietary factors associated with renal stone development were assessed during long duration Mir Space Station missions. METHODS: Twenty-four-hour urine samples were collected prior to, during and following long duration space flight. The relative urinary supersaturation of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were determined. RESULTS: Changes in the urinary biochemistry of crewmembers during long duration spaceflight demonstrated increases in the supersaturation of the stone-forming salts. In-flight hypercalciuria was evident in a number of individual crewmembers and 24-hour dietary fluid intake and urine volume were significantly lower. During flight, there was a significant increase in brushite supersaturation. CONCLUSIONS: These data suggest acute effects of space flight and postflight changes in the urinary biochemistry favoring increased crystallization in the urine. The effects of dietary intake, especially fluid intake, may have a significant impact on the potential for renal stone formation. Efforts are now underway to assess the efficacy of a countermeasure to mitigate the increased risk. Copyright 2001 S. Karger AG, Basel.

  12. Nucleation at surfaces: the importance of interfacial energy.

    PubMed

    Wu, W; Gerard, D E; Nancollas, G H

    1999-11-01

    The nucleation and growth of stone-forming minerals on the surfaces of other crystalline phases, cellular material, and immobilized macromolecules must be important in the formation of stones in the urinary tract. The nucleation and growth of calcium oxalate monohydrate (COM) crystals were studied using the constant composition kinetics technique, in solution supersaturated with respect to COM (sigmaCOM = 1.44). The solid phases during the reaction were examined by x-ray diffraction, scanning electron microscopy, and diffuse reflectance Fourier transform infrared spectroscopy. Human serum albumin was found to nucleate COM crystals when immobilized on hydroxyapatite (HAP) surfaces. The induction period for nucleation of COM on HAP surfaces preadsorbed with albumin significantly decreased to about 65 min from about 230 min for pure HAP particles. The initial growth rate of COM on pure HAP particles, Rm approximately/= 0.56 X 10(-7) mol/min per m2, was slower than that for HAP surfaces preadsorbed with albumin, 2.14 x 10(-7) mol/min per m2. The surface properties were characterized using contact angle measurements by sessile drop and thin layer wicking. The thermodynamic results suggested that surfaces with high Lewis base parameter values (gamma-) and low interfacial tension with water (gammaSL) are more effective in the nucleation and growth of crystal phases.

  13. Histopathology Predicts the Mechanism of Stone Formation

    NASA Astrophysics Data System (ADS)

    Evan, Andrew P.

    2007-04-01

    About 5% of American women and 12% of men will develop a kidney stone at some time in their life and these numbers appear to be on the rise. Despite years of scientific research into the mechanisms of stone formation and growth, limited advances have been made until recently. Randall's original observations and thoughts on the mechanisms for kidney stone formation have been validated for idiopathic calcium oxalate stone formers (ICSF) but not for most other stone forming groups. Our current studies on selected groups of human stone formers using intraoperative papillary biopsies has shown overwhelming evidence for the presence of Randall's plaque in ICSF and that stone formation and growth are exclusively linked to its availability to urinary ions and proteins. Intense investigation of the plaque-stone junction is needed if we are to understand the factors leading to the overgrowth process on exposed regions of plaque. Such information should allow the development of treatment strategies to block stone formation in ICSF patients. Patients who form brushite stones, or who form apatite stones because of distal renal tubular acidosis (dRTA), or patients with calcium oxalate stones due to obesity bypass procedures, or patients with cystinuria, get plugged inner medullary collecting ducts (IMCD) which leads to total destruction of the lining cells and focal sites of interstitial fibrosis. These stone formers have plaque but at levels equal to or below non-stone formers, which would suggest that they form stones by a different mechanism than do ICSF patients.

  14. An Explanation of the Underlying Mechanisms for the In Vitro and In Vivo Antiurolithic Activity of Glechoma longituba

    PubMed Central

    Liang, Qiang; Li, Xiaoran; Zhou, Wangning; Su, Yu; He, Shenbao; Cheng, Shuanglei; Lu, Jianzhong; Cao, Wenjuan; Yan, Yuke; Pei, Xiaxia; Qi, Jin; Xu, Guangli

    2016-01-01

    Purpose. To use in vitro and in vivo models to evaluate Glechoma longituba extract to provide scientific evidence for this extract's antiurolithic activity. Materials and Methods. Potassium citrate was used as a positive control group. Oxidative stress (OS) markers and the expression of osteopontin (OPN) and kidney injury molecule-1 (KIM-1) were measured to assess the protective effects of Glechoma longituba. Multiple urolithiasis-related biochemical parameters were evaluated in urine and serum. Kidneys were harvested for histological examination and the assessment of crystal deposits. Results. In vitro and in vivo experiments demonstrated that treatment with Glechoma longituba extract significantly decreased calcium oxalate- (CaOx-) induced OPN expression, KIM-1 expression, and OS compared with the positive control group (P < 0.05). Additionally, in vivo rats that received Glechoma longituba extract exhibited significantly decreased CaOx deposits and pathological alterations (P < 0.05) compared with urolithic rats. Significantly lower levels of oxalate, creatinine, and urea and increased citrate levels were observed among rats that received Glechoma longituba (P < 0.05) compared with urolithic rats. Conclusion. Glechoma longituba has antiurolithic effects due to its possible combined effects of increasing antioxidant levels, decreasing urinary stone-forming constituents and urolithiasis-related protein expression, and elevating urinary citrate levels. PMID:27840669

  15. Protective effects of the aqueous extract of Crocus sativus against ethylene glycol induced nephrolithiasis in rats.

    PubMed

    Amin, Bahareh; Feriz, Hanieh Moghri; Hariri, Alireza Timcheh; Meybodi, Naser Tayyebi; Hosseinzadeh, Hossein

    2015-01-01

    This study evaluated the possible protective effect of Crocus sativus L. (saffron) in the treatment of renal calculi. Aqueous extract of saffron (25, 50 and 100 mg/kg, daily) was administered intraperitoneally in two regimens of protective or curative, using male Wistar rats. Urolithiasis was induced by ethylene glycol (% 0.75) in drinking water. Urine was collected for biochemical analysis and the kidneys were prepared for total lipid peroxide and histological evaluation. Ethylene glycol feeding resulted in an increased urine output, renal excretion of oxalate and decreased excretion of citrate and magnesium. Saffron did not show diuretic effect; however, it significantly reduced the elevated urinary oxalate in prophylactic (50 and 100 mg/kg) and curative (100 mg/kg) studies. Only the high dose of prophylactic regimen restored citrate concentration of urine. Increased number of calcium oxalate crystals deposits in the kidney tissue of calculogenic rats was significantly reverted by the prophylactic and high dose of curative saffron treatment. Malondialdehyde (MDA, a lipid peroxidation product) in the kidneys was increased following the lithogenic treatment; however, prophylactic (50, 100 mg/kg) and curative (100 mg/kg) regimens with saffron reduced the elevated levels of MDA. Results in the current study indicate that saffron can protect against ethylene glycol induced calcium oxalate (CaOx) nephrolithiasis. The mechanisms underlying this effect are mediated possibly through effect on the urinary concentration of stone-forming constituents and an antioxidant effect.

  16. Urolithiasis in adults. Clinical and biochemical aspects.

    PubMed

    Abdel-Halim, Rabie E

    2005-05-01

    Urolithiasis is a multifactorial recurrent disease of world-wide distribution in rural, urban, industrial and non-industrial regions. Changes in urinary pH is a risk factor especially with hyperuricosuria, hypercalciuria or hyperoxaluria. With recurrence, hypercalcuria and higher urinary oxalate levels are more frequent. Hypercalciuria and hyperuricosuria showed correlation with family history of stones. The ionic relations between various stone forming salts in urine of patients are opposite to that in controls and are well represented in stone composition. Obesity is a risk factor in both genders. Over eating a diet rich in all nutrients was associated with hyperuricosuria while a diet high only in fat was associated with other urinary disturbances. High protein and fat intake are risk factors. High or low calcium diet was associated with urolithiasis and supplemental calcium is not a risk factor. Potassium and magnesium citrate are potent in inhibiting the growth of stone fragments after extracorporeal shock wave lithotripsy. Whether in patients or normal subjects, drinking hard water should be avoided; tap water or low calcium content water is preferable. Seasonal variations in temperature affected urinary volume, pH and relative saturation of uric acid. To prevent recurrence, patients should maintain high fluid intake achieving a urine volume of 2 liters per day.

  17. Application of SERS spectroscopy for detection of trace components in urinary deposits

    NASA Astrophysics Data System (ADS)

    Pucetaite, Milda; Velicka, Martynas; Tamosaityte, Sandra; Sablinskas, Valdas

    2014-03-01

    Surface-enhanced Raman scattering (SERS) spectroscopy can be a useful tool in regard to disease diagnosis and prevention. Advantage of SERS over conventional Raman spectroscopy is its significantly increased signal (up to factor of 106-108) which allows detection of trace amounts of substances in the sample. So far, this technique is successfully used for analysis of food, pieces of art and various biochemical/biomedical samples. In this work, we survey the possibility of applying SERS spectroscopy for detection of trace components in urinary deposits. Early discovery together with the identification of the exact chemical composition of urinary sediments could be crucial for taking appropriate preventive measures that inhibit kidney stone formation or growth processes. In this initial study, SERS spectra (excitation wavelength - 1064 nm) of main components of urinary deposits (calcium oxalate, uric acid, cystine, etc.) were recorded by using silver (Ag) colloid. Spectra of 10-3-10-5 M solutions were obtained. While no/small Raman signal was detected without the Ag colloid, characteristic peaks of the substances could be clearly separated in the SERS spectra. This suggests that even small amounts of the components could be detected and taken into account while determining the type of kidney stone forming in the urinary system. We found for the first time that trace amounts of components constituting urinary deposits could be detected by SERS spectroscopy. In the future study, the analysis of centrifuged urine samples will be carried out.

  18. Micovascular integration into porous polyHEMA scaffold

    NASA Astrophysics Data System (ADS)

    Cho, Eugenia H.; Boico, Alina; Wisniewski, Natalie A.; Gant, Rebecca; Helton, Kristen L.; Brown, Nga L.; Register, Janna K.; Vo-Dinh, Tuan; Schroeder, Thies; Klitzman, Bruce

    2014-03-01

    Surface-enhanced Raman scattering (SERS) spectroscopy can be a useful tool in regard to disease diagnosis and prevention. Advantage of SERS over conventional Raman spectroscopy is its significantly increased signal (up to factor of 106-108) which allows detection of trace amounts of substances in the sample. So far, this technique is successfully used for analysis of food, pieces of art and various biochemical/biomedical samples. In this work, we survey the possibility of applying SERS spectroscopy for detection of trace components in urinary deposits. Early discovery together with the identification of the exact chemical composition of urinary sediments could be crucial for taking appropriate preventive measures that inhibit kidney stone formation or growth processes. In this initial study, SERS spectra (excitation wavelength - 1064 nm) of main components of urinary deposits (calcium oxalate, uric acid, cystine, etc.) were recorded by using silver (Ag) colloid. Spectra of 10-3-10-5 M solutions were obtained. While no/small Raman signal was detected without the Ag colloid, characteristic peaks of the substances could be clearly separated in the SERS spectra. This suggests that even small amounts of the components could be detected and taken into account while determining the type of kidney stone forming in the urinary system. We found for the first time that trace amounts of components constituting urinary deposits could be detected by SERS spectroscopy. In the future study, the analysis of centrifuged urine samples will be carried out.

  19. Prospects for laser-induced breakdown spectroscopy for biomedical applications: a review.

    PubMed

    Singh, Vivek Kumar; Rai, Awadhesh Kumar

    2011-09-01

    We review the different spectroscopic techniques including the most recent laser-induced breakdown spectroscopy (LIBS) for the characterization of materials in any phase (solid, liquid or gas) including biological materials. A brief history of the laser and its application in bioscience is presented. The development of LIBS, its working principle and its instrumentation (different parts of the experimental set up) are briefly summarized. The generation of laser-induced plasma and detection of light emitted from this plasma are also discussed. The merit and demerits of LIBS are discussed in comparison with other conventional analytical techniques. The work done using the laser in the biomedical field is also summarized. The analysis of different tissues, mineral analysis in different organs of the human body, characterization of different types of stone formed in the human body, analysis of biological aerosols using the LIBS technique are also summarized. The unique abilities of LIBS including detection of molecular species and calibration-free LIBS are compared with those of other conventional techniques including atomic absorption spectroscopy, inductively coupled plasma atomic emission spectroscopy and mass spectroscopy, and X-ray fluorescence.

  20. Nutrition and renal stone disease in space

    NASA Technical Reports Server (NTRS)

    Zerwekh, Joseph E.

    2002-01-01

    There is a growing body of evidence from the National Aeronautics and Space Administration and the Russian space program showing that humans exposed to the microgravity environment of space have a greater risk for developing renal stones. Increased bone resorption and the attendant hypercalciuria and hyperphosphaturia contribute significantly to raising the urinary state of saturation with respect to the calcium salts, namely calcium oxalate and calcium phosphate. In addition, other environmental and dietary factors may adversely affect urine composition and increase stone formation risk during space flight. For example, reductions in urinary volume, pH, and citrate contribute to raising stone formation risk. In addition to raising the risk for calcium stone formation, this metabolic profile is conducive to the formation of uric acid stones. Although observations to date have suggested that there may actually be a reduced food intake during the early phase of flight, crew members on longer-duration flights may increase food intake and be at increased risk for stone formation. Taken together, these findings support the use of nutritional recommendations for crew members that would serve to reduce the stone-forming propensity of the urinary environment. Pharmacologic intervention should be directed at raising urinary volumes, diminishing bone losses, and preventing reductions in urinary pH and citrate. Success in reducing the risk for stone formation in astronauts would also be of potential major benefit to the estimated 20 million Americans with nephrolithiasis.

  1. Defining hypercalciuria in nephrolithiasis

    PubMed Central

    Pak, Charles Y.C.; Sakhaee, Khashayar; Moe, Orson W.; Poindexter, John; Adams-Huet, Beverley

    2014-01-01

    The classic definition of hypercalciuria, an upper normal limit of 200 mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200 mg/day, and the mean for all patients was 127±46 mg/day with an upper limit of 219 mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200 mg/day in all studies with a combined mean of 259±55 mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172 mg/day on a restricted diet, a value that approximates the traditional limit of 200 mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid. PMID:21775970

  2. Chemistry and Materials Science Directorate 2002 Postdoctoral Symposium

    SciTech Connect

    Wirth, B D

    2002-08-14

    The understanding of the physical mechanisms by which important biological inhibitors control the nucleation, growth, aggregation, and phase transformation of calcium oxalate crystals at fundamental level is of importance not only to the advances in biomineralization but also to the development of stone disease therapy. Of the three phases of calcium oxalate crystalline, calcium oxalate monohydrate (COM) and dehydrate (COD) are found in the majority of stones formed in the urinary system. Only COM, a major inorganic component of kidney stones, produces adverse physiological effects to human, however. Although a great deal of research has been carried out on the modulation of nucleation, growth, aggregation, and phase transformation of calcium oxalates by biological molecules, the basic mechanism has not yet been determined due to inherent limitations of those techniques that have been utilized The invention of atomic force microscopy (AFM) has opened a new avenue for the study of the crystal growth in general. One can now probe the growth kinetics and dynamics, and morphology of crystal surfaces down to molecular levels as a typical AFM has a lateral resolution of nanometers. In this study, in situ AFM was used to monitor the COM surface under controlled growth conditions. The growth on both (-101) and (010) faces was investigated. The effect of the macromolecules such as citrate and uropontin to the growth of surfaces was also explored. In this presentation, the structural basis for the observed results will be discussed and the implications of the findings to the field of medicine will also be addressed.

  3. Mechanisms of human kidney stone formation.

    PubMed

    Evan, Andrew P; Worcester, Elaine M; Coe, Fredric L; Williams, James; Lingeman, James E

    2015-01-01

    The precise mechanisms of kidney stone formation and growth are not completely known, even though human stone disease appears to be one of the oldest diseases known to medicine. With the advent of the new digital endoscope and detailed renal physiological studies performed on well phenotyped stone formers, substantial advances have been made in our knowledge of the pathogenesis of the most common type of stone former, the idiopathic calcium oxalate stone former as well as nine other stone forming groups. The observations from our group on human stone formers and those of others on model systems have suggested four entirely different pathways for kidney stone formation. Calcium oxalate stone growth over sites of Randall's plaque appear to be the primary mode of stone formation for those patients with hypercalciuria. Overgrowths off the ends of Bellini duct plugs have been noted in most stone phenotypes, do they result in a clinical stone? Micro-lith formation does occur within the lumens of dilated inner medullary collecting ducts of cystinuric stone formers and appear to be confined to this space. Lastly, cystinuric stone formers also have numerous small, oval, smooth yellow appearing calyceal stones suggestive of formation in free solution. The scientific basis for each of these four modes of stone formation are reviewed and used to explore novel research opportunities.

  4. Placental calcification: a metastatic process?

    PubMed

    Poggi, S H; Bostrom, K I; Demer, L L; Skinner, H C; Koos, B J

    2001-07-01

    Placental calcification commonly increases with gestational age. The mechanism of apatite mineralization probably involves one of three known mechanisms of tissue calcification: physiological (like bone), dystrophic (ischaemia-related) or metastatic (mineralization in a supersaturated environment). This study was designed to determine the mechanism of calcification by examining (1) the mineral content of placental calcifications in comparison to other physiological and pathological apatites, and (2) the expression of bone morphogenetic proteins (BMPs), which are important in physiological calcification, across gestational age. By energy-dispersive x-ray analysis (EDXA), the Ca/P weight ratio for apatitic mineral from mature calcifications was 2.00+/-0.05 (s.e.), which is similar to that for stones formed in a metastatic, supersaturated environment and lower than that observed in physiological calcification. Biologically active BMP, which was determined by bioassay, was demonstrated in mature and postmature placentae. The BMPs PLAB, PDF and related protein INSL-4 were identified by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), but their mRNA expression was independent of gestational age (7-41 weeks of gestation). We conclude that (1) the identified BMPs were not related directly to placental calcification, which argues against physiological calcification, and (2) the chemical composition of the apatitic mineral was suggestive of rapid formation in a supersaturated environment, which is consistent with a metastatic mechanism of calcification.

  5. Do Kidney Stone Formers Have A Kidney Disease?

    PubMed Central

    Zisman, Anna L.; Evan, Andrew P.; Coe, Fredric L.; Worcester, Elaine M.

    2015-01-01

    Nephrolithiasis is a highly prevalent disorder affecting approximately one in eleven people and is associated with multiple complications including hypertension, cardiovascular disease, and chronic kidney disease. Significant epidemiologic associations with chronic kidney disease and ESRD have been noted and are reviewed herein, but debate persists in the literature as to whether kidney stone formation is a pathogenic process contributing to kidney disease. Corroborating evidence supporting the presence of kidney disease in stone formers includes the variability of renal function by stone type, the positive association of stone size with renal dysfunction, the presence of markers of renal injury in the urine of even asymptomatic stone formers, and direct evidence of renal tissue injury on histopathology. Proposed pathogenic mechanisms include recurrent obstruction and comorbid conditions such as recurrent urinary tract infections and structural abnormalities. Recent work evaluating the renal histopathology of different groups of stone formers adds further granularity, suggesting variability in mechanisms of renal injury by stone type and confirming the pathogenic effects of crystal formation. Genetic abnormalities leading to stone formation including cystinuria and primary hyperoxaluria, among others, contribute to the burden of disease in the stone-forming population. PMID:26376133

  6. Computational fluid dynamics analysis of salivary flow and its effect on sialolithogenesis

    PubMed Central

    Zhu, P; Lin, Y; Lin, H; Xu, Y; Zheng, QY; Han, Y

    2014-01-01

    OBJECTIVE Sialolithiasis is a common disease caused by intraductal stones, formed by reduction in salivary flow, salivary stagnation, and metabolic events. We used computational fluid dynamics to investigate changes in salivary flow field around parotid stones of different shapes. MATERIALS AND METHODS Three-dimensional configurations of the Stensen’s duct were reconstructed from computed tomography sialographic images. Fluid dynamics modeling was used to analyze the salivary flow field around stones under unstimulated and stimulated conditions. RESULTS The majority of sialoliths were oval-shaped (59/98), followed by irregular (24/98) and round (15/98). Salivary velocity was significantly higher around streamlined stones, compared with round (P = 0.013) and oval (P = 0.025) types. Changes in salivary flow field around sialoliths were found to affect the pattern of mineral deposition in saliva. The area of low velocity around the round stone was double the size observed around the streamlined stone during the unstimulated state, whereas in the stimulated state, local vortexes were formed on the downstream side of round and oval stones. CONCLUSIONS Salivary flow field around sialoliths plays an important role in the progression of multicentric stones, and analysis of the salivary dynamics during sialolithiasis may provide deeper understandings of the condition and aid in developing successful treatment strategies. PMID:24164693

  7. Antiurolithiatic effect of lithocare against ethylene glycol-induced urolithiasis in Wistar rats

    PubMed Central

    Lulat, Sumaiya I.; Yadav, Yogesh Chand; Balaraman, R.; Maheshwari, Rajesh

    2016-01-01

    Aim: This study is aimed to investigate the protective effect of Lithocare (LC) (a polyherbal formulation) against ethylene glycol (EG) induced urolithiasis in Wistar rats. Materials and Methods: The protective effect of LC (400 and 800 mg/kg) was evaluated using EG-induced urolithiasis in rats. Results: Administration of EG in drinking water resulted in hyperoxaluria, hypocalcemia as well as an increased renal excretion of phosphate. Supplementation with LC significantly reduced the urinary calcium, oxalate, and phosphate excretion dose-dependently. There was a significant reduction in the levels of calcium, oxalate as well as a number of calcium oxalate crystals deposits in the kidney tissue of rats administered with LC in EG-treated rats. There was a significant reduction in creatinine, urea, uric acid, and blood urea nitrogen when LC was administered in EG-treated rats. Conclusions: From this study, it was concluded that the supplementation of LC protected EG-induced urolithiasis as it reduced the growth of urinary stones. The mechanism underlying this effect might be due to its antioxidant, diuretic, and reduction in stone-forming constituents. PMID:26997728

  8. 21 Ma Eclogite From the Main Central Thrust Sheet, Eastern Nepal Himalaya

    NASA Astrophysics Data System (ADS)

    Corrie, S. L.; Kohn, M. J.; Vervoort, J. D.; Parkinson, C. D.

    2007-12-01

    Though uncommon throughout the Himalaya, eclogites have been documented in the Kaghan Valley of Pakistan, the Tso Morari dome in India, the Kharta region of Tibet, and the Makalu-Everest region of the Arun River valley in eastern Nepal. The Kaghan and Tso Morari UHP eclogites have been dated at ~50 Ma, and are commonly viewed as reflecting aborted subduction of the leading edge of the Indian plate during the initial stages of Indo- Asian collision. Here we show that the Arun eclogites are significantly younger, only ~21 Ma, so reflect either different origins, or substantial time lags in tectonics along strike. The Arun eclogites are stratigraphically continuous with the surrounding Greater Himalayan Sequence (GHS) felsic gneisses, and have been interpreted as metamorphosed basaltic sills. P-T conditions have been estimated at >14 kbar at 670-710 °C. The GHS in this region overlies Lesser Himalayan rocks along the Main Central Thrust (MCT), which can be traced for over 2000 km along strike. Lu-Hf dates from garnet separates in one relict eclogite indicate an age of 20.7±0.4 Ma (MSWD = 2.2). Five garnet amphibolites from nearby were also dated via Lu-Hf, and their ages range from 14-20 Ma (13.9±2.5, 14.1±0.3, 14.5±2.8, 15.1±0.6, and 19.8±1.1 Ma). The ~21 Ma age obtained from the eclogite postdates eclogite ages from the western Himalaya (Kaghan and Tso Morari) by ~30 Myr, and has important implications for tectonic models of Himalayan orogenesis. One possible model is that (aborted) subduction, slab breakoff, and ascent of India's leading edge occurred diachronously: ~50 Ma in the western Himalaya, ~20 Ma in eastern Nepal, and presumably even younger in the eastern Himalaya. Alternatively, because the Arun eclogites did not reach ultra-high pressure conditions seen by western eclogites (only ≥45, not ≥90 km depth), they may simply reflect deepening or longer transport of the MCT in the Arun area. Regardless, a ~21 Ma age for these eclogites combined with

  9. Evaluation of information in nanomaterial safety data sheets and development of international standard for guidance on preparation of nanomaterial safety data sheets.

    PubMed

    Lee, Ji Hyun; Kuk, Won Kwen; Kwon, Miran; Lee, Jong Han; Lee, Kwon Sub; Yu, Il Je

    2013-05-01

    Safety data sheets (SDSs) and labelling are the basic hazard communication tools for hazardous chemicals as regards their manufacture, storage, transport and other handling activities. Thus, in the context of the growing use of nanomaterials and nanomaterial-containing materials, this study evaluated the information provided in 97 nanomaterial-related SDSs according to the criteria set by the GHS (Globally Harmonized System of Classification and Labelling of Chemicals) and found that most of the SDSs did not include sufficient information on the safety of nanomaterials, such as their toxicity and physicochemical properties. The reasons for this lack of information in the nanomaterial SDSs can mainly be attributed to (1) a lack of toxicity and physicochemical property information on nanomaterials, (2) unawareness of the effectiveness of conventional exposure controls, such as local exhaust ventilation and encapsulation, and personal protective equipment (PPE), in protecting against nanomaterial exposure, (3) a lack of information on emergency and firefighting measures and (4) a lack of knowledge on how existing regulations apply to nanomaterials. Therefore, to create a consistent standard for the information provided on safety, health and environmental matters for manufactured nanomaterial-containing products, guidance for the preparation of nanomaterial-specific SDSs, including both nanomaterials and mixtures of nanomaterials with conventional non-nanoscale materials, was recently initiated by the ISO TC 229. Their guidance, in the form of a technical report, recommends that nanomaterial-related SDSs should be prepared based on a precautionary approach in terms of the toxicity and other risks associated with the nanomaterial contents within the mixture in question. One of the key recommendations in the technical report is to include additional physicochemical properties, including the particle size (average and range), size distribution aggregation

  10. Regulation of Pit-1 expression by ghrelin and GHRP-6 through the GH secretagogue receptor.

    PubMed

    García, A; Alvarez, C V; Smith, R G; Diéguez, C

    2001-09-01

    GH secretagogues are an expanding class of synthetic peptide and nonpeptide molecules that stimulate the pituitary gland to secrete GH through their own specific receptor, the GH-secretagogue receptor. The cloning of the receptor for these nonclassical GH releasing molecules, together with the more recent characterization of an endogenous ligand, named ghrelin, have unambiguously demonstrated the existence of a physiological system that regulates GH secretion. Somatotroph cell-specific expression of the GH gene is dependent on a pituitary-specific transcription factor (Pit-1). This factor is transcribed in a highly restricted manner in the anterior pituitary gland. The present experiments sought to determine whether the synthetic hexapeptide GHRP-6, a reference GH secretagogue compound, as well as an endogenous ligand, ghrelin, regulate pit-1 expression. By a combination of Northern and Western blot analysis we found that GHRP-6 elicits a time- and dose-dependent activation of pit-1 expression in monolayer cultures of infant rat anterior pituitary cells. This effect was blocked by pretreatment with actinomycin D, but not by cycloheximide, suggesting that this action was due to direct transcriptional activation of pit-1. Using an established cell line (HEK293-GHS-R) that overexpresses the GH secretagogue receptor, we showed a marked stimulatory effect of GHRP-6 on the pit-1 -2,500 bp 5'-region driving luciferase expression. We truncated the responsive region to -231 bp, a sequence that contains two CREs, and found that both CREs are needed for GHRP-6-induced transcriptional activation in both HEK293-GHS-R cells and infant rat anterior pituitary primary cultures. The effect was dependent on PKC, MAPK kinase, and PKA activation. Increasing Pit-1 by coexpression of pCMV-pit-1 potentiated the GHRP-6 effect on the pit-1 promoter. Similarly, we showed that the endogenous GH secretagogue receptor ligand ghrelin exerts a similar effect on the pit-1 promoter. These data

  11. Ghrelin inhibition of ethanol-induced gastric epithelial cell apoptosis is mediated by miR-21

    PubMed Central

    Jiang, Miao; Gao, Peng-Fei; Li, Huan-Qing; Tian, Pei-Ying; Fan, Xiao-Ming

    2015-01-01

    Aim: To investigate the underlying mechanism of ghrelin-induced gastro-protection in a cell culture model of ethanol-induced gastric epithelial cell injury. Methods: The human gastric epithelial cell line GES-1 was incubated with ghrelin (0.01-1 µM), 1 µM ghrelin and 1 µM D-Lys3-growth hormone releasing peptide-6 (GHRP-6), or 1 µM ghrelin and 400 nM antagomiR-21 for 24 h, followed by treatment with 8% ethanol for 3 h to induce apoptosis. Cell viability was determined by MTT assays and flow cytometry was used for detection of apoptosis rates. miR-21 transcription was analyzed by qRT-PCR and Akt, Bcl-2, Bax and caspase 3 expressions were measured by Western blot. Results: Flow cytometry and a quantitative RT-PCR analysis of the expression of miR-21 showed that ghrelin inhibited apoptosis in a dose dependent manner through a signaling pathway that was both growth hormone secretagogue receptor (GHS-R) and miR-21 dependent, as the antiapoptotic effect of ghrelin was blocked by both D-Lys3-GHRP-6 and antagomiR-21, respectively. Western blotting of Akt, Bcl-2, Bax, and caspase 3 showed that the levels of the antiapoptotic proteins, Akt and Bcl-2, in the cells pretreated with ghrelin alone were higher than those in the cells pretreated with D-Lys3-GHRP-6 or antagomiR-21. By contrast, the levels of the proapoptotic proteins, Bax and caspase 3, in the cells pretreated with ghrelin alone were lower than those in the cells pretreated with D-Lys3-GHRP-6 or antagomiR-21. Conclusion: Ghrelin inhibits GES-1 cell apoptosis through GHS-R-dependent signaling in which miR-21 activates the PI3K/Akt pathway, which upregulates Bcl-2 and downregulates Bax and caspase 3 expression. PMID:26191156

  12. Ghrelin inhibits LPS-induced release of IL-6 from mouse dopaminergic neurones

    PubMed Central

    2013-01-01

    Background Ghrelin is an orexigenic stomach hormone that acts centrally to increase mid-brain dopamine neurone activity, amplify dopamine signaling and protect against neurotoxin-induced dopamine cell death in the mouse substantia nigra pars compacta (SNpc). In addition, ghrelin inhibits the lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines from peripheral macrophages, T-cells and from LPS stimulated microglia. Here we sought to determine whether ghrelin attenuates pro-inflammatory cytokine release from dopaminergic neurones. Findings The dopaminergic SN4741 cell-line, which derives from the mouse substantia nigra (SN) and expresses the ghrelin-receptor (growth hormone secretagogue receptor (GHS-R)) and the ghrelin-O-acyl transferase (GOAT) enzyme, was used to determine the neuro-immunomodulatory action of ghrelin. We induced innate immune activation via LPS challenge (1 μg/ml) of SN4741 neurones that had been pre-cultured in the presence or absence of ghrelin (1, 10, 100 nM) for 4 h. After 24 h supernatants were collected for detection of IL-1 beta (IL-1β ), TNF alpha (TNF-α) and IL-6 cytokines via enzyme linked immunosorbent assay (ELISA) analysis. Nuclear translocation of the transcription factor nuclear factor kappa B (NF-κB) was analyzed by Western blotting, and to determine viability of treatments a cell viability assay and caspase-3 immunohistochemistry were performed. We provide evidence that while IL-1β and TNF-α were not detectable under any conditions, SN4741 neurones constitutively released IL-6 under basal conditions and treatment with LPS significantly increased IL-6 secretion. Pre-treatment of neurones with ghrelin attenuated LPS-mediated IL-6 release at 24 h, an affect that was inhibited by the GHS-R antagonist [D-Lys3]-GHRP-6. However, while ghrelin pre-treatment attenuated the LPS-mediated increase in NF-κB, there was no alteration in its nuclear translocation. Cell viability assay and caspase-3 immunocytochemistry

  13. Correction: Comparative analysis of fungal genomes reveals different plant cell wall degrading capacity in fungi

    PubMed Central

    2014-01-01

    Abstract The version of this article published in BMC Genomics 2013, 14: 274, contains 9 unpublished genomes (Botryobasidium botryosum, Gymnopus luxurians, Hypholoma sublateritium, Jaapia argillacea, Hebeloma cylindrosporum, Conidiobolus coronatus, Laccaria amethystina, Paxillus involutus, and P. rubicundulus) downloaded from JGI website. In this correction, we removed these genomes after discussion with editors and data producers whom we should have contacted before downloading these genomes. Removing these data did not alter the principle results and conclusions of our original work. The relevant Figures 1, 2, 3, 4 and 6; and Table 1 have been revised. Additional files 1, 3, 4, and 5 were also revised. We would like to apologize for any confusion or inconvenience this may have caused. Background Fungi produce a variety of carbohydrate activity enzymes (CAZymes) for the degradation of plant polysaccharide materials to facilitate infection and/or gain nutrition. Identifying and comparing CAZymes from fungi with different nutritional modes or infection mechanisms may provide information for better understanding of their life styles and infection models. To date, over hundreds of fungal genomes are publicly available. However, a systematic comparative analysis of fungal CAZymes across the entire fungal kingdom has not been reported. Results In this study, we systemically identified glycoside hydrolases (GHs), polysaccharide lyases (PLs), carbohydrate esterases (CEs), and glycosyltransferases (GTs) as well as carbohydrate-binding modules (CBMs) in the predicted proteomes of 94 representative fungi from Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota. Comparative analysis of these CAZymes that play major roles in plant polysaccharide degradation revealed that fungi exhibit tremendous diversity in the number and variety of CAZymes. Among them, some families of GHs and CEs are the most prevalent CAZymes that are distributed in all of the fungi analyzed

  14. Self-reported utilization of mental health services in the adult German population--evidence for unmet needs? Results of the DEGS1-Mental Health Module (DEGS1-MH).

    PubMed

    Mack, Simon; Jacobi, Frank; Gerschler, Anja; Strehle, Jens; Höfler, Michael; Busch, Markus A; Maske, Ulrike E; Hapke, Ulfert; Seiffert, Ingeburg; Gaebel, Wolfgang; Zielasek, Jürgen; Maier, Wolfgang; Wittchen, Hans-Ulrich

    2014-09-01

    This paper provides up-to-date data on service use for mental health problems and disorders among adults aged 18-79 years in Germany derived from the Mental Health Module of the German Health Interview and Examination Survey for Adults (DEGS1-MH; N=4483). Data are based exclusively on self-report. Respondents were examined by clinically trained interviewers with a modified version of the Composite International Diagnostic Interview DIA-X/M-CIDI to assess diagnoses according to the criteria of DSM-IV-TR. Service use, i.e. contact to mental health care services, due to mental health problems was assessed for the past 12 months and lifetime, by type of sector and type of institution. Among respondents with a 12-month diagnosis of a mental disorder, 23.5% of the women and 11.6% of the men reported any service use in the past 12 months. Service use depends on type of diagnosis, comorbidity and socio-demographic characteristics. Lowest 12-month utilization rates were found for substance use disorders (15.6%; lifetime use 37.3%), highest for psychotic disorders (40.5%; lifetime 72.1%). Further, a considerable time lap was found between disorder onset and subsequent service use among the majority of cases with anxiety and mood disorders. This paper provides self-reported epidemiological data on mental health service use in Germany, complementing administrative statistics and the predecessor mental health module of the German Health Interview and Examination Survey (GHS-MHS) from 1998. Despite considerable changes in the mental health field in Germany and the existence of a comprehensive mental health care system without major financial barriers, we find no indications of substantially higher utilization rates for mental disorders as compared to other comparable European countries. Further, no indications of major overall changes in utilization rates are apparent. To pinpoint areas with unmet needs, more detailed analyses of the data are needed taking into account type

  15. GUESS-ing Polygenic Associations with Multiple Phenotypes Using a GPU-Based Evolutionary Stochastic Search Algorithm

    PubMed Central

    Hastie, David I.; Zeller, Tanja; Liquet, Benoit; Newcombe, Paul; Yengo, Loic; Wild, Philipp S.; Schillert, Arne; Ziegler, Andreas; Nielsen, Sune F.; Butterworth, Adam S.; Ho, Weang Kee; Castagné, Raphaële; Munzel, Thomas; Tregouet, David; Falchi, Mario; Cambien, François; Nordestgaard, Børge G.; Fumeron, Fredéric; Tybjærg-Hansen, Anne; Froguel, Philippe; Danesh, John; Petretto, Enrico; Blankenberg, Stefan; Tiret, Laurence; Richardson, Sylvia

    2013-01-01

    Genome-wide association studies (GWAS) yielded significant advances in defining the genetic architecture of complex traits and disease. Still, a major hurdle of GWAS is narrowing down multiple genetic associations to a few causal variants for functional studies. This becomes critical in multi-phenotype GWAS where detection and interpretability of complex SNP(s)-trait(s) associations are complicated by complex Linkage Disequilibrium patterns between SNPs and correlation between traits. Here we propose a computationally efficient algorithm (GUESS) to explore complex genetic-association models and maximize genetic variant detection. We integrated our algorithm with a new Bayesian strategy for multi-phenotype analysis to identify the specific contribution of each SNP to different trait combinations and study genetic regulation of lipid metabolism in the Gutenberg Health Study (GHS). Despite the relatively small size of GHS (n = 3,175), when compared with the largest published meta-GWAS (n>100,000), GUESS recovered most of the major associations and was better at refining multi-trait associations than alternative methods. Amongst the new findings provided by GUESS, we revealed a strong association of SORT1 with TG-APOB and LIPC with TG-HDL phenotypic groups, which were overlooked in the larger meta-GWAS and not revealed by competing approaches, associations that we replicated in two independent cohorts. Moreover, we demonstrated the increased power of GUESS over alternative multi-phenotype approaches, both Bayesian and non-Bayesian, in a simulation study that mimics real-case scenarios. We showed that our parallel implementation based on Graphics Processing Units outperforms alternative multi-phenotype methods. Beyond multivariate modelling of multi-phenotypes, our Bayesian model employs a flexible hierarchical prior structure for genetic effects that adapts to any correlation structure of the predictors and increases the power to identify associated variants. This

  16. Development of the EpiOcular(TM) eye irritation test for hazard identification and labelling of eye irritating chemicals in response to the requirements of the EU cosmetics directive and REACH legislation.

    PubMed

    Kaluzhny, Yulia; Kandárová, Helena; Hayden, Patrick; Kubilus, Joseph; d'Argembeau-Thornton, Laurence; Klausner, Mitchell

    2011-09-01

    The recently implemented 7th Amendment to the EU Cosmetics Directive and the EU REACH legislation have heightened the need for in vitro ocular test methods. To address this need, the EpiOcular(TM) eye irritation test (EpiOcular-EIT), which utilises the normal (non-transformed) human cell-based EpiOcular tissue model, has been developed. The EpiOcular-EIT prediction model is based on an initial training set of 39 liquid and 21 solid test substances and uses a single exposure period and a single cut-off in tissue viability, as determined by the MTT assay. A chemical is classified as an irritant (GHS Category 1 or 2), if the tissue viability is ≤ 60%, and as a non-irritant (GHS unclassified), if the viability is > 60%. EpiOcular-EIT results for the training set, along with results for an additional 52 substances, which included a range of alcohols, hydrocarbons, amines, esters, and ketones, discriminated between ocular irritants and non-irritants with 98.1% sensitivity, 72.9% specificity, and 84.8% accuracy. To ensure the long-term commercial viability of the assay, EpiOcular tissues produced by using three alternative cell culture inserts were evaluated in the EpiOcular-EIT with 94 chemicals. The assay results obtained with the initial insert and the three alternative inserts were very similar, as judged by correlation coefficients (r²) that ranged from 0.82 to 0.96. The EpiOcular-EIT was pre-validated in 2007/2008, and is currently involved in a formal, multi-laboratory validation study sponsored by the European Cosmetics Association (COLIPA) under the auspices of the European Centre for the Validation of Alternative Methods (ECVAM). The EpiOcular-EIT, together with EpiOcular's long history of reproducibility and proven utility for ultra-mildness testing, make EpiOcular a useful model for addressing current legislation related to animal use in the testing of potential ocular irritants.

  17. Progression from South-Directed to Orogen-Parallel Mid-Crustal Flow on the Southern Margin of the Tibetan Plateau, Ama Drime Massif, Tibet

    NASA Astrophysics Data System (ADS)

    Jessup, M. J.; Cottle, J. M.; Newell, D. L.; Berger, A. L.; Spotila, J. A.

    2008-12-01

    In the South Tibetan Himalaya, two major detachment systems are exposed in the Ama Drime and Mount Everest Massifs. These structures represent a fundamental shift in the dynamics of the Himalayan orogen, recording a progression from south-directed to orogen-parallel mid-crustal flow and exhumation. The South Tibetan detachment system (STDS) accommodated exhumation of the Greater Himalayan series (GHS) until the Middle Miocene. A relatively narrow mylonite zone that progressed into a brittle detachment accommodated exhumation of the GHS. Northward, in the down-dip direction (Dzakaa Chu and Doya La), a 1-km-wide distributed zone of deformation that lacks a foliation-parallel brittle detachment characterizes the STDS. Leucogranites in the footwall of the STDS range between 17-18 Ma. Previously published 40Ar/39Ar ages suggest that movement on the STDS ended by ~ 16 Ma in Rongbuk Valley and ~ 13 Ma near Dinggye. This once continuous section of the STDS is displaced by the trans- Himalayan Ama Drime Massif and Xainza-Dinggye graben. Two oppositely dipping normal faults and shear zones that bound the Ama Drime Massif record orogen-parallel extension. During exhumation, deformation was partitioned into relatively narrow (100-300-m-thick) mylonite zones that progressed into brittle faults/detachments, which offset Quaternary deposits. U(-Th-)Pb geochronology of mafic lenses suggests that the core of the ADM reached granulite facies at ~ 15 Ma. Leucogranites in the footwall of the detachment faults range between 12-11 Ma: significantly younger than those related to movement on the STDS. Previously published 40Ar/39Ar ages from the eastern limb of the Ama Drime Massif suggest that exhumation progressed into the footwall of the Nyüonno detachment between ~ 13-10 Ma. (U-Th)/He apatite ages record a minimum exhumation rate of ~ 1mm/yr between 1.5-3.0 Ma that was enhanced by focused denudation in the trans-Himalayan Arun River gorge. Together these bracket the timing (~ 12 Ma

  18. South African farm workers' interpretation of risk assessment data expressed as pictograms on pesticide labels

    SciTech Connect

    Rother, Hanna-Andrea

    2008-11-15

    chemical labels under the new Globally Harmonized System for the Classification and Labelling of Chemicals (GHS). Particularly as the GHS pictograms were not piloted prior to adoption of the system and represent complex risk assessment data such as chronic hazards. Public health and pesticide policy, backed by relevant research, need to address developing applicable and effective pesticide risk communication tools, particularly for developing country populations. Merely providing risk assessment derived information in a pictogram does not ensure that an end-user will interpret the message as intended and be able to make risk decisions which mitigate risks from exposures to pesticides or chemicals in general.

  19. The Gutenberg Health Study: measuring psychosocial factors at work and predicting health and work-related outcomes with the ERI and the COPSOQ questionnaire

    PubMed Central

    2013-01-01

    Background Several instruments have been developed to assess psychosocial workload. We compared two of these instruments, the Effort-Reward Imbalance (ERI) model and the Copenhagen Psychosocial Questionnaire (COPSOQ) with regard to congruent validity and internal validity. Methods This analysis is based on a population-based sample of the baseline examination of 2,783 employees from the Gutenberg Health Study (GHS). About half of the participants completed the ERI questionnaire (n = 1,342), the other half completed the COPSOQ (n = 1,441). First, the two samples were compared and descriptive analyses were carried out calculating mean values for both instruments in general, then separately for age, gender and main occupational groups. Second, we analyzed the relationship between ERI and COPSOQ scales on the workplace situation and on the workplace outcomes: job satisfaction, general health, burnout, satisfaction with life, by applying stepwise logistic regression analysis. Results and discussion For the majority of occupations, high effort as reflected by the ERI corresponded with high demands as reflected by the COPSOQ. Comparably, high reward (according to ERI) yielded a good agreement with high “influence and development” (according to COPSOQ). However, we could also find differences between ERI and COPSOQ concerning the intensity of psychosocial workload in some occupations (e.g., physicians/pharmacists or warehouse managers/warehousemen/transport workers). These differences point to differing theoretical concepts of ERI and COPSOQ. When the ability of ERI and COPSOQ was examined to determine the associations with health and work outcomes, burnout could be better predicted by the COPSOQ; this might be due to the fact that COPSOQ comprises the constructs “work-privacy conflict” and “emotional demand”, which are closely related to burnout. However, methodological differences between these instruments limit their direct comparability. Conclusions

  20. Effect of Deletion of Ghrelin-O-Acyltransferase on the Pulsatile Release of Growth Hormone in Mice.

    PubMed

    Xie, T Y; Ngo, S T; Veldhuis, J D; Jeffery, P L; Chopin, L K; Tschöp, M; Waters, M J; Tolle, V; Epelbaum, J; Chen, C; Steyn, F J

    2015-12-01

    Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of

  1. Identification of a ghrelin-like peptide in two species of shark, Sphyrna lewini and Carcharhinus melanopterus.

    PubMed

    Kawakoshi, Akatsuki; Kaiya, Hiroyuki; Riley, Larry G; Hirano, Tetsuya; Grau, E Gordon; Miyazato, Mikiya; Hosoda, Hiroshi; Kangawa, Kenji

    2007-05-01

    In this study, we identified a ghrelin-like peptide (ghrelin-LP) in two elasmobranchs. The peptide, isoforms and cDNA encoding its precursor were isolated from the stomach of two sharks, the hammerhead (HH) shark (Sphyrna lewini) and the black-tip reef (BTR) shark (Carcharhinus melanopterus). The ghrelin-LP isolated from each shark was found to be 25 amino acids in length and exhibit high sequence homology with each other; only three amino acids were different. As has been shown in tetrapod and teleost fish ghrelins, shark ghrelin-LPs possess two forms that are distinguished by having the third serine residue (Ser) acylated by either octanoic or decanoic acid. The N-terminal four residues (GVSF), known as the active core of ghrelin, are not identical to those of other species (GSSF). Nevertheless, shark ghrelin-LP elevated Ca(2+) levels in CHO cell line expressing the growth hormone secretagogue receptor (GHS-R). Unlike teleosts ghrelin's, shark ghrelin-LPs are not amidated at the C-terminus. Messenger RNA of ghrelin-LP in the HH shark was predominantly expressed in the stomach as seen in other species, followed by the brain, intestine, gill, heart and liver. The nucleotide sequence of the ghrelin-LP gene in the HH shark was characterized to compare organization of the ghrelin gene with those in other species. The size of the HH ghrelin-LP gene was 8541 bp, two to ten times larger than that of other species studied to date. The HH ghrelin-LP gene is composed of five exons and four introns, which is the same as ghrelin genes in mammals, chicken and rainbow trout. In conclusion, the shark ghrelin-LPs identified in this study exhibit many characteristics for ghrelin in terms of peptide modifications, GHS-R activation, tissue distribution, and gene organization; however, it is necessary to further clarify their biological properties such as growth hormone-releasing or orexigenic activity before designating these peptides as ghrelin.

  2. The Neurobiological Impact of Ghrelin Suppression after Oesophagectomy

    PubMed Central

    Murphy, Conor F.; le Roux, Carel W.

    2016-01-01

    Ghrelin, discovered in 1999, is a 28-amino-acid hormone, best recognized as a stimulator of growth hormone secretion, but with pleiotropic functions in the area of energy homeostasis, such as appetite stimulation and energy expenditure regulation. As the intrinsic ligand of the growth hormone secretagogue receptor (GHS-R), ghrelin appears to have a broad array of effects, but its primary role is still an area of debate. Produced mainly from oxyntic glands in the stomach, but with a multitude of extra-metabolic roles, ghrelin is implicated in complex neurobiological processes. Comprehensive studies within the areas of obesity and metabolic surgery have clarified the mechanism of these operations. As a stimulator of growth hormone (GH), and an apparent inducer of positive energy balance, other areas of interest include its impact on carcinogenesis and tumour proliferation and its role in the cancer cachexia syndrome. This has led several authors to study the hormone in the cancer setting. Ghrelin levels are acutely reduced following an oesophagectomy, a primary treatment modality for oesophageal cancer. We sought to investigate the nature of this postoperative ghrelin suppression, and its neurobiological implications. PMID:28035969

  3. DSMC-computation of the Rarefied Gas Flow through a Slit into a Vacuum

    NASA Astrophysics Data System (ADS)

    Sazhin, Oleg

    2008-12-01

    The gas rarefaction, gas molecule-molecule interaction and gas-surface scattering influence on the gas flow through a slit into a vacuum is investigated by the direct simulation Monte Carlo (DSMC) method. To study the gas molecule-molecule interaction influence on the gas flow we used the hard sphere (HS), variable hard sphere (VHS) anc variable soft sphere (VSS) models defined for the inverse-power-law (IPL) potential and also the generalized hard sphere (GHS) model defined for the 12-6 Lennard-Jones (LJ) potential. Maxwell (specular-diffuse scheme), Cercignani-Lampis (CL) and Epstein approaches were used to simulate the gas-surface scattering. The results of computations of the mas; flow rate in a wide range of rarefactions and distributions of the density, temperature and mass velocity, and streamlines are presented. This study demonstrates that the gas molecule-molecule interaction significantly interferes with the gas flow through a slit, while the influence of the gas-surface scattering is negligibly small. Our results are in agreement with the corresponding theoretical asymptotes, experimental and numerical data.

  4. Progress in Small Molecule and Biologic Therapeutics Targeting Ghrelin Signaling.

    PubMed

    McGovern, Kayleigh R; Darling, Joseph E; Hougland, James L

    2016-01-01

    Ghrelin is a circulating peptide hormone involved in regulation of a wide array of physiological processes. As an endogenous ligand for growth hormone secretagogue receptor (GHSR1a), ghrelin is responsible for signaling involved in energy homeostasis, including appetite stimulation, glucose metabolism, insulin signaling, and adiposity. Ghrelin has also been implicated in modulation of several neurological processes. Dysregulation of ghrelin signaling is implicated in diseases related to these pathways, including obesity, type II diabetes, and regulation of appetite and body weight in patients with Prader-Willi syndrome. Multiple steps in the ghrelin signaling pathway are available for targeting in the development of therapeutics for these diseases. Agonists and antagonists of GHS-R1a have been widely studied and have shown varying levels of effectiveness within ghrelin-related physiological pathways. Agents targeting ghrelin directly, either through depletion of ghrelin levels in circulation or inhibitors of ghrelin O-acyltransferase whose action is required for ghrelin to become biologically active, are receiving increasing attention as potential therapeutic options. We discuss the approaches utilized to target ghrelin signaling and highlight the current challenges toward developing small-molecule agents as potential therapeutics for ghrelin-related diseases.

  5. Comparative Community Proteomics Demonstrates the Unexpected Importance of Actinobacterial Glycoside Hydrolase Family 12 Protein for Crystalline Cellulose Hydrolysis

    PubMed Central

    Hiras, Jennifer; Wu, Yu-Wei; Deng, Kai; Nicora, Carrie D.; Aldrich, Joshua T.; Frey, Dario; Kolinko, Sebastian; Robinson, Errol W.; Jacobs, Jon M.; Adams, Paul D.; Northen, Trent R.; Simmons, Blake A.

    2016-01-01

    ABSTRACT Glycoside hydrolases (GHs) are key enzymes in the depolymerization of plant-derived cellulose, a process central to the global carbon cycle and the conversion of plant biomass to fuels and chemicals. A limited number of GH families hydrolyze crystalline cellulose, often by a processive mechanism along the cellulose chain. During cultivation of thermophilic cellulolytic microbial communities, substantial differences were observed in the crystalline cellulose saccharification activities of supernatants recovered from divergent lineages. Comparative community proteomics identified a set of cellulases from a population closely related to actinobacterium Thermobispora bispora that were highly abundant in the most active consortium. Among the cellulases from T. bispora, the abundance of a GH family 12 (GH12) protein correlated most closely with the changes in crystalline cellulose hydrolysis activity. This result was surprising since GH12 proteins have been predominantly characterized as enzymes active on soluble polysaccharide substrates. Heterologous expression and biochemical characterization of the suite of T. bispora hydrolytic cellulases confirmed that the GH12 protein possessed the highest activity on multiple crystalline cellulose substrates and demonstrated that it hydrolyzes cellulose chains by a predominantly random mechanism. This work suggests that the role of GH12 proteins in crystalline cellulose hydrolysis by cellulolytic microbes should be reconsidered. PMID:27555310

  6. Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits.

    PubMed

    Haam, Juhee; Halmos, Katalin C; Di, Shi; Tasker, Jeffrey G

    2014-04-30

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal-glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal-glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal-glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis.

  7. Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism

    NASA Astrophysics Data System (ADS)

    Liberato, Marcelo V.; Silveira, Rodrigo L.; Prates, Érica T.; de Araujo, Evandro A.; Pellegrini, Vanessa O. A.; Camilo, Cesar M.; Kadowaki, Marco A.; Neto, Mario De O.; Popov, Alexander; Skaf, Munir S.; Polikarpov, Igor

    2016-04-01

    Glycoside hydrolases (GHs) play fundamental roles in the decomposition of lignocellulosic biomaterials. Here, we report the full-length structure of a cellulase from Bacillus licheniformis (BlCel5B), a member of the GH5 subfamily 4 that is entirely dependent on its two ancillary modules (Ig-like module and CBM46) for catalytic activity. Using X-ray crystallography, small-angle X-ray scattering and molecular dynamics simulations, we propose that the C-terminal CBM46 caps the distal N-terminal catalytic domain (CD) to establish a fully functional active site via a combination of large-scale multidomain conformational selection and induced-fit mechanisms. The Ig-like module is pivoting the packing and unpacking motions of CBM46 relative to CD in the assembly of the binding subsite. This is the first example of a multidomain GH relying on large amplitude motions of the CBM46 for assembly of the catalytically competent form of the enzyme.

  8. ILO activities in the area of chemical safety.

    PubMed

    Obadia, Isaac

    2003-08-21

    The ILO has been active in the area of safety in the use of chemicals at work since the year of its creation in 1919, including the development of international treaties and other technical instruments, the provision of technical assistance to its member States, and the development of chemical safety information systems. The two key ILO standards in this area are the Conventions on safety in the use of chemicals at work (No. 170, 1990), and the Prevention of Major Industrial Accidents (No. 174, 1993). The ILO Programme on occupational safety, health and environment (Safe Work) is currently responsible for ILO chemical safety activities. In the past two decades, most of ILO work in this area has been carried out within the context of inter-agency collaboration frameworks linking the ILO, WHO, UNEP, FAO, UNIDO, UNITAR, and the OECD, including the International Programme on Chemical Safety (IPCS), the Inter-Organisation Programme for the Sound Management of Chemicals (IOMC), and the Intergovernmental Forum on Chemical Safety (IFCS). Apart from the regular development, updating and dissemination of chemical safety information data bases such as the IPCS International Chemical Cards, the elaboration of a Globally harmonized system for the classification and labelling of Chemicals (GHS) has been the most outstanding achievement of this international collaboration on chemical safety.

  9. Cloning of novel cellulases from cellulolytic fungi: heterologous expression of a family 5 glycoside hydrolase from Trametes versicolor in Pichia pastoris.

    PubMed

    Salinas, Alejandro; Vega, Marcela; Lienqueo, María Elena; Garcia, Alejandro; Carmona, Rene; Salazar, Oriana

    2011-12-10

    Total cDNA isolated from cellulolytic fungi cultured in cellulose was examined for the presence of sequences encoding for endoglucanases. Novel sequences encoding for glycoside hydrolases (GHs) were identified in Fusarium oxysporum, Ganoderma applanatum and Trametes versicolor. The cDNA encoding for partial sequences of GH family 61 cellulases from F. oxysporum and G. applanatum shares 58 and 68% identity with endoglucanases from Glomerella graminicola and Laccaria bicolor, respectively. A new GH family 5 endoglucanase from T. versicolor was also identified. The cDNA encoding for the mature protein was completely sequenced. This enzyme shares 96% identity with Trametes hirsuta endoglucanase and 22% with Trichoderma reesei endoglucanase II (EGII). The enzyme, named TvEG, has N-terminal family 1 carbohydrate binding module (CBM1). The full length cDNA was cloned into the pPICZαB vector and expressed as an active, extracellular enzyme in the methylotrophic yeast Pichia pastoris. Preliminary studies suggest that T. versicolor could be useful for lignocellulose degradation.

  10. Utilisation of Mucin Glycans by the Human Gut Symbiont Ruminococcus gnavus Is Strain-Dependent

    PubMed Central

    Crost, Emmanuelle H.; Tailford, Louise E.; Le Gall, Gwenaelle; Fons, Michel; Henrissat, Bernard; Juge, Nathalie

    2013-01-01

    Commensal bacteria often have an especially rich source of glycan-degrading enzymes which allow them to utilize undigested carbohydrates from the food or the host. The species Ruminococcus gnavus is present in the digestive tract of ≥90% of humans and has been implicated in gut-related diseases such as inflammatory bowel diseases (IBD). Here we analysed the ability of two R. gnavus human strains, E1 and ATCC 29149, to utilize host glycans. We showed that although both strains could assimilate mucin monosaccharides, only R. gnavus ATCC 29149 was able to grow on mucin as a sole carbon source. Comparative genomic analysis of the two R. gnavus strains highlighted potential clusters and glycoside hydrolases (GHs) responsible for the breakdown and utilization of mucin-derived glycans. Transcriptomic and functional activity assays confirmed the importance of specific GH33 sialidase, and GH29 and GH95 fucosidases in the mucin utilisation pathway. Notably, we uncovered a novel pathway by which R. gnavus ATCC 29149 utilises sialic acid from sialylated substrates. Our results also demonstrated the ability of R. gnavus ATCC 29149 to produce propanol and propionate as the end products of metabolism when grown on mucin and fucosylated glycans. These new findings provide molecular insights into the strain-specificity of R. gnavus adaptation to the gut environment advancing our understanding of the role of gut commensals in health and disease. PMID:24204617

  11. Ghrelin in obesity and endocrine diseases.

    PubMed

    Scerif, Miski; Goldstone, Anthony P; Korbonits, Márta

    2011-06-20

    Ghrelin shows orexigenic effect through its action on the hypothalamic appetite-regulating pathways, while in the periphery ghrelin increases adipose tissue accumulation and has a diabetogenic effect on the liver and pancreas. Adenosine monophosphate-activated protein kinase (AMPK) has been suggested as one of the mediators of ghrelin's effects. Plasma ghrelin levels are dependent on body mass index as well as food intake patterns. Ghrelin levels are in general reduced in obese individuals and in subjects with insulin resistance. In contrast to other forms of obesity, patients with Prader-Willi syndrome (PWS) display high levels of ghrelin, reduced visceral adiposity and relative hypoinsulinemia. Relationships between obesity and common genomic variants of GHRL and GHS-R genes have been studied. Ghrelin may have a role in the weight-reducing effect of bariatric surgery; however, this is a much debated issue. Altered ghrelin levels have also been observed in Cushing's syndrome and thyroid disease probably due to the secondary insulin resistance in these subjects.

  12. Ghrelin--a novel generation of anti-obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues.

    PubMed

    Chollet, Constance; Meyer, Karolin; Beck-Sickinger, Annette G

    2009-11-01

    Ghrelin is a unique bioactive peptide with respect to both the structure and its biological function. This 28-amino acid peptide is modified with an n-octanoyl group at serine-3, and accordingly is the only lipidated biologically active peptide hormone known so far. Ghrelin binds to the so-called ghrelin or GHS receptor, a member of the class A of G-protein coupled receptors, which leads to Ca(2+) release intracellularly due to the activation of the Gq-system. Interestingly, the ghrelin receptor shows a significant constitutive activity which means that in addition to agonists and antagonists, inverse agonists play an important role in receptor modulation. In this review, the major activities of ghrelin are summarized with a strong focus on the regulation of food intake. So far reported agonists, antagonists and inverse agonists are shown and structure activitiy relationships are discussed. Furthermore, the application of ghrelin ligands as novel anti-obesity drugs is outlined and the state of the art in this field is summarized.

  13. Hazard and risk assessment of teratogenic chemicals under REACH.

    PubMed

    Prutner, Wiebke

    2013-01-01

    In 2007, a new European chemicals legislation was implemented: Regulation (EC) No. 1907/2006, also known as "REACH." It obliges companies to take the main responsibility for the valid information on the safe use of the chemicals they manufacture and/or place on the European market. So they must, for example, register their chemicals at the European Chemicals Agency (ECHA) and submit extensive substance-related registration dossiers containing information on the substances' intrinsic hazardous properties and documentation of their risk assessment. REACH regulates the registration and evaluation process as well as the authorization and restriction procedure. In addition, classification, labeling, and packaging of chemicals apply in accordance with Regulation (EC) No. 1272/2008 ("CLP Regulation"). It implements almost completely the provisions of the United Nations Globally Harmonised System of Classification and Labelling of Chemicals (UN GHS) into European legislation and will fully replace the Dangerous Substances Directive (67/548/EEC) and the Dangerous Preparations Directive (1999/45/EC) by 2015. According to both the old and the new classification system, teratogenic chemicals are classified as developmental toxicants, with developmental toxicity falling within the hazard class of reproductive toxicity. REACH as well as the CLP Regulation provide several procedures in which reproductive toxicants take a special position because their harmful effects are considered particularly serious. Teratogenic substances are not explicitly named by these legal texts but, as they constitute as developmental toxicants a hazard differentiation of reproductive toxicity, they are implicitly always included by the provisions.

  14. Nutritional State-Dependent Ghrelin Activation of Vasopressin Neurons via Retrograde Trans-Neuronal–Glial Stimulation of Excitatory GABA Circuits

    PubMed Central

    Haam, Juhee; Halmos, Katalin C.; Di, Shi

    2014-01-01

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal–glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal–glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal–glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID:24790191

  15. Ghrelin Protects against Dexamethasone-Induced INS-1 Cell Apoptosis via ERK and p38MAPK Signaling

    PubMed Central

    2016-01-01

    Glucocorticoid excess induces apoptosis of islet cells, which may result in diabetes. In this study, we investigated the protective effect of ghrelin on dexamethasone-induced INS-1 cell apoptosis. Our data showed that ghrelin (0.1 μM) inhibited dexamethasone-induced (0.1 μM) apoptosis of INS-1 cells and facilitated cell proliferation. Moreover, ghrelin upregulated Bcl-2 expression, downregulated Bax expression, and decreased caspase-3 activity. The protective effect of ghrelin against dexamethasone-induced INS-1 cell apoptosis was mediated via growth hormone secretagogue receptor 1a. Further studies revealed that ghrelin increased ERK activation and decreased p38MAPK expression after dexamethasone treatment. Ghrelin-mediated protection of dexamethasone-induced apoptosis of INS-1 cells was attenuated using the ERK inhibitor U0126 (10 μM), and cell viability increased using the p38MAPK inhibitor SB203580 (10 μM). In conclusion, ghrelin could protect against dexamethasone-induced INS-1 cell apoptosis, at least partially via GHS-R1a and the signaling pathway of ERK and p38MAPK. PMID:27190513

  16. Ghrelin protects human umbilical vein endothelial cells against advanced glycation end products-induced apoptosis via NO/cGMP signaling

    PubMed Central

    Li, Pengjie; Liu, Ying; Xiang, Ying; Lin, Miao; Gao, Jinling

    2015-01-01

    Objectives: The aim of this study was to investigate the intracellular mechanism involved in the anti-apoptotic effect of ghrelin on human umbilical vein endothelial cells (HUVECs). Methods: HUVECs were pretreated with ghrelin before exposure to 200 μg/ml advanced glycation end products (AGEs)-BSA for 48 h. Cell viability and apoptosis were determined by MTT assay and Annexin V/PI staining. Intracellular cGMP levels evaluation and cGMP analogs were employed to explore possible mechanisms. Results: The inhibitory effect on AGEs induced HUVECs apoptosis could be exerted by ghrelin and co-incubation with growth hormone secretagogue receptor (GHSR)-1a antagonist [D-Lys3]-GHRP-6 abolished this inhibition. Decreased cGMP level in AGEs induced HUVECs apoptosis was restored by ghrelin pretreatment and abolished by [D-Lys3]-GHRP-6 co-incubation. cGMP analogs (8 Br-cGMP and DB-cGMP) pretreatment also exhibited inhibitory effect on AGEs induced HUVECs apoptosis. Conclusions: Our results demonstrated that ghrelin produces a protective effect on HUVECs through GHS-R1a and cGMP/NO signaling pathway mediates the effect of ghrelin. These observations suggest a novel intracellular mechanism in the process of AGEs induced HUVECs apoptosis. PMID:26629013

  17. Intraportal Infusion of Ghrelin Could Inhibit Glucose-Stimulated GLP-1 Secretion by Enteric Neural Net in Wistar Rat

    PubMed Central

    Zhang, Xiyao; Li, Wensong; Li, Ping; Chang, Manli; Huang, Xu; Li, Qiang; Cui, Can

    2014-01-01

    As a regulator of food intake and energy metabolism, the role of ghrelin in glucose metabolism is still not fully understood. In this study, we determined the in vivo effect of ghrelin on incretin effect. We demonstrated that ghrelin inhibited the glucose-stimulated release of glucagon-like peptide-1 (GLP-1) when infused into the portal vein of Wistar rat. Hepatic vagotomy diminished the inhibitory effect of ghrelin on glucose-stimulated GLP-1 secretion. In addition, phentolamine, a nonselective α receptor antagonist, could recover the decrease of GLP-1 release induced by ghrelin infusion. Pralmorelin (an artificial growth hormone release peptide) infusion into the portal vein could also inhibit the glucose-stimulated release of GLP-1. And growth hormone secretagogue receptor antagonist, [D-lys3]-GHRP-6, infusion showed comparable increases of glucose stimulated GLP-1 release compared to ghrelin infusion into the portal vein. The data showed that intraportal infusion of ghrelin exerted an inhibitory effect on GLP-1 secretion through growth hormone secretagogue receptor 1α (GHS1α receptor), which indicated that the downregulation of ghrelin secretion after food intake was necessary for incretin effect. Furthermore, our results suggested that the enteric neural net involved hepatic vagal nerve and sympathetic nerve mediated inhibition effect of ghrelin on incretin effect. PMID:25247193

  18. Uronic polysaccharide degrading enzymes.

    PubMed

    Garron, Marie-Line; Cygler, Miroslaw

    2014-10-01

    In the past several years progress has been made in the field of structure and function of polysaccharide lyases (PLs). The number of classified polysaccharide lyase families has increased to 23 and more detailed analysis has allowed the identification of more closely related subfamilies, leading to stronger correlation between each subfamily and a unique substrate. The number of as yet unclassified polysaccharide lyases has also increased and we expect that sequencing projects will allow many of these unclassified sequences to emerge as new families. The progress in structural analysis of PLs has led to having at least one representative structure for each of the families and for two unclassified enzymes. The newly determined structures have folds observed previously in other PL families and their catalytic mechanisms follow either metal-assisted or Tyr/His mechanisms characteristic for other PL enzymes. Comparison of PLs with glycoside hydrolases (GHs) shows several folds common to both classes but only for the β-helix fold is there strong indication of divergent evolution from a common ancestor. Analysis of bacterial genomes identified gene clusters containing multiple polysaccharide cleaving enzymes, the Polysaccharides Utilization Loci (PULs), and their gene complement suggests that they are organized to process completely a specific polysaccharide.

  19. Bayesian generalized linear mixed modeling of Tuberculosis using informative priors

    PubMed Central

    Woldegerima, Woldegebriel Assefa

    2017-01-01

    TB is rated as one of the world’s deadliest diseases and South Africa ranks 9th out of the 22 countries with hardest hit of TB. Although many pieces of research have been carried out on this subject, this paper steps further by inculcating past knowledge into the model, using Bayesian approach with informative prior. Bayesian statistics approach is getting popular in data analyses. But, most applications of Bayesian inference technique are limited to situations of non-informative prior, where there is no solid external information about the distribution of the parameter of interest. The main aim of this study is to profile people living with TB in South Africa. In this paper, identical regression models are fitted for classical and Bayesian approach both with non-informative and informative prior, using South Africa General Household Survey (GHS) data for the year 2014. For the Bayesian model with informative prior, South Africa General Household Survey dataset for the year 2011 to 2013 are used to set up priors for the model 2014. PMID:28257437

  20. Comparison between bioconcentration factor (BCF) data provided by industry to the European Chemicals Agency (ECHA) and data derived from QSAR models.

    PubMed

    Petoumenou, Maria I; Pizzo, Fabiola; Cester, Josep; Fernández, Alberto; Benfenati, Emilio

    2015-10-01

    The bioconcentration factor (BCF) is the ratio of the concentration of a chemical in an organism to the concentration in the surrounding environment at steady state. It is a valuable indicator of the bioaccumulation potential of a substance. BCF is an essential environmental property required for regulatory purposes within the Registration, Evaluation, Authorization and restriction of Chemicals (REACH) and Globally Harmonized System (GHS) regulations. In silico models for predicting BCF can facilitate the risk assessment for aquatic toxicology and reduce the cost and number of animals used. The aim of the present study was to examine the correlation of BCF data derived from the dossiers of registered chemicals submitted to the European Chemical Agency (ECHA) with the results of a battery of Quantitative Structure-Activity Relationship (QSAR). After data pruning, statistical analysis was performed using the predictions of the selected models. Results in terms of R(2) had low rating around 0.5 for the pruned dataset. The use of the model applicability domain index (ADI) led to an improvement of the performance for compounds falling within it. The variability of the experimental data and the use of different parameters to define the applicability domain can influence the performance of each model. All available information should be adapted to the requirements of the regulation to obtain a safe decision.

  1. Potency values from the local lymph node assay: application to classification, labelling and risk assessment.

    PubMed

    Loveless, S E; Api, A-M; Crevel, R W R; Debruyne, E; Gamer, A; Jowsey, I R; Kern, P; Kimber, I; Lea, L; Lloyd, P; Mehmood, Z; Steiling, W; Veenstra, G; Woolhiser, M; Hennes, C

    2010-02-01

    Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local lymph node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: 'extreme', 'strong', 'moderate' and 'weak'. Since draining lymph node cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.

  2. Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism.

    PubMed

    Liberato, Marcelo V; Silveira, Rodrigo L; Prates, Érica T; de Araujo, Evandro A; Pellegrini, Vanessa O A; Camilo, Cesar M; Kadowaki, Marco A; Neto, Mario de O; Popov, Alexander; Skaf, Munir S; Polikarpov, Igor

    2016-04-01

    Glycoside hydrolases (GHs) play fundamental roles in the decomposition of lignocellulosic biomaterials. Here, we report the full-length structure of a cellulase from Bacillus licheniformis (BlCel5B), a member of the GH5 subfamily 4 that is entirely dependent on its two ancillary modules (Ig-like module and CBM46) for catalytic activity. Using X-ray crystallography, small-angle X-ray scattering and molecular dynamics simulations, we propose that the C-terminal CBM46 caps the distal N-terminal catalytic domain (CD) to establish a fully functional active site via a combination of large-scale multidomain conformational selection and induced-fit mechanisms. The Ig-like module is pivoting the packing and unpacking motions of CBM46 relative to CD in the assembly of the binding subsite. This is the first example of a multidomain GH relying on large amplitude motions of the CBM46 for assembly of the catalytically competent form of the enzyme.

  3. Analysis of the Local Lymph Node Assay (LLNA) variability for assessing the prediction of skin sensitisation potential and potency of chemicals with non-animal approaches.

    PubMed

    Dumont, Coralie; Barroso, João; Matys, Izabela; Worth, Andrew; Casati, Silvia

    2016-08-01

    The knowledge of the biological mechanisms leading to the induction of skin sensitisation has favoured in recent years the development of alternative non-animal methods. During the formal validation process, results from the Local Lymph Node Assay (LLNA) are generally used as reference data to assess the predictive capacity of the non-animal tests. This study reports an analysis of the variability of the LLNA for a set of chemicals for which multiple studies are available and considers three hazard classification schemes: POS/NEG, GHS/CLP and ECETOC. As the type of vehicle used in a LLNA study is known to influence to some extent the results, two analyses were performed: considering the solvent used to test the chemicals and without considering the solvent. The results show that the number of discordant classifications increases when a chemical is tested in more than one solvent. Moreover, it can be concluded that study results leading to classification in the strongest classes (1A and EXT) seem to be more reliable than those in the weakest classes. This study highlights the importance of considering the variability of the reference data when evaluating non-animal tests.

  4. Black holes in models with dilaton field and electric or electric and magnetic charges

    NASA Astrophysics Data System (ADS)

    Kyriakopoulos, E.

    2006-12-01

    Exact static spherically symmetric charged black holes in four dimensions are presented. One of them has only electric charge and another electric and magnetic charges. In these solutions the metric is asymptotically flat, has two horizons, irremovable singularity only at r = 0, and the dilaton field is singular only at r = 0. The solution with electric charge only is characterized by three free parameters, the ADM mass, the electric charge and an additional free parameter. It can be considered as a modification of the GHS-GM solution obtained by changing the coupling between dilaton and electromagnetic field. The general dyonic solution is again characterized by three free parameters, the ADM mass, the magnetic charge and an additional free parameter, which is not the electric charge. According to a definition of the no-hair conjecture the solutions are 'hairy'. A very interesting special case of the dyonic solution is characterized by three free parameters, the ADM mass and the electric and magnetic charges. The solutions satisfy the dominant as well as the strong energy condition outside and on the external horizon.

  5. Positional scanning for peptide secondary structure by systematic solid-phase synthesis of amino lactam peptides.

    PubMed

    Jamieson, Andrew G; Boutard, Nicolas; Beauregard, Kim; Bodas, Mandar S; Ong, Huy; Quiniou, Christiane; Chemtob, Sylvain; Lubell, William D

    2009-06-10

    Incorporation of amino lactams into biologically active peptides has been commonly used to restrict conformational mobility, enhance selectivity, and increase potency. A solid-phase method using a Fmoc-protection strategy has been developed for the systematic synthesis of peptides containing configurationally defined alpha- and beta-amino gamma-lactams. N-Alkylation of N-silyl peptides with five- and six-member cyclic sulfamidates 9 and 8 minimized bis-alkylation and provided N-alkyl peptides, which underwent lactam annulation under microwave heating. Employing this solid-phase protocol on the growth hormone secretagogue GHRP-6, as well as on the allosteric modulator of the IL-1 receptor 101.10, has furnished 16 lactam derivatives and validated the effectiveness of this approach on peptides bearing aliphatic, aromatic, branched, charged, and heteroatomic side chains. The binding affinity IC(50) values of the GHRP-6 lactam analogues on both the GHS-R1a and CD36 receptors are reported as well as inhibition of thymocyte proliferation measurements for the 101.10 lactam analogues. In these cases, lactam analogues were prepared exhibiting similar or improved properties compared with the parent peptide. Considering the potential for amino lactams to induce peptide turn conformations, the effective method described herein for their supported construction on growing peptides, and for the systematical amino lactam scan of peptides, has proven useful for the rapid identification of the secondary structure necessary for peptide biological activity.

  6. Bayesian generalized linear mixed modeling of Tuberculosis using informative priors.

    PubMed

    Ojo, Oluwatobi Blessing; Lougue, Siaka; Woldegerima, Woldegebriel Assefa

    2017-01-01

    TB is rated as one of the world's deadliest diseases and South Africa ranks 9th out of the 22 countries with hardest hit of TB. Although many pieces of research have been carried out on this subject, this paper steps further by inculcating past knowledge into the model, using Bayesian approach with informative prior. Bayesian statistics approach is getting popular in data analyses. But, most applications of Bayesian inference technique are limited to situations of non-informative prior, where there is no solid external information about the distribution of the parameter of interest. The main aim of this study is to profile people living with TB in South Africa. In this paper, identical regression models are fitted for classical and Bayesian approach both with non-informative and informative prior, using South Africa General Household Survey (GHS) data for the year 2014. For the Bayesian model with informative prior, South Africa General Household Survey dataset for the year 2011 to 2013 are used to set up priors for the model 2014.

  7. Glycoside Hydrolase MoGls2 Controls Asexual/Sexual Development, Cell Wall Integrity and Infectious Growth in the Rice Blast Fungus

    PubMed Central

    Li, Mengying; Liu, Xinyu; Liu, Zhixi; Sun, Yi; Liu, Muxing; Wang, Xiaoli; Zhang, Haifeng; Zheng, Xiaobo; Zhang, Zhengguang

    2016-01-01

    N-linked glycosylation is a way of glycosylation for newly synthesized protein, which plays a key role in the maturation and transport of proteins. Glycoside hydrolases (GHs) are essential in this process, and are involved in processing of N-linked glycoproteins or degradation of carbohydrate structures. Here, we identified and characterized MoGls2 in Magnaporthe oryzae, which is a yeast glucosidase II homolog Gls2 and is required for trimming the final glucose in N-linked glycans and normal cell wall synthesis. Target deletion of MoGLS2 in M. oryzae resulted in a reduced mycelial growth, an increased conidial production, delayed conidial germination and loss the ability of sexual reproduction. Pathogenicity assays revealed that the ΔMogls2 mutant showed significantly decreased in virulence and infectious growth. Further studies showed that the mutant was less sensitive to salt and osmotic stress, and increased sensitivity to cell wall stresses. Additionally, the ΔMogls2 mutant showed a defect in cell wall integrity. Our results indicate that MoGls2 is a key protein for the growth and development of M. oryzae, involving in the regulation of asexual/sexual development, stress response, cell wall integrity and infectious growth. PMID:27607237

  8. In vivo-in vitro comparison of acute respiratory tract toxicity using human 3D airway epithelial models and human A549 and murine 3T3 monolayer cell systems.

    PubMed

    Sauer, Ursula G; Vogel, Sandra; Hess, Annemarie; Kolle, Susanne N; Ma-Hock, Lan; van Ravenzwaay, Bennard; Landsiedel, Robert

    2013-02-01

    The usefulness of in vitro systems to predict acute inhalation toxicity was investigated. Nineteen substances were tested in three-dimensional human airway epithelial models, EpiAirway™ and MucilAir™, and in A549 and 3T3 monolayer cell cultures. IC(50) values were compared to rat four-hour LC(50) values classified according to EPA and GHS hazard categories. Best results were achieved with a prediction model distinguishing toxic from non-toxic substances, with satisfactory specificities and sensitivities. Using a self-made four-level prediction model to classify substances into four in vitro hazard categories, in vivo-in vitro concordance was mediocre, but could be improved by excluding substances causing pulmonary edema and emphysema in vivo. None of the test systems was outstanding, and there was no evidence that tissue or monolayer systems using respiratory tract cells provide an added value. However, the test systems only reflected bronchiole epithelia and alveolar cells and investigated cytotoxicity. Effects occurring in other cells by other mechanisms could not be recognised. Further work should optimise test protocols and expand the set of substances tested to define applicability domains. In vivo respiratory toxicity data for in vitro comparisons should distinguish different modes of action, and their relevance for human health effects should be ensured.

  9. Effects of ghrelin and motilin on smooth muscle contractility of the isolated gastrointestinal tract from the bullfrog and Japanese fire belly newt.

    PubMed

    Kitazawa, Takio; Shimazaki, Misato; Kikuta, Ayumi; Yaosaka, Noriko; Teraoka, Hiroki; Kaiya, Hiroyuki

    2016-06-01

    Ghrelin has been identified in some amphibians and is known to stimulate growth hormone release and food intake as seen in mammals. Ghrelin regulates gastrointestinal motility in mammals and birds. The aim of this study was to determine whether ghrelin affects gastrointestinal smooth muscle contractility in bullfrogs (anuran) and Japanese fire belly newts (urodelian) in vitro. Neither bullfrog ghrelin nor rat ghrelin affected longitudinal smooth muscle contractility of gastrointestinal strips from the bullfrog. Expression of growth hormone secretagogue receptor 1a (GHS-R1a) mRNA was confirmed in the bullfrog gastrointestinal tract, and the expression level in the gastric mucosa was lower than that in the intestinal mucosa. In contrast, some gastrointestinal peptides, including substance P, neurotensin and motilin, and the muscarinic receptor agonist carbachol showed marked contraction, indicating normality of the smooth muscle preparations. Similar results were obtained in another amphibian, the Japanese fire belly newt. Newt ghrelin and rat ghrelin did not cause any contraction in gastrointestinal longitudinal muscle, whereas substance P and carbachol were effective causing contraction. In conclusion, ghrelin does not affect contractility of the gastrointestinal smooth muscle in anuran and urodelian amphibians, similar to results for rainbow trout and goldfish (fish) but different from results for rats and chickens. The results suggest diversity of ghrelin actions on the gastrointestinal tract across animals. This study also showed for the first time that motilin induces gastrointestinal contraction in amphibians.

  10. Phenyl amide linker improves the pharmacokinetics and pharmacodynamics of N-terminally mono-PEGylated human growth hormone.

    PubMed

    Wu, Ling; Ji, Shaoyang; Shen, Lijuan; Hu, Tao

    2014-09-02

    Human growth hormone (hGH) suffers from a short plasma half-life of ∼15 min, necessitating frequent injections to maintain its physiological effect. PEGylation, conjugation of polyethylene glycol (PEG), is an effective strategy to prolong the plasma half-life of hGH. However, PEGylation can significantly decrease the bioactivity of hGH. Thus, a new PEGylation approach is desired to improve the pharmacokinetics (PK) and pharmacodynamics (PD) of the PEGylated hGH. In the present study, two N-terminally mono-PEGylated hGHs were prepared using aldehyde chemistry. Phenyl amide and ethyl moieties were used as the linkers between PEG and hGH, respectively. The hydrodynamic volume, proteolytic sensitivity, and immunogenicity of the PEGylated hGH with phenyl amide linker (hGH-phenyl-PEG) were lower than those of the one with propyl linker (hGH-prop-PEG). In addition, hGH-phenyl-PEG showed a higher in vitro bioactivity and better PK and PD than hGH-prop-PEG. The better PK of hGH-phenyl-PEG was mainly due to its lower proteolytic sensitivity and low immunogenicity. The better PD of hGH-phenyl-PEG was mainly due to its higher in vitro bioactivity. Thus, the phenyl amide linker can improve the overall pharmacological profiles of the PEGylated hGH. Our study is expected to advance the development of long-acting protein biotherapeutics with high therapeutic efficacy.

  11. The Ghrelin Axis in Disease; Potential Therapeutic Indications

    PubMed Central

    Nass, Ralf; Gaylinn, Bruce D.; Thorner, Michael O.

    2011-01-01

    Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood main effects of acylated ghrelin administration include anorexic effects, increased appetite and the stimulation of GH secretion. Ghrelin also seems to plays a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease. PMID:21356273

  12. Inhalation toxicity of 316L stainless steel powder in relation to bioaccessibility.

    PubMed

    Stockmann-Juvala, H; Hedberg, Y; Dhinsa, N K; Griffiths, D R; Brooks, P N; Zitting, A; Wallinder, I Odnevall; Santonen, T

    2013-11-01

    The Globally Harmonized System for Classification and Labelling of Chemicals (GHS) considers metallic alloys, such as nickel (Ni)-containing stainless steel (SS), as mixtures of substances, without considering that alloys behave differently compared to their constituent metals. This study presents an approach using metal release, explained by surface compositional data, for the prediction of inhalation toxicity of SS AISI 316L. The release of Ni into synthetic biological fluids is >1000-fold lower from the SS powder than from Ni metal, due to the chromium(III)-rich surface oxide of SS. Thus, it was hypothesized that the inhalation toxicity of SS is significantly lower than what could be predicted based on Ni metal content. A 28-day inhalation study with rats exposed to SS 316L powder (<4 µm, mass median aerodynamic diameter 2.5-3.0 µm) at concentrations up to 1.0 mg/L showed accumulation of metal particles in the lung lobes, but no signs of inflammation, although Ni metal caused lung toxicity in a similar published study at significantly lower concentrations. It was concluded that the bioaccessible (released) fraction, rather than the elemental nominal composition, predicts the toxicity of SS powder. The study provides a basis for an approach for future validation, standardization and risk assessment of metal alloys.

  13. Treatment protocols for growth hormone-secreting pituitary adenomas combined with craniofacial fibrous dysplasia: A case report of atypical McCune-Albright syndrome.

    PubMed

    Xu, Jia; Li, Xi; Lv, Chang-Sheng; Chen, Ying; Wang, Meng; Liu, Jian-Feng; Gui, Lai

    2014-09-01

    McCune-Albright syndrome (MAS) is a rare, post-zygotic (non-germline) disorder, characterized by hypersecretory endocrinopathies, fibrous dysplasia of the bone and café-au-lait macules. The most common endocrine dysfunction is gonadal hyperfunction; thus, hypersecretion of growth hormones (GHs) as a manifestation of endocrine hyperfunction in MAS is rarely reported. MAS affects both genders, although the majority of cases have been reported in young females. Atypical presentations of MAS, with only one or two of the classic symptoms, have been previously described, but remain particularly challenging due to the lack of a diagnostic phenotype. In patients with atypical MAS, analysis of mutations in the gene of the α-subunit of the stimulatory G-protein is limited; thus, diagnosis is based on clinical judgment. In the present study, a male with polyostotic fibrous dysplasia and GH-secreting pituitary adenomas, diagnosed with atypical MAS, was reported. The pituitary adenoma was effectively treated with radiotherapy and the patient underwent surgery for the polyostotic fibrous dysplasia, with marked improvements observed in appearance.

  14. Effect of zink oxyde nanoparticles on the test function of water organisms of different trophic levels

    NASA Astrophysics Data System (ADS)

    Morgalev, Yu; Morgaleva, T.; Gosteva, I.; Morgalev, S.; Kulizhskiy, S.; Astafurova, T.

    2015-11-01

    The toxicity of zinc oxide nanoparticles (nZnO) with particle size Δ50 = 20 nm was evaluated according to the degree of toxicity of the aqueous disperse system (DS) with biological testing methods using a set of test organisms representing the major trophic levels.We observed the influence of the concentration degree of nZnO on toxic effects level on the fluorescence of the bacterial biosensor "Ekolyum-13", the chemotactic response of ciliates Paramecium caudatum, the rate of growth of unicellular algae Chlorella vulgaris Bayer, mortality of entomostracans Daphnia magna Straus and fish Danio rerio. The detected values of L(E)C50 are: for biosensor "Ekolyum-13" - 0.30 mg/L, for ciliates Paramecium caudatum - 0.14 mg/L, for Chlorella vulgaris Bayer - 0.17 mg/L and for Daphnia magna Straus - 0.52 mg/L. No toxicity of nZnO was detected in relation to fish Danio rerio, L(E)C50 > 100 mg/L. In assessing the maximum effect of nZnO according to GHS and EU Directive 93/67/ EEC, it is assigned to dangerous substances with a high degree of toxicity "Acute toxicity 1".

  15. Carbohydrate-active enzymes from the zygomycete fungus Rhizopus oryzae: a highly specialized approach to carbohydrate degradation depicted at genome level

    PubMed Central

    2011-01-01

    Background Rhizopus oryzae is a zygomycete filamentous fungus, well-known as a saprobe ubiquitous in soil and as a pathogenic/spoilage fungus, causing Rhizopus rot and mucomycoses. Results Carbohydrate Active enzyme (CAZy) annotation of the R. oryzae identified, in contrast to other filamentous fungi, a low number of glycoside hydrolases (GHs) and a high number of glycosyl transferases (GTs) and carbohydrate esterases (CEs). A detailed analysis of CAZy families, supported by growth data, demonstrates highly specialized plant and fungal cell wall degrading abilities distinct from ascomycetes and basidiomycetes. The specific genomic and growth features for degradation of easily digestible plant cell wall mono- and polysaccharides (starch, galactomannan, unbranched pectin, hexose sugars), chitin, chitosan, β-1,3-glucan and fungal cell wall fractions suggest specific adaptations of R. oryzae to its environment. Conclusions CAZy analyses of the genome of the zygomycete fungus R. oryzae and comparison to ascomycetes and basidiomycete species revealed how evolution has shaped its genetic content with respect to carbohydrate degradation, after divergence from the Ascomycota and Basidiomycota. PMID:21241472

  16. Suitability of the isolated chicken eye test for classification of extreme pH detergents and cleaning products.

    PubMed

    Cazelle, Elodie; Eskes, Chantra; Hermann, Martina; Jones, Penny; McNamee, Pauline; Prinsen, Menk; Taylor, Hannah; Wijnands, Marcel V W

    2015-04-01

    A.I.S.E. investigated the suitability of the regulatory adopted ICE in vitro test method (OECD TG 438) with or without histopathology to identify detergent and cleaning formulations having extreme pH that require classification as EU CLP/UN GHS Category 1. To this aim, 18 extreme pH detergent and cleaning formulations were tested covering both alkaline and acidic extreme pHs. The ICE standard test method following OECD Test Guideline 438 showed good concordance with in vivo classification (83%) and good and balanced specificity and sensitivity values (83%) which are in line with the performances of currently adopted in vitro test guidelines, confirming its suitability to identify Category 1 extreme pH detergent and cleaning products. In contrast to previous findings obtained with non-extreme pH formulations, the use of histopathology did not improve the sensitivity of the assay whilst it strongly decreased its specificity for the extreme pH formulations. Furthermore, use of non-testing prediction rules for classification showed poor concordance values (33% for the extreme pH rule and 61% for the EU CLP additivity approach) with high rates of over-prediction (100% for the extreme pH rule and 50% for the additivity approach), indicating that these non-testing prediction rules are not suitable to predict Category 1 hazards of extreme pH detergent and cleaning formulations.

  17. Assessment of skin sensitization under REACH: A case report on vehicle choice in the LLNA and its crucial role preventing false positive results.

    PubMed

    Watzek, Nico; Berger, Franz; Kolle, Susanne Noreen; Kaufmann, Tanja; Becker, Matthias; van Ravenzwaay, Bennard

    2017-04-01

    In the EU, chemicals with a production or import volume in quantities of one metric ton per year or more have to be tested for skin sensitizing properties under the REACH regulation. The murine Local Lymph Node Assay (LLNA) and its modifications are widely used to fulfil the data requirement, as it is currently considered the first-choice method for in vivo testing to cover this endpoint. This manuscript describes a case study highlighting the importance of understanding the chemistry of the test material during testing for 'skin sensitization' of MCDA (mixture of 2,4- and 2,6-diamino-methylcyclohexane) with particular focus on the vehicle used. While the BrdU-ELISA modification of the LLNA using acetone/olive oil (AOO) as vehicle revealed expectable positive results. However, the concentration control analysis unexpectedly revealed an instability of MCDA in the vehicle AOO. Further studies on the reactivity showed MCDA to rapidly react with AOO under formation of various imine structures, which might have caused the positive LLNA result. The repetition of the LLNA using propylene glycol (PG) as vehicle did not confirm the positive results of the LLNA using AOO. Finally, a classification of MCDA as skin sensitizer according to the Globally Harmonized System (GHS) was not justified.

  18. Acute toxicological impact of nano- and submicro-scaled zinc oxide powder on healthy adult mice

    NASA Astrophysics Data System (ADS)

    Wang, Bing; Feng, Weiyue; Wang, Meng; Wang, Tiancheng; Gu, Yiqun; Zhu, Motao; Ouyang, Hong; Shi, Junwen; Zhang, Fang; Zhao, Yuliang; Chai, Zhifang; Wang, Haifang; Wang, Jing

    2008-02-01

    In this work, the acute oral toxicity of 20- and 120-nm ZnO powder at doses of 1-, 2-, 3-, 4-, 5-g/kg body weight was evaluated referred to the OECD guidelines for testing of chemicals. As the results, both 20- and 120-nm ZnO belong to non-toxic chemicals according to the Globally Harmonized Classification System (GHS) for the classification of chemicals. The distribution determination showed that Zn was mainly retained in the bone, kidney and pancreas after 20- and 120-nm ZnO administration. However, the results of blood measurement suggest that the increase in blood viscosity could be induced by low and median dose of 20-nm ZnO but high dose of 120-nm ZnO. The pathological examination showed that the 120-nm ZnO treated mice had dose-effect pathological damages in stomach, liver, heart and spleen, whereas, 20-nm ZnO displayed negative dose-effect damages in liver, spleen and pancreas. Therefore, we conclude that the liver, spleen, heart, pancreas and bone are the target organs for 20- and 120-nm ZnO oral exposure. More attention should be paid on the potential toxicity induced by low dose of 20-nm ZnO oral exposure.

  19. The Role of Semantics in Open-World, Integrative, Collaborative Science Data Platforms

    NASA Astrophysics Data System (ADS)

    Fox, Peter; Chen, Yanning; Wang, Han; West, Patrick; Erickson, John; Ma, Marshall

    2014-05-01

    As collaborative science spreads into more and more Earth and space science fields, both participants and funders are expressing stronger needs for highly functional data and information capabilities. Characteristics include a) easy to use, b) highly integrated, c) leverage investments, d) accommodate rapid technical change, and e) do not incur undue expense or time to build or maintain - these are not a small set of requirements. Based on our accumulated experience over the last ~ decade and several key technical approaches, we adapt, extend, and integrate several open source applications and frameworks to handle major portions of functionality for these platforms. This includes: an object-type repository, collaboration tools, identity management, all within a portal managing diverse content and applications. In this contribution, we present our methods and results of information models, adaptation, integration and evolution of a networked data science architecture based on several open source technologies (Drupal, VIVO, the Comprehensive Knowledge Archive Network; CKAN, and the Global Handle System; GHS). In particular we present the Deep Carbon Observatory - a platform for international science collaboration. We present and discuss key functional and non-functional attributes, and discuss the general applicability of the platform.

  20. In vitro assessment of eye irritancy using the Reconstructed Human Corneal Epithelial SkinEthic HCE model: application to 435 substances from consumer products industry.

    PubMed

    Cotovio, José; Grandidier, Marie-Hélène; Lelièvre, Damien; Bremond, Christelle; Amsellem, Carolle; Maloug, Saber; Ovigne, Jean-Marc; Loisel-Joubert, Sophie; Lee, Aline Van Der; Minondo, Anne-Marie; Capallere, Christophe; Bertino, Béatrice; Alépée, Nathalie; Tinois-Tessonneaud, Estelle; de Fraissinette, Anne De Brugerolle; Meunier, Jean-Roch; Leclaire, Jacques

    2010-03-01

    The 7th amendment of the EU Cosmetics Directive led to the ban of eye irritation testing for cosmetic ingredients in animals, effective from March 11th 2009. Over the last 20years, many efforts have been made to find reliable and relevant alternative methods. The SkinEthic HCE model was used to evaluate the in vitro eye irritancy potential of substances from a cosmetic industry portfolio. An optimized protocol based on a specific 1-h treatment and a 16-h post-treatment incubation period was first assessed on a set of 102 substances. The prediction model (PM) based on a 50% viability cut-off, allowed to draw up two classes (Irritants and Non-Irritants), with good associated sensitivity (86.2%) and specificity (83.5%). To check the robustness of the method, the evaluated set was expanded up to 435 substances. Final performances maintained a high level and were characterized by an overall accuracy value > 82% when using EU or GHS classification rules. Results showed that the SkinEthic HCE test method is a promising in vitro tool for the prediction of eye irritancy. Optimization datasets were shared with the COLIPA Eye Irritation Project Team and ECVAM experts, and reviewed as part of an ongoing progression to enter an ECVAM prospective validation study for eye irritation.

  1. Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance.

    PubMed

    Sun, Yuxiang; Butte, Nancy F; Garcia, Jose M; Smith, Roy G

    2008-02-01

    Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R), are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and negative (caloric restriction) energy balance. In contrast to results from young N2 mutant mice, changes in body weight and energy expenditure are not clearly distinguishable across genotypes. Although respiratory quotient was lower in mice fed a high-fat diet, no differences were evident between littermate wild-type and null genotypes. With normal chow, a modest decrease trend in respiratory quotient was detected in ghrelin(-/-) mice but not in Ghsr(-/-) mice. Under caloric restriction, the weight loss of ghrelin(-/-) and Ghsr(-/-) mice was identical to wild-type littermates, but blood glucose levels were significantly lower. We conclude that adult congenic ghrelin(-/-) and Ghsr(-/-) mice are not resistant to diet-induced obesity but under conditions of negative energy balance show impairment in maintaining glucose homeostasis. These results support our hypothesis that the primary metabolic function of ghrelin in adult mice is to modulate glucose sensing and insulin sensitivity, rather than directly regulate energy intake and energy expenditure.

  2. Subsite-specific contributions of different aromatic residues in the active site architecture of glycoside hydrolase family 12

    PubMed Central

    Zhang, Xiaomei; Wang, Shuai; Wu, Xiuyun; Liu, Shijia; Li, Dandan; Xu, Hao; Gao, Peiji; Chen, Guanjun; Wang, Lushan

    2015-01-01

    The active site architecture of glycoside hydrolase (GH) is a contiguous subregion of the enzyme constituted by residues clustered in the three-dimensional space, recognizing the monomeric unit of ligand through hydrogen bonds and hydrophobic interactions. Mutations of the key residues in the active site architecture of the GH12 family exerted different impacts on catalytic efficiency. Binding affinities between the aromatic amino acids and carbohydrate rings were quantitatively determined by isothermal titration calorimetry (ITC) and the quantum mechanical (QM) method, showing that the binding capacity order of Tyr>Trp>His (and Phe) was determined by their side-chain properties. The results also revealed that the binding constant of a certain residue remained unchanged when altering its location, while the catalytic efficiency changed dramatically. Increased binding affinity at a relatively distant subsite, such as the mutant of W7Y at the −4 subsite, resulted in a marked increase in the intermediate product of cellotetraose and enhanced the reactivity of endoglucanase by 144%; while tighter binding near the catalytic center, i.e. W22Y at the −2 subsite, enabled the enzyme to bind and hydrolyze smaller oligosaccharides. Clarification of the specific roles of the aromatics at different subsites may pave the way for a more rational design of GHs. PMID:26670009

  3. Aquatic Toxicity Comparison of Silver Nanoparticles and Silver Nanowires.

    PubMed

    Sohn, Eun Kyung; Johari, Seyed Ali; Kim, Tae Gyu; Kim, Jin Kwon; Kim, Ellen; Lee, Ji Hyun; Chung, Young Shin; Yu, Il Je

    2015-01-01

    To better understand the potential ecotoxicological impact of silver nanoparticles (AgNPs) and silver nanowires (AgNWs) released into freshwater environments, the toxicities of these nanomaterials were assessed and compared using Organization for Economic Cooperation and Development (OECD) test guidelines, including a "Daphnia sp., acute immobilization test," "Fish, acute toxicity test," and "freshwater alga and cyanobacteria, growth inhibition test." Based on the estimated median lethal/effective concentrations of AgNPs and AgNWs, the susceptibility to the nanomaterials was different among test organisms (daphnia > algae > fish), suggesting that the AgNPs are classified as "category acute 1" for Daphnia magna, "category acute 2" for Oryzias latipes, and "category acute 1" for Raphidocelis subcapitata, while the AgNWs are classified as "category acute 1" for Daphnia magna, "category acute 2" for Oryzias latipes, and "category acute 2" for Raphidocelis subcapitata, according to the GHS (Globally Harmonized System of Classification and Labelling of Chemicals). In conclusion, the present results suggest that more attention should be paid to prevent the accidental or intentional release of silver nanomaterials into freshwater aquatic environments.

  4. Expression and Possible Immune-regulatory Function of Ghrelin in Oral Epithelium

    PubMed Central

    Ohta, K.; Laborde, N.J.; Kajiya, M.; Shin, J.; Zhu, T.; Thondukolam, A.K.; Min, C.; Kamata, N.; Karimbux, N.Y.; Stashenko, P.; Kawai, T.

    2011-01-01

    Originally found in stomach mucosa, ghrelin is a peptide appetite hormone that has been implicated as an immuno-modulatory factor. Ghrelin has also been found in salivary glands and saliva; however, its expression patterns and biological properties in the oral cavity remain unclear. Therefore, we investigated the expression patterns of ghrelin in saliva, gingival crevicular fluid (GCF), and gingival tissue, as well as its in vitro effects on IL-8 production by TNF-α or LPS-stimulated oral epithelial cells. In the clinical samples obtained from 12 healthy volunteers, the concentration of ghrelin in GCF remarkably exceeded that detected in saliva. The expression of ghrelin mRNAs and growth hormone secretagogue (GHS) receptors could be detected in human oral epithelial cells. Immunohistochemical analysis revealed the expression of ghrelin in gingival epithelium, as well as in fibroblasts in the lamina propria. Ghrelin increased intracellular calcium mobilization and cAMP levels in oral epithelial cells, suggesting that ghrelin acts on epithelial cells to induce cell signaling. Furthermore, synthetic ghrelin inhibited the production of IL-8 from TNF-α or LPS-stimulated oral epithelial cells. These results indicate that ghrelin produced in the oral cavity appears to play a regulatory role in innate immune responses to inflammatory infection. PMID:21865591

  5. Toxicity of various silver nanoparticles compared to silver ions in Daphnia magna

    PubMed Central

    2012-01-01

    Background To better understand the potential ecotoxicological impacts of silver nanoparticles released into freshwater environments, the Daphnia magna 48-hour immobilization test was used. Methods The toxicities of silver nitrate, two types of colloidal silver nanoparticles, and a suspension of silver nanoparticles were assessed and compared using standard OECD guidelines. Also, the swimming behavior and visible uptake of the nanoparticles by Daphnia were investigated and compared. The particle suspension and colloids used in the toxicity tests were well-characterized. Results The results obtained from the exposure studies showed that the toxicity of all the silver species tested was dose and composition dependent. Plus, the silver nanoparticle powders subsequently suspended in the exposure water were much less toxic than the previously prepared silver nanoparticle colloids, whereas the colloidal silver nanoparticles and AgNO3 were almost similar in terms of mortality. The silver nanoparticles were ingested by the Daphnia and accumulated under the carapace, on the external body surface, and connected to the appendages. All the silver species in this study caused abnormal swimming by the D. magna. Conclusion According to the present results, silver nanoparticles should be classified according to GHS (Globally Harmonized System of classification and labeling of chemicals) as "category acute 1" to Daphnia neonates, suggesting that the release of nanosilver into the environment should be carefully considered. PMID:22472056

  6. Inhibition of mercapturic acid pathway-mediated disposal of 4-hydroxynonenal causes complete and sustained remission of human cancer xenografts in nude mice.

    PubMed

    Kumar, Sushil; Kokate, Rutika A; Sahu, Mukesh; Chaudhary, Pankaj; Sharma, Rajendra; Awasthi, Sanjay; Awasthi, Yogesh C

    2011-11-01

    Environmental electrophilic chemical carcinogens are detoxified via mercapturic acid pathway to be excreted as mercapturic acid derivatives. Mercapturic acid pathway is also involved in the metabolism of pro-apoptotic and toxic endogenous electrophiles such as 4-hydroxynonenal (HNE). HNE is a common denominator in stress induced signaling and is a pro-apoptotic second messenger that affects cell cycle signaling in a concentration dependent manner. It can regulate signaling for apoptosis, differentiation, and gene expression by interacting with the transcriptional factors, transcriptional repressors, membrane receptors and other proteins. First two rate limiting enzymes of the mercapturic acid pathway, GSTs that conjugate HNE to glutathione (GSH), and RLIP76 that excludes GHS-HNE conjugate from cells, regulate the intracellular concentration of HNE. Thus GSTs and RLIP76 can have a profound effect on cell cycle signaling. Our studies have established that increased HNE levels in cells promote apoptotic signaling while at decreased levels below its basal constituted levels HNE promote proliferation. A major outcome of these findings is that by blocking the mercapturic acid pathway mediated detoxification of HNE through the inhibition of RLIP76 catalyzed transport of GS-HNE, a complete remission of many human cancer xenografts in mice can be achieved.

  7. Glutathione (GSH) production is increased in copper deficient isolated hepatocytes and inhibition of GSH synthesis decreases intracellular cholesterol

    SciTech Connect

    Pi Yu Chao; Allen, K.G.D )

    1991-03-15

    Thirty male weanling Sprague Dawley rats were assigned to three groups of 10 animals each and fed AIN based copper deficient ad libitum, copper control meal fed and copper deficient meal fed diets. 12h meals were provided. Beginning on day 54 animals were used to prepare isolated hepatocytes, following a 4h meal, by portal vein collagenase infusion. Washed isolated hepatocytes were incubated in Krebs Henseleit bicarbonate buffer pH 7.4 under 95/5 O{sub 2}/CO{sub 2} at 37{degree} with 2.5 mM Ca, 0.75% gelatin and 10 mM glucose, either with or without 1 mM buthionine sulfoximine (BSO) a specific inhibitor of GSH synthesis. Hepatocyte viability was assessed by trypan blue exclusion. Copper deficiency significantly increased GSH production by 30-50% at 1.5 and 3 h, with no changes in GSSG. GSH production was inhibited by BSO which also significantly inhibited intracellular cholesterol appearance at 3 h. The intracellular (GHS){sup 2}/GSSG at 3 hr showed a significant correlation with cholesterol appearance rate at 3 h. Copper deficiency increases hepatocyte GSH production. Inhibition of GSH production is correlated with decreased cholesterol appearance.

  8. Structure of Bacteroides thetaiotaomicron BT2081 at 2.05 Å resolution: the first structural representative of a new protein family that may play a role in carbohydrate metabolism

    PubMed Central

    Yeh, Andrew P.; Abdubek, Polat; Astakhova, Tamara; Axelrod, Herbert L.; Bakolitsa, Constantina; Cai, Xiaohui; Carlton, Dennis; Chen, Connie; Chiu, Hsiu-Ju; Chiu, Michelle; Clayton, Thomas; Das, Debanu; Deller, Marc C.; Duan, Lian; Ellrott, Kyle; Farr, Carol L.; Feuerhelm, Julie; Grant, Joanna C.; Grzechnik, Anna; Han, Gye Won; Jaroszewski, Lukasz; Jin, Kevin K.; Klock, Heath E.; Knuth, Mark W.; Kozbial, Piotr; Krishna, S. Sri; Kumar, Abhinav; Lam, Winnie W.; Marciano, David; McMullan, Daniel; Miller, Mitchell D.; Morse, Andrew T.; Nigoghossian, Edward; Nopakun, Amanda; Okach, Linda; Puckett, Christina; Reyes, Ron; Tien, Henry J.; Trame, Christine B.; van den Bedem, Henry; Weekes, Dana; Wooten, Tiffany; Xu, Qingping; Hodgson, Keith O.; Wooley, John; Elsliger, Marc-André; Deacon, Ashley M.; Godzik, Adam; Lesley, Scott A.; Wilson, Ian A.

    2010-01-01

    BT2081 from Bacteroides thetaiotaomicron (GenBank accession code NP_810994.1) is a member of a novel protein family consisting of over 160 members, most of which are found in the different classes of Bacteroidetes. Genome-context analysis lends support to the involvement of this family in carbohydrate metabolism, which plays a key role in B. thetaiotaomicron as a predominant bacterial symbiont in the human distal gut microbiome. The crystal structure of BT2081 at 2.05 Å resolution represents the first structure from this new protein family. BT2081 consists of an N-terminal domain, which adopts a β-sandwich immunoglobulin-like fold, and a larger C-terminal domain with a β-sandwich jelly-roll fold. Structural analyses reveal that both domains are similar to those found in various carbohydrate-active enzymes. The C-terminal β-jelly-roll domain contains a potential carbohydrate-binding site that is highly conserved among BT2081 homologs and is situated in the same location as the carbohydrate-binding sites that are found in structurally similar glycoside hydrolases (GHs). However, in BT2081 this site is partially occluded by surrounding loops, which results in a deep solvent-accessible pocket rather than a shallower solvent-exposed cleft. PMID:20944224

  9. A case series of thermal scald injuries in dogs exposed to hot water from garden hoses (garden hose scalding syndrome).

    PubMed

    Quist, Erin M; Tanabe, Mika; Mansell, Joanne E K L; Edwards, Jeffrey L

    2012-04-01

    In this report, we present a series of cases of thermal burns (scalds) in dogs resulting from exposure to hot water from a garden hose that had been lying in the sun. These dogs typically inhabited the southern and western regions of the USA, where the recorded high temperatures often exceed 32°C (90°F) during the warm summer months. Dogs with thermal scald injury in these cases presented with linear thermal burns along the dorsum, in addition to a variety of other macroscopic lesions that were dependent upon the degree of burn exposure and ranged from local erythema to ulcerated, necrotic and sloughing skin. Chronic, healed wounds were often alopecic, with markedly thickened skin and characteristically smooth and glassy scar tissue formation. Histologically, the lesions of thermal scald injury in these dogs were indistinguishable from any other second or third degree burn, and consisted of full-thickness dermal and epidermal necrosis with occasional fibrinoid necrosis of vessel walls, vasculitis and intravascular thrombosis. Here, we closely examine 10 cases of dogs with dorsal thermal burns collected from Texas, Arizona, California, Utah, Nevada, Indiana, Michigan and North Carolina and propose the term 'garden hose scalding syndrome (GHS)' to describe this unique type of scald injury.

  10. Non- and semi-parametric estimation of age and time heterogeneity in repeated cross-sections: an application to self-reported morbidity and general practitioner utilization.

    PubMed

    Parkin, D; Rice, N; Sutton, M

    1999-08-01

    Patterns of self-reported morbidity and general practitioner (GP) utilization exhibit complex age, sex and time heterogeneity. Underlying patterns are often obscured by data which are overly 'rough' because of noise associated with adjacent year fluctuations. In this paper we describe methods to obtain smoothed estimates of age, time and birth-cohort effects using data from the General Household Survey (GHS), covering the period 1984-1995/6 inclusive. The methods outlined offer powerful analytic tools to research complex profiles or trends, particularly over age or time. The relationships of the morbidity and GP utilization measures with age, sex and survey year characteristics are estimated non-parametrically using roughness penalized least squares (RPLS). A semi-parametric extension of this model is used to estimate the effect of the morbidity variables on GP utilization. Tests are employed for various forms of age and time heterogeneity including birth-cohort effects. Linear age specifications are rejected for all variables and evidence is found of time heterogeneity in one of the morbidity measures--limiting long-standing illness (LS)--and GP utilization. The advantages of employing non- and semi-parametric estimations in the presence of complex relationships such as those observed for age and time profiles are discussed. Adoption of these techniques by applied econometricians working in health economics is encouraged.

  11. Protecting Space Travelers from Kidney Stones: Renal Stone Risk During Space Flight

    NASA Technical Reports Server (NTRS)

    Whitson, Peggy; Bloomberg, Jacob; Lee, Angie (Technical Monitor)

    2002-01-01

    Renal stones, popularly known as kidney or bladder stones, are small rock-like objects formed in the kidneys or urinary tract by deposits of calcium and other minerals. The problem arises when the stones block the drainage of the kidney, resulting in urinary obstruction and pain. Passing these stones can be one of the most painful experiences a person will endure so doctors often prescribe pain relievers to ease the experience. Drinking plenty of fluids, which help flush waste out of the body, and eating a well-balanced diet are the first steps to preventing stones. For individuals at risk, this may not be enough, and a doctor may recommend a special diet and medications. Unfortunately, approximately 60 percent of people who have had a renal stone will experience a recurrence. This is particularly true of men, who are four to five times more likely to develop stones than women. Renal stones do not discriminate based on age; even children are at risk. Astronauts are particularly at risk of developing renal stones because they lose bone and muscle mass; calcium, other minerals, and protein normally used for bone and muscle end up in the bloodstream and then in the kidneys. Without plenty of fluid to wash them away, crystals can form and then grow into stones. This factor compounds the risk for astronauts, since they also perceive that they are less thirsty in space and will drink less than normal during the mission. To minimize all of these factors, doctors must instead treat the stone-forming compounds with medication. This study will use potassium citrate to reduce the risk of stone formation. Renal stones are never convenient, but they are a particular concern for astronauts who have limited access to treatment during flight. Researchers are examining how earthbound preventions for renal stone formation work in flight, ensuring missions are not ended prematurely due to this medical condition. During STS-107, earthbound preventions and treatments become astronauts

  12. Molecular modifiers reveal a mechanism of pathological crystal growth inhibition

    NASA Astrophysics Data System (ADS)

    Chung, Jihae; Granja, Ignacio; Taylor, Michael G.; Mpourmpakis, Giannis; Asplin, John R.; Rimer, Jeffrey D.

    2016-08-01

    Crystalline materials are crucial to the function of living organisms, in the shells of molluscs, the matrix of bone, the teeth of sea urchins, and the exoskeletons of coccoliths. However, pathological biomineralization can be an undesirable crystallization process associated with human diseases. The crystal growth of biogenic, natural and synthetic materials may be regulated by the action of modifiers, most commonly inhibitors, which range from small ions and molecules to large macromolecules. Inhibitors adsorb on crystal surfaces and impede the addition of solute, thereby reducing the rate of growth. Complex inhibitor-crystal interactions in biomineralization are often not well elucidated. Here we show that two molecular inhibitors of calcium oxalate monohydrate crystallization—citrate and hydroxycitrate—exhibit a mechanism that differs from classical theory in that inhibitor adsorption on crystal surfaces induces dissolution of the crystal under specific conditions rather than a reduced rate of crystal growth. This phenomenon occurs even in supersaturated solutions where inhibitor concentration is three orders of magnitude less than that of the solute. The results of bulk crystallization, in situ atomic force microscopy, and density functional theory studies are qualitatively consistent with a hypothesis that inhibitor-crystal interactions impart localized strain to the crystal lattice and that oxalate and calcium ions are released into solution to alleviate this strain. Calcium oxalate monohydrate is the principal component of human kidney stones and citrate is an often-used therapy, but hydroxycitrate is not. For hydroxycitrate to function as a kidney stone treatment, it must be excreted in urine. We report that hydroxycitrate ingested by non-stone-forming humans at an often-recommended dose leads to substantial urinary excretion. In vitro assays using human urine reveal that the molecular modifier hydroxycitrate is as effective an inhibitor of nucleation

  13. Randall's plaque: pathogenesis and role in calcium oxalate nephrolithiasis.

    PubMed

    Evan, A; Lingeman, J; Coe, F L; Worcester, E

    2006-04-01

    The purpose of these studies was to test the hypothesis that Randall's plaque develops in unique anatomical sites of the kidney and their formation is conditioned by specific stone-forming pathophysiologies. We performed intraoperative papillary biopsies from kidneys of idiopathic-calcium oxalate (CaOx), intestinal bypass for obesity, brushite (BR) and cystine stone formers (SF) during percutaneous nephrolithotomy. Tissues were examined by infrared analysis and light and electron microscopy. Our analysis revealed a distinct pattern of mineral deposition and papillary pathology for each type of SF. CaOx SF had interstitial apatite crystals beginning at thin loops of Henle. These deposits termed Randall's plaque are thought to serve as sites for stone attachment. No tubular injury was noted. Intestinal bypass patients possessed intraluminal apatite deposits in inner medullary collecting ducts (IMCD) with associated cell injury. BR SF showed the most severe form of cortical and medullary changes with sites of Randall's plaque, and yellowish intraluminal deposits of apatite in IMCD. Cystine SF had plugging of ducts of Bellini with cystine crystals and apatite deposits in IMCD and loops of Henle. Intratubular sites of crystalline deposits were always associated to adjacent regions of interstitial fibrosis. The metabolic, anatomic, and surgical pathologic findings in four distinct groups of SF clearly show that 'the histology of the renal papilla from a stone former, is particular to the clinical setting'. We believe our approach to studying stone disease will provide insights into the pathogenesis of stone formation for each type of SF that will lead to improved clinical treatment.

  14. Studies on renal function in patients with cystinuria.

    PubMed

    Lindell, A; Denneberg, T; Granerus, G

    1997-01-01

    Total and separate renal functions were evaluated in 40 patients with cystinuria. The average duration of the renal stone disease was 26 years (range 1-53). The patients had been subjected to a stone-preventing regimen composed of increased fluid intake, urinary alkalinization and treatment with a sulphydryl compound, tiopronin or D-penicillamine, for an average of 11.7 years (range 1-24). Urinary cystine concentration was determined regularly to monitor the treatment. All patients were examined with gamma camera renography and an assessment of glomerular filtration rate (GFR), and early and late renographic results could be compared in 30 patients. The early renographic evaluation showed that 43% of binephric patients (13/30) had an abnormal relative renal function (RRF) before the start of the stone-preventing treatment. At the late evaluation, 50% of binephric patients (17/34) had an abnormal RRF, while 30% of all patients (12/40) had a GFR below the age-related normal range. Thirty percent of 74 evaluated kidneys (22/74) had a separate GFR below an estimated age-related normal range. At the late evaluation only 30% of the patients had functionally unaffected kidneys with both normal GFR and bilateral normal renography. There was, however, no case with terminal renal failure. The separate GFR of kidneys with a history of staghorn stones was significantly lower than for kidneys without that special type of stones, but otherwise there was no relationship between renal functional impairment and other estimates of the activity of the renal stone disease. In conclusion, impairment of renal function is common in patients with stone-forming cystinuria. Stone-preventive treatment appears to be effective in preserving renal function. The high frequency of renal functional impairment justifies close surveillance of this group of patients. By renographic examination, unilateral changes in renal function can be detected at an early stage and patients at risk for further

  15. Effect of hydro-alcoholic extract of Vernonia cinerea Less. against ethylene glycol-induced urolithiasis in rats

    PubMed Central

    Hiremath, Ravindra D.; Jalalpure, Sunil S.

    2016-01-01

    Objective: Aim of this study is to evaluate antiurolithiatic potential of whole plant hydro-alcoholic (30:70) extract of Vernonia cinerea Less. in accordance to its claims made in ancient literature and also being one of the ingredients of cystone, a marketed formulation widely used in the management of urolithiasis. Materials and Methods: To induce urolithiasis, 0.75% v/v ethylene glycol was administered orally for 14 days. The curative dose of 400 mg/kg b.w. and preventive doses of 100, 200, and 400 mg/kg b.w. were administered from 15th to 28th and 1st to 28 days, respectively. Cystone 750 mg/kg b.w. was selected as the reference standard for both curative and preventive doses. On 28th day, urinate of 24 h was collected and subjected for estimation of calcium, oxalate, and phosphates. Serum biochemical and kidney homogenate analysis was done for determination of renal oxalate contents. Results: The diseased Group II showed marked increase (P < 0.001 vs. normal Group I) in levels of urine calcium, oxalate, and phosphate. Serum creatinine, urea, and uric acid levels were also increased. Histopathological studies of kidney sections revealed significant changes. Treatment with hydro-alcoholic extract of V. cinerea showed significant (P < 0.01 vs. calculi-induced Group II) dose-dependent activity. A progressive increase in urine output, body weight, and decline in concentrations of stone-forming components such as calcium, oxalates, and phosphates was observed. Conclusion: It can be inferred that V. cinerea Less. is effective in ethylene glycol-induced urolithiasis and may have a potential in preventing and curing urolithiasis. PMID:27756957

  16. Recent advances in managing and understanding nephrolithiasis/nephrocalcinosis

    PubMed Central

    Gambaro, Giovanni; Trinchieri, Alberto

    2016-01-01

    Urinary stone disease is a very common disease whose prevalence is still increasing. Stone formation is frequently associated with other diseases of affluence such as hypertension, osteoporosis, cardiovascular disease, metabolic syndrome, and insulin resistance. The increasing concentration of lithogenic solutes along the different segments of the nephron involves supersaturation conditions leading to the formation, growth, and aggregation of crystals. Crystalline aggregates can grow free in the tubular lumen or coated on the wall of the renal tubule. Plugs of crystalline material have been highlighted in the tubular lumen in some patients, but crystalline growth starting from plaques of calcium phosphate within the renal papillae has been demonstrated in others. Urinary supersaturation is the result of a complex interaction between predisposing genetic features and environmental factors. Dietary intake is certainly the most important environmental risk factor. In particular, an insufficient intake of dietary calcium (<600 mg/day) can increase the intestinal absorption of oxalate and the risk of calcium oxalate stone formation. Other possible risk factors that have been identified include excessive intake of salt and proteins. The potential role of dietary acid load seems to play an important role in causing a state of subclinical chronic acidosis; therefore, the intake of vegetables is encouraged in stone-forming patients. Consumption of sugar-sweetened soda and punch is associated with a higher risk of stone formation, whereas consumption of coffee, tea, beer, wine, and orange juice is associated with a lower risk. A high fluid intake is widely recognized as the cornerstone of prevention of all forms of stones. The effectiveness of protein and salt restriction has been evaluated in some studies that still do not allow definitive conclusions to be made. Calcium stone formation can be prevented by the use of different drugs with different mechanisms of action

  17. Physicochemical action of potassium-magnesium citrate in nephrolithiasis

    NASA Technical Reports Server (NTRS)

    Pak, C. Y.; Koenig, K.; Khan, R.; Haynes, S.; Padalino, P.

    1992-01-01

    Effect of potassium-magnesium citrate on urinary biochemistry and crystallization of stone-forming salts was compared with that of potassium citrate at same dose of potassium in five normal subjects and five patients with calcium nephrolithiasis. Compared to the placebo phase, urinary pH rose significantly from 6.06 +/- 0.27 to 6.48 +/- 0.36 (mean +/- SD, p less than 0.0167) during treatment with potassium citrate (50 mEq/day for 7 days) and to 6.68 +/- 0.31 during therapy with potassium-magnesium citrate (containing 49 mEq K, 24.5 mEq Mg, and 73.5 mEq citrate per day). Urinary pH was significantly higher during potassium-magnesium citrate than during potassium citrate therapy. Thus, the amount of undissociated uric acid declined from 118 +/- 61 mg/day during the placebo phase to 68 +/- 54 mg/day during potassium citrate treatment and, more prominently, to 41 +/- 46 mg/day during potassium-magnesium citrate therapy. Urinary magnesium rose significantly from 102 +/- 25 to 146 +/- 37 mg/day during potassium-magnesium citrate therapy but not during potassium citrate therapy. Urinary citrate rose more prominently during potassium-magnesium citrate therapy (to 1027 +/- 478 mg/day from 638 +/- 252 mg/day) than during potassium citrate treatment (to 932 +/- 297 mg/day). Consequently, urinary saturation (activity product) of calcium oxalate declined significantly (from 1.49 x 10(-8) to 1.03 x 10(-8) M2) during potassium-magnesium citrate therapy and marginally (to 1.14 x 10(-8) M2) during potassium citrate therapy.(ABSTRACT TRUNCATED AT 250 WORDS).

  18. The influence of maternal and paternal history on stone composition and clinical course of calcium nephrolithiasis in subjects aged between 15 and 25.

    PubMed

    Guerra, Angela; Ticinesi, Andrea; Allegri, Franca; Nouvenne, Antonio; Pinelli, Silvana; Folesani, Giuseppina; Lauretani, Fulvio; Maggio, Marcello; Borghi, Loris; Meschi, Tiziana

    2016-11-01

    Our aim was to compare the influence of maternal history of stones (MHS) and paternal history of stones (PHS) on composition of calculi and disease course in a group of patients with calcium nephrolithiasis (CN) aged between 15 and 25, the age range with the maximal influence of family history on disease expression. One-hundred thirty-five patients (68 F) with CN and one stone-forming parent were retrospectively selected from the database of our outpatient stone clinic, and categorized according to MHS or PHS. Data about stone disease course and composition of passed calculi, determined by chemical analysis or Fourier-transformed infrared spectrophotometry, were collected together with information on blood chemistry and 24-h urinary profile of lithogenic risk. The characteristics of disease course and stone composition were compared using logistic regression tests adjusted for age, sex, and BMI or analysis of covariance where appropriate. Patients with MHS (n = 46) had significantly higher urinary calcium/creatinine ratio and ammonium, a higher prevalence of urological treatments (57 vs 27 %, p < 0.001) and mixed calcium oxalate/calcium phosphate stone composition (69 vs 35 %, p = 0.002) than those with PHS. At multivariate logistic regression models, MHS was independently associated with urological treatments (OR 4.5, 95 %CI 1.9-10.7, p < 0.001) and the formation of calculi with mixed calcium oxalate/calcium phosphate composition (OR 5.8, 95 %CI 1.9-17.9, p = 0.002). The method of stone analysis did not affect this result. In conclusion, in subjects aged 15-25, MHS is associated with mixed calcium stones and with a higher risk for urological procedures, and should be, therefore, considered in the management of urolithiasis.

  19. Guaifenesin stone matrix proteomics: a protocol for identifying proteins critical to stone formation.

    PubMed

    Kolbach-Mandel, A M; Mandel, N S; Cohen, S R; Kleinman, J G; Ahmed, F; Mandel, I C; Wesson, J A

    2016-07-19

    Drug-related kidney stones are a diagnostic problem, since they contain a large matrix (protein) fraction and are frequently incorrectly identified as matrix stones. A urine proteomics study patient produced a guaifenesin stone during her participation, allowing us to both correctly diagnose her disease and identify proteins critical to this drug stone-forming process. The patient provided three random midday urine samples for proteomics studies; one of which contained stone-like sediment with two distinct fractions. These solids were characterized with optical microscopy and Fourier transform infrared spectroscopy. Immunoblotting and quantitative mass spectrometry were used to quantitatively identify the proteins in urine and stone matrix. Infrared spectroscopy showed that the sediment was 60 % protein and 40 % guaifenesin and its metabolite guaiacol. Of the 156 distinct proteins identified in the proteomic studies, 49 were identified in the two stone-components with approximately 50 % of those proteins also found in this patient's urine. Many proteins observed in this drug-related stone have also been reported in proteomic matrix studies of uric acid and calcium containing stones. More importantly, nine proteins were highly enriched and highly abundant in the stone matrix and 8 were reciprocally depleted in urine, suggesting a critical role for these proteins in guaifenesin stone formation. Accurate stone analysis is critical to proper diagnosis and treatment of kidney stones. Many matrix proteins were common to all stone types, but likely not related to disease mechanism. This protocol defined a small set of proteins that were likely critical to guaifenesin stone formation based on their high enrichment and high abundance in stone matrix, and it should be applied to all stone types.

  20. Determination of thermodynamic parameters for complexation of calcium and magnesium with chondroitin sulfate isomers using isothermal titration calorimetry: Implications for calcium kidney-stone research

    NASA Astrophysics Data System (ADS)

    Rodgers, Allen L.; Jackson, Graham E.

    2017-04-01

    Chondroitin sulfate (CS) occurs in human urine. It has several potential binding sites for calcium and as such may play an inhibitory role in calcium oxalate and calcium phosphate (kidney stone disease by reducing the supersaturation (SS) and crystallization of these salts. Urinary magnesium is also a role player in determining speciation in stone forming processes. This study was undertaken to determine the thermodynamic parameters for binding of the disaccharide unit of two different CS isomers with calcium and magnesium. These included the binding constant K. Experiments were performed using an isothermal titration calorimeter (ITC) at 3 different pH levels in the physiological range in human urine. Data showed that interactions between the CS isomers and calcium and magnesium occur via one binding site, thought to be sulfate, and that log K values are 1.17-1.93 and 1.77-1.80 for these two metals respectively. Binding was significantly stronger in Mg-CS than in Ca-CS complexes and was found to be dependent on pH in the latter but not in the former. Furthermore, binding in Ca-CS complexes was dependent on the location of the sulfate binding site. This was not the case in the Mg-CS complexes. Interactions were shown to be entropy driven and enthalpy unfavourable. These findings can be used in computational modeling studies to predict the effects of the calcium and magnesium CS complexes on the speciation of calcium and the SS of calcium salts in real urine samples.

  1. Risk factors for urolithiasis in children on the ketogenic diet.

    PubMed

    Furth, S L; Casey, J C; Pyzik, P L; Neu, A M; Docimo, S G; Vining, E P; Freeman, J M; Fivush, B A

    2000-11-01

    Kidney stones have been associated with use of the ketogenic diet in children with refractory seizure disorders. We performed a case-control study examining risk factors for the development of stones on the ketogenic diet, and prospectively followed children initiating the ketogenic diet to evaluate the incidence of urolithiasis. Clinical characteristics of 18 children presenting with stones (8 uric acid stones, 6 mixed calcium/uric acid stones, 1 calcium oxalate/phosphate stone, 3 stones not evaluated) were compared with characteristics of non-stone-forming children initiating the ketogenic diet at Johns Hopkins since July 1996. Since July 1996, 112 children initiating the ketogenic diet have been followed for development of stones. Follow-up times on the diet range from 2 months to 2.5 years. Of 112 children, 6 have developed stones (3 uric acid, 3 mixed calcium/uric acid stones) (0.8 children developing stones/ 100 patient-months at risk). Comparisons of children presenting with stones on the ketogenic diet with characteristics of the entire cohort initiating the ketogenic diet suggest younger age at diet initiation and hypercalciuria are risk factors for the development of stones. Prospective evaluation of children initiating the ketogenic diet revealed that almost 40% of patients had elevated fasting urine calcium: creatinine ratios at baseline; this increased to 75% after 6 months on the diet. Median urine pH was 5.5 at diet initiation, and remained at 6.0 thereafter. In a subset of patients tested, urinary citrate excretion fell from a mean of 252 mg/24 h pre diet initiation to 52 mg/24 h while on the diet. Uric acid excretion remained normal. Patients maintained on the ketogenic diet often have evidence of hypercalciuria, acid urine, and low urinary citrate excretion. In conjunction with low fluid intake, these patients are at high risk for both uric acid and calcium stone formation.

  2. Quality Assessment of Urinary Stone Analysis: Results of a Multicenter Study of Laboratories in Europe

    PubMed Central

    Siener, Roswitha; Buchholz, Noor; Daudon, Michel; Hess, Bernhard; Knoll, Thomas; Osther, Palle J.; Reis-Santos, José; Sarica, Kemal; Traxer, Olivier; Trinchieri, Alberto

    2016-01-01

    After stone removal, accurate analysis of urinary stone composition is the most crucial laboratory diagnostic procedure for the treatment and recurrence prevention in the stone-forming patient. The most common techniques for routine analysis of stones are infrared spectroscopy, X-ray diffraction and chemical analysis. The aim of the present study was to assess the quality of urinary stone analysis of laboratories in Europe. Nine laboratories from eight European countries participated in six quality control surveys for urinary calculi analyses of the Reference Institute for Bioanalytics, Bonn, Germany, between 2010 and 2014. Each participant received the same blinded test samples for stone analysis. A total of 24 samples, comprising pure substances and mixtures of two or three components, were analysed. The evaluation of the quality of the laboratory in the present study was based on the attainment of 75% of the maximum total points, i.e. 99 points. The methods of stone analysis used were infrared spectroscopy (n = 7), chemical analysis (n = 1) and X-ray diffraction (n = 1). In the present study only 56% of the laboratories, four using infrared spectroscopy and one using X-ray diffraction, fulfilled the quality requirements. According to the current standard, chemical analysis is considered to be insufficient for stone analysis, whereas infrared spectroscopy or X-ray diffraction is mandatory. However, the poor results of infrared spectroscopy highlight the importance of equipment, reference spectra and qualification of the staff for an accurate analysis of stone composition. Regular quality control is essential in carrying out routine stone analysis. PMID:27248840

  3. Alcea rosea root extract as a preventive and curative agent in ethylene glycol-induced urolithiasis in rats

    PubMed Central

    Ahmadi, Marzieh; Rad, Abolfazl Khajavi; Rajaei, Ziba; Hadjzadeh, Mousa-Al-Reza; Mohammadian, Nema; Tabasi, Nafiseh Sadat

    2012-01-01

    Introduction: Alcea rosea L. is used in Asian folk medicine as a remedy for a wide range of ailments. The aim of the present study was to investigate the effect of hydroalcoholic extract of Alcea rosea roots on ethylene glycol-induced kidney calculi in rats. Materials and Methods: Male Wistar rats were randomly divided into control, ethylene glycol (EG), curative and preventive groups. Control group received tap drinking water for 28 days. Ethylene glycol (EG), curative and preventive groups received 1% ethylene glycol for induction of calcium oxalate (CaOx) calculus formation; preventive and curative subjects also received the hydroalcoholic extract of Alcea rosea roots in drinking water at dose of 170 mg/kg, since day 0 or day 14, respectively. Urinary oxalate concentration was measured by spectrophotometer on days 0, 14 and 28. On day 28, the kidneys were removed and examined histopathologically under light microscopy for counting the calcium oxalate deposits in 50 microscopic fields. Results: In both preventive and curative protocols, treatment of rats with hydroalcoholic extract of Alcea rosea roots significantly reduced the number of kidney calcium oxalate deposits compared to ethylene glycol group. Administration of Alcea rosea extract also reduced the elevated urinary oxalate due to ethylene glycol. Conclusion: Alcea rosea showed a beneficial effect in preventing and eliminating calcium oxalate deposition in the rat kidney. This effect is possibly due to diuretic and anti-inflammatory effects or presence of mucilaginous polysaccharides in the plant. It may also be related to lowering of urinary concentration of stone-forming constituents. PMID:22701236

  4. Renal stones in the tropics.

    PubMed

    Robertson, William G

    2003-01-01

    Urolithiasis is a problem that is generally increasing in the tropics as it is in most Western countries. There are 2 main types of the disorder-bladder stones in children, a form of the disorder that disappeared from Europe in the late 19th and early 20th centuries, and upper urinary tract stones in adults. The former has been decreasing in most countries in the so-called endemic bladder stone belt with gradual improvements in levels of nutrition. However, as living standards increase, particularly in the urban areas of the more affluent developing countries, so the incidence of upper urinary tract stones in adults is increasing. The types of stones formed depend mainly on the composition of urine, which, in turn, reflects the type of diet consumed in the countries concerned. The main factor that leads to the formation of bladder stones in children is a nutritionally poor diet that is low in animal protein, calcium, and phosphate, but high in cereal and is acidogenic. This leads to the formation of urine with a relatively high content of ammonium and urate ions and consequently to the formation of ammonium acid urate crystals and stones. In countries where there is also a high intake of oxalate from local leaves and vegetables, urinary oxalate is increased and, as a result, the ammonium acid urate stones often contain calcium oxalate as well. The stone problem in the tropics is compounded by low urine volumes resulting in some areas from poor drinking water, which causes chronic diarrhea, and in others from the hot climate and fluid losses through the skin. As nutrition improves in these countries, the formation of bladder stones gives way to upper urinary tract stones consisting of calcium oxalate, often mixed with calcium phosphate or uric acid, such as are formed in most Western countries.

  5. Prevention of renal crystal deposition by an extract of Ammi visnaga L. and its constituents khellin and visnagin in hyperoxaluric rats.

    PubMed

    Vanachayangkul, P; Chow, N; Khan, S R; Butterweck, Veronika

    2011-06-01

    In Egypt, teas prepared from the fruits of Ammi visnaga L. (syn. "Khella") are traditionally used by patients with urolithiasis. The aim of this study was to evaluate whether oral administration of an aqueous extract prepared from the fruits of A. visnaga as well as two major constituents khellin and visnagin could prevent crystal deposition in stone-forming rats. Hyperoxaluria was induced in male Sprague-Dawley rats by giving 0.75% ethylene glycol and 1% ammonium chloride via the drinking water. The Khella extract (KE; 125, 250 or 500 mg/kg) was orally administered for 14 days. The histopathological examination of the kidneys revealed that KE significantly reduced the incidence of calcium oxalate (CaOx) crystal deposition. In addition, KE significantly increased urinary excretion of citrate along with a decrease of oxalate excretion. Comparable to the extract, khellin and visnagin significantly reduced the incidence of CaOx deposition in the kidneys. However, both compounds did not affect urinary citrate or oxalate excretion indicating a mechanism of action that differs from that of the extract. For KE, a reasonably good correlation was observed between the incidence of crystal deposition, the increase in citrate excretion and urine pH suggesting a mechanisms that may interfere with citrate reabsorption. In conclusion, our data suggest that KE and its compounds, khellin and visnagin, may be beneficial in the management of kidney stone disease caused by hyperoxaluria but that it is likely that different mechanism of action are involved in mediating these effects.

  6. Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

    PubMed Central

    Hopp, Katharina; Cogal, Andrea G.; Bergstralh, Eric J.; Seide, Barbara M.; Olson, Julie B.; Meek, Alicia M.; Lieske, John C.; Milliner, Dawn S.

    2015-01-01

    Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial. PMID:25644115

  7. RANKL Is a Mediator of Bone Resorption in Idiopathic Hypercalciuria

    PubMed Central

    Gomes, Samirah Abreu; dos Reis, Luciene Machado; Noronha, Irene Lourdes; Jorgetti, Vanda; Heilberg, Ita Pfeferman

    2008-01-01

    Background and objectives: This study aimed to determine the expression of osteoprotegerin, receptor activator of nuclear factor κB ligand, interleukin-1α, transforming growth factor-β, and basic fibroblast growth factor in stone-forming patients with idiopathic hypercalciuria. Design, setting, participants, & measurements: Immunohistochemical analysis was performed in undecalcified bone samples previously obtained from 36 transiliac bone biopsies of patients who had idiopathic hypercalciuria and whose histomorphometry had shown lower bone volume, increased bone resorption, and prolonged mineralization lag time. Results: Bone expression of receptor activator of nuclear factor κB ligand and osteoprotegerin was significantly higher in patients with idiopathic hypercalciuria versus control subjects. Transforming growth factor-β immunostaining was lower in patients with idiopathic hypercalciuria than in control subjects and correlated directly with mineralization surface. Interleukin-1α and basic fibroblast growth factor staining did not differ between groups. Receptor activator of nuclear factor κB ligand bone expression was significantly higher in patients who had idiopathic hypercalciuria and exhibited higher versus normal bone resorption. Conclusion: A higher expression of receptor activator of nuclear factor κB ligand in bone tissue suggests that increased bone resorption in patients with idiopathic hypercalciuria is mediated by receptor activator of nuclear factor κB ligand. Osteoprotegerin bone expression might have been secondarily increased in an attempt to counteract the actions of receptor activator of nuclear factor κB ligand. The low bone expression of transforming growth factor-β could contribute to the delayed mineralization found in such patients. PMID:18480302

  8. Reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria.

    PubMed

    Heller, H J; Zerwekh, J E; Gottschalk, F A; Pak, C Y C

    2007-04-01

    Absorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8+/-2.1 vs 3.0+/-1.5%, P=0.04; wall thickness 35.8+/-6.9 vs 47.2+/-7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4+/-0.2 vs 0.2+/-0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14+/-0.06 to 0.06+/-0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute.

  9. History to the discovery of ghrelin.

    PubMed

    Bowers, Cyril Y

    2012-01-01

    The most important initial historical time points in the development of the enlarging ghrelin system were 1973, 1976, 1982, 1984, 1990, 1996, 1998, and 1999. At these respective times, the following occurred sequentially: isolation of somatostatin, discovery of unnatural growth-hormone-releasing peptides (GHRPs), isolation of growth-hormone-releasing hormone (GHRH), hypothesis of a new natural GHRP different from GHRH, GHRP+GHRH synergism in humans, discovery of the growth hormone secretagogue GHS/GHRP receptor, cloning of the receptor, and finally, isolation and identification of the new natural endogenous GHRP ghrelin. To understand the pharmacology and probably also the physiological regulation of growth hormone (GH) secretion, an important finding was that GHRP increased pulsatile GH secretion in children as well as normal younger and older men and women. This requires endogenous GHRH secretion, even though GHRP alone substantially releases GH from the pituitary in vitro without the addition of GHRH. Unnatural GHRP gave rise to natural GHRP ghrelin because of many talented researchers worldwide. GHRP was first envisioned to be an analog of GHRH but, from comparison of the activity of GHRH and GHRPs between 1982 and1984, it was hypothesized to reflect the activity of a new hormone regulator of GH secretion yet to be isolated and identified. Intravenous bolus GHRP releases more GH than GHRH in humans, but the reverse occurs in vitro. GHRPs are pleiotropic peptides with major effects on GH, nutrition, and metabolism, especially as an additional hormone in combination with GHRH as a new regulator of pulsatile GH secretion. The first indication of pleiotropism was an increase of food intake by GHRP. A major reason for the prolonged initial interest in the GHRPs has been its similar, yet different and complementary, action with GHRH on GH regulation and secretion. Particularly noteworthy is the variable chemistry of the GHRPs. They consist of three major chemical

  10. P-T data from central Bhutan imply distributed extensional shear at the Black Mountain "klippe"

    NASA Astrophysics Data System (ADS)

    Corrie, S. L.; Kohn, M. J.; Long, S. P.; McQuarrie, N.; Tobgay, T.

    2011-12-01

    The Southern Tibetan Detachment system (STDS) occurs along the entire length of the Himalayan orogen, and extensionally emplaces low-grade to unmetamorphosed Tethyan Himalayan (TH) rocks over highly metamorphosed Greater Himalayan sequence (GH) rocks. The base of TH remnants preserved in northern Bhutan all have top-to-the-north shear sense indicators (C'-type shear bands, asymmetric folds, and boudinaged leucogranite dikes) that are interpreted to reflect a discrete shear zone. In contrast, the GH-TH contact in the southernmost TH remnant (the Black Mountain region, central Bhutan) has been interpreted as depositional. A depositional contact limits the magnitude of displacement along the early STDS to 10's of km. If the GH-TH contact in the Black Mountain region is instead a discrete shear zone, as observed farther north, displacement on the STDS could be as high as 100's of km. To discriminate between these two interpretations, we determined peak metamorphic P-T conditions through the GH and TH sections, reasoning that a discrete shear zone would produce a distinct jump in metamorphic temperature, pressure or both. Thin section-scale kinematic indicators reveal pervasive top-to-the-north shear from 2-3 km structurally above the Main Central thrust (MCT) through the rest of the 11 km thick GH and TH sections. P-T conditions were determined from immediately above the MCT to 4 km above the GH-TH contact, with 19 samples from the GH, 6 from the overlying Chekha Fm (TH), and 9 from the overlying Maneting Fm (TH). We applied standard Fe-Mg exchange thermometers and Ca net-transfer barometers involving garnet. P-T conditions range from 700 °C and 11 kbar in migmatitic GHS to 600 °C and 8 kbar at the GH-Chekha contact, and 500 °C and 5 kbar at the top of the Maneting. We found no jumps in either temperature or pressure at any level, but a steeper than lithostatic pressure gradient, which we interpret to result from distributed extensional shear. The average thermal

  11. Orogen-scale along-strike continuity in quartz recrystallization microstructures adjacent to the Main Central Thrust: implications for deformation temperatures, strain rates and flow stresses

    NASA Astrophysics Data System (ADS)

    Law, Richard

    2015-04-01

    Traced for ~ 1500 km along the foreland edge of the Himalaya from NW India to Bhutan published reports indicate a remarkable along-strike continuity of quartz recrystallization microstructures in the footwall and hanging wall to the Main Central Thrust (MCT). Recrystallization in Lesser Himalayan Series (LHS) rocks in the footwall to the MCT is dominated by grain boundary bulging (BLG) microstructures, while recrystallization in Greater Himalayan Series (GHS) rocks in the hanging wall is dominated by grain boundary migration microstructures that traced structurally upwards transition in to the anatectic core of the GHS. In foreland-positioned high-strain rocks adjacent to the MCT recrystallization is dominated by subgrain rotation (SGR) with transitional BLG-SGR and SGR-GBM microstructures being recorded at structural distances of up to a few hundred meters below and above the MCT, respectively. Correlation with available information on temperatures of metamorphism indicated by mineral phase equilibria and RSCM data suggests that recrystallization in the structural zones dominated by BLG, SGR and GBM occurred at temperatures of ~ 350-450, 450-550 and 550- > 650 °C, respectively. It should be kept in mind, however, that these temperatures are likely to be 'close-to-peak' temperatures of metamorphism, whereas penetrative shearing and recrystallization may have continued during cooling. The dominance of SGR along the more foreland-positioned exposures of the MCT intuitively suggests that shearing occurred under a relatively restricted range of deformation temperatures and strain rates. Plotting the 'close-to-peak' 450-500 °C temperatures of metamorphism indicated for SGR-dominated rocks located at up to a few hundred meters below/above the MCT on the quartz recrystallization map developed by Stipp et al. (2002) indicates 'ball-park' strain rates of ~ 10-13 to 10-10 sec-1. However, only strain rates slower than 10-12 sec-1 on the MCT are likely to be compatible with

  12. Distribution of Central Corneal Thickness and its Association with Ocular Parameters in a Large Central European Cohort: The Gutenberg Health Study

    PubMed Central

    Hoffmann, Esther M.; Lamparter, Julia; Mirshahi, Alireza; Elflein, Heike; Hoehn, René; Wolfram, Christian; Lorenz, Katrin; Adler, Max; Wild, Philipp S.; Schulz, Andreas; Mathes, Barbara; Blettner, Maria; Pfeiffer, Norbert

    2013-01-01

    Main objective To evaluate the distribution of central corneal thickness (CCT) in a large German cohort and to analyse its relationship with intraocular pressure and further ocular factors. Design Population-based, prospective, cohort study. Methods The Gutenberg Health Study (GHS) cohort included 4,698 eligible enrollees of 5,000 subjects (age range 35–74 years) who participated in the survey from 2007 to 2008. All participants underwent an ophthalmological examination including slitlamp biomicroscopy, intraocular pressure measurement, central corneal thickness measurement, fundus examination, and were given a questionnaire regarding glaucoma history. Furthermore, all subjects underwent fundus photography and visual field testing using frequency doubling perimetry. Results Mean CCT was 557.3±34.3 µm (male) and 551.6±35.2 µm in female subjects (Mean CCT from right and left eyes). Younger male participants (35–44 years) presented slightly thicker CCT than those older. We noted a significant CCT difference of 4 µm between right and left eyes, but a high correlation between eyes (Wilcoxon test for related samples: p<0.0001). Univariable linear regression stratified by gender showed that IOP was correlated with CCT (p<0.0001). A 10 µm increase in CCT led to an increase in IOP between 0.35–0.38 mm Hg, depending on the eye and gender. Multivariable linear regression analysis revealed correlations between gender, spherical equivalent (right eyes), and CCT (p<.0001 and p = 0.03, respectively). Conclusions We observed positive correlations between CCT and IOP and gender. CCT was not correlated with age, contact lens wear, positive family history for glaucoma, lens status, or iris colour. PMID:23936291

  13. Differential Associations of Depressive Symptom Dimensions with Cardio-Vascular Disease in the Community: Results from the Gutenberg Health Study

    PubMed Central

    Michal, Matthias; Wiltink, Jörg; Kirschner, Yvonne; Wild, Philipp S.; Münzel, Thomas; Ojeda, Francisco M.; Zeller, Tanja; Schnabel, Renate B.; Lackner, Karl; Blettner, Maria; Zwiener, Isabella; Beutel, Manfred E.

    2013-01-01

    A current model suggested that the somatic symptom dimension accounts for the adverse effect of depression in patients with coronary heart disease (CHD). In order to test this model we sought to determine in a large population-based sample how symptom dimensions of depression are associated with CHD, biomarkers and traditional risk factors. The associations of cognitive and somatic symptom dimensions of depression with CHD, risk factors, endothelial function, and biomarkers of inflammation and myocardial stress were analyzed cross-sectionally in a sample of n = 5000 Mid-Europeans aged 35–74 years from the Gutenberg Health Study (GHS). Only the somatic symptom dimension of depression was associated with CHD, biomarkers (inflammation, vascular function) and cardio-vascular risk factors. When multivariable adjustment was applied by demographic and cardiovascular risk factors, the weak associations of the somatic symptom dimension with the biomarkers disappeared. However, the associations of the somatic symptom dimension with CHD, myocardial infarction, obesity, dyslipidemia and family history of myocardial infarction remained. Both dimensions of depression were independently associated with a previous diagnosis of depression and distressed personality (type D). Thus, our results partly confirm current models: Somatic, but not cognitive-affective symptom dimensions are responsible for the association bet