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Sample records for glyceryl trinitrate gtn

  1. Steady-state maternal and fetal plasma concentrations of glyceryl trinitrate (GTN) in the preterm sheep.

    PubMed

    Bustard, Mark A; Farley, Anne E; Bennett, Brian M; Smith, Graeme N

    2003-09-01

    The administration of glyceryl trinitrate (GTN; nitroglycerin) is increasing during preterm pregnancies, yet its disposition and, importantly, the extent of fetal exposure remain to be elucidated. When used as a tocolytic (pharmacological agent that stops uterine contractions), it is administered transdermally (24-48 h). Here, we quantified the maternal and fetal steady-state plasma concentrations of maternal intravenous GTN in preterm sheep and continuously monitored maternal and fetal vascular parameters to observe possible dose-dependent vascular effects. Preterm (120 days gestation) pregnant sheep (n = 6) were instrumented with maternal femoral arterial (MA) and venous (MV) and fetal femoral arterial (FA) and umbilical venous (UV) polyethylene blood-sampling catheters. During maternal GTN infusion (3.0 micro g.kg-1.min-1, 60-min duration) the steady-state GTN concentrations ([GTN]) were as follows: MA, 98.6 +/- 9.0 nM; UV, 17.4 +/- 7.6 nM; and FA, <5 nM. There were no changes in maternal and fetal mean arterial pressure and heart rate or in uterine activity. Overall, the steady-state [GTN] was established by 5 min, and the UV/MA ratio of [GTN] was 0.18. The FA [GTN] (<5 nM) indicates that the fetus cleared essentially all GTN in the UV, and the maternal and fetal heart rate and mean arterial pressure appear to be independent of maternal GTN infusion.

  2. Biodegradation of glyceryl trinitrate by Penicillium corylophilum Dierckx.

    PubMed Central

    Zhang, Y Z; Sundaram, S T; Sharma, A; Brodman, B W

    1997-01-01

    Penicillium corylophilum Dierckx, isolated from a contaminated water wet, double-base propellant, was able to completely degrade glyceryl trinitrate (GTN) in a buffered medium (pH 7.0) containing glucose and ammonium nitrate. In the presence of 12 mg of initial fungal inoculum, GTN (48.5 to 61.6 mumol) was quantitatively transformed in a stepwise process to glyceryl dinitrate (GDN) and glyceryl mononitrate (GMN) within 48 h followed by a decrease in the GDN content with a concomitant increase in the GMN level. GDN was totally transformed to GMN within 168 h, and the complete degradation of GMN was achieved within 336 h. The presence of glucose and ammonium nitrate in the growth medium was essential for completion of the degradation of GTN and its metabolites. Complete degradation of GTN by a fungal culture has not been previously reported in the literature. PMID:9143106

  3. Topical glyceryl trinitrate for rotator cuff disease.

    PubMed

    Cumpston, Miranda; Johnston, Renea V; Wengier, Lainie; Buchbinder, Rachelle

    2009-07-08

    Rotator cuff disease is a common cause of shoulder pain. Topical glyceryl trinitrate is a possible new treatment. To determine the effectiveness and safety of topical glyceryl trinitrate for rotator cuff disease. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, SPORTDiscus, PEDro, the Australian Clinical Trials Registry, Current Controlled Trials (to October 2007) and the references and citations of included studies. We included randomised controlled trials and controlled clinical trials of people with rotator cuff disease who received topical glyceryl trinitrate, alone or in combination, compared to placebo or active therapy. Two authors independently assessed risk of bias and extracted data. Three small studies, one at moderate risk of bias and two at high risk of bias, were included. Meta-analysis was precluded due to different interventions and outcome measures. Study participants also had differing durations of symptoms and data for pain and function could only be extracted from one study. One placebo-controlled trial (20 participants) tested 5 mg glyceryl trinitrate patches, used daily for three days, among participants with 'acute supraspinatus tendinitis' of less than seven days duration. Treatment resulted in reduced pain intensity (adjusted MD -3.50, 95% CI -3.96 to -3.04). Function was not measured. One trial (53 participants) compared one quarter of a 5 mg glyceryl trinitrate patch used daily for up to 24 weeks combined with rehabilitation to placebo patches and rehabilitation among participants with 'supraspinatus tendinopathy' for longer than six months. A third trial (48 participants) tested 5 mg glyceryl trinitrate patches, used daily for three days, compared to corticosteroid injection among participants with 'rotator cuff tendinitis' of less than six-weeks duration. Fifteen out of 24 participants in the glyceryl trinitrate treatment reported headache (RR 0.11, 95% CI 0.01 to 1.96). There is some

  4. Topical glyceryl trinitrate as adjunctive treatment in Raynaud's disease.

    PubMed

    Franks, A G

    1982-01-09

    The effects of topical glyceryl trinitrate in Raynaud's disease were compared with those of placebo in a double-blind, crossover trial in 17 patients with bilateral Raynaud's disease and an associated collagen disease, who were receiving oral sympatholytic agents at the maximum levels they could tolerate. 1% glyceryl trinitrate ointment or a placebo of lanolin was applied to one hand only for 6 weeks, then patients changed to the other preparation for 6 weeks. The results were evaluated every 2 weeks. The frequency of attacks, severity of attacks, and size of ulcers in the treated hand were significantly lower when the patients were using glyceryl trinitrate ointment than when they were using placebo. The treatment of Raynaud's disease may be improved by using topical glyceryl trinitrate ointment as an adjunct to a basic regimen of oral sympatholytic agents. Glyceryl trinitrate ointment may obviate the need for more aggressive treatment, such as intraarterial reserpine, in selected patients.

  5. Time-dependent interactions of the hypotensive effects of sildenafil citrate and sublingual glyceryl trinitrate

    PubMed Central

    Oliver, James J; Kerr, Debra M; Webb, David J

    2009-01-01

    AIM To investigate the time course of the hypotensive interaction between sildenafil and glyceryl trinitrate (GTN). METHODS Two double-blind, placebo-controlled, randomized, crossover studies were performed. Subjects were challenged with sublingual GTN 400 µg at different times after oral sildenafil 100 mg. After each GTN challenge frequent measures of blood pressure (BP) were made. In the first study GTN was given 1–48 h after sildenafil/placebo to 33 healthy men. In the second study GTN was given 1–8 h after sildenafil/placebo to 20 men with stable angina. RESULTS In healthy men there was a greater mean maximum reduction in BP with sildenafil/GTN than with placebo/GTN only at 1 h. In angina patients, there was a greater mean maximum reduction in BP with sildenafil/GTN than with placebo/GTN for up to 8 h. The mean (95% confidence interval) differences in maximum systolic BP reduction (mmHg) at 1, 4, 6 and 8 h were −16 (−12, −21), −12 (−4, −20), −6 (1, −12) and −9 (−3, −15), all P < 0.05 except at 6 h (NS). At 6 and 8 h the interaction was not more than additive, and hypotensive symptoms did not occur. CONCLUSIONS In men with angina there is an interaction on BP reduction between sildenafil and GTN for ≥ 8 h after sildenafil administration, but this is no more than additive from 6 h. These data may be helpful to clinicians who are considering the use of GTN in patients presenting with angina who have received sildenafil within 24 h. PMID:19371313

  6. Effect of topical glyceryl trinitrate on anodermal blood flow in patients with chronic anal fissures.

    PubMed

    Kua, K B; Kocher, H M; Kelkar, A; Patel, A G

    2001-09-01

    Recent studies have highlighted the role of increased internal anal sphincter pressure and decreased anodermal blood flow in the pathogenesis of chronic anal fissures. The duration of the effect of topical 0.2% glyceryl trinitrate (GTN) ointment on anodermal blood flow in fissure and normal areas was investigated in patients with chronic anal fissures. Six patients with chronic anal fissures in the posterior midline participated in the study. Blood flow measurements were performed on the anoderm using laser Doppler flowmetry before and immediately after the topical application of 0.2% GTN ointment and subsequent readings were taken at 5, 15, 30, 45 and 60 min in all four quadrants. The mean anodermal blood flow in the fissure region is significantly lower than the mean blood flow of the rest of the anoderm before 0.2% GTN ointment is applied (228.7 +/- 61.8 flux units vs 439.3 +/- 25.5 flux units, respectively; P < 0.05). Immediately after the application of local 0.2% GTN ointment there is a significant increase in anodermal blood flow over the anal fissure region (457.8 +/- 56.5 flux units; P < 0.05) compared to the rest of the anoderm (457.4 +/- 30.8 flux units). This increase is most marked at 5 min post-GTN ointment application in the fissure area (474.6 +/- 41.1 flux units) and the blood flow in the fissure region is consistently above the rest of the anoderm for most of the 60 min. There is clearly reduced blood flow to the chronic anal fissure region compared to the rest of the anoderm. Topical application of glyceryl trinitrate ointment seems to significantly improve the blood flow to the fissured area in the first hour. This may therefore help in the healing of chronic anal fissures.

  7. H89 enhances the sensitivity of cancer cells to glyceryl trinitrate through a purinergic receptor-dependent pathway

    PubMed Central

    Cortier, Marion; Boina-Ali, Rahamata; Racoeur, Cindy; Paul, Catherine; Solary, Eric; Jeannin, Jean-François; Bettaieb, Ali

    2015-01-01

    High doses of the organic nitrate glyceryl trinitrate (GTN), a nitric oxide (NO) donor, are known to trigger apoptosis in human cancer cells. Here, we show that such a cytotoxic effect can be obtained with subtoxic concentrations of GTN when combined with H89, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide.2HCl. This synergistic effect requires the generation of reactive oxygen species (ROS) from H89 and NO from GTN treatment that causes cGMP production and PKG activation. Furthermore, the GTN/H89 synergy was attenuated by inhibition of P2-purinergic receptors with suramin and competition with ATP/UDP. By down-regulating genes with antisense oligonucleotides, P2-purinergic receptors P2X3, P2Y1, and P2Y6 were found to have a role in creating this cytotoxic effect. Thus, H89 likely acts as an ATP mimetic synergizing with GTN to trigger apoptosis in aggressive cancer cells. PMID:25762630

  8. Improved preservation of the rat heart with celsior solution supplemented with cariporide plus glyceryl trinitrate.

    PubMed

    Gao, Ling; Hicks, Mark; MacDonald, Peter S

    2005-08-01

    Our aim was to investigate whether the addition of glyceryl trinitrate (GTN), a source of nitric oxide, and/or cariporide, a Na/H exchange inhibitor, to a commercial preservation solution (Celsior) improved and extended cardiac preservation. After baseline indices of cardiac function (aortic flow, coronary flow, heart rate, cardiac output) were measured in an isolated working rat heart model, hearts were arrested and stored at 2-3 degrees C for 6 or 10 h in Celsior solution alone, Celsior supplemented with either 0.1 mg/mL GTN or 10 microM cariporide or both. After storage, functional measurements were repeated and recovery of each parameter was expressed as a percentage of its pre-storage baseline. After 6 h storage, recovery of cardiac function was significantly better in hearts stored in GTN- or cariporide-supplemented Celsior solution compared with Celsior solution alone. The beneficial effect of GTN was significantly abrogated in hearts perfused with glibenclamide prior to storage. Significant recovery of cardiac function after 10 h storage was only observed in hearts stored in Celsior solution supplemented with both GTN and cariporide. Combined supplementation with GTN and cariporide extends the safe period of storage of the rat heart and may be a useful approach to enhancing preservation of the donor heart.

  9. RNA Sequencing of Trigeminal Ganglia in Rattus Norvegicus after Glyceryl Trinitrate Infusion with Relevance to Migraine

    PubMed Central

    Hougaard Pedersen, Sara; Maretty, Lasse; Ramachandran, Roshni; Sibbesen, Jonas Andreas; Yakimov, Victor; Elgaard-Christensen, Rikke; Hansen, Thomas Folkmann; Krogh, Anders; Olesen, Jes; Jansen-Olesen, Inger

    2016-01-01

    Introduction Infusion of glyceryl trinitrate (GTN), a donor of nitric oxide, induces immediate headache in humans that in migraineurs is followed by a delayed migraine attack. In order to achieve increased knowledge of mechanisms activated during GTN-infusion this present study aims to investigate transcriptional responses to GTN-infusion in the rat trigeminal ganglia. Methods Rats were infused with GTN or vehicle and trigeminal ganglia were isolated either 30 or 90 minutes post infusion. RNA sequencing was used to investigate transcriptomic changes in response to the treatment. Furthermore, we developed a novel method for Gene Set Analysis Of Variance (GSANOVA) to identify gene sets associated with transcriptional changes across time. Results 15 genes displayed significant changes in transcription levels in response to GTN-infusion. Ten of these genes showed either sustained up- or down-regulation in the 90-minute period after infusion. The GSANOVA analysis demonstrate enrichment of pathways pointing towards an increase in immune response, signal transduction, and neuroplasticity in response to GTN-infusion. Future functional in-depth studies of these mechanisms are expected to increase our understanding of migraine pathogenesis. PMID:27213950

  10. Glyceryl Trinitrate Ointment Did Not Reduce Pain After Stapled Hemorrhoidectomy: A Randomized Controlled Trial

    PubMed Central

    Cross, Trent; Bartlett, Lynne; Mushaya, Chrispen; Ashour, Mohamed; Ho, Yik-Hong

    2012-01-01

    Medications, including topical 0.2% glyceryl trinitrate (GTN), can reduce anal spasm and pain after excisional hemorrhoidectomy. GTN after stapled hemorrhoidopexy was compared with routine postoperative management. Patients with symptomatic grade 3/4 hemorrhoids were recruited. After stapled hemorrhoidopexy, residual perianal skin tags were excised as appropriate. Those requiring double purse-string mucosectomy were excluded. Postoperative pain, pain duration, and complications were assessed. One hundred ten patients (74 men; mean age 50.6 years) were enrolled in the control group and 100 patients (57 men; mean age 49.8 years) in the GTN group. Maximum pain was higher in the GTN group (P  =  0.015). There were no differences between the two groups in residual perianal skin tags requiring excision, postoperative complications, recurrence rates, follow-up period, average pain, duration of pain, or satisfaction scores. Sixteen GTN patients were noncompliant due to side effects. None had persistent perianal skin tags. GTN did not reduce postoperative pain after stapled hemorrhoidectomy. PMID:23102076

  11. Role of 0.4% glyceryl trinitrate ointment after haemorrhoidectomy: results of a prospective randomised study.

    PubMed

    Franceschilli, Luana; D'Ugo, Stefano; de Luca, Elisabetta; Cadeddu, Federica; Milito, Giovanni; di Lorenzo, Nicola; Gaspari, Achille L; Sileri, Pierpaolo

    2013-03-01

    Conventional haemorrhoidectomy (CH) is well known to cause significant post-operative pain and delayed return to daily activities. Both surgical wounds and sphincterial apparatus spasms are likely responsible for the pain. In this study, we evaluated the role of glyceryl trinitrate ointment (GTN) in reducing post-operative pain, ameliorating wound healing and recovery after CH. Between 01/08 and 12/11, 203 patients with symptomatic haemorrhoids were enrolled in the study and received (103 patients) or not (100 patients) 0.4 % GTN ointment for 6 weeks after surgery. Pain was assessed using a 10-cm linear visual analogue scale (VAS). Data on post-operative pain, wound secretion and bleeding, return to normal activities and complications were recorded. Data were analysed using Fisher's exact and Mann-Whitney tests. GTN-treated group experienced significantly less pain during the first week after surgery (p < 0.0001). This difference was more evident starting from post-operative day 4 (p < 0.0001). A significant higher percentage of untreated patients experienced severe pain (mean VAS score > 7) (10 % vs 31 %). There were significant differences in terms of secretion time (p = 0.0052) and bleeding time (p = 0.02) in favor of GTN. In addition, the duration of itching was less in the GTN group (p = 0.0145). Patients treated with GTN were able to an early return to daily activities compared to untreated (p < 0.0001). Fifteen GTN-treated patients (14.6 %) discontinued the application because of local discomfort and headache. GTN ointment enhances significantly post-operative recovery, reducing pain in terms of duration and intensity. This effect might be secondary to a faster wound healing expressed by reduced secretion, bleeding and itching time.

  12. Comparative study of glyceryl trinitrate ointment versus surgical management of chronic anal fissure.

    PubMed

    Tauro, Leo Francis; Shindhe, Vittal V; Aithala, P Sathyamoorthy; Martis, John J S; Shenoy, H Divakar

    2011-08-01

    Chronic Anal Fissure (CAF) is common perineal condition and well-known painful entity. Standard surgical treatment even though available, may require long hospital stay and sometimes have worrying complications like anal incontinence. So non-surgical treatment, Glyceryl Trinitrate has been shown to be an effective for chronic anal fissure. It decreases anal tone and ultimately heals the anal fissure. The present study is the attempt to know the efficacy of 0.2% Glyceryl Trinitrate ointment in the treatment of chronic anal fissure and to compare the effectiveness of 0.2% Glyceryl Trinitrate ointment (GTN) versus fissurectomy with lateral internal sphincterotomy (LIS) and fissurectomy with posterior internal sphincterotomy (PIS) in the management of chronic anal fissure. This is a prospective comparative study of management of chronic anal fissure done in our hospital during the period of one and half year from October 2005 to March 2007. Thirty patients treated with 0.2% Glyceryl Trinitrate ointment and 30 patients treated with fissurectomy and lateral internal sphincterotomy and 30 patients treated with posterior internal sphincterotomy, for chronic anal fissure were selected for study. A single brand of 0.2% Glyceryl Trinitrate ointment (Nitrogesic) used for trial arm. Dose of administration was 1.5 cm to 2 cm in the anal canal with device provided by manufacturers of the proprietary preparation and applied twice a daily for 12 weeks. Patients were followed up for 12 weeks and thereafter evaluated for relief of symptoms in all three groups. Observations were recorded at 2 weeks; 6 weeks and 12 weeks of follow up period, regarding symptoms like pain and bleeding during defecation, healing of CAF and also for side effects like headache in GTN group and flatus, fecal incontinence in surgical groups. Data collected in proforma and analyzed. Study revealed CAF was more in male 59 patients (66%) than the female 31 patients (34%), the ratio being 1: 0.52. The

  13. Randomised controlled trial shows that glyceryl trinitrate heals anal fissures, higher doses are not more effective, and there is a high recurrence rate

    PubMed Central

    Carapeti, E; Kamm, M; McDonald, P; Chadwick, S; Melville, D; Phillips, R

    1999-01-01

    BACKGROUND—Topical application of glyceryl trinitrate (GTN) ointment heals chronic anal fissures, providing an alternative to the traditional first line treatment of surgical sphincterotomy. 
AIMS—To determine the most effective dose of topical GTN for treatment of chronic anal fissures and to assess long term results. 
METHODS—Seventy consecutive patients with chronic anal fissure, were randomly allocated to eight weeks treatment with placebo, 0.2% GTN three times daily, or GTN starting at 0.2% with weekly 0.1% increments to a maximum of 0.6%, in a double blind study. 
RESULTS—After eight weeks fissure had healed in 67% of patients treated with GTN compared with 32% with placebo (p=0.008). No significant difference was seen between the two active treatments. Headaches were reported by 72% of patients on GTN compared with 27% on placebo (p<0.001). Maximum anal sphincter pressure reduced significantly from baseline by GTN treatment (p=0.02), but not placebo (p=0.8). Mean pain scores were lower after treatment with GTN compared with placebo (NS). Of fissures healed with placebo 43% recurred, compared with 33% of those healed with 0.2% GTN and 25% healed with escalating dose GTN (p=0.7). 
CONCLUSIONS—GTN is a good first line treatment for two thirds of patients with anal fissure. An escalating dose of GTN does not result in earlier healing. Significant recurrence of symptomatic fissures and a high incidence of headaches are limitations of the treatment. 

 Keywords: glyceryl trinitrate; anal fissures PMID:10205213

  14. Sublingual glyceryl trinitrate during colonoscopy and terminal ileal intubation: a randomized controlled trial.

    PubMed

    Hill, Patsy-Anne; Panteleimonitis, Sofoklis; McKay, Graham; Watson, Carol; Prach, Andre; Macdonald, Angus

    2017-02-01

    Background and aims Sublingual glyceryl trinitrate has been used as an aid to cannulate the Sphincter of Oddi during endoscopic retrograde cholangiopancreatography. Its role in terminal ileal intubation during colonoscopy is unknown. This study examines the role of sublingual glyceryl trinitrate in terminal ileal intubation during colonoscopy. Methods A triple-blind randomized controlled trial comparing sublingual glyceryl trinitrate (800 µg) vs. placebo (saline) in relation to terminal ileal intubation during colonoscopy was performed. Following caecal intubation, participants received sublingual glyceryl trinitrate/placebo followed by a 2-min observation period before intubation was attempted. Data on time to intubate the terminal ileum and intubation rate were collected. Results A total of 110 patients (age: 58 years (18-75)) were recruited and randomised as per protocol: 54 received sublingual glyceryl trinitrate. Terminal ileal intubation was successful in all patients receiving sublingual glyceryl trinitrate and in 53 (94.6%) of those receiving saline ( p = 0.243: Fischer's exact). The median time taken for ileal intubation after application of spray was 72.5 (7-900) s in the glyceryl trinitrate group compared with 125 (5-900) s in the placebo group ( p = 0.150: Mann-Whitney). There were no major adverse events reported in either group. Conclusions Terminal ileal intubation rates and timing were very good in both groups. Routine sublingual glyceryl trinitrate was not proven to be beneficial in improving terminal ileal intubation or intubation success rates in the hands of experienced colonoscopists. However, trends in this small study might suggest that glyceryl trinitrate could be useful in the hands of less experienced colonoscopists or in difficult terminal ileal intubation cases.

  15. Glyceryl trinitrate metabolism in the quail embryo by the glutathione S-transferases leads to a perturbation in redox status and embryotoxicity.

    PubMed

    Bardai, Ghalib K; Hales, Barbara F; Sunahara, Geoffrey I

    2013-07-01

    Exposure of stage 9 quail (Coturnix coturnix japonica) embryos to glyceryl trinitrate (GTN) induces malformations that were associated in previous studies with an increase in protein nitration. Increased nitration suggests metabolism of GTN by the embryo. The goals of this study were to characterize the enzymes and co-factors required for GTN metabolism by quail embryos, and to determine the effects of in ovo treatment with N-acetyl cysteine (NAC), a precursor of glutathione (GSH), on GTN embryotoxicity. GTN treatment of quail embryos resulted in an increase in nitrite, a decrease in total GSH, and an increase in the ratio of NADP(+)/NADPH, indicating that redox balance may be compromised in exposed embryos. Glutathione S-transferases (GSTs; EC 2.5.1.18) purified from the whole embryo (K(m) 0.84 mM; V(max) 36 μM/min) and the embryonic eye (K(m) 0.20 mM; V(max) 30 μM/min) had GTN-metabolizing activity (1436 and 34 nmol/min/mg, respectively); the addition of ethacrynic acid, an inhibitor of GST activity, decreased GTN metabolism. Peptide sequencing of the GST isozymes indicated that alpha- or mu-type GSTs in the embryo and embryonic eye had GTN metabolizing activity. NAC co-treatment partially protected against the effects of GTN exposure. Thus, GTN denitration by quail embryo GSTs may represent a key initial step in the developmental toxicity of GTN.

  16. Investigation of oxidant stress and vasodepression to glyceryl trinitrate in the obese Zucker rat in vivo

    PubMed Central

    Laight, David W; Kengatharan, K M; Gopaul, Nitin K; Änggård, Erik E; Carrier, Martin J

    1998-01-01

    We examined the relationship between oxidant stress and the vasodepressor activity of glyceryl trinitrate (GTN) in vivo, including rapid GTN tolerance development, in 13-week old obese and age-matched lean Zucker rats which had been maintained for 4 weeks on either control diet or diets enriched with the lipophilic, chain-breaking antioxidants vitamin E (0.5% w w−1) or probucol (0.5% w w−1) or the superoxide anion scavenger tiron (1% w v−1 in drinking water).The basal plasma level of the isoprostane 8-epi-PGF2α, an in vivo marker of lipid peroxidation, was elevated by approximately 5 fold in the obese Zucker rat and markedly reduced by dietary lipophilic antioxidants and depressed by dietary tiron.Vasodepression to bolus does GTN (0.1–100 μg kg−1 i.v.), but not endothelium-dependent vasodepression to bolus dose acetylcholine (ACh, 0.02–2.0 μg kg−1 i.v.), was impaired in obese animals and completely restored by dietary antioxidants.Nitrate tolerance developed in vivo during a 1 h infusion of GTN (40 μg kg−1 min−1 i.v.) appeared more severe in obese animals. However, rapid nitrate tolerance was not affected by dietary antioxidants in either the obese or lean Zucker rat.We therefore provide evidence that elevated oxidant stress in the obese Zucker rat is associated with an impairment in nitrate vasodepressor activity. However, our data are not consistent with either a role for oxidant stress in rapid nitrate tolerance development in the anaesthetized Zucker rat or the aggravation of this tolerance by pre-existing oxidant stress. PMID:9831930

  17. 0.4% glyceryl trinitrate ointment: new drug. Not useful for anal fissures.

    PubMed

    2008-04-01

    (1) Anal fissures are very painful but often heal spontaneously. After eliminating other diagnoses, various treatments can be tried while waiting for fissures to heal: warm seat baths, local anaesthetics, and adequate fibre and fluid intake. (2) Clinical evaluation of glyceryl trinitrate 0.4% ointment, a nitrate derivative, is mainly based on a double-blind trial versus excipient in 193 adults with "chronic" fissures. This trial failed to show a clinically relevant analgesic effect of glyceryl trinitrate 0.4%, with only a 3-mm difference versus the excipient on a 100-mm pain rating scale. In another trial including 229 patients, neither 0.2% nor 0.4% glyceryl trinitrate was more effective on pain than placebo. (3) Another placebo-controlled trial including 304 adults treated for 8 weeks showed no efficacy of various doses of glyceryl trinitrate, versus the excipient, on the healing of anal fissures. (4) The most frequent adverse effect, as expected with a nitrate derivative, is headache, which affects about two-thirds of patients and is severe in 20% of cases. Abrupt-onset hypotension is a risk during concomitant use of other vasodilatory drugs. (5) There are no data on pregnant women exposed to glyceryl trinitrate. (6) In summary, glyceryl trinitrate 0.4% ointment does not reduce the pain linked to chronic anal fissures, but it does carry a risk of sometimes severe headache. It is best to continue using simple, non-aggressive treatments.

  18. Blood levels of the metabolites of glyceryl trinitrate and pentaerythritol tetranitrate after administration of a two-step preparation.

    PubMed

    Neurath, G B; Dünger, M

    1977-02-01

    Blood levels and urinary excretion rates of glyceryl trinitrate- pentaerythritol tetranitrate, and their less nitrate containing metabolites have been determined in ten human volunteers after a single dose of a two- step preparation containing glyceryl trinitrate and pentaerythritol tetranitrate. Blood levels accounted for peak levels of about 40% of the glyceryl trinitrate and 0.4% of the pentaerythritol tetranitrate metabolites, respectively. Within the first 24 h post administration 22% of the glyceryl trinitrate and 19% of the pentaerythritol tetranitrate were excreted as nitrate metabolites, chiefly in form of conjugates. The determinations were obtained by gas chromatography on extremely inactive columns and electron capture detection by means of derivatives.

  19. The role of topical diltiazem in the treatment of chronic anal fissures that have failed glyceryl trinitrate therapy.

    PubMed

    Griffin, N; Acheson, A G; Jonas, M; Scholefield, J H

    2002-11-01

    The treatment of anal fissures has evolved over the last 5 years with the development of topical treatments aimed at reducing sphincter hypertonia. This is thought to improve anal mucosal blood flow and promote healing of the fissure. This study reports the use of topical diltiazem in patients with chronic anal fissures that have failed previous treatment with topical 0.2% glyceryl trinitrate (GTN). Forty-seven patients with chronic anal fissure who had previously failed at least one course of topical GTN were recruited prospectively from a single centre. Patients were instructed to apply 2 cm (approximately 0.7 g) of 2% diltiazem cream to the anal verge twice daily for eight weeks. Symptoms of pain, bleeding and itching were recorded on a linear analogue score prior to starting the cream and then repeated at 2 weekly intervals. Patients were asked to report side-effects throughout the study period. Healing of the fissure was assessed after 8 weeks of treatment. Forty-six patients completed treatment; of these, 22 had healed fissures (48%). Ten of the 24 patients with persistent fissures were symptomatically improved and wished no further treatment. Of the 14 patients who remained symptomatic, one was given a repeat course of 0.2% glyceryl trinitrate with subsequent healing of the fissure, 10 were recruited into an ongoing study involving injections of botulinum toxin into the internal anal sphincter and three were referred for surgery. This study shows that topical 2% diltiazem is an effective and safe treatment for chronic anal fissure in patients who have failed topical 0.2% GTN. The need for sphincterotomy can be avoided in up to 70% of cases.

  20. Glyceryl trinitrate is a novel inhibitor of quorum sensing in Pseudomonas aeruginosa.

    PubMed

    Abbas, Hisham A; Shaldam, Moutaz A

    2016-12-01

    Targeting quorum sensing is an alternative approach to antibiotics.Targeting quorum sensing-regulated virulence will disarm the pathogen without exerting pressure on its growth. As a result, emergence of resistance is avoided and the immune system can easily eradicate bacteria. Investigation of the possible inhibition of quorum sensing-regulated virulence of Pseudomonas aeruginosa by glyceryltrinitrate. The quorum sensing inhibiting activity of glyceryl trinitrate was assessed by inhibition of violacein production in Chromobacterium violaceum ATCC 12472. Its ability to inhibit pyocyanin, protease, biofilm and tolerance to oxidative stress was evaluated. Docking study was performed to study the interference of glyceryl trinitrate with the binding of autoinducers with LasR and rhlR receptors. Glyceryl trinitrate exerted a significant biofilm inhibiting and eradicating activities. It decreased the production of quorum-sensing dependent violacein production. It significantly inhibited the production of pyocyanin and protease and diminished the tolerance against oxidative stress. Molecular docking study showed that glyceryl trinitrate interferes with the binding of autoinducers to their receptors. It could bind to Las Rand rhlr receptors with binding energy of -93.47 and -77.23, respectively. Glyceryl trinitrate can be an antivirulence agent in the treatment of Pseudomonas aeruginosa topical infections such as burn infections.

  1. Diltiazem heals glyceryl trinitrate-resistant chronic anal fissures: a prospective study.

    PubMed

    Jonas, Marion; Speake, William; Scholefield, John H

    2002-08-01

    Both topical diltiazem, a calcium channel blocker, and glyceryl trinitrate, a nitric oxide donor, lower anal pressure and heal two-thirds of chronic anal fissures. This study evaluated the efficacy of diltiazem for fissures that failed to heal with glyceryl trinitrate. Consecutive patients with persistent chronic fissures despite treatment with 0.2 percent glyceryl trinitrate ointment underwent anal manometry before and for 1 hour after application of 700 mg of 2 percent diltiazem gel to the distal anal canal. Patients applied diltiazem twice daily for eight weeks or until the fissure had healed. At fortnightly review, fissure healing was assessed, and side effects were noted. Patients scored symptoms of pain, bleeding, and irritation using linear visual analog scales at the initial and follow-up visits. In 39 patients (13 males; median age, 42 (range, 20- 80) years), topical 2 percent diltiazem gel lowered anal resting pressure by 20 percent from a median of 93 to 74 cm H2O (P < 0.0001, Wilcoxon), and fissures healed in 19 (49 percent) within 8 weeks. Before diltiazem, 27 patients (69 percent) had used a complete course of glyceryl trinitrate (0.5 g twice daily for 8 weeks), and 12 (44 percent) of these healed with diltiazem. The remaining 12 patients had discontinued glyceryl trinitrate prematurely or used less because of headaches; 7 (58 percent) of these healed with diltiazem, and 5 (42 percent) did not. Side effects occurred in four patients (10 percent): three reported perianal itching but continued with treatment, and one developed headaches, drowsiness, and mood swings six weeks into treatment and stopped diltiazem at that time. Topical 2 percent diltiazem is effective treatment for glyceryl trinitrate-resistant chronic anal fissures. Side effects, mainly perianal itching, may occur in 10 percent of patients but are generally tolerated.

  2. Effect of intracoronary glyceryl trinitrate on perfusion distribution in the collateralised human myocardium.

    PubMed

    Wald, R W; Sternberg, L; Feiglin, D H; Morch, J E

    1980-08-01

    The effect on myocardial perfusion distribution of intracoronary glyceryl trinitrate in a dose (60 micrograms) insufficient to cause alterations in systemic blood pressure or heart rate was studied in eight patients with angiographically demonstrated collaterals from the left coronary system to the distal right coronary artery. Double isotope imaging using technetium-99m and iodine-131 labelled albumin macroaggregates allowed each patient to serve as his own control. The reproducibility of the imaging and data handling techniques was shown in 12 control patients. Glyceryl trinitrate caused a significant diminution in the collateral-mediated fractional perfusion while increasing that of the native coronary bed.

  3. Effect of intracoronary glyceryl trinitrate on perfusion distribution in the collateralised human myocardium.

    PubMed Central

    Wald, R W; Sternberg, L; Feiglin, D H; Morch, J E

    1980-01-01

    The effect on myocardial perfusion distribution of intracoronary glyceryl trinitrate in a dose (60 micrograms) insufficient to cause alterations in systemic blood pressure or heart rate was studied in eight patients with angiographically demonstrated collaterals from the left coronary system to the distal right coronary artery. Double isotope imaging using technetium-99m and iodine-131 labelled albumin macroaggregates allowed each patient to serve as his own control. The reproducibility of the imaging and data handling techniques was shown in 12 control patients. Glyceryl trinitrate caused a significant diminution in the collateral-mediated fractional perfusion while increasing that of the native coronary bed. PMID:6775646

  4. Glyceryl trinitrate and caprylic acid for the mitigation of the Desulfovibrio vulgaris biofilm on C1018 carbon steel.

    PubMed

    Li, Y; Zhang, P; Cai, W; Rosenblatt, J S; Raad, I I; Xu, D; Gu, T

    2016-02-01

    Microbiologically influenced corrosion (MIC), also known as biocorrosion, is caused by corrosive biofilms. MIC is a growing problem, especially in the oil and gas industry. Among various corrosive microbes, sulfate reducing bacteria (SRB) are often the leading culprit. Biofilm mitigation is the key to MIC mitigation. Biocide applications against biofilms promote resistance over time. Thus, it is imperative to develop new biodegradable and cost-effective biocides for large-scale field applications. Using the corrosive Desulfovibrio vulgaris (an SRB) biofilm as a model biofilm, this work demonstrated that a cocktail of glyceryl trinitrate (GTN) and caprylic acid (CA) was very effective for biofilm prevention and mitigation of established biofilms on C1018 carbon steel coupons. The most probable number sessile cell count data and confocal laser scanning microscope biofilm images proved that the biocide cocktail of 25 ppm (w/w) GTN + 0.1% (w/w) CA successfully prevented the D. vulgaris biofilm establishment on C1018 carbon steel coupons while 100 ppm GTN + 0.1% CA effectively mitigated pre-established D. vulgaris biofilms on C1018 carbon steel coupons. In both cases, the cocktails were able to reduce the sessile cell count from 10(6) cells/cm(2) to an undetectable level.

  5. Haemodynamic effects of glyceryl trinitrate following repeated application of a transdermal delivery system with a phasic release profile.

    PubMed

    Wiegand, A; Bonn, R; Wagner, F; Trenk, D; Jähnchen, E

    1991-01-01

    The haemodynamic effects and plasma concentrations of glyceryl trinitrate (GTN) and its dinitrate metabolites were investigated in 8 healthy male volunteers during 5 days of application of a new transdermal delivery system (TDS) with time-dependent release characteristics, which were considered to prevent or to diminish development of nitrate tolerance. On the first and fifth day of administration the following haemodynamic parameters were determined: digital pulse ratio of height of systolic peak to height of dicrotic wave (i.e. a/b-ratio), heart rate and systolic blood pressure under orthostatic conditions. Peak plasma concentrations of GTN were 139 and 155 pg.ml-1 on the first and fifth day of treatment, and the corresponding trough concentrations (i.e. 24 h after administration) were 52.5 and 36.6 pg.ml-1, respectively. Compared to placebo, the area under the effect curve of the a/b-ratio of the digital pulse was increased on the first (25.6%) and fifth day (13%). A significant increase of heart rate and a decrease of systolic blood pressure were seen only on the first day of treatment. The haemodynamic effects of sublingual GTN 0.8 mg were reduced by 69% (a/b-ratio) and 52% (standing heart rate) on the fifth day compared to the pretreatment values. Thus, the phasic release of GTN from the new TDS can be demonstrated by the time course of the plasma concentrations of GTN and its metabolites. Nevertheless, following repeated administration the hemodynamic effects are blunted.

  6. Randomised, double-blind, placebo-controlled clinical trial of a new topical glyceryl trinitrate patch for chronic lateral epicondylosis.

    PubMed

    Paoloni, J A; Murrell, G A C; Burch, R M; Ang, R Y

    2009-04-01

    This study aimed to determine whether a new glyceryl trinitrate patch preparation is effective in treating chronic lateral epicondylosis. Randomised double-blind controlled clinical trial. Private practice 154 adult patients with chronic lateral epicondylosis were recruited, with 136 patients completing the trial. 8 weeks of glyceryl trinitrate patch application (dosages of 72 mg/24 h, 1.44 mg/24 h, and 3.6 mg/24 h), or placebo patch application. Subjective global assessment of change in elbow symptoms, patient-rated tennis elbow evaluation, visual analogue pain at rest, visual analogue pain with activity, visual analogue pain intensity, grip strength, and strength testing using the Orthopaedic Research Institute-Tennis Elbow Testing System. At 8 weeks there was a significant decrease in elbow pain with activity in the glyceryl trinitrate 0.72 mg/24 h group compared with placebo (p = 0.04). There were no other significant differences. Continuous 1.25 mg/24 h topical glyceryl trinitrate treatment, when combined with daily exercise rehabilitation, has previously demonstrated efficacy in treating chronic lateral epicondylosis. There was significantly decreased elbow pain with activity at 8 weeks in the glyceryl trinitrate 0.72 mg/24 h group (p = 0.04). This short-term dose-ranging study did not demonstrate a treatment effect of a new topical glyceryl trinitrate patch in dosages of 1.44 mg/24 h or 3.6 mg/24 h, which conflicts with previous studies on topical glyceryl trinitrate treatment. NCT00447928.

  7. Oral nitric-oxide donor glyceryl-trinitrate induces sensitization in spinal cord pain processing in migraineurs: a double-blind, placebo-controlled, cross-over study.

    PubMed

    Perrotta, Armando; Serrao, Mariano; Tassorelli, Cristina; Arce-Leal, Natalia; Guaschino, Elena; Sances, Grazia; Rossi, Paolo; Bartolo, Michelangelo; Pierelli, Francesco; Sandrini, Giorgio; Nappi, Giuseppe

    2011-05-01

    Nitric-oxide donor glyceryl-trinitrate (GTN) modulates cerebral and spinal regions that are involved in migraine and pain processing. We hypothesized that in migraineurs, the susceptibility to develop a migraine attack after GTN administration should parallel with an high sensitivity to GTN-induced change in the pain processing at spinal level. We used the temporal summation threshold (TST) of the lower limb nociceptive withdrawal reflex (NWR) and the related pain sensation to study in parallel the time-course of the effect of the GTN administration on the pain processing at spinal level in migraine and healthy subjects. Twenty-eight (21 F; 7M; mean age 34.2 ± 8.2) migraine and 15 (11 F; 4M; mean age 35.9 ± 8.9) healthy subjects were recruited in a double-blind, placebo-controlled, cross-over trial. Neurophysiological examinations were carried out before (baseline) and 30', 60', 120', 180' and 240' after GTN (0.9 mg sublingual) or placebo administration during two different sessions. In migraineurs, GTN administration was associated to a significant facilitation in temporal summation of pain (reduced TST and increased painful sensation) 60', 120' and 180' after drug intake when compared to baseline, to placebo condition and to controls after GTN intake. Furthermore, in migraineurs who developed migraine after GTN, a significant facilitation in temporal summation of pain was detected 60', 120' and 180' after drug intake when compared to patients without clinical response. In migraineurs the susceptibility to develop migraine attack after GTN administration seems to be a specific trait of a subgroup of patients linked to a supersensitivity of the pain system to GTN. Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

  8. Opposite Reactivity of Meningeal versus Cortical Microvessels to the Nitric Oxide Donor Glyceryl Trinitrate Evaluated In Vivo with Two-Photon Imaging

    PubMed Central

    Pryazhnikov, Evgeny; Kislin, Mikhail; Tibeykina, Marina; Toptunov, Dmytro; Ptukha, Anna; Shatillo, Artem; Gröhn, Olli; Giniatullin, Rashid; Khiroug, Leonard

    2014-01-01

    Vascular changes underlying headache in migraine patients induced by Glyceryl trinitrate (GTN) were previously studied with various imaging techniques. Despite the long history of medical and experimental use of GTN, its effects on the brain vasculature are still poorly understood presumably due to low spatial resolution of the imaging modalities used so far. We took advantage of the micrometer-scale vertical resolution of two-photon microscopy to differentiate between the vasodynamic effects of GTN on meningeal versus cortical vessels imaged simultaneously in anesthetized rats through either thinned skull or glass-sealed cranial window. Intermediate and small calibre vessels were visualized in vivo by imaging intravascular fluorescent dextran, and detection of blood flow direction allowed identification of individual arterioles and venules. We found that i.p.-injected GTN induced a transient constriction of meningeal arterioles, while their cortical counterparts were, in contrast, dilated. These opposing effects of GTN were restricted to arterioles, whereas the effects on venules were insignificant. Interestingly, the NO synthase inhibitor L-NAME did not affect the diameter of meningeal vessels but induced a constriction of cortical vessels. The different cellular environment in cortex versus meninges as well as distinct vessel wall anatomical features probably play crucial role in the observed phenomena. These findings highlight differential region- and vessel-type-specific effects of GTN on cranial vessels, and may implicate new vascular mechanisms of NO-mediated primary headaches. PMID:24586970

  9. Systemic glyceryl trinitrate reduces anal sphincter tone: is there a therapeutic indication?

    PubMed

    Connolly, C; Tierney, S; Grace, P

    2017-09-13

    Nitric oxide (NO) has diverse roles as a biological messenger. [1] Topically applied nitrate donors cause relaxation of the internal anal sphincter (IAS) and facilitate healing of anal fissures [2,3]. Systemic nitrates are commonly used for the treatment of ischaemic heart disease, yet the effects of systemically administered nitrates on the smooth muscle of the IAS are unknown. Our aim was to test the hypothesis that systemically administered nitrates at a normal dose, cause inhibition of anal sphincter activity. With fully informed consent, anal manometry was performed on nine volunteers. Maximum and mean anal resting pressure (representing the IAS), maximum squeeze pressure (representing the external anal sphincter), heart rate and blood pressure were measured, before and after administration of a normal 400 μg dose of sublingual glyceryl trinitrate spray. Data are expressed as mean (± standard error of the mean (SEM)). In four females and five males ranging from 19 to 50 years of age, administration of GTN resulted in a significant reduction in systolic blood pressure from 138 ± 5 to 127 ± 4 mmHg, P < 0.01. Mean resting pressure, over 5 min, was significantly reduced from 70 ± 10 to 62 ± 10 mmHg P < 0.05. The maximum resting pressure was also significantly reduced from 109 ± 12 to 86 ± 10 mmHg P = 0.04. Maximum squeeze pressure, heart rate and diastolic blood pressure were not significantly reduced. Systemic nitrates significantly inhibit internal anal sphincter function.

  10. Protective effects of riboflavin and selenium on brain microsomal Ca2+-ATPase and oxidative damage caused by glyceryl trinitrate in a rat headache model.

    PubMed

    Nazıroğlu, Mustafa; Çelik, Ömer; Uğuz, Abdulhadi Cihangir; Bütün, Ayşe

    2015-03-01

    Migraine headaches are considered to be associated with increased mitochondrial energy metabolism. Mitochondrial oxidative stress is also important in migraine headache pathophysiology although riboflavin and selenium (Se) induced a modulator role on mitochondrial oxidative stress in the brain. The current study aimed to determine the effects of Se with/without riboflavin on the microsomal membrane Ca(2+)-ATPase (MMCA), lipid peroxidation, antioxidant, and electroencephalography (EEG) values in glyceryl trinitrate (GTN)-induced brain injury rats. Thirty-two rats were randomly divided into four groups. The first group was used as the control, and the second group was the GTN group. Se and Se plus oral riboflavin were administered to rats constituting the third and fourth groups for 10 days prior to GTN administration. The second, third, and fourth groups received GTN to induce headache. Ten hours after the administration of GTN, the EEG records and brain cortex samples were obtained for all groups. Brain cortex microsomes were obtained from the brain samples. The brain and microsomal lipid peroxidation levels were higher in the GTN group compared to the control group, whereas they were decreased by selenium and selenium + riboflavin treatments. Vitamin A, vitamin C, vitamin E, and reduced glutathione (GSH) concentrations of the brain and MMCA, GSH and glutathione peroxidase values of microsomes were decreased by the GTN administration, although the values and β-carotene concentrations were increased by Se and Se + riboflavin treatments. There was no significant change in EEG records of the four groups. In conclusion, Se with/without riboflavin administration protected against GTN-induced brain oxidative toxicity by inhibiting free radicals and the modulation of MMCA activity and supporting the antioxidant redox system.

  11. Glyceryl trinitrate for the treatment of preterm labor

    PubMed Central

    Çalışkan, Şafak; Narin, Mehmet Ali; Dede, Faruk Suat; Narin, Raziye; Dede, Hülya; Kandemir, Ömer

    2015-01-01

    Objective This study was conducted to compare the tocolytic efficacy of glyceryltrinitrate (GTN) with that of magnesium sulfate (MgSO4) and to investigate serum nitric oxide metabolites before and after tocolysis. Material and Methods In total, 48 women between 27 and 34 weeks’ gestation with threatened preterm labor and intact membranes were randomly allocated to receive either GTN or MgSO4 tocolysis. Main outcome measures included tocolytic efficacy and maternal side effect(s) of the tocolytic agent. Obstetric and neonatal outcomes as well as pretreatment and posttreatment nitric oxide (NO) metabolites were assessed. Results Forty-one patients were included into the final analysis. Uterine contraction cessation times were 3.66±1.28 and 6.83±3.47 hours for GTN and MgSO4 groups, respectively. Similarly, maternal side effects were significantly lower in the GTN group than in the MgSO4 group, and no serious maternal side effects were recorded. Serum NO metabolite levels before treatment were significantly lower in the treatment groups than in the controls. Serum nitrite levels were significantly increased after tocolytic treatment both in MgSO4 and GTN groups. Conclusion GTN effectively delays preterm delivery and reduces neonatal morbidity and mortality with less maternal side effects and seems to be an effective and safe alternative to MgSO4. PMID:26401112

  12. Sustained anti-anginal action of glyceryl trinitrate cream

    PubMed Central

    Bennett, David; Davies, Adrian; Davis, Audrey

    1983-01-01

    1 In an acute study, 45 min following topical application of 9.2 mg of nitroglycerin (GTN) cream, exercise time increased by 100s (P < 0.005) and this increase persisted for 270 min. Systolic blood pressure showed a progressive fall. 2 In the second study 1 h following application of 9.2 mg GTN cream, a significant reduction in left ventricular diastolic dimension was seen. 3 In a subsequent chronic randomised double blind study, exercise time increased by 47 s (P < 0.05) at 6 h, following 3 weeks continual use. 4 An increased dose for a further 3 weeks produced no further increase in exercise time; however, a significant decrease in left ventricular end diastolic dimension was seen. 5 No evidence of pharmacological tolerance was seen, as patients continued to show a maximal response to sublingual nitroglycerin during the course of the study. PMID:6405770

  13. A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures.

    PubMed

    Scholefield, J H; Bock, J U; Marla, B; Richter, H J; Athanasiadis, S; Pröls, M; Herold, A

    2003-02-01

    Anal fissure is a common painful condition affecting the anal canal. The majority of acute fissures heal spontaneously. However, some of these acute fissures do not resolve but become chronic. Chronic anal fissures were traditionally treated by anal dilation or by lateral sphincterotomy. However, both of these surgical treatments may cause a degree of incontinence in up to 30% of patients. Several recent trials have shown that nitric oxide donors such as glyceryl trinitrate (GTN) can reduce sphincter pressure and heal up to 70% of chronic fissures. This study addressed the dose-response to three different concentrations of GTN ointment compared with placebo in a double blind randomised controlled trial. A double blind, multicentre, randomised controlled trial was set up to compare placebo ointment against three active treatment arms (0.1%, 0.2%, and 0.4% GTN ointment applied at a dose of 220 mg twice daily) in chronic anal fissures. The primary end point was complete healing of the fissure. Two hundred patients were recruited over an eight month period from 18 centres. After eight weeks of treatment the healing rate in the placebo group was 37.5% compared with 46.9% for 0.1%, 40.4% for 0.2%, and 54.1% for 0.4% GTN. None was significantly better than the placebo response. A secondary analysis excluded fissures without secondary criteria for chronicity. Healing rates were then found to be 24% in the placebo group compared with 50% in the 0.1% GTN group, 36% in the 0.2% group, and 57% in the 0.4% GTN group. These values were statistically significantly different for the placebo group compared with 0.1% GTN, 0.4% GTN, and for the GTN treated group as a whole. The results of this study have demonstrated the significant benefit of topical GTN when applied to patients suffering from chronic anal fissures but acute fissures showed a tendency to resolve spontaneously. The high proportion of fissures which healed in the placebo group suggests that the definition of

  14. A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures

    PubMed Central

    Scholefield, J H; Bock, J U; Marla, B; Richter, H J; Athanasiadis, S; Pröls, M; Herold, A

    2003-01-01

    Background: Anal fissure is a common painful condition affecting the anal canal. The majority of acute fissures heal spontaneously. However, some of these acute fissures do not resolve but become chronic. Chronic anal fissures were traditionally treated by anal dilation or by lateral sphincterotomy. However, both of these surgical treatments may cause a degree of incontinence in up to 30% of patients. Several recent trials have shown that nitric oxide donors such as glyceryl trinitrate (GTN) can reduce sphincter pressure and heal up to 70% of chronic fissures. Aim: This study addressed the dose-response to three different concentrations of GTN ointment compared with placebo in a double blind randomised controlled trial. Method: A double blind, multicentre, randomised controlled trial was set up to compare placebo ointment against three active treatment arms (0.1%, 0.2%, and 0.4% GTN ointment applied at a dose of 220 mg twice daily) in chronic anal fissures. The primary end point was complete healing of the fissure. Results: Two hundred patients were recruited over an eight month period from 18 centres. After eight weeks of treatment the healing rate in the placebo group was 37.5% compared with 46.9% for 0.1%, 40.4% for 0.2%, and 54.1% for 0.4% GTN. None was significantly better than the placebo response. A secondary analysis excluded fissures without secondary criteria for chronicity. Healing rates were then found to be 24% in the placebo group compared with 50% in the 0.1% GTN group, 36% in the 0.2% group, and 57% in the 0.4% GTN group. These values were statistically significantly different for the placebo group compared with 0.1% GTN, 0.4% GTN, and for the GTN treated group as a whole. Conclusions: The results of this study have demonstrated the significant benefit of topical GTN when applied to patients suffering from chronic anal fissures but acute fissures showed a tendency to resolve spontaneously. The high proportion of fissures which healed in the placebo

  15. Glyceryl trinitrate ointment (0.25%) and anal cryothermal dilators in the treatment of chronic anal fissures.

    PubMed

    Schiano di Visconte, Michele; Munegato, Gabriele

    2009-07-01

    Chronic anal fissure is a common benign disorder; for this condition, lateral internal sphincterotomy is the "gold standard" of treatment. Alternative medical treatments have not proven to be as effective as left lateral internal sphincterotomy. This randomized trial was designed to compare the use of 0.25% glyceryl trinitrate ointment and anal cryothermal dilators with the use of 0.4% glyceryl trinitrate ointment alone in the treatment of chronic anal fissures. Between 1 June 2006 and 31 December 2007, 60 consecutive patients who were suffering from chronic anal fissures were randomized into two groups. The patients in group A (n = 30) were treated with 0.25% glyceryl trinitrate ointment and anal cryothermal dilators twice daily, and those in group B (n = 30) were treated with 0.4% glyceryl trinitrate ointment alone twice daily. The treatment was administered to the patients in each group for 6 weeks, and all patients were examined 7 weeks after the start of the trial. Prior to treatment, the symptoms and the measurements of anal pressure were similar in both groups. At 7 weeks, the maximum resting pressure was significantly lower in group A (P < 0.05), in which 86.6% of the patients were asymptomatic in comparison with 73.3% of the patients in group B. After 1 year of follow-up, 25 patients (83.3%) in group A and 18 patients (60%) in group B presented no recurrence of symptoms (P < 0.05) Treatment of chronic anal fissures with 0.25% glyceryl trinitrate ointment and anal cryothermal dilators was more effective than the administration of 0.4% glyceryl trinitrate ointment alone.

  16. Ambulance-delivered transdermal glyceryl trinitrate versus sham for ultra-acute stroke: Rationale, design and protocol for the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) trial (ISRCTN26986053).

    PubMed

    Appleton, Jason P; Scutt, Polly; Dixon, Mark; Howard, Harriet; Haywood, Lee; Havard, Diane; Hepburn, Trish; England, Tim; Sprigg, Nikola; Woodhouse, Lisa J; Wardlaw, Joanna M; Montgomery, Alan A; Pocock, Stuart; Bath, Philip M

    2017-01-01

    Rationale Vascular nitric oxide levels are low in acute stroke and donors such as glyceryl trinitrate have shown promise when administered very early after stroke. Potential mechanisms of action include augmentation of cerebral reperfusion, thrombolysis and thrombectomy, lowering blood pressure, and cytoprotection. Aim To test the safety and efficacy of four days of transdermal glyceryl trinitrate (5 mg/day) versus sham in patients with ultra-acute presumed stroke who are recruited by paramedics prior to hospital presentation. Sample size estimates The sample size of 850 patients will allow a shift in the modified Rankin Scale with odds ratio 0.70 (glyceryl trinitrate versus sham, ordinal logistic regression) to be detected with 90% power at 5% significance (two-sided). Design The Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) is a multicentre UK prospective randomized sham-controlled outcome-blinded parallel-group trial in 850 patients with ultra-acute (≤4 h of onset) FAST-positive presumed stroke and systolic blood pressure ≥120 mmHg who present to the ambulance service following a 999 emergency call. Data collection is performed via a secure internet site with real-time data validation. Study outcomes The primary outcome is the modified Rankin Scale measured centrally by telephone at 90 days and masked to treatment. Secondary outcomes include: blood pressure, impairment, recurrence, dysphagia, neuroimaging markers of the acute lesion including vessel patency, discharge disposition, length of stay, death, cognition, quality of life, and mood. Neuroimaging and serious adverse events are adjudicated blinded to treatment. Discussion RIGHT-2 has recruited more than 500 participants from seven UK ambulance services. Status Trial is ongoing. Funding British Heart Foundation. Registration ISRCTN26986053.

  17. Selective anti-platelet aggregation synergism between a prostacyclin-mimetic, RS93427 and the nitrodilators sodium nitroprusside and glyceryl trinitrate.

    PubMed Central

    Willis, A. L.; Smith, D. L.; Loveday, M.; Fulks, J.; Lee, C. H.; Hedley, L.; VanAntwerp, D.

    1989-01-01

    1. Citrated platelet-rich plasma from human donors was used to examine turbidometrically the platelet aggregation response to collagen (2.5 micrograms ml-1) and ADP (1.6 microgram ml-1). 2. With collagen as an aggregating agent, the limited (35% maximal inhibition) inhibitory effects of glyceryl trinitrate (GTN, 0.78-50 micrograms ml-1) were markedly potentiated by threshold (3.3-10 ng ml-1) concentrations of RS93427, an orally active prostacyclin-mimetic. Almost complete inhibition of aggregation could then be produced. 3. A threshold concentration of RS93427 (3.3 ng ml-1) similarly potentiated the ability of sodium nitroprusside (NaNp, 0.78-10 micrograms ml-1) to inhibit collagen-induced platelet aggregation. There was an 8 fold reduction in the IC25 concentration of NaNp. 4. Threshold concentrations of the nitrodilators were also able to potentiate the anti-aggregatory effects of RS93427 (0.03-30 ng ml-1) on collagen-induced platelet aggregation. With threshold concentrations of either GTN (6.3-25 micrograms ml-1) or NaNp (0.3-1.3 microgram ml-1), the mean IC50 concentration of RS93427 was reduced 4 or 6 fold, respectively, while the IC25 concentration was reduced 6 or 10 fold, respectively. 5. No similar synergistic interactions were seen between RS93427 and the nitrodilators when ADP was used as an aggregating agent. 6. In spontaneously hypertensive rats, the dose-response for the hypotensive response to bolus doses of RS93427 was not altered by concomitant steady state infusion of a threshold dose (1 micrograms kg-1 min-1) of GTN. 7. Possible therapeutic implications of these findings are discussed. PMID:2514949

  18. Selective anti-platelet aggregation synergism between a prostacyclin-mimetic, RS93427 and the nitrodilators sodium nitroprusside and glyceryl trinitrate.

    PubMed

    Willis, A L; Smith, D L; Loveday, M; Fulks, J; Lee, C H; Hedley, L; VanAntwerp, D

    1989-12-01

    1. Citrated platelet-rich plasma from human donors was used to examine turbidometrically the platelet aggregation response to collagen (2.5 micrograms ml-1) and ADP (1.6 microgram ml-1). 2. With collagen as an aggregating agent, the limited (35% maximal inhibition) inhibitory effects of glyceryl trinitrate (GTN, 0.78-50 micrograms ml-1) were markedly potentiated by threshold (3.3-10 ng ml-1) concentrations of RS93427, an orally active prostacyclin-mimetic. Almost complete inhibition of aggregation could then be produced. 3. A threshold concentration of RS93427 (3.3 ng ml-1) similarly potentiated the ability of sodium nitroprusside (NaNp, 0.78-10 micrograms ml-1) to inhibit collagen-induced platelet aggregation. There was an 8 fold reduction in the IC25 concentration of NaNp. 4. Threshold concentrations of the nitrodilators were also able to potentiate the anti-aggregatory effects of RS93427 (0.03-30 ng ml-1) on collagen-induced platelet aggregation. With threshold concentrations of either GTN (6.3-25 micrograms ml-1) or NaNp (0.3-1.3 microgram ml-1), the mean IC50 concentration of RS93427 was reduced 4 or 6 fold, respectively, while the IC25 concentration was reduced 6 or 10 fold, respectively. 5. No similar synergistic interactions were seen between RS93427 and the nitrodilators when ADP was used as an aggregating agent. 6. In spontaneously hypertensive rats, the dose-response for the hypotensive response to bolus doses of RS93427 was not altered by concomitant steady state infusion of a threshold dose (1 micrograms kg-1 min-1) of GTN. 7. Possible therapeutic implications of these findings are discussed.

  19. Percutaneous Posterior Tibial Nerve Stimulation vs Perianal Application of Glyceryl Trinitrate Ointment in the Treatment of Chronic Anal Fissure: A Randomized Clinical Trial.

    PubMed

    Ruiz-Tovar, Jaime; Llavero, Carolina

    2017-01-01

    Current therapeutic guidelines for the treatment of chronic anal fissure establish a medical approach as the first step. Glyceryl trinitrate ointment is the most popular of the available topical treatments in Spain but it is associated with the appearance of headache. The purpose of this study was to compare the compliance rate among patients receiving glyceryl trinitrate treatment for chronic anal fissure with that among patients receiving percutaneous posterior tibial nerve stimulation. This was a prospective randomized study. The study was conducted at Garcilaso Clinic (Madrid, Spain). Subjects with persistent anal fissure despite hygiene and dietary measures applied over at least a 6-week period were included. Study interventions were perianal application of glyceryl trinitrate ointment (twice daily for 8 weeks) and percutaneous posterior tibial nerve stimulation (30-minute session 2 days per week for 8 weeks). Compliance with the treatment and healing rate of chronic anal fissure in patients receiving glyceryl trinitrate ointment or undergoing percutaneous posterior tibial nerve stimulation were evaluated. Forty patients were included in each group. In the glyceryl trinitrate ointment group, 15% of the patients discontinued treatment because of disabling headaches. There were no adverse effects or treatment withdrawals in the percutaneous posterior tibial nerve stimulation group (p = 0.033). After 8 weeks of treatment, the healing rate in the percutaneous posterior tibial nerve stimulation group was 87.5% vs 65.0% in the glyceryl trinitrate ointment group (p = 0.018). Because the patients were not blinded to the treatment, we cannot rule out a placebo effect derived from the needle insertion in the percutaneous posterior tibial nerve stimulation group. Percutaneous posterior tibial nerve stimulation is a safe and effective alternative that is in some ways superior to glyceryl trinitrate ointment for the treatment of chronic anal fissure.

  20. Effect of Treatment Delay, Stroke Type, and Thrombolysis on the Effect of Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome after Acute Stroke: A Systematic Review and Meta-Analysis of Individual Patient from Randomised Trials

    PubMed Central

    Bath, Philip M.; Woodhouse, Lisa; Krishnan, Kailash; Anderson, Craig; Berge, Eivind; Ford, Gary A.; Robinson, Thompson G.; Saver, Jeffrey L.; Sprigg, Nikola; Wardlaw, Joanna M.; in Acute Stroke Collaboration (BASC), Blood pressure

    2016-01-01

    Background. Nitric oxide (NO) donors are a candidate treatment for acute stroke and two trials have suggested that they might improve outcome if administered within 4–6 hours of stroke onset. We assessed the safety and efficacy of NO donors using individual patient data (IPD) from completed trials. Methods. Randomised controlled trials of NO donors in patients with acute or subacute stroke were identified and IPD sought from the trialists. The effect of NO donor versus control on functional outcome was assessed using the modified Rankin scale (mRS) and death, by time to randomisation. Secondary outcomes included measures of disability, mood, and quality of life. Results. Five trials (4,197 participants) were identified, all involving glyceryl trinitrate (GTN). Compared with control, GTN lowered blood pressure by 7.4/3.3 mmHg. At day 90, GTN did not alter any clinical measures. However, in 312 patients randomised within 6 hours of stroke onset, GTN was associated with beneficial shifts in the mRS (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.34–0.78) and reduced death (OR 0.32, 95% CI 0.14–0.78). Conclusions. NO donors do not alter outcome in patients with recent stroke. However, when administered within 6 hours, NO donors might improve outcomes in both ischaemic and haemorrhagic stroke. PMID:27190674

  1. Comparative study of lateral internal sphincterotomy versus local 0.2% glyceryl trinitrate ointment for the treatment of chronic anal fissure.

    PubMed

    Siddique, Md Ibrahim; Murshed, Khandker Manzoor; Majid, M A

    2008-04-01

    The gold standard surgical treatment of chronic anal fissure is lateral internal sphincterotomy which lowers the resting anal pressure and effectively heals the majority of fissures. Local application of 0.2% glyceryl trinitrate ointment has been used as an agent for chemical sphincterotomy, causing temporary alleviation of sphincter spasm and allowing the fissure to heal without compromising the anal continence. The aim of the present study was to compare the results of surgical sphincterotomy with that of local 0.2% glyceryl trinitrate ointment in the treatment of chronic anal fissure. Seventy adult patients between the age of 18 and 50 years with chronic anal fissure were randomized in a prospective trial to receive either surgical sphincterotomy or 0.2% glyceryl trinitrate ointment locally. Patients were followed up at 2 weeks' interval for 10 weeks. Symptom relief, fissure healing and continence scores were the outcomes assessed. Six patients were excluded for protocol violations. Surgical sphincterotomy was significantly more effective in providing pain relief and was associated with significantly better fissure healing rates at 6 weeks and 10 weeks (both p < 0.001). There were substantial problems with compliance in ointment group related to slow healing and longer time needed for symptomatic relief. Minor incontinence was 6% in sphincterotomy group and none in ointment group (p > 0.05). Considering early symptomatic relief, rapid fissure healing and better patient compliance surgical sphincterotomy is the treatment of choice for chronic anal fissure.

  2. Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine.

    PubMed

    Schankin, Christoph J; Maniyar, Farooq H; Seo, Youngho; Kori, Shashidar; Eller, Michael; Chou, Denise E; Blecha, Joseph; Murphy, Stephanie T; Hawkins, Randall A; Sprenger, Till; VanBrocklin, Henry F; Goadsby, Peter J

    2016-07-01

    SEE DREIER DOI 101093/AWW112 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: For many decades a breakdown of the blood-brain barrier has been postulated to occur in migraine. Hypothetically this would facilitate access of medications, such as dihydroergotamine or triptans, to the brain despite physical properties otherwise restricting their entry. We studied the permeability of the blood-brain barrier in six migraineurs and six control subjects at rest and during acute glyceryl trinitrate-induced migraine attacks using positron emission tomography with the novel radioligand (11)C-dihydroergotamine, which is chemically identical to pharmacologically active dihydroergotamine. The influx rate constant Ki, average dynamic image and time activity curve were assessed using arterial blood sampling and served as measures for receptor binding and thus blood-brain barrier penetration. At rest, there was binding of (11)C-dihydroergotamine in the choroid plexus, pituitary gland, and venous sinuses as expected from the pharmacology of dihydroergotamine. However, there was no binding to the brain parenchyma, including the hippocampus, the area with the highest density of the highest-affinity dihydroergotamine receptors, and the raphe nuclei, a postulated brainstem site of action during migraine, suggesting that dihydroergotamine is not able to cross the blood-brain barrier. This binding pattern was identical in migraineurs during glyceryl trinitrate-induced migraine attacks as well as in matched control subjects. We conclude that (11)C-dihydroergotamine is unable to cross the blood-brain barrier interictally or ictally demonstrating that the blood-brain barrier remains tight for dihydroergotamine during acute glyceryl trinitrate-induced migraine attacks. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

  3. Rectogesic (glyceryl trinitrate 0.2%) ointment relieves symptoms of haemorrhoids associated with high resting anal canal pressures.

    PubMed

    Tjandra, J J; Tan, J J Y; Lim, J F; Murray-Green, C; Kennedy, M L; Lubowski, D Z

    2007-06-01

    Some haemorrhoids are associated with high resting anal canal pressures. The aim of this study was to assess if Rectogesic, a topical glyceryl trinitrate 0.2% ointment was effective in relieving symptoms of early grade haemorrhoids associated with high resting anal canal pressures. This was a prospective, two-centre, open label study of 58 patients with persistent haemorrhoidal symptoms. Patients with first or second degree haemorrhoids and a maximum resting anal canal pressure > 70 mmHg were included. Rectogesic was applied three times a day for 14 days. Anorectal manometry was performed 30 min after the first application of Rectogesic. A 28-day diary was completed during 14 days of therapy and for 14 days after cessation of treatment. This recorded the incidence of rectal bleeding, and visual analogue scales for anal pain, throbbing, pruritus, irritation and difficulty in bowel movement. Maximum resting anal canal pressures were reduced after application of Rectogesic (115.0 +/- 40.4 mmHg vs 94.7 +/- 34.1 mmHg, P < 0.001). In the study period and at 14 days after cessation of Rectogesic, there was significant reduction in rectal bleeding (P = 0.0002), and significant improvement of anal pain (P = 0.0024), throbbing (P = 0.0355), pruritus (P = 0.0043), irritation (P = 0.0000) and difficulty in bowel movement (P = 0.001). The main adverse event was headache in 43.1% of patients. Rectogesic is a safe and feasible treatment for patients with early grade haemorrhoids associated with high resting anal canal pressures.

  4. Improved preservation of saphenous vein grafts by the use of glyceryl trinitrate-verapamil solution during harvesting.

    PubMed

    Roubos, N; Rosenfeldt, F L; Richards, S M; Conyers, R A; Davis, B B

    1995-11-01

    High-pressure distension during harvesting damages the saphenous vein (SV) and may contribute to subsequent coronary artery bypass graft (CABG) occlusion. Application of vasodilator agents to the SV during harvesting may reduce the need for high-pressure distension and improve graft quality. We tested the effects of a vasodilator solution containing glyceryl trinitrate and verapamil (GV) or the conventional agent papaverine (Pap) on the pressure necessary to overcome SV spasm and on the structure and biochemistry of the SV graft. Thirty-six patients undergoing CABG were randomly allocated to receive an application of either topical and intraluminal GV solution, topical Pap, or topical and intraluminal Ringer's solution (untreated) to the SV during harvesting. The peak and mean pressures required to distend the vein were recorded. Samples of SV were taken for microscopy and biochemical analysis just before we performed the anastomosis. The percentage of endothelial coverage was calculated by area measurements of stained en face preparations of the vein intima. The results for peak pressures (mmHg) were: untreated, 479.2 +/- 27.5; Pap, 384.8 +/- 29.0; and GV, 309.5 +/- 28.3 (P < .001, GV plus Pap versus untreated); and the results for mean pressures (mm Hg) were untreated, 136.2 +/- 9.6; Pap, 102.2 +/- 10.8; and GV, 98.0 +/- 8.3 (P < .01, GV plus Pap versus untreated). The results for endothelial cover (%) were: untreated, 43.7 +/- 7.0; Pap, 44.1 +/- 9.2; and GV, 68.7 +/- 7.0 (P < .05, GV versus Pap); and the results for ATP (nmol/g wet wt) were: untreated, 67.3 +/- 12.7; Pap, 112.0 +/- 19.4; and GV, 132.5 +/- 22.7 (P < .05, GV plus Pap versus untreated). First, pharmacological treatment of SV during harvesting, especially with GV solution, allows the use of a lower distension pressure and reduces the breakdown of high-energy phosphates in the vein wall. Second, topical and intraluminal use of GV solution during vein harvesting improves endothelial coverage compared

  5. NO donors. Part 18: Bioactive metabolites of GTN and PETN--synthesis and vasorelaxant properties.

    PubMed

    Lange, Kathrin; Koenig, Andreas; Roegler, Carolin; Seeling, Andreas; Lehmann, Jochen

    2009-06-01

    The vasodilators glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) are supposed to be degraded in vivo to the lower nitrates PETriN, PEDN, PEMN, 1,2-GDN, 1,3-GDN, 1-GMN, and 2-GMN. We synthesized these bioactive metabolites as reference compounds for pharmacokinetic studies. The use of HPLC-methods for monitoring the stepwise reduction of PETN to lower nitrates and the syntheses of the glyceryl dinitrates proved advantageous. Furthermore, we measured the vasorelaxant properties of all metabolites by performing organ bath experiments with porcine pulmonary arteries. In general, the vasodilator potency increases with the number of nitrate moieties in the compound.

  6. Topical 0.2% glyceryl trinitrate ointment for anal fissures: long-term efficacy in routine clinical practice.

    PubMed

    Jonas, M.; Lund, J. N.; Scholefield, J. H.

    2002-09-01

    OBJECTIVE: Randomized controlled trials have reported fissure healing rates of 60-70% using topical 0.2% GTN ointment, but the effectiveness of this therapy in routine clinical practice, particularly in the long term, is uncertain. This study aimed to evaluate the efficacy of topical GTN for anal fissures in an outpatient setting. PATIENTS AND METHODS: A case note review and postal questionnaire survey were undertaken for patients with a diagnosis of anal fissure dispensed 0.2% GTN ointment from one hospital pharmacy over a two year period (June 1996-May 1998). RESULTS: Ninety-three patients (53 male) applied 0.2% GTN ointment twice daily to the anoderm for anal fissure. They were reviewed on average 8 (2-16), weeks later, by which time 57 (61%) fissures had healed, 33 persisted and 3 patients were lost to follow up. Seventy-two patients (41male), median age 42 (22-83) years, returned completed questionnaires (77% response rate). Forty-nine (68%) had healed with GTN, but 25 had recurrent symptoms after a median of 6 (1-18) months. Sixteen of those patients reporting symptomatic recurrence were prescribed further GTN for a recurrent fissure: 14 (88%) healed, but 2 persisted, and had surgery. In the other nine patients symptoms resolved spontaneously. Thirty-five (49%) experienced headaches, 3 (4%) discontinuing treatment as a result. The median follow up was 25 (13-36) months. CONCLUSION: 0.2% GTN heals 60% of fissures in the outpatient setting but half the patients develop headaches. Up to one third of healed fissures may recur within 18 months but the majority respond to further GTN. Only 4% of patients initially healed with GTN later require sphincterotomy for recurrences.

  7. Haemodynamics and plasma concentrations following sublingual GTN and intravenous, or inhaled, isosorbide dinitrate.

    PubMed Central

    Culling, W; Singh, H; Bashir, A; Griffiths, B E; Dalal, J J; Sheridan, D J

    1984-01-01

    We measured plasma nitrate levels and haemodynamics following sublingual glyceryl trinitrate (GTN) (0.5 mg), or isosorbide dinitrate (ISDN) administered intravenously (0.5 mg) or by inhalation (1.25 mg) in 23 patients undergoing cardiac catheterisation for investigation of chest pain. Peak levels were detected at 90 s and 5 min following intravenous and inhaled ISDN respectively and at 3 min following sublingual GTN. Intravenous and inhaled ISDN produced similar plasma levels at 30 s and both were significantly greater than following sublingual GTN. Plasma levels were maintained for longer following inhaled ISDN than intravenous ISDN or sublingual GTN. Haemodynamic responses were qualitatively similar following each treatment; reduction in pulmonary vascular resistance and pressure and left ventricular end diastolic pressure occurred in each group. Heart rate, cardiac output and LV dP/dt.P-1 remained unchanged. Maximal haemodynamic responses were greater following ISDN than GTN, with little difference between the two preparations of ISDN. Haemodynamic responses were more sustained following inhaled ISDN than following sublingual GTN or intravenous ISDN, the latter two being similar in this respect. These findings suggest that inhaled ISDN may provide more rapid and sustained relief from angina than sublingual GTN. PMID:6422972

  8. The inhibitory effect of 3-amino-1,2,4-triazole on relaxation induced by hydroxylamine and sodium azide but not hydrogen peroxide or glyceryl trinitrate in rat aorta.

    PubMed Central

    Mian, K. B.; Martin, W.

    1995-01-01

    1. In this study we investigated the role of catalase in relaxation induced by hydroxylamine, sodium azide, glyceryl trinitrate and hydrogen peroxide in isolated rings of rat aorta. 2. Hydrogen peroxide (1 microM-1 mM)-induced concentration-dependent relaxation of phenylephrine (PE)-induced tone in endothelium-containing rings. In endothelium-denuded rings, however, higher concentrations (30 microM-1 mM) of hydrogen peroxide were required to produce relaxation. The endothelium-dependent component of hydrogen peroxide-induced relaxation was abolished following pretreatment with N(O)-nitro-L-arginine methyl ester (L-NAME, 30 microM). L-NAME (30 microM) had no effect, however, on hydrogen peroxide-induced relaxation in endothelium-denuded rings. 3. Pretreatment of endothelium-denuded rings with catalase (1000 u ml-1) blocked relaxation induced by hydrogen peroxide (10 microM-1 mM). The ability of catalase to inhibit hydrogen peroxide-induced relaxation was partially blocked following incubation with 3-amino-1,2, 4-triazole (AT, 50 mM) for 30 min and completely blocked at 90 min. 4. Pretreatment of endothelium-denuded rings with methylene blue (MeB, 30 microM) inhibited relaxation induced by hydrogen peroxide (10 microM-1 mM), sodium azide (1-300 nM), hydroxylamine (1-300 nM) and glyceryl trinitrate (1-100 nM) suggesting that each acted by stimulation of soluble guanylate cyclase. 5. Pretreatment of endothelium-denuded rings with AT (1-50 mM, 90 min) to inhibit endogenous catalase blocked relaxation induced by sodium azide (1-300 nM) and hydroxylamine (1-300 nM) but had no effect on relaxation induced by hydrogen peroxide (10 microM-1 mM) or glyceryl trinitrate (1-100 nM). 6. In a cell-free system, incubation of sodium azide (10 microM-3 mM) and hydroxylamine (10 microM-30 mM) but not glyceryl trinitrate (10 microM-1 mM) with catalase (1000 u ml-1) in the presence of hydrogen peroxide (1 mM) led to production of nitrite, a major breakdown product of nitric oxide. AT (1

  9. Efficacy of combination of 0.2% GTN and lignocaine ointments in wound healing and pain relief after Milligan Morgan hemorrhoidectomy--a comparison with lignocaine and 0.2% GTN ointments separately.

    PubMed

    Khan, Khizar Ishtiaque; Waqas, Ahmed; Akmal, Muhammad; Mahmood, Shahid; Iqbal, Afaq

    2014-01-01

    To compare the analgesic efficacy and rate of wound healing of combination of 0.2% Glyceryl Trinitrate and 2% lignocaine ointments with 0.2% Glyceryl Trinitrate and 2% lignocaine ointment separately after Milligan Morgan hemorrhoidectomy. Randomized control trial. Combined Military Hospital, Kharian, Malir and Bannu. November 2007 to August 2011. Patients undergoing Milligan Morgan hemorrhoidectomy were randomized into 3 groups by using computer generated table. Group A received combination of 0.2% Glyceryl Trinitrate and 2% lignocaine ointment, Group B 2% lignocaine and Group C received 0.2% Glyceryl Trinitrate ointment. These ointments were given on twice daily basis. Pain scores were measured on a 100 mm Visual Analog Scale. Pain scores and quantity of oral analgesics used were compared daily until the 7th post-operative day. The time required for complete healing (in weeks) was also compared. Out of 210 patients, 192 (67 Group A, 64 Group B and 61 Group C) completed the study. Demographic data were comparable in all three groups. There were statistically significant reductions in pain scores and quantity of analgesics used from the first to the fourth post-operative days in Group A. The time required for complete healing was also significantly reduced in the combination group. There were no significant side effects in any group. The combination of 0.2% GTN and 2% lignocaine showed better pain relief resulting in less use of oral analgesics and faster healing of the wound after Milligan Morgan hemorrhoidectomy. Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

  10. Perianal versus endoanal application of glyceryl trinitrate 0.4% ointment in the treatment of chronic anal fissure: results of a randomized controlled trial. Is this the solution to the headaches?

    PubMed

    Pérez-Legaz, Juan; Arroyo, Antonio; Moya, Pedro; Ruiz-Tovar, Jaime; Frangi, Andres; Candela, Fernando; Oliver, Miguel I; Calpena, Rafael

    2012-08-01

    Application of nitroglycerin (glyceryl trinitrate) ointment with perianal administration is a widely used treatment for chronic anal fissure. However, headache occurs after application in 20% to 70% patients and leads to withdrawal in 10% of patients. The aim of the study was to investigate whether endoanal application of the ointment may lower the frequency of headaches without sacrificing effectiveness. compare the effects of perianal versus endoanal administration of nitroglycerin ointment on frequency of headache and rate of healing in the treatment of chronic anal fissure. This was a prospective randomized clinical trial (ClinicalTrial.gov, NCT01132391). Study participants were consecutive patients with a diagnosis of chronic anal fissure treated at a university teaching hospital in Elche, Alicante, Spain. Patients were randomly assigned to receive perianal (n = 26) or endoanal (n = 26) administration of 0.4% nitroglycerin ointment (375 mg of ointment containing 1.5 mg of glyceryl trinitrate), applied every 12 hours over an 8-week period. The primary endpoint of the study was the number of patients with headache within 3 hours after application of the ointment, analyzed with the intention-to-treat principle. Intensity of headache pain was rated on a 10-point visual analog scale. Secondary endpoints included frequencies of fissure healing, anorectal pain, rectal bleeding, pruritus, and incontinence. Headaches were reported in 14 (54%) patients with perianal treatment and in 6 patients (23%) with anorectal treatment (p = 0.003). The median headache pain score was 6 (range, 0-10) in the perianal group and 4.5 (range, 0-10) in the endoanal group (p = 0.03). Disabling headaches led to crossover from perianal to endoanal treatment in 4 patients (15%), and from endoanal to perianal treatment in 1 patient (4%) (p = 0.004). Of the 4 patients who switched from perianal to endoanal treatment, 2 reported improvement in headaches and 2 stopped treatment. The patient who

  11. Chronic administration of the HNO donor Angeli's salt does not lead to tolerance, cross-tolerance, or endothelial dysfunction: comparison with GTN and DEA/NO.

    PubMed

    Irvine, Jennifer C; Kemp-Harper, Barbara K; Widdop, Robert E

    2011-05-01

    Nitroxyl (HNO) displays distinct pharmacology to its redox congener nitric oxide (NO(•)) with therapeutic potential in the treatment of heart failure. It remains unknown if HNO donors are resistant to tolerance development following chronic in vivo administration. Wistar-Kyoto rats received a 3-day subcutaneous infusion of one of the NO(•) donors, glyceryl trinitrate (GTN) or diethylamine/NONOate (DEA/NO), or the HNO donor Angeli's salt (AS). GTN infusion (10 μg/kg/min) resulted in significantly blunted depressor responses to intravenous bolus doses of GTN, demonstrating tolerance development. By contrast, infusion with AS (20 μg/kg/min) or DEA/NO (2 μg/kg/min) did not alter their subsequent depressor responses. Similarly, ex vivo vasorelaxation responses in isolated aortae revealed that GTN infusion elicited a significant 6-fold decrease in the sensitivity to GTN and reduction in the maximum response to acetylcholine (ACh). Chronic infusion of AS or DEA/NO had no effect on subsequent vasorelaxation responses to themselves or to ACh. No functional cross-tolerance between nitrovasodilators was evident, either in vivo or ex vivo, although an impaired ability of a nitrovasodilator to increase tissue cGMP content was not necessarily indicative of a reduced functional response. In conclusion, HNO donors may represent novel therapies for cardiovascular disease with therapeutic potential over clinically used organic nitrates.

  12. Biodegradation of Glycerol Trinitrate and Pentaerythritol Tetranitrate by Agrobacterium radiobacter

    PubMed Central

    White, G. F.; Snape, J. R.; Nicklin, S.

    1996-01-01

    Bacteria capable of metabolizing highly explosive and vasodilatory glycerol trinitrate (GTN) were isolated under aerobic and nitrogen-limiting conditions from soil, river water, and activated sewage sludge. One of these strains (from sewage sludge) chosen for further study was identified as Agrobacterium radiobacter subgroup B. A combination of high-pressure liquid chromatography and nuclear magnetic resonance analyses of the culture medium during the growth of A. radiobacter on basal salts-glycerol-GTN medium showed the sequential conversion of GTN to glycerol dinitrates and glycerol mononitrates. Isomeric glycerol 1,2-dinitrate and glycerol 1,3-dinitrate were produced simultaneously and concomitantly with the disappearance of GTN, with significant regioselectivity for the production of the 1,3-dinitrate. Dinitrates were further degraded to glycerol 1- and 2-mononitrates, but mononitrates were not biodegraded. Cells were also capable of metabolizing pentaerythritol tetranitrate, probably to its trinitrate and dinitrate analogs. Extracts of broth-grown cells contained an enzyme which in the presence of added NADH converted GTN stoichiometrically to nitrite and the mixture of glycerol dinitrates. The specific activity of this enzyme was increased 160-fold by growth on GTN as the sole source of nitrogen. PMID:16535244

  13. Final report of the amended safety assessment of Glyceryl Laurate, Glyceryl Laurate SE, Glyceryl Laurate/Oleate, Glyceryl Adipate, Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Citrate/Lactate/Linoleate/Oleate, Glyceryl Cocoate, Glyceryl Collagenate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyceryl Isopalmitate, Glyceryl Isostearate, Glyceryl Isostearate/Myristate, Glyceryl Isostearates, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl Isotridecanoate/Stearate/Adipate, Glyceryl Oleate SE, Glyceryl Oleate/Elaidate, Glyceryl Palmitate, Glyceryl Palmitate/Stearate, Glyceryl Palmitoleate, Glyceryl Pentadecanoate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryl/Sorbitol Oleate/Hydroxystearate, Glyceryl Stearate/Acetate, Glyceryl Stearate/Maleate, Glyceryl Tallowate, Glyceryl Thiopropionate, and Glyceryl Undecylenate.

    PubMed

    2004-01-01

    The safety of 43 glyceryl monoesters listed as cosmetic ingredients was reviewed in a safety assessment completed in 2000. Additional safety test data pertaining to Glyceryl Rosinate and Glyceryl Hydrogenated Rosinate were received and served as the basis for this amended report. Glyceryl monoesters are used mostly as skin-conditioning agents--emollients and/or surfactant--emulsifying agents in cosmetics. The following 20 glyceryl monoesters are currently reported to be used in cosmetics: Glyceryl Laurate, Glyceryl Alginate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Cocoate, Glyceryl Erucate, Glyceryl Hydroxystearate, Glyceryl Isostearate, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Myristate, Glyceryl Oleate/Elaidate, Glyceryl Palmitate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Stearate/Acetate, and Glyceryl Undecylenate. Concentration of use data received from the cosmetics industry in 1999 indicate that Glyceryl Monoesters are used at concentrations up to 12% in cosmetic products. Glyceryl Monoesters are not pure monoesters, but are mostly mixtures with mono-, di-, and tri-esters. The purity of commercial and conventional Monoglyceride (Glyceryl Monoester) is a minimum of 90%. Glyceryl Monoesters (monoglycerides) are metabolized to free fatty acids and glycerol, both of which are available for the resynthesis of triglycerides. Glyceryl Laurate enhanced the penetration of drugs through cadaverous skin and hairless rat skin in vitro and has been described as having a wide spectrum of antimicrobial activity. A low-grade irritant response was observed following inhalation of an aerosol containing 10% Glyceryl Laurate by test animals. Glyceryl monoesters have little acute or short-term toxicity in animals, and no toxicity was noted following chronic administration of a mixture consisting mostly of glyceryl di- and mono- esters. Glyceryl Laurate did have strong hemolytic

  14. Determining the Feasibility of Ambulance-Based Randomised Controlled Trials in Patients with Ultra-Acute Stroke: Study Protocol for the "Rapid Intervention with GTN in Hypertensive Stroke Trial" (RIGHT, ISRCTN66434824).

    PubMed

    Ankolekar, Sandeep; Sare, Gillian; Geeganage, Chamila; Fuller, Michael; Stokes, Lynn; Sprigg, Nikola; Parry, Ruth; Siriwardena, A Niroshan; Bath, Philip M W

    2012-01-01

    Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown. Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included. Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited. Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40.

  15. Determining the Feasibility of Ambulance-Based Randomised Controlled Trials in Patients with Ultra-Acute Stroke: Study Protocol for the “Rapid Intervention with GTN in Hypertensive Stroke Trial” (RIGHT, ISRCTN66434824)

    PubMed Central

    Ankolekar, Sandeep; Sare, Gillian; Geeganage, Chamila; Fuller, Michael; Stokes, Lynn; Sprigg, Nikola; Parry, Ruth; Siriwardena, A. Niroshan; Bath, Philip M. W.

    2012-01-01

    Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown. Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included. Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited. Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40. PMID:23125943

  16. Amended final report on the safety assessment of glyceryl dilaurate, glyceryl diarachidate, glyceryl dibehenate, glyceryl dierucate, glyceryl dihydroxystearate, glyceryl diisopalmitate, glyceryl diisostearate, glyceryl dilinoleate, glyceryl dimyristate, glyceryl dioleate, glyceryl diricinoleate, glyceryl dipalmitate, glyceryl dipalmitoleate, glyceryl distearate, glyceryl palmitate lactate, glyceryl stearate citrate, glyceryl stearate lactate, and glyceryl stearate succinate.

    PubMed

    2007-01-01

    Glyceryl Dilaurate, Glyceryl Diarachidate, Glyceryl Dibehenate, Glyceryl Dierucate, Glyceryl Dihydroxystearate, Glyceryl Diisopalmitate, Glyceryl Diisostearate, Glyceryl Dilinoleate, Glyceryl Dimyristate, Glyceryl Dioleate, Glyceryl Diricinoleate, Glyceryl Dipalmitate, Glyceryl Dipalmitoleate, Glyceryl Distearate, Glyceryl Palmitate Lactate, Glyceryl Stearate Citrate, Glyceryl Stearate Lactate, and Glyceryl Stearate Succinate are diacylglycerols (also known as diglycerides or glyceryl diesters) that function as skin conditioning agents - emollients in cosmetics. Only Glyceryl Dilaurate (up to 5%), Glyceryl Diisostearate (up to 43%), Glyceryl Dioleate (up to 2%), Glyceryl Distearate (up to 7%), and Glyceryl Stearate Lactate (up to 5%) are reported to be in current use. Production proceeds from fully refined vegetable oils, which are further processed using hydrogenation and fractionation techniques, and the end products are produced by reacting selected mixtures of the partly hydrogenated, partly fractionated oils and fats with vegetable-derived glycerine to yield partial glycerides. In the final stage of the production process, the products are purified by deodorization, which effectively removes pesticide residues and lower boiling residues such as residues of halogenated solvents and aromatic solvents. Diglycerides have been approved by the Food and Drug Administration (FDA) for use as indirect food additives. Nominally, these ingredients are 1,3-diglycerides, but are easily isomerized to the 1,2-diglycerides form. The 1,3-diglyceride isomer is not a significant toxicant in acute, short-term, subchronic, or chronic animal tests. Glyceryl Dilaurate was a mild primary irritant in albino rabbits, but not a skin sensitizer in guinea pig maximization tests. Diacylglycerol Oil was not genotoxic in the Ames test, in mammalian Chinese hamster lung cells, or in a rodent bone marrow micronucleus assay. An eye shadow containing 1.5% Glyceryl Dilaurate did not induce skin

  17. Denitration of glycerol trinitrate by resting cells and cell extracts of Bacillus thuringiensis/cereus and Enterobacter agglomerans.

    PubMed Central

    Meng, M; Sun, W Q; Geelhaar, L A; Kumar, G; Patel, A R; Payne, G F; Speedie, M K; Stacy, J R

    1995-01-01

    A number of microorganisms were selected from soil and sediment samples which were known to have been previously exposed to nitrate ester contaminants. The two most effective bacteria for transforming glycerol trinitrate (GTN) were identified as Bacillus thuringiensis/cereus and Enterobacter agglomerans. For both isolates, denitration activities were expressed constitutively and GTN was not required for induction. Dialysis of cell extracts from both isolates did not affect denitration, which indicates that dissociable and depletable cofactors are not required for denitration. With thin-layer chromatography and high-performance liquid chromatography, the denitration pathway for both isolates was shown to be a sequential denitration of GTN to glycerol dinitrate isomers, glycerol mononitrate isomers, and ultimately to glycerol. GTN was observed to be completely converted to glycerol during a long-term incubation of cell extracts. PMID:7618866

  18. Denitration of glycerol trinitrate by resting cells and cell extracts of Bacillus thuringiensis/cereus and Enterobacter agglomerans.

    PubMed

    Meng, M; Sun, W Q; Geelhaar, L A; Kumar, G; Patel, A R; Payne, G F; Speedie, M K; Stacy, J R

    1995-07-01

    A number of microorganisms were selected from soil and sediment samples which were known to have been previously exposed to nitrate ester contaminants. The two most effective bacteria for transforming glycerol trinitrate (GTN) were identified as Bacillus thuringiensis/cereus and Enterobacter agglomerans. For both isolates, denitration activities were expressed constitutively and GTN was not required for induction. Dialysis of cell extracts from both isolates did not affect denitration, which indicates that dissociable and depletable cofactors are not required for denitration. With thin-layer chromatography and high-performance liquid chromatography, the denitration pathway for both isolates was shown to be a sequential denitration of GTN to glycerol dinitrate isomers, glycerol mononitrate isomers, and ultimately to glycerol. GTN was observed to be completely converted to glycerol during a long-term incubation of cell extracts.

  19. The use of 0.2% glyceryl trinirate oinment for anal fissures.

    PubMed

    El Tinay, Omer El Farouq; Guraya, Salman Yousuf

    2005-01-01

    To assess the clinical efficacy of 0.2% glyceryl trinitrate ointment in the management of acute and chronic anal fissures. A prospective clinical study conducted on consecutive patients presented to the surgical clinic of King Khalid University Hospital, Riyadh with acute and chronic anal fissures, from January to December 2003. These patients were treated with topical 0.2% glyceryl trinitrate paste in soft white paraffin three times a day. Patients were examined at regular intervals to evaluate the fissure status, adverse reactions, symptomatic control and recurrence. This study comprised 121 patients, six of them were lost to follow-up and 109 (94.7%) of the remaining 115 patients were cured. Of those cured, 13 patients (11.3%) presented with acute and 102 (88.7%) with chronic fissures. There were 98 male and 17 female patients with median age of 41 years (range, 14-70 years). Complete symptomatic relief was achieved in all patients within one month of therapy. Two patients, with chronic anal fissures presented with recurrent symptoms within one month of the completion of therapy both of them were successfully treated with repeat glyceryl trinitrate course. Treatment had to be terminated in six (5.2%) patients: five (4.3%) experienced intolerable adverse effects and one (0.8%) patient failed to respond. All these patients were successfully treated with lateral internal sphincterotomy. No patient complained of change in continence. Glyceryl trinitrate ointment produces adequate symptomatic control and healing of the anal fissures and can be considered as one of the recommended treatment options.

  20. Purification, properties, and sequence of glycerol trinitrate reductase from Agrobacterium radiobacter.

    PubMed Central

    Snape, J R; Walkley, N A; Morby, A P; Nicklin, S; White, G F

    1997-01-01

    Glycerol trinitrate (GTN) reductase, which enables Agrobacterium radiobacter to utilize GTN and related explosives as sources of nitrogen for growth, was purified and characterized, and its gene was cloned and sequenced. The enzyme was a 39-kDa monomeric protein which catalyzed the NADH-dependent reductive scission of GTN (Km = 23 microM) to glycerol dinitrates (mainly the 1,3-isomer) with a pH optimum of 6.5, a temperature optimum of 35 degrees C, and no dependence on metal ions for activity. It was also active on pentaerythritol tetranitrate (PETN), on isosorbide dinitrate, and, very weakly, on ethyleneglycol dinitrate, but it was inactive on isopropyl nitrate, hexahydro-1,3,5-trinitro-1,3,5-triazine, 2,4,6-trinitrotoluene, ammonium ions, nitrate, or nitrite. The amino acid sequence deduced from the DNA sequence was homologous (42 to 51% identity and 61 to 69% similarity) to those of PETN reductase from Enterobacter cloacae, N-ethylmaleimide reductase from Escherichia coli, morphinone reductase from Pseudomonas putida, and old yellow enzyme from Saccharomyces cerevisiae, placing the GTN reductase in the alpha/beta barrel flavoprotein group of proteins. GTN reductase and PETN reductase were very similar in many respects except in their distinct preferences for NADH and NADPH cofactors, respectively. PMID:9401040

  1. Old yellow enzyme: Reduction of nitrate esters, glycerin trinitrate, and propylene 1,2-dinitrate

    PubMed Central

    Meah, Younus; Brown, Bette Jo; Chakraborty, Sumita; Massey, Vincent

    2001-01-01

    The reaction of the old yellow enzyme and reduced flavins with organic nitrate esters has been studied. Reduced flavins have been found to react readily with glycerin trinitrate (GTN ) (nitroglycerin) and propylene dinitrate, with rate constants at pH 7.0, 25°C of 145 M−1s−1 and 5.8 M−1s−1, respectively. With GTN, the secondary nitrate was removed reductively 6 times faster than the primary nitrate, with liberation of nitrite. With propylene dinitrate, on the other hand, the primary nitrate residue was 3 times more reactive than the secondary residue. In the old yellow enzyme-catalyzed NADPH-dependent reduction of GTN and propylene dinitrate, ping-pong kinetics are displayed, as found for all other substrates of the enzyme. Rapid-reaction studies of mixing reduced enzyme with the nitrate esters show that a reduced enzyme–substrate complex is formed before oxidation of the reduced flavin. The rate constants for these reactions and the apparent Kd values of the enzyme–substrate complexes have been determined and reveal that the rate-limiting step in catalysis is reduction of the enzyme by NADPH. Analysis of the products reveal that with the enzyme-catalyzed reactions, reduction of the primary nitrate in both GTN and propylene dinitrate is favored by comparison with the free-flavin reactions. This preferential positional reactivity can be rationalized by modeling of the substrates into the known crystal structure of the enzyme. In contrast to the facile reaction of free reduced flavins with GTN, reduced 5-deazaflavins have been found to react some 4–5 orders of magnitude slower. This finding implies that the chemical mechanism of the reaction is one involving radical transfers. PMID:11438708

  2. 21 CFR 582.1324 - Glyceryl monostearate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Additives § 582.1324 Glyceryl monostearate. (a) Product. Glyceryl monostearate. (b) Conditions of use. This substance is generally recognized as safe when used in accordance with good manufacturing or feeding...

  3. Dermal Sensitization Potential of Trimethylolethane Trinitrate (TMETN) in Guinea Pigs

    DTIC Science & Technology

    1989-07-01

    27 LeTellier et a/.-15 Appendix A: CHEMICAL DATA Chemical Name: 1,3- Propanediol , 2-methyl-2[(nitrooxy)methyl]-dinitrate (ester) Other...Names: 1,3- Propanediol -2-(hydroxymethyl)-2-methyl-, trinitrate; 1,1,1-Trimethylolethane trinitrate(TMETN), Metriol trinitrate (MTN); Nitropentaglycerin

  4. Acute Oral Toxicity of Trimethylolethane Trinitrate (TMETN) in ICR Mice

    DTIC Science & Technology

    1989-07-01

    56 Brown et al.--16 Appendix A: CHEMICAL DATA Chemical Name: 1,3- Propanediol , 2-methyl-2 [(nitroxy)methyl]-dinitrate (ester) Other Names: 1,3... Propanediol -2-(hydroxymethyl)-2-methyl-, trinitrate; 1,1,1-trimethylolethane trinitrate (TMETN), metriol trinitrate (MTN); nitropentaglycerin Lot Number: 53...0.5 0.6 Brown et al.--56 Appendix G: PATHOLOGY REPORT Oral Lethal Dose (MLD) Test in Mice of 1, 3 - Propanediol , 2-(hydroxymethyl)-2-methyl

  5. 21 CFR 184.1323 - Glyceryl monooleate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... prepared by esterification of commerical oleic acid that is derived either from edible sources or from tall oil fatty acids meeting the requirements of § 172.862 of this chapter. It contains glyceryl monooleate (C21H40O4, CAS Reg. No. 25496-72-4) and glyceryl esters of fatty acids present in commercial oleic acid. (b...

  6. 21 CFR 172.811 - Glyceryl tristearate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.811 Glyceryl tristearate. The food additive glyceryl tristearate may be safely used in food in accordance with the following prescribed conditions: (a) The food additive (CAS Reg....

  7. 21 CFR 184.1324 - Glyceryl monostearate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... esters of fatty acids present in commercial stearic acid. Glyceryl monostearate is prepared by..., of stearic acid that is derived from edible sources. (b) The ingredient must be of a purity suitable...

  8. 21 CFR 184.1324 - Glyceryl monostearate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... esters of fatty acids present in commercial stearic acid. Glyceryl monostearate is prepared by..., of stearic acid that is derived from edible sources. (b) The ingredient must be of a purity suitable...

  9. 21 CFR 184.1323 - Glyceryl monooleate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... esterification of commerical oleic acid that is derived either from edible sources or from tall oil fatty acids.... No. 25496-72-4) and glyceryl esters of fatty acids present in commercial oleic acid. (b)...

  10. 21 CFR 184.1323 - Glyceryl monooleate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... commerical oleic acid that is derived either from edible sources or from tall oil fatty acids meeting the...) and glyceryl esters of fatty acids present in commercial oleic acid. (b) The ingredient must be of...

  11. Bioaequivalence of sublingual glycerol trinitrate. Bioavailability and haemodynamic effects after application of a fluorochlorohydrocarbons-dependent spray and a new pumping system.

    PubMed

    Huber, T; Merz, P G; Harder, S; Rietbrock, N

    1990-12-01

    Bioaequivalence of glycerol trinitrate (GTN, CAS 55630) was investigated in 16 healthy volunteers after sublingual application of 2 x 0.41 mg GTN from two different spray-formulations (A: fluorochlorohydrocarbons (FHC)-dependent formulation; B: FHC-free pumping system). Plasma concentrations of GTN (measured by a gas chromatographic method) and haemodynamic effects (measured by digital plethysmography) were monitored 30 min after application. EC50 of the individual concentration-effect curves were calculated and linked to the individual concentration-time curves to establish the time of reaching EC50 (tEC50). AUC0-infinity, Cmax, tmax and the haemodynamic parameters were compared intraindividually (Wilcoxons matched pairs sign rank test), bioequivalence of B to A was tested on the basis of nonparametric 95%-confidence intervals (Tukey). There was no significant difference in the AUC0-infinity (A: 14.2 ng min/ml, B: 16.3 ng min/ml), but significant differences were obtained in Cmax (A: 1.41 ng/ml, B: 2.77 ng/ml, p less than 0.01) and tmax (A: 6.8 min, B: 3.9 min, p less than 0.01). The confidence intervals of the ratio B/A were 0.81-1.56 for AUC0-infinity, 1.3-3.13 for Cmax and 0.50-0.58 for tmax. The GTN-response did not differ after both formulations (EC50 A: 0.441 ng/ml, EC50 B: 0.421 ng/ml), but significant differences were observed for tEC50 (A: 2.82 min, B: 1.05 min, p less than 0.01). Preparation B exhibits a superior bioavailability and a more rapid onset of haemodynamic efficacy.

  12. Acute Oral Toxicity of Trimethylolethane Trinitrate (TMETN) in Sprague- Dawley Rats

    DTIC Science & Technology

    1989-07-01

    61 LeTellier et al.--16 Appendix A: CHEMICAL DATA Chemical Name: 1,3- Propanediol , 2-methyl-2 [(nitroxy)methyl]-dinitrate (ester) Other Names: 1,3... Propanediol -2-(hydroxymethyl)-2-methyl-, trinitrate; 1,1,1-trimethylolethane trinitrate (TMETN), metriol trinitrate (MTN); nitropentaglycerin Lot... Propanediol , 2-(hydroxymethyl)- 2-methyl -, trinitrate (TMETN). Species: Rat Strain: Sprague-Dawley. History: See LAIR SOP-OP-STX-36. Animals that

  13. 21 CFR 184.1328 - Glyceryl behenate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... not more than 2.5 percent free fatty acids. (2) Behenic acid. Between 80 and 90 percent of the total fatty acid content. (3) Acid value. Not more than 4. (4) Saponification value. Between 145 and 165. (5... glyceryl esters of behenic acid made from glycerin and behenic acid (a saturated C22 fatty acid). The...

  14. 21 CFR 184.1328 - Glyceryl behenate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... not more than 2.5 percent free fatty acids. (2) Behenic acid. Between 80 and 90 percent of the total fatty acid content. (3) Acid value. Not more than 4. (4) Saponification value. Between 145 and 165. (5... glyceryl esters of behenic acid made from glycerin and behenic acid (a saturated C22 fatty acid). The...

  15. 21 CFR 184.1328 - Glyceryl behenate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... not more than 2.5 percent free fatty acids. (2) Behenic acid. Between 80 and 90 percent of the total fatty acid content. (3) Acid value. Not more than 4. (4) Saponification value. Between 145 and 165. (5... glyceryl esters of behenic acid made from glycerin and behenic acid (a saturated C22 fatty acid). The...

  16. 21 CFR 184.1329 - Glyceryl palmitostearate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...-, di-, and triglycerides of palmitic acid and stearic acid. (2) Heavy metals (as lead): Not more than... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Glyceryl palmitostearate. 184.1329 Section 184.1329 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  17. 21 CFR 184.1329 - Glyceryl palmitostearate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... substance is a mixture of mono-, di-, and triglycerides of palmitic acid and stearic acid. (2) Heavy metals... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Glyceryl palmitostearate. 184.1329 Section 184.1329 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  18. 21 CFR 184.1329 - Glyceryl palmitostearate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... substance is a mixture of mono-, di-, and triglycerides of palmitic acid and stearic acid. (2) Heavy metals... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Glyceryl palmitostearate. 184.1329 Section 184.1329 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED)...

  19. 21 CFR 184.1329 - Glyceryl palmitostearate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... substance is a mixture of mono-, di-, and triglycerides of palmitic acid and stearic acid. (2) Heavy metals... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Glyceryl palmitostearate. 184.1329 Section 184.1329 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  20. 21 CFR 184.1329 - Glyceryl palmitostearate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... substance is a mixture of mono-, di-, and triglycerides of palmitic acid and stearic acid. (2) Heavy metals... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Glyceryl palmitostearate. 184.1329 Section 184.1329 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  1. 21 CFR 184.1328 - Glyceryl behenate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Glyceryl behenate. 184.1328 Section 184.1328 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) DIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE Listing of Specific Substances Affirmed as GRAS §...

  2. Pharmacology of reflex blinks in the rat: a novel model for headache research.

    PubMed

    Jones, M G; Andreou, A P; McMahon, S B; Spanswick, D

    2016-12-01

    Migraineurs are highly sensitive to the nitric oxide donor glyceryl trinitrate which triggers attacks in many sufferers. In animal studies, glyceryl trinitrate increases neuronal activity in the trigeminovascular pathway and elevates neurotransmitter levels in the brainstem. Many migraineurs also display alterations in blink reflexes, known to involve brainstem circuits. We investigated the effect of GTN on evoked blinks in the anaesthetised rat to determine whether such reflexes may prove useful as the basis for a novel animal model to evaluate potential anti-migraine therapeutic agents. In anaesthetised rats the electromyogram associated with the reflex blink evoked by corneal airpuff was recorded. Rats were infused with glyceryl trinitrate, sumatriptan plus glyceryl trinitrate or vehicle control. Changes in the magnitude of the reflex blink-associated electromyogram following these treatments were measured. Glyceryl trinitrate potentiated the evoked reflex blink-associated EMG response from 2 h after infusion. That effect was abolished by simultaneous infusion of sumatriptan with glyceryl trinitrate. These results show that simple skin surface measurements of evoked electromyographic activity in the rat can reliably detect the evoked blink reflex that can be potentiated by nitric oxide donors. This novel model may be an effective tool for evaluating putative anti-migraine therapeutic agents.

  3. 21 CFR 178.3505 - Glyceryl tri-(12-acetoxy-stearate).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Glyceryl tri-(12-acetoxy-stearate). 178.3505... SANITIZERS Certain Adjuvants and Production Aids § 178.3505 Glyceryl tri-(12-acetoxy-stearate). Glyceryl tri... calcium carbonate/glyceryl tri-(12-acetoxystearate) mixture is used as an adjuvant in polymers in contact...

  4. 21 CFR 172.852 - Glyceryl-lacto esters of fatty acids.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Glyceryl-lacto esters of fatty acids. 172.852... HUMAN CONSUMPTION Multipurpose Additives § 172.852 Glyceryl-lacto esters of fatty acids. Glyceryl-lacto esters of fatty acids (the lactic acid esters of mono- and diglycerides) may be safely used in food in...

  5. 21 CFR 172.852 - Glyceryl-lacto esters of fatty acids.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Glyceryl-lacto esters of fatty acids. 172.852... HUMAN CONSUMPTION Multipurpose Additives § 172.852 Glyceryl-lacto esters of fatty acids. Glyceryl-lacto esters of fatty acids (the lactic acid esters of mono- and diglycerides) may be safely used in food in...

  6. 21 CFR 172.852 - Glyceryl-lacto esters of fatty acids.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Glyceryl-lacto esters of fatty acids. 172.852... HUMAN CONSUMPTION Multipurpose Additives § 172.852 Glyceryl-lacto esters of fatty acids. Glyceryl-lacto esters of fatty acids (the lactic acid esters of mono- and diglycerides) may be safely used in food...

  7. 21 CFR 172.852 - Glyceryl-lacto esters of fatty acids.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Glyceryl-lacto esters of fatty acids. 172.852... HUMAN CONSUMPTION Multipurpose Additives § 172.852 Glyceryl-lacto esters of fatty acids. Glyceryl-lacto esters of fatty acids (the lactic acid esters of mono- and diglycerides) may be safely used in food...

  8. 21 CFR 172.852 - Glyceryl-lacto esters of fatty acids.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Glyceryl-lacto esters of fatty acids. 172.852... § 172.852 Glyceryl-lacto esters of fatty acids. Glyceryl-lacto esters of fatty acids (the lactic acid esters of mono- and diglycerides) may be safely used in food in accordance with the following...

  9. High School Observations of AGN Using the GTN

    NASA Astrophysics Data System (ADS)

    McLin, Kevin M.; Jordan, R.; Perkins, A.; Adkins, J.; Cominsky, L.

    2008-03-01

    Students at Deer Valley High School in Antioch, California have undertaken an AGN monitoring program using telescopes of the Global Telescope Network (GTN) and SkyNet. The GTN is a network of small telescopes funded by GLAST to support the science of high energy astrophysics missions, specifically GLAST, Swift and XMM-Newton. It is managed by the NASA E/PO Group at Sonoma State University. SkyNet is a network of small telescopes managed from the University of North Carolina to catch gamma ray burst afterglows. A primary motivator behind both networks is education. In the program outlined here, high school students will schedule, reduce and analyze observations of active galaxies in order to determine if any microflaring activity has occurred. Students will compare their results with previous studies reported in the literature and then report their own results at the Contra Costa County Science and Engineering Fair. This work will give the students direct experience with several aspects of scientific research, including literature searches, data acquisition and analysis, and reporting of results.

  10. Formation of the NO donors glyceryl mononitrate and glyceryl mononitrite from the reaction of peroxynitrite with glycerol.

    PubMed

    White, C R; Moellering, D; Patel, R P; Kirk, M; Barnes, S; Darley-Usmar, V M

    1997-12-01

    Peroxynitrite (ONOO-), formed from the rapid reaction of superoxide (O2-.) with NO, is known to generate stable compounds capable of donating NO on reaction with thiols and molecules containing hydroxy groups. Using glycerol as a model compound for the reactions of ONOO- with biomolecules containing hydroxy groups, we separated the products and identified them by HPLC/MS. It was shown that both glyceryl mononitrate and glyceryl mononitrite were formed and released NO on incubation with copper and l-cysteine. The compounds were stable over a period of 4h when shielded from light and kept on ice. Slow spontaneous decomposition occurred in the buffer used for the bioassay, but this was not sufficient to explain the vasorelaxing properties of these NO donors. It is concluded that the stable organic nitrate and nitrite have the capacity to be metabolized by vascular tissues, resulting in vasorelaxation.

  11. Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates.

    PubMed

    Daiber, Andreas; Oelze, Matthias; Coldewey, Meike; Bachschmid, Markus; Wenzel, Philip; Sydow, Karsten; Wendt, Maria; Kleschyov, Andrei L; Stalleicken, Dirk; Ullrich, Volker; Mülsch, Alexander; Münzel, Thomas

    2004-12-01

    Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and pentaerythritol trinitrate in phenylephrine-constricted rat aorta, whereas vasodilator responses to isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, and the endothelium-dependent vasodilator acetylcholine were not affected. Likewise, benomyl decreased GTN- and PETN-elicited phosphorylation of the cGMP-activated protein kinase substrate vasodilator-stimulated phosphoprotein (VASP) but not that elicited by other nitrates. The vasodilator potency of organic nitrates correlated with their potency to inhibit ALDH-2 dehydrogenase activity in mitochondria from rat heart and increase mitochondrial superoxide formation, as detected by chemiluminescence. In contrast, mitochondrial ALDH-2 esterase activity was not affected by PETN and its metabolites, whereas it was inhibited by benomyl, GTN applied in vitro and in vivo, and some sulfhydryl oxidants. The bioactivation-related metabolism of GTN to glyceryl-1,2-dinitrate by isolated RAW macrophages was reduced by the ALDH-2 inhibitors benomyl and daidzin, as well as by GTN at concentrations >1 microM. We conclude that mitochondrial ALDH-2, specifically its esterase activity, is required for the bioactivation of the organic nitrates with high vasodilator potency, such as GTN and PETN, but not for the less potent nitrates. It is interesting that ALDH-2 esterase activity was inhibited by GTN only, not by the other nitrates tested. This difference might explain why GTN elicits mitochondrial superoxide formation and nitrate tolerance with the highest potency.

  12. Stable isotope-assisted LC-MS/MS monitoring of glyceryl trinitrate bioactivation in a cell culture model of nitrate tolerance.

    PubMed

    Axton, Elizabeth R; Hardardt, Elizabeth A; Stevens, Jan F

    2016-04-15

    The nitric oxide (NO) metabolites nitrite (NO2(-)) and nitrate (NO3(-)) can be quantified as an endpoint of endothelial function. We developed a LC-MS/MS method of measuring nitrite and nitrate isotopologues, which has a lower limit of quantification (LLOQ) of 1 nM. This method allows for isotopic labeling to differentiate newly formed nitrite and nitrate from nanomolar to micromolar background levels of nitrite and nitrate in biological matrices. This method utilizes 2,3-diaminonaphthalene (DAN) derivatization, which reacts with nitrite under acidic conditions to produce 2,3-naphthotriazole (NAT). NAT was chromatographically separated on a Shimadzu LC System with an Agilent Extend-C18 5 μm 2.1 × 150 mm column and detected using a multiple reaction monitoring (MRM) method on an ABSciex 3200 QTRAP mass spectrometer operated in positive mode. Mass spectrometry allows for the quantification of (14)N-NAT (m/z 170.1) and (15)N-NAT (m/z 171.1). Both nitrite and nitrate demonstrated a linear detector response (1 nM - 10 μM, 1 nM - 100 nM, respectively), and were unaffected by common interferences (Dulbecco's Modified Eagle Medium (DMEM), fetal bovine serum (FBS), phenol red, and NADPH). This method requires minimal sample preparation, making it ideal for most biological applications. We applied this method to develop a cell culture model to study the development of nitrate tolerance in human endothelial cells (EA.hy926).

  13. Serelaxin Treatment Reduces Oxidative Stress and Increases Aldehyde Dehydrogenase-2 to Attenuate Nitrate Tolerance

    PubMed Central

    Leo, Chen Huei; Fernando, Dhanushke T.; Tran, Lillie; Ng, Hooi Hooi; Marshall, Sarah A.; Parry, Laura J.

    2017-01-01

    Background: Glyceryl trinitrate (GTN) is a commonly prescribed treatment for acute heart failure patients. However, prolonged GTN treatment induces tolerance, largely due to increased oxidative stress and reduced aldehyde dehydrogenase-2 (ALDH-2) expression. Serelaxin has several vasoprotective properties, which include reducing oxidative stress and augmenting endothelial function. We therefore tested the hypothesis in rodents that serelaxin treatment could attenuate low-dose GTN-induced tolerance. Methods and Results: Co-incubation of mouse aortic rings ex vivo with GTN (10 μM) and serelaxin (10 nM) for 1 h, restored GTN responses, suggesting that serelaxin prevented the development of GTN tolerance. Male Wistar rats were subcutaneously infused with ethanol (control), low-dose GTN+placebo or low-dose GTN+serelaxin via osmotic minipumps for 3 days. Aortic vascular function and superoxide levels were assessed using wire myography and lucigenin-enhanced chemiluminescence assay respectively. Changes in aortic ALDH-2 expression were measured by qPCR and Western blot respectively. GTN+placebo infusion significantly increased superoxide levels, decreased ALDH-2 and attenuated GTN-mediated vascular relaxation. Serelaxin co-treatment with GTN significantly enhanced GTN-mediated vascular relaxation, reduced superoxide levels and increased ALDH-2 expression compared to GTN+placebo-treated rats. Conclusion: Our data demonstrate that a combination of serelaxin treatment with low dose GTN attenuates the development of GTN-induced tolerance by reducing superoxide production and increasing ALDH-2 expression in the rat aorta. We suggest that serelaxin may improve nitrate efficacy in a clinical setting. PMID:28377719

  14. Nitric oxide signaling pathway activation inhibits the immune escape of pancreatic carcinoma cells

    PubMed Central

    LU, YEBIN; HU, JUANJUAN; SUN, WEIJIA; DUAN, XIAOHUI; CHEN, XIONG

    2014-01-01

    The aim of the present study was to investigate the effect of the nitric oxide signaling pathway on immune escape; thus, a tumorigenesis model was established using nude mice. The mice were inoculated with pancreatic carcinoma cells and divided into two groups, a glyceryl trinitrate (GTN) and a placebo group. When tumor volumes reached 150 mm3, the mice in the GTN group were treated with GTN transdermal patches (dose, 7.3 μg/h) while the mice in the placebo group were administered untreated patches. Following treatment, the tumor volume was recorded every 3–4 days and after 28 days, the tumors were analyzed. The results indicated that GTN treatment may reduce the levels of soluble major histocompatibility complex class I chain-related molecules, and natural killer group 2 member D, as well as inhibiting tumor growth. PMID:25364398

  15. Numerical study of electron beam welded butt joints with the GTN model

    NASA Astrophysics Data System (ADS)

    Tu, Haoyun; Schmauder, Siegfried; Weber, Ulrich

    2012-08-01

    The fracture behavior of S355NL electron beam welded steel joints is investigated experimentally and numerically. The simulation of crack propagation in an electron beam welded steel joint was performed with the Gurson-Tvergaard-Needleman (GTN) damage model. A parameter study of the GTN model was adopted which reveals the influence of parameters on the material behavior of notched round and compact tension specimens. Based on the combined method of metallographic investigations and numerical calibration, the GTN parameters were fixed. The same parameters were used to predict the ductile fracture of compact tension specimens with the initial crack located at different locations. Good match can be found between the numerical and experimental results in the form of force versus Crack Opening Displacement as well as fracture resistance curves.

  16. Glyceryl ether monooxygenase resembles aromatic amino acid hydroxylases in metal ion and tetrahydrobiopterin dependence.

    PubMed

    Watschinger, Katrin; Keller, Markus A; Hermetter, Albin; Golderer, Georg; Werner-Felmayer, Gabriele; Werner, Ernst R

    2009-01-01

    Glyceryl ether monooxygenase is a tetrahydrobiopterin-dependent membrane-bound enzyme which catalyses the cleavage of lipid ethers into glycerol and the corresponding aldehyde. Despite many different characterisation and purification attempts, so far no gene and primary sequence have been assigned to this enzyme. The seven other tetrahydrobiopterin-dependent enzymes can be divided in the family of aromatic amino acid hydroxylases - comprising phenylalanine hydroxylase, tyrosine hydroxylase and the two tryptophan hydroxylases - and into the three nitric oxide synthases. We tested the influences of different metal ions and metal ion chelators on glyceryl ether monooxygenase, phenylalanine hydroxylase and nitric oxide synthase activity to elucidate the relationship of glyceryl ether monooxygenase to these two families. 1,10-Phenanthroline, an inhibitor of non-heme iron-dependent enzymes, was able to potently block glyceryl ether monooxygenase as well as phenylalanine hydroxylase, but had no effect on inducible nitric oxide synthase. Two tetrahydrobiopterin analogues, N(5)-methyltetrahydrobiopterin and 4-aminotetrahydrobiopterin, had a similar impact on glyceryl ether monooxygenase activity, as has already been shown for phenylalanine hydroxylase. These observations point to a close analogy of the role of tetrahydrobiopterin in glyceryl ether monooxygenase and in aromatic amino acid hydroxylases and suggest that glyceryl ether monooxygenase may require a non-heme iron for catalysis.

  17. Compressibility of tableting materials and properties of tablets with glyceryl behenate.

    PubMed

    Mužíková, Jitka; Muchová, Sandra; Komersová, Alena; Lochař, Václav

    2015-03-01

    The paper studies the compressibility of directly compressible tableting materials with dry binders, spray-dried lactose and microcrystalline cellulose, and glyceryl dibehenate at various concentrations. Compressibility was evaluated by means of the energy profile of compression and tensile strength of tablets. Release rate of the active ingredient, salicylic acid, from the tablets was also examined. In the case of microcrystalline cellulose, a higher concentration of glyceryl dibehenate increased the strength of tablets, while this did not occur in the case of spray-dried lactose. Increasing concentration of glyceryl dibehenate prolonged the release of salicylic acid; however, no statistically significant difference was found compared to the type of the dry binder used.

  18. Synthesis, chiral HPLC resolution and configuration assignment of 1-phenylglyceryl trinitrate stereomers.

    PubMed

    Chegaev, Konstantin; Lazzarato, Loretta; Tron, Gian Cesare; Marabello, Domenica; Stilo, Antonella Di; Cena, Clara; Fruttero, Roberta; Gasco, Alberto; Vanthuyne, Nicolas; Roussel, Christian

    2006-06-01

    As an introductory study of in vitro vasodilating activity, the access to the four stereomers of 1-phenylglyceryl trinitrate is described using achiral and chiral chromatography. For semi-preparative separation of the enantiomers, a Chiralcel OD (250 x 10 mm, 10 microm) was used. Catalytic reduction leading to the corresponding stereomers of 1-phenylglycerol allowed absolute configuration assignments. The same methods were used for the separation and configuration assignment of the enantiomers of 3-phenylpropane-1,2-diyl dinitrate.

  19. The GTN-P Data Management System: A central database for permafrost monitoring parameters of the Global Terrestrial Network for Permafrost (GTN-P) and beyond

    NASA Astrophysics Data System (ADS)

    Lanckman, Jean-Pierre; Elger, Kirsten; Karlsson, Ævar Karl; Johannsson, Halldór; Lantuit, Hugues

    2013-04-01

    Permafrost is a direct indicator of climate change and has been identified as Essential Climate Variable (ECV) by the global observing community. The monitoring of permafrost temperatures, active-layer thicknesses and other parameters has been performed for several decades already, but it was brought together within the Global Terrestrial Network for Permafrost (GTN-P) in the 1990's only, including the development of measurement protocols to provide standardized data. GTN-P is the primary international observing network for permafrost sponsored by the Global Climate Observing System (GCOS) and the Global Terrestrial Observing System (GTOS), and managed by the International Permafrost Association (IPA). All GTN-P data was outfitted with an "open data policy" with free data access via the World Wide Web. The existing data, however, is far from being homogeneous: it is not yet optimized for databases, there is no framework for data reporting or archival and data documentation is incomplete. As a result, and despite the utmost relevance of permafrost in the Earth's climate system, the data has not been used by as many researchers as intended by the initiators of the programs. While the monitoring of many other ECVs has been tackled by organized international networks (e.g. FLUXNET), there is still no central database for all permafrost-related parameters. The European Union project PAGE21 created opportunities to develop this central database for permafrost monitoring parameters of GTN-P during the duration of the project and beyond. The database aims to be the one location where the researcher can find data, metadata, and information of all relevant parameters for a specific site. Each component of the Data Management System (DMS), including parameters, data levels and metadata formats were developed in cooperation with the GTN-P and the IPA. The general framework of the GTN-P DMS is based on an object oriented model (OOM), open for as many parameters as possible, and

  20. The new database of the Global Terrestrial Network for Permafrost (GTN-P)

    NASA Astrophysics Data System (ADS)

    Biskaborn, B. K.; Lanckman, J.-P.; Lantuit, H.; Elger, K.; Streletskiy, D. A.; Cable, W. L.; Romanovsky, V. E.

    2015-09-01

    The Global Terrestrial Network for Permafrost (GTN-P) provides the first dynamic database associated with the Thermal State of Permafrost (TSP) and the Circumpolar Active Layer Monitoring (CALM) programs, which extensively collect permafrost temperature and active layer thickness (ALT) data from Arctic, Antarctic and mountain permafrost regions. The purpose of GTN-P is to establish an early warning system for the consequences of climate change in permafrost regions and to provide standardized thermal permafrost data to global models. In this paper we introduce the GTN-P database and perform statistical analysis of the GTN-P metadata to identify and quantify the spatial gaps in the site distribution in relation to climate-effective environmental parameters. We describe the concept and structure of the data management system in regard to user operability, data transfer and data policy. We outline data sources and data processing including quality control strategies based on national correspondents. Assessment of the metadata and data quality reveals 63 % metadata completeness at active layer sites and 50 % metadata completeness for boreholes. Voronoi tessellation analysis on the spatial sample distribution of boreholes and active layer measurement sites quantifies the distribution inhomogeneity and provides a potential method to locate additional permafrost research sites by improving the representativeness of thermal monitoring across areas underlain by permafrost. The depth distribution of the boreholes reveals that 73 % are shallower than 25 m and 27 % are deeper, reaching a maximum of 1 km depth. Comparison of the GTN-P site distribution with permafrost zones, soil organic carbon contents and vegetation types exhibits different local to regional monitoring situations, which are illustrated with maps. Preferential slope orientation at the sites most likely causes a bias in the temperature monitoring and should be taken into account when using the data for global

  1. 21 CFR 178.3505 - Glyceryl tri-(12-acetoxy-stearate).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... provisions of this section. (a) The additive is applied to the surface of calcium carbonate at a level not to exceed 1 weight-percent of the total mixture. (b) The calcium carbonate/glyceryl tri-(12-acetoxystearate...

  2. 21 CFR 178.3505 - Glyceryl tri-(12-acetoxy-stearate).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... surface of calcium carbonate at a level not to exceed 1 weight-percent of the total mixture. (b) The calcium carbonate/glyceryl tri-(12-acetoxystearate) mixture is used as an adjuvant in polymers in contact...

  3. 21 CFR 178.3505 - Glyceryl tri-(12-acetoxy-stearate).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... surface of calcium carbonate at a level not to exceed 1 weight-percent of the total mixture. (b) The calcium carbonate/glyceryl tri-(12-acetoxystearate) mixture is used as an adjuvant in polymers in contact...

  4. 21 CFR 178.3505 - Glyceryl tri-(12-acetoxy-stearate).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... surface of calcium carbonate at a level not to exceed 1 weight-percent of the total mixture. (b) The calcium carbonate/glyceryl tri-(12-acetoxystearate) mixture is used as an adjuvant in polymers in contact...

  5. Binary blend of glyceryl monooleate and glyceryl monostearate for magnetically induced thermo-responsive local drug delivery system.

    PubMed

    Mengesha, Abebe E; Wydra, Robert J; Hilt, J Zach; Bummer, Paul M

    2013-12-01

    To develop a novel monoglycerides-based thermal-sensitive drug delivery system, specifically for local intracavitary chemotherapy. Lipid matrices containing mixtures of glyceryl monooleate (GMO) and glyceryl monostearate (GMS) were evaluated for their potential application as magnetically induced thermo-responsive local drug delivery systems using a poorly water-soluble model drug, nifedipine (NF). Oleic acid-modified iron oxide (OA-Fe3O4) nanoparticles were embedded into the GMO-GMS matrix for remote activation of the drug release using an alternating magnetic field (AMF). The crystallization behavior of binary blends of GMO and GMS as characterized by DSC did show temperature dependent phase transition. GMO-GMS (75:25 wt%) blend showed a melting (T m ) and crystallization (T c ) points at 42°C and 37°C, respectively indicating the potential of the matrix to act as an 'on-demand' drug release. The matrix released only 35% of the loaded drug slowly in 10 days at 37°C whereas 96% release was obtained at 42°C. A concentration of 0.5% OA-Fe3O4 heated the matrix to 42.3 and 45.5°C within 5 min and 10 min of AMF exposure, respectively. The in vitro NF release profiles form the monoglycerides matrix containing 0.5% OA-Fe3O4 nanoparticles after AMF activation confirmed the thermo-responsive nature of the matrix that could provide pulsatile drug release 'on-demand'.

  6. Failure analysis of AZ31 magnesium alloy sheets based on the extended GTN damage model

    NASA Astrophysics Data System (ADS)

    Wang, Rui-ze; Chen, Zhang-hua; Li, Yu-jie; Dong, Chao-fang

    2013-12-01

    Based on the Gurson-Tvergaard-Needleman (GTN) model and Hill's quadratic anisotropic yield criterion, a combined experimental-numerical study on fracture initiation in the process of thermal stamping of Mg alloy AZ31 sheets was carried out. The aim is to predict the formability of thermal stamping of the Mg alloy sheets at different temperatures. The presented theoretical framework was implemented into a VUMAT subroutine for ABAQUS/EXPLICIT. Internal damage evolution due to void growth and coalescence developed at different temperatures in the Mg alloy sheets was observed by scanning electron microscopy (SEM). Moreover, the thermal effects on the void growth, coalescence, and fracture behavior of the Mg alloy sheets were analyzed by the extended GTN model and forming limit diagrams (FLD). Parameters employed in the GTN model were determined from tensile tests and numerical iterative computation. The distribution of major and minor principal strains in the specimens was determined from the numerical results. Therefore, the corresponding forming limit diagrams at different stress levels and temperatures were drawn. The comparison between the predicted forming limits and the experimental data shows a good agreement.

  7. Preparation and optimization of glyceryl behenate-based highly porous pellets containing cilostazol.

    PubMed

    Hwang, Kyu-Mok; Byun, Woojin; Cho, Cheol-Hee; Park, Eun-Seok

    2016-11-03

    The aim of this study was to prepare a highly porous multiparticulate dosage form containing cilostazol for gastroretentive drug delivery. The floating pellets were prepared with glyceryl behenate as a matrix former and camphor as a sublimating agent by extrusion/spheronization and sublimation under vacuum. Granules prepared with sublimation at 60 °C displayed a slower dissolution rate and smoother surface morphology than those prepared at lower temperatures. This was unexpected as the reported melting point of glyceryl behenate is higher than 69 °C. The DSC study revealed that melting began at a lower temperature owing to the multicomponent property of glyceryl behenate, which led to a sintering effect. The prepared pellets were spherical with unimodal size distribution. They also had porous structures with increased porosity, which led to immediate buoyancy. As cilostazol is a hydrophobic drug that has an erosion-based release mechanism, drug release profile was highly correlated with the percentage of disintegrated pellets. Various excipients were added to the glyceryl behenate-based formulation to increase the floating duration. When hydroxyethyl cellulose was added to the glyceryl behenate-based pellets, acceptable dissolution rate and buoyancy were acquired. This system could potentially be used for gastroretentive delivery of various hydrophobic drugs, which was generally considered difficult.

  8. STUDY OF DUAL MATRIX TABLETS CONTAINING HYPROMELLOSE OF DIFFERENT VISCOSITY DEGREE AND GLYCERYL DIBEHENATE.

    PubMed

    Mužíková, Jitka; Holubová, Katerina; Komersová, Alena; Lochar, Václav

    2016-01-01

    Studies are described on the compressibility of directly compressible tableting materials containing two viscosity types of hypromellose in two concentrations and tableting materials containing additional glyceryl dibehenate, also in two concentrations. Compressibility is evaluated by means of the energy profile of the compression process and determination of tensile strength of tablets. Dissolution test examines the rate of release of the active ingredient from matrix tablets, which is subsequently evaluated mathematically. Increased concentrations of both hypromelloses and an addition of glyceryl dibehenate into tablets with both types of hypromellose improved compressibility. The rate of drug release was decreased with increasing viscosity degree of hypromellose and its increasing concentration. An addition of glyceryl dibehenate exerted the same influence on release as increased concentrations of the pertinent hypromellose.

  9. Parameter Identification of GTN Model Using Response Surface Methodology for High-Strength Steel BR1500HS

    NASA Astrophysics Data System (ADS)

    Wang, Li-yong; Li, Le

    2017-08-01

    In order to investigate the damage evolution of ultra-high-strength steels at different temperatures, a series of the uniaxial tensile tests were carried out at different temperatures (20-800 °C) with a constant true strain rate (1 s-1). And then, two different deformation mechanisms were employed to describe the flow behaviors of BR1500HS. It is found that dynamic recrystallization (DRX) occurs during the deformation process at high temperatures (600-800 °C), while the tensile flow behaviors exhibit a very long work hardening period before a short flow softening stages without DRX at lower temperatures of 20-400 °C Furthermore, the Gurson-Tvergaard-Needleman (GTN) damage model was employed in this work to evaluate the ductile damage phenomena of BR1500HS. To determine the four vital parameters in GTN model, several numerical simulations were designed by central composite design and conducted by finite element simulation, and then the error evaluation functions ( R) were established using four GTN parameters. Thereafter, the four parameters of GTN model were determined along with four minimum values of R by use of response surface methodology (RSM) and least square method. The results show that temperature affects the microvoid volume fraction significantly. Additionally, the parameters of GTN model were applied in the finite element simulation model and a comparison between the simulation results and the scanning electron microscopic observations was conducted.

  10. Parameter Identification of GTN Model Using Response Surface Methodology for High-Strength Steel BR1500HS

    NASA Astrophysics Data System (ADS)

    Wang, Li-yong; Li, Le

    2017-06-01

    In order to investigate the damage evolution of ultra-high-strength steels at different temperatures, a series of the uniaxial tensile tests were carried out at different temperatures (20-800 °C) with a constant true strain rate (1 s-1). And then, two different deformation mechanisms were employed to describe the flow behaviors of BR1500HS. It is found that dynamic recrystallization (DRX) occurs during the deformation process at high temperatures (600-800 °C), while the tensile flow behaviors exhibit a very long work hardening period before a short flow softening stages without DRX at lower temperatures of 20-400 °C Furthermore, the Gurson-Tvergaard-Needleman (GTN) damage model was employed in this work to evaluate the ductile damage phenomena of BR1500HS. To determine the four vital parameters in GTN model, several numerical simulations were designed by central composite design and conducted by finite element simulation, and then the error evaluation functions (R) were established using four GTN parameters. Thereafter, the four parameters of GTN model were determined along with four minimum values of R by use of response surface methodology (RSM) and least square method. The results show that temperature affects the microvoid volume fraction significantly. Additionally, the parameters of GTN model were applied in the finite element simulation model and a comparison between the simulation results and the scanning electron microscopic observations was conducted.

  11. Integration of glacier databases within the Global Terrestrial Network for Glaciers (GTN-G)

    NASA Astrophysics Data System (ADS)

    Zemp, M.; Raup, B. H.; Armstrong, R.; Ballagh, L.; Gärtner-Roer, I.; Haeberli, W.; Hoelzle, M.; Kääb, A.; Kargel, J.; Paul, F.

    2009-04-01

    Changes in glaciers and ice caps provide some of the clearest evidence of climate change and have impacts on global sea level fluctuations, regional hydrological cycles and local natural hazard situations. Internationally coordinated collection and distribution of standardized information about glaciers and ice caps was initiated in 1894 and is today coordinated within the Global Terrestrial Network for Glaciers (GTN-G). A recently established GTN-G Steering Committee coordinates, supports and advices the operational bodies responsible for the international glacier monitoring, which are the World Glacier Monitoring Service (WGMS), the US National Snow and Ice Data Center (NSIDC) and the Global Land Ice Measurements from Space (GLIMS) initiative. In this presentation, we provide an overview of (i) the integration of the various operational databases, (ii) the development of a one-stop web-interface to these databases, and (iii) the available datasets. By joint efforts consistency and interoperability of the different glacier databases is elaborated. Thereby, the lack of a complete worldwide, detailed glacier inventory as well as different historical developments and methodological contexts of the datasets are major challenges for linking individual glaciers throughout the databases. A map-based web-interface, implemented based on OpenLayer 2.0 and Web Map/Feature Services, is elaborated to spatially link the available data and to provide data users a fast overview of all available data. With this new online service, GTN-G provides fast access to information on glacier inventory data from 100,000 glaciers mainly based on aerial photographs and from 80,000 glaciers mainly based on satellite images, length change series from 1,800 glaciers, mass balance series from 230 glaciers, special events (e.g., hazards, surges, calving instabilities) from 130 glaciers, as well as 10,000 photographs from some 470 glaciers.

  12. Final report on the safety assessment of trilaurin, triarachidin, tribehenin, tricaprin, tricaprylin, trierucin, triheptanoin, triheptylundecanoin, triisononanoin, triisopalmitin, triisostearin, trilinolein, trimyristin, trioctanoin, triolein, tripalmitin, tripalmitolein, triricinolein, tristearin, triundecanoin, glyceryl triacetyl hydroxystearate, glyceryl triacetyl ricinoleate, and glyceryl stearate diacetate.

    PubMed

    Johnson, W

    2001-01-01

    Triesters of glycerin and aliphatic acids, known generically as glyceryl triesters and specifically as Trilaurin, etc., are used in cosmetic products as occlusive skin-conditioning agents and/or nonaqueous viscosity-increasing agents. Hundreds of glyceryl triesters are used in a wide variety of cosmetic products at concentrations ranging from a few tenths of a percent to 46%. Glyceryl triesters are also known as triglycerides; ingested triglycerides are metabolized to monoglycerides, free fatty acids, and glycerol, all of which are absorbed in the intestinal mucosa and undergo further metabolism. Dermal absorption of Triolein in mice was nil; the oil remained at the application site. Only slight absorption was seen in guinea pig skin. Tricaprylin and other glyceryl triesters have been shown to increase the skin penetration of drugs. Little or no acute, subchronic, or chronic oral toxicity was seen in animal studies unless levels approached a significant percentage of caloric intake. Subcutaneous injections of Tricaprylin in rats over a period of 5 weeks caused a granulomatous reaction characterized by oil deposits surrounded by macrophages. Dermal application was not associated with significant irritation in rabbit skin. Ocular exposures were, at most, mildly irritating to rabbit eyes. No evidence of sensitization or photosensitization was seen in a guinea pig maximization test. Most of the genotoxicity test systems were negative. Tricaprylin, Trioctanoin, and Triolein have historically been used as vehicles in carcinogenicity testing of other chemicals. In one study, subcutaneous injection of Tricaprylin in newborn mice produced more tumors in lymphoid tissue than were seen in untreated animals, whereas neither subcutaneous or intraperitoneal injection in 4- to 6-week-old female mice produced any tumors in another study. Trioctanoin injected subcutaneously in hamsters produced no tumors. Trioctanoin injected intraperitoneally in pregnant rats was associated with

  13. Water quantitatively induces the mucoadhesion of liquid crystalline phases of glyceryl monooleate.

    PubMed

    Lee, J; Young, S A; Kellaway, I W

    2001-05-01

    The possible role of water in the mucoadhesion phenomenon exhibited by the liquid crystalline phases of glyceryl monooleate was investigated using an in-vitro tensile strength technique. The mucoadhesion of the liquid crystalline phases of glyceryl monooleate was found to occur following uptake of water. The mucoadhesive force of the cubic phase was consistent since it is not capable of taking up additional water. An increase in pre-load period greatly facilitated the mucoadhesion of glyceryl monooleate (0% w/w initial water content), suggesting that the mucoadhesion is dependent upon the extent of the dehydration of the substrate. A good linear relationship between initial water content of the liquid crystalline phases and mucoadhesive force led to the conclusion that the mucoadhesive force increased with decreasing initial water concentration. Rheological properties of the liquid crystalline phases were also studied to allow a correlation between physical changes and mucoadhesion of the liquid crystalline phases, revealing that higher water concentrations in the liquid crystalline phases led to a more ordered structure that showed less mucoadhesion. The results of this study indicated that the mucoadhesive force of the liquid crystalline phases of glyceryl monooleate is determined by the capability to take up water from a water-rich environment. It may, therefore, be advantageous to use the lamellar phase as a buccal drug carrier as opposed to the relatively less mucoadhesive cubic phase.

  14. Numerical Simulation of Tension Properties for Al-Cu Alloy Friction Stir-Welded Joints with GTN Damage Model

    NASA Astrophysics Data System (ADS)

    Sun, Guo-Qin; Sun, Feng-Yang; Cao, Fang-Li; Chen, Shu-Jun; Barkey, Mark E.

    2015-11-01

    The numerical simulation of tensile fracture behavior on Al-Cu alloy friction stir-welded joint was performed with the Gurson-Tvergaard-Needleman (GTN) damage model. The parameters of the GTN model were studied in each region of the friction stir-welded joint by means of inverse identification. Based on the obtained parameters, the finite element model of the welded joint was built to predict the fracture behavior and tension properties. Good agreement can be found between the numerical and experimental results in the location of the tensile fracture and the mechanical properties.

  15. A central database for the Global Terrestrial Network for Permafrost (GTN-P)

    NASA Astrophysics Data System (ADS)

    Elger, Kirsten; Lanckman, Jean-Pierre; Lantuit, Hugues; Karlsson, Ævar Karl; Johannsson, Halldór

    2013-04-01

    The Global Terrestrial Network for Permafrost (GTN-P) is the primary international observing network for permafrost sponsored by the Global Climate Observing System (GCOS) and the Global Terrestrial Observing System (GTOS), and managed by the International Permafrost Association (IPA). It monitors the Essential Climate Variable (ECV) permafrost that consists of permafrost temperature and active-layer thickness, with the long-term goal of obtaining a comprehensive view of the spatial structure, trends, and variability of changes in the active layer and permafrost. The network's two international monitoring components are (1) CALM (Circumpolar Active Layer Monitoring) and the (2) Thermal State of Permafrost (TSP), which is made of an extensive borehole-network covering all permafrost regions. Both programs have been thoroughly overhauled during the International Polar Year 2007-2008 and extended their coverage to provide a true circumpolar network stretching over both Hemispheres. GTN-P has gained considerable visibility in the science community in providing the baseline against which models are globally validated and incorporated in climate assessments. Yet it was until now operated on a voluntary basis, and is now being redesigned to meet the increasing expectations from the science community. To update the network's objectives and deliver the best possible products to the community, the IPA organized a workshop to define the user's needs and requirements for the production, archival, storage and dissemination of the permafrost data products it manages. From the beginning on, GNT-P data was "outfitted" with an open data policy with free data access via the World Wide Web. The existing data, however, is far from being homogeneous: is not yet optimized for databases, there is no framework for data reporting or archival and data documentation is incomplete. As a result, and despite the utmost relevance of permafrost in the Earth's climate system, the data has not been

  16. Reversion of nitrate tolerance in rat aorta rings by freeze-dried red wine.

    PubMed

    Fusi, Fabio; Sgaragli, Giampietro

    2015-04-01

    Chronically administered organic nitrates induce nitrate tolerance and endothelial dysfunction, which limit their therapeutic use. eNOS uncoupling, ROS over-production, aldehyde dehydrogenase-2 as well as superoxide dismutase (SOD) oxidative inhibition, and cGMP desensitization are thought to play an important role. Natural polyphenols are effective antioxidants, which might counteract the mechanisms leading to nitrate tolerance. The aim of this work was to verify whether freeze-dried (dealcoholized) red wine (FDRW) was able to revert glyceryl trinitrate (GTN) tolerance and endothelial dysfunction induced in rat aorta rings with either GTN or diethyldithiocarbamate (DETCA), an irreversible inhibitor of Cu/Zn SOD. GTN induced a concentration-dependent relaxation of rings pre-contracted with phenylephrine. GTN spasmolysis was significantly reduced in rings pre-incubated with either GTN or DETCA. FDRW, at 2.8 µg of gallic acid equivalents (GAE)/mL concentration, was able to revert partially, though significantly, GTN-induced tolerance but not tolerance and endothelial dysfunction induced by DETCA. This work provides the first evidence in vitro that red wine components, at concentrations comparable to those achieved in human blood after moderate consumption of red wine, revert tolerance to nitrates with a mechanism possibly mediated by SOD. Copyright © 2015 John Wiley & Sons, Ltd.

  17. The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles.

    PubMed

    Mayer, B; Beretta, M

    2008-09-01

    Nitroglycerin (glyceryl trinitrate; GTN) is the most prominent representative of the organic nitrates or nitrovasodilators, a class of compounds that have been used clinically since the late nineteenth century for the treatment of coronary artery disease (angina pectoris), congestive heart failure and myocardial infarction. Medline lists more than 15 000 publications on GTN and other organic nitrates, but the mode of action of these drugs is still largely a mystery. In the first part of this article, we give an overview on the molecular mechanisms of GTN biotransformation resulting in vascular cyclic GMP accumulation and vasodilation with focus on the role of mitochondrial aldehyde dehydrogenase (ALDH2) and the link between the ALDH2 reaction and activation of vascular soluble guanylate cyclase (sGC). In particular, we address the identity of the bioactive species that activates sGC and the potential involvement of nitrite as an intermediate, describe our recent findings suggesting that ALDH2 catalyses direct 3-electron reduction of GTN to NO and discuss possible reaction mechanisms. In the second part, we discuss contingent processes leading to markedly reduced sensitivity of blood vessels to GTN, referred to as vascular nitrate tolerance. Again, we focus on ALDH2 and describe the current controversy on the role of ALDH2 inactivation in tolerance development. Finally, we emphasize some of the most intriguing, in our opinion, unresolved puzzles of GTN pharmacology that urgently need to be addressed in future studies.

  18. The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles

    PubMed Central

    Mayer, B; Beretta, M

    2008-01-01

    Nitroglycerin (glyceryl trinitrate; GTN) is the most prominent representative of the organic nitrates or nitrovasodilators, a class of compounds that have been used clinically since the late nineteenth century for the treatment of coronary artery disease (angina pectoris), congestive heart failure and myocardial infarction. Medline lists more than 15 000 publications on GTN and other organic nitrates, but the mode of action of these drugs is still largely a mystery. In the first part of this article, we give an overview on the molecular mechanisms of GTN biotransformation resulting in vascular cyclic GMP accumulation and vasodilation with focus on the role of mitochondrial aldehyde dehydrogenase (ALDH2) and the link between the ALDH2 reaction and activation of vascular soluble guanylate cyclase (sGC). In particular, we address the identity of the bioactive species that activates sGC and the potential involvement of nitrite as an intermediate, describe our recent findings suggesting that ALDH2 catalyses direct 3-electron reduction of GTN to NO and discuss possible reaction mechanisms. In the second part, we discuss contingent processes leading to markedly reduced sensitivity of blood vessels to GTN, referred to as vascular nitrate tolerance. Again, we focus on ALDH2 and describe the current controversy on the role of ALDH2 inactivation in tolerance development. Finally, we emphasize some of the most intriguing, in our opinion, unresolved puzzles of GTN pharmacology that urgently need to be addressed in future studies. PMID:18574453

  19. Kinetic Studies and Product Characterization during the Basic Hydrolysis of Glyceryl Nitrate Esters

    DTIC Science & Technology

    1979-08-01

    spectra of several available nitrate esters within this category, e.g., allyl nitrate, butyl nitrate, diethylene glycol dinitrate, and triethylene ...which on drying in a vacuum desiccator , yielded a weight for Viscous Fraction (VR). Synthesis of MNG’s and DNG’s The procedures used for the... glycol dinitrate, did not match the spectra of the unknown. 29 A review of the chemistry of the basic hydrolysis of glyceryl nitrate esters suggested

  20. Biocompatible microemulsions for fabrication of glyceryl monostearate solid lipid nanoparticles (SLN) of tretinoin.

    PubMed

    Shah, Kumar A; Joshi, Medha D; Patravale, Vandana B

    2009-08-01

    The objective of the present investigation was to fabricate glyceryl monostearate SLN by employing a biocompatible microemulsion as a template. Biocompatible excipients such as Tween 20 (as a surfactant) and Transcutol P (a cosourfactant) (at different K(m) ratios) were selected for the fabrication of microemulsions. Pseudo-ternary phase diagrams were plotted to identify the area of the microemulsion existence. Glyceryl monostearate SLN were fabricated by dispersing the microemulsion (maintained at 65 degrees C) into cold water (maintained at 2-3 degrees C). The particle size of the SLN was determined by photon correlation spectroscopy. Tretinoin, a lipophilic anti-acne agent was incorporated into SLN as a model drug. The encapsulation efficiency of tretinoin in the SLN was determined by using Nanosep ultrafilteration device at different lipid loads viz. 1%, 1.5% and 2%. Glyceryl monostearate SLN fabricated from biocompatible microemulsion template exhibited average particle size of 175 nm and polydispersity index of 0.833. Tretinoin could be successfully incorporated into SLN and the encapsulation efficiency ranged from 37-48% at different lipid loads.

  1. Novel glyceryl glucoside is a low toxic alternative for cryopreservation agent

    SciTech Connect

    Su, Cathy; Allum, Allison J.; Aizawa, Yasushi; Kato, Takamitsu A.

    2016-08-05

    Glyceryl glucoside (GG, α-D-glucosyglycerol) is a natural glycerol derivative found in alcoholic drinks. Recently GG has been used as an alternative for glycerol in cosmetic products. However, the safety of using GG is still unclear. Currently, dimethyl sulfoxide (DMSO) and glycerol are wildly used in cryopreservation. Despite GG being a derivative of glycerol, the ability of GG in cryopreservation is still unknown. By using a system of Chinese Hamster Ovary cells (CHO), A549 cells and AG1522 cells, the study examined the cryoprotective effects of DMSO, glycerol and GG. Cytotoxic and genotoxic responses induced by the three chemicals were also investigated with CHO to determine the safety of GG for cosmetic products. Our data suggests that GG has great cryopresearvation ability in the concentration of 30%–40% (v/v). For cytotoxic studies, DMSO showed the highest cytotoxicity above 3% (v/v) in cell doubling time delay among three chemicals. For the acute cytotoxicity with trypan blue dye exclusion assay, GG showed stronger cell killing effect within 24 h above 4% (v/v). For the continuous cytotoxicity with colony formation assay for 7 days, DMSO showed significantly reduced clonogenic ability above 2%. In genotoxicity studies, CHO treated with glycerol at 2% concentration induced three times higher frequencies of sister chromatid exchange (SCE) than background levels. GG did not induce significant amounts of SCE compared to background. Micronuclei formation was equally observed in the 2% and above concentrations of glycerol and GG. Our data showed that GG has significant effects on cryopreservation compared to DMSO. Glycerol and GG have similar cytotoxicity effects to CHO, but glycerol induced genotoxic responses in the same concentration. Therefore, we conclude that GG may be a safer alternative compound to glycerol in cosmetic products and safer alternative to DMSO in cryopreservation. -- Highlights: •Glyceryl Glucoside is low cytotoxicity and genotoxicity

  2. Modern Perspectives in the Treatment of Chronic Anal Fissures

    PubMed Central

    Bhardwaj, R; Parker, MC

    2007-01-01

    INTRODUCTION Anal fissures are commonly encountered in routine colorectal practice. Developments in the pharmacological understanding of the internal anal sphincter have resulted in more conservative approaches towards treatment. Simple measures are often effective for early fissures. Glyceryl trinitrate is well established as a first-line pharmacological therapy. The roles of diltiazem and botulinum, particularly as rescue therapy, are not well understood. Surgery has a defined role and should not be discounted completely. METHODS Data were obtained from Medline publications citing ‘anal fissure’. Manual cross-referencing of salient articles was conducted. We have sought to highlight various controversies in the management of anal fissures. FINDINGS Acute fissures may heal spontaneously, although simple conservative measures are sufficient. Idiopathic chronic anal fissures need careful evaluation to decide what therapy is suitable. Pharmacological agents such as glyceryl trinitrate (GTN), diltiazem and botulinum toxin have been subjected to most scrutiny. Though practices in the UK vary, GTN or diltiazem would be suitable as first-line therapy with botulinum toxin used as rescue treatment. Sphincterotomy is indicated for unhealed fissures; fissurectomy has been revisited and advancement flaps have a role in patients in whom sphincter division is not suitable. PMID:17688717

  3. Modern perspectives in the treatment of chronic anal fissures.

    PubMed

    Bhardwaj, R; Parker, M C

    2007-07-01

    Anal fissures are commonly encountered in routine colorectal practice. Developments in the pharmacological understanding of the internal anal sphincter have resulted in more conservative approaches towards treatment. Simple measures are often effective for early fissures. Glyceryl trinitrate is well established as a first-line pharmacological therapy. The roles of diltiazem and botulinum, particularly as rescue therapy, are not well understood. Surgery has a defined role and should not be discounted completely. Data were obtained from Medline publications citing 'anal fissure'. Manual cross-referencing of salient articles was conducted. We have sought to highlight various controversies in the management of anal fissures. Acute fissures may heal spontaneously, although simple conservative measures are sufficient. Idiopathic chronic anal fissures need careful evaluation to decide what therapy is suitable. Pharmacological agents such as glyceryl trinitrate (GTN), diltiazem and botulinum toxin have been subjected to most scrutiny. Though practices in the UK vary, GTN or diltiazem would be suitable as first-line therapy with botulinum toxin used as rescue treatment. Sphincterotomy is indicated for unhealed fissures; fissurectomy has been revisited and advancement flaps have a role in patients in whom sphincter division is not suitable.

  4. Innovations in chronic anal fissure treatment: A systematic review

    PubMed Central

    Poh, Aaron; Tan, Kok-Yang; Seow-Choen, Francis

    2010-01-01

    A chronic anal fissure is a common perianal condition. This review aims to evaluate both existing and new therapies in the treatment of chronic fissures. Pharmacological therapies such as glyceryl trinitrate (GTN), Diltiazem ointment and Botulinum toxin provide a relatively non-invasive option, but with higher recurrence rates. Lateral sphincterotomy remains the gold standard for treatment. Anal dilatation has no role in treatment. New therapies include perineal support devices, Gonyautoxin injection, fissurectomy, fissurotomy, sphincterolysis, and flap procedures. Further research is required comparing these new therapies with existing established therapies. This paper recommends initial pharmacological therapy with GTN or Diltiazem ointment with Botulinum toxin as a possible second line pharmacological therapy. Perineal support may offer a new dimension in improving healing rates. Lateral sphincterotomy should be offered if pharmacological therapy fails. New therapies are not suitable as first line treatments, though they can be considered if conventional treatment fails. PMID:21160880

  5. Validation of formability of laminated sheet metal for deep drawing process using GTN damage model

    NASA Astrophysics Data System (ADS)

    Lim, Yongbin; Cha, Wan-gi; Ko, Sangjin; Kim, Naksoo

    2013-12-01

    In this study, we studied formability of PET/PVC laminated sheet metal which named VCM (Vinyl Coated Metal). VCM offers various patterns and good-looking metal steel used for appliances such as refrigerator and washing machine. But, this sheet has problems which are crack and peeling of film when the material is formed by deep drawing process. To predict the problems, we used finite element method and GTN (Gurson-Tvergaard-Needleman) damage model to represent damage of material. We divided the VCM into 3 layers (PET film, adhesive and steel added PVC) in finite element analysis model to express the crack and peeling phenomenon. The material properties of each layer are determined by reverse engineering based on tensile test result. Furthermore, we performed the simple rectangular deep drawing and simulated it. The simulation result shows good agreement with drawing experiment result in position, punch stroke of crack occurrence. Also, we studied the fracture mechanism of PET film on VCM by comparing the width direction strain of metal and PET film.

  6. Validation of formability of laminated sheet metal for deep drawing process using GTN damage model

    SciTech Connect

    Lim, Yongbin; Cha, Wan-gi; Kim, Naksoo; Ko, Sangjin

    2013-12-16

    In this study, we studied formability of PET/PVC laminated sheet metal which named VCM (Vinyl Coated Metal). VCM offers various patterns and good-looking metal steel used for appliances such as refrigerator and washing machine. But, this sheet has problems which are crack and peeling of film when the material is formed by deep drawing process. To predict the problems, we used finite element method and GTN (Gurson-Tvergaard-Needleman) damage model to represent damage of material. We divided the VCM into 3 layers (PET film, adhesive and steel added PVC) in finite element analysis model to express the crack and peeling phenomenon. The material properties of each layer are determined by reverse engineering based on tensile test result. Furthermore, we performed the simple rectangular deep drawing and simulated it. The simulation result shows good agreement with drawing experiment result in position, punch stroke of crack occurrence. Also, we studied the fracture mechanism of PET film on VCM by comparing the width direction strain of metal and PET film.

  7. Stable, hydroxyl functional polycarbonates with glycerol side chains synthesized from CO(2) and isopropylidene(glyceryl glycidyl ether).

    PubMed

    Geschwind, Jeannette; Frey, Holger

    2013-01-25

    A series of functional polycarbonates, poly((isopropylidene glyceryl glycidyl ether)-co-(glycidyl methyl ether) carbonate) (P((IGG-co-GME) C)) random copolymers with different fractions of 1,2-isopropylidene glyceryl glycidyl ether (IGG) units, is synthesized. After acidic hydrolysis of the acetal protecting groups, a new type of functional polycarbonate prepared directly from CO(2) and glycerol is obtained, namely poly((glyceryl glycerol)-co-(glycidyl methyl ether) carbonate) (P((GG-co-GME) C)). All hydroxyl functional samples exhibit monomodal molecular weight distributions with PDIs between 2.5 and 3.3 and M(n) between 12 000 and 25 000 g mol(-1) . Thermal properties reflect the amorphous structure of the polymers. The materials are stable in bulk and solution. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Application of the Flory-Huggins theory to the solubility of solids in glyceryl trioleate

    USGS Publications Warehouse

    Chiou, Cary T.; Manes, Milton

    1986-01-01

    The conventional thermodynamic deviation for ideal solid–liquid solubilities is modified by substituting the Flory–Huggins model for Raoult's law. A comparison of published data for eleven solides in glyceryl trioleate with the predictions of the conventional and modified equations shows that the significantly higher athermal solubilities from the modified equation are in much better agreement with the experimental data. This suggests that discrepancies between the data and the predictions of the conventional model for ideal systems result from the inappropriate use of Raoult's law for systems with significant solute–solvent size disparity rather than from specific interactions.

  9. Microsatellite (GT)(n) repeats and SNPs in the von Willebrand factor gene promoter do not influence circulating von Willebrand factor levels under normal conditions.

    PubMed

    Daidone, Viviana; Cattini, Maria Grazia; Pontara, Elena; Sartorello, Francesca; Gallinaro, Lisa; Marotti, Alberto; Scaroni, Carla; Pagnan, Antonio; Casonato, Alessandra

    2009-02-01

    Von Willebrand factor (VWF) levels vary considerably in normal individuals, influenced by inherited and acquired modulators. ABO blood group is the major inherited determinant of VWF levels, but a role has also been attributed to the VWF gene promoter, haplotype 1 (-3268G/-2709C/-2661A/-2527G) being associated with higher VWF levels than haplotype 2 (-3268C/-2709T/-2661G/-2527A), and the polymorphic locus (GT)(n) modulating the shear stress-induced activation of the VWF promoter. We characterized the (GT)(n) of the VWF promoter in 394 healthy individuals and assessed whether its variable length influenced VWF levels in normal conditions. (GT)(n) proved highly polymorphic, with alleles from 15 to 24 repeats long. (GT)(21) and (GT)(19) were the most common variants (37.4% and 34.4%, respectively). Short GT repeats (15-19) segregated mainly with haplotype 1, long GT repeats (20-24) with haplotype 2 (p < 0.0001). The number of GT repeats did not correlate with VWF levels, nor did such levels correlate with haplotypes 1 and 2, considered alone or in association with the (GT)(n) locus. We conclude that (GT)(n) and -3268/-2709/-2661/-2527 loci are in strong linkage disequilibrium. This polymorphic region of the VWF promoter does not affect VWF levels under normal conditions, though it might represent an environmentally activable VWF regulation site.

  10. A new class of organic nitrates: investigations on bioactivation, tolerance and cross-tolerance phenomena

    PubMed Central

    Schuhmacher, S; Schulz, E; Oelze, M; König, A; Roegler, C; Lange, K; Sydow, L; Kawamoto, T; Wenzel, P; Münzel, T; Lehmann, J; Daiber, A

    2009-01-01

    Background and purpose: The chronic use of organic nitrates is limited by serious side effects including oxidative stress, nitrate tolerance and/or endothelial dysfunction. The side effects and potency of nitroglycerine depend on mitochondrial aldehyde dehydrogenase (ALDH-2). We sought to determine whether this concept can be extended to a new class of organic nitrates with amino moieties (aminoalkyl nitrates). Experimental approach: Vasodilator potency of the organic nitrates, in vitro tolerance and in vivo tolerance (after continuous infusion for 3 days) were assessed in wild-type and ALDH-2 knockout mice by isometric tension studies. Mitochondrial oxidative stress was analysed by L-012-dependent chemiluminescence and protein tyrosine nitration. Key results: Aminoethyl nitrate (AEN) showed an almost similar potency to glyceryl trinitrate (GTN), even though it is only a mononitrate. AEN-dependent vasodilatation was mediated by cGMP and nitric oxide. In contrast to triethanolamine trinitrate (TEAN) and GTN, AEN bioactivation did not depend on ALDH-2 and caused no in vitro tolerance. In vivo treatment with TEAN and GTN, but not with AEN, induced cross-tolerance to acetylcholine (ACh)-dependent and GTN-dependent relaxation. Although all nitrates tested induced tolerance to themselves, only TEAN and GTN significantly increased mitochondrial oxidative stress in vitro and in vivo. Conclusions and implications: The present results demonstrate that not all high potency nitrates are bioactivated by ALDH-2 and that high potency of a given nitrate is not necessarily associated with induction of oxidative stress or nitrate tolerance. Obviously, there are distinct pathways for bioactivation of organic nitrates, which for AEN may involve xanthine oxidoreductase rather than P450 enzymes. PMID:19563531

  11. GTN-G, WGI, RGI, DCW, GLIMS, WGMS, GCOS - What's all this about? (Invited)

    NASA Astrophysics Data System (ADS)

    Paul, F.; Raup, B. H.; Zemp, M.

    2013-12-01

    In a large collaborative effort, the glaciological community has compiled a new and spa-tially complete global dataset of glacier outlines, the so-called Randolph Glacier Inventory or RGI. Despite its regional shortcomings in quality (e.g. in regard to geolocation, gener-alization, and interpretation), this dataset was heavily used for global-scale modelling ap-plications (e.g. determination of total glacier volume and glacier contribution to sea-level rise) in support of the forthcoming 5th Assessment Report (AR5) of Working Group I of the IPCC. The RGI is a merged dataset that is largely based on the GLIMS database and several new datasets provided by the community (both are mostly derived from satellite data), as well as the Digital Chart of the World (DCW) and glacier attribute information (location, size) from the World Glacier Inventory (WGI). There are now two key tasks to be performed, (1) improving the quality of the RGI in all regions where the outlines do not met the quality required for local scale applications, and (2) integrating the RGI in the GLIMS glacier database to improve its spatial completeness. While (1) requires again a huge effort but is already ongoing, (2) is mainly a technical issue that is nearly solved. Apart from this technical dimension, there is also a more political or structural one. While GLIMS is responsible for the remote sensing and glacier inventory part (Tier 5) of the Global Terrestrial Network for Glaciers (GTN-G) within the Global Climate Observing System (GCOS), the World Glacier Monitoring Service (WGMS) is collecting and dis-seminating the field observations. Along with new global products derived from satellite data (e.g. elevation changes and velocity fields) and the community wish to keep a snap-shot dataset such as the RGI available, how to make all these datasets available to the community without duplicating efforts and making best use of the very limited financial resources available must now be discussed. This

  12. Identification of peptide sequences that selectively bind to pentaerythritol trinitrate hemisuccinate-a surrogate of PETN, via phage display technology.

    PubMed

    Kubas, George; Rees, William; Caguiat, Jonathan; Asch, David; Fagan, Diana; Cortes, Pedro

    2017-03-01

    The present research investigates the identification of amino acid sequences that selectively bind to a pentaerythritol tetranitrate (PETN) explosive surrogate. Through the use of a phage display technique and enzyme-linked immunosorbent assays (ELISA), a peptide library was tested against pentaerythritol trinitrate hemisuccinate (PETNH), a surrogate of PETN, to screen for those with amino acids having affinity toward the explosive. The results suggest that the library contains peptides selective to PETNH. Following three rounds of panning, clones were picked and tested for specificity toward PETNH. ELISA results from these samples show that each phage clone has some level of selectivity for binding to PETNH. The peptides from these clones have been sequenced and shown to contain certain common amino acid segments among them. This work represents a technological platform for identifying amino-acid sequences selective toward any bio-chem analyte of interest.

  13. Antitumor efficacy, tumor distribution and blood pharmacokinetics of chitosan/glyceryl-monooleate nanostructures containing paclitaxel.

    PubMed

    Trickler, William J; Munt, Daniel J; Jain, Neha; Joshi, Shantaram S; Dash, Alekha K

    2011-04-01

    This investigation compared the tumor distribution, efficacy, blood pharmacokinetic parameters and hematological alterations following treatment with chitosan/glyceryl-monooleate (GMO) nanostructures containing paclitaxel (PTX) to a conventional formulation of PTX (Taxol(®)) in BALB/c female mice. The tumor and blood concentrations of PTX were evaluated by HPLC and the pharmacokinetic parameters were determined through noncompartmental methods. Tumor development was evaluated by histopathological methods and hematological composition was monitored through differential white blood cells counts. Lower localized or intravenous doses of PTX-chitosan/GMO nanostructures significantly increased the antitumor activity of paclitaxel. The tumor distribution studies showed effective concentrations in the tumors with the chitosan/GMO formulation while systemic blood levels remained lower than after administration of the conventional formulation. Delivery systems consisting of chitosan/GMO and PTX are safe and effective administered locally (intratumorally) or intravenously.

  14. Preparation and evaluation of glyceryl monooleate-coated hollow-bioadhesive microspheres for gastroretentive drug delivery.

    PubMed

    Liu, Yuanfen; Zhang, Jianjun; Gao, Yuan; Zhu, Jiabi

    2011-07-15

    The purpose of this study was to produce hollow and bioadhesive microspheres to lengthen drug retention time in the stomach. In these microspheres, ethylcellulose was used as the matrix, Eudragit EPO was employed to modulate the release rate, and glyceryl monooleate (GMO) was the bioadhesive polymer in situ. The morphological characteristics of the microspheres were defined using scanning electron microscopy. The in vitro release test showed that the release rate of drug from the microspheres was pH-dependent, and was not influenced by the GMO coating film. The prepared microspheres demonstrated strong mucoadhesive properties with good buoyancy both in vitro and in vivo. Pharmacokinetic analysis indicated that the elimination half-life time of the hollow-bioadhesive microspheres was prolonged, and that the elimination rate was decreased. In conclusion, the hollow-bioadhesive synergic drug delivery system may be advantageous in the treatment of stomach diseases. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Parasite impairment by targeting Plasmodium-infected RBCs using glyceryl-dilaurate nanostructured lipid carriers.

    PubMed

    Jain, Soniya A; Basu, Himanish; Prabhu, Priyanka S; Soni, Umangi; Joshi, Medha D; Mathur, Deepak; Patravale, Vandana B; Pathak, Sulabha; Sharma, Shobhona

    2014-08-01

    Antimalarial therapy is a major contributor to declining malaria morbidity and mortality. However, the high toxicity and low bioavailability of current antimalarials and emerging drug resistance necessitates drug-delivery research. We have previously developed glyceryl-dilaurate nanolipid carriers (GDL-NLCs) for antimalarial drug delivery. Here, we show evidence that GDL-NLCs themselves selectively target Plasmodium-infected red blood cells (iRBCs), and cause severe parasite impairment. The glyceryl-dilaurate lipid-moiety was important in the targeting. GDL-NLCs localized to the parasite mitochondrion and uptake led to mitochondrial-membrane polarization and Ca(2+) ion accumulation, ROS release, and stage-specific iRBC lysis. GDL-NLC treatment also resulted in externalization of iRBC-membrane phosphatidylserine and enhanced iRBC clearance by macrophages. GDL-NLC uptake disrupted the parasite-induced tubulovesicular network, which is vital for nutrient import by the parasite. Laser optical trap studies revealed that GDL-NLCs also restored iRBC flexibility. Such restoration of iRBC flexibility may help mitigate the vasculature clogging that can lead to cerebral malaria. We demonstrate the suitability of GDL-NLCs for intravenous delivery of antimalarial combinations artemether-clindamycin and artemether-lumefantrine in the murine model. Complete parasite clearance was achieved at 5-20% of the therapeutic dose of these combinations. Thus, this nanostructured lipid formulation can solubilize lipophilic drugs, selectively target and impair the parasite-infected red cell, and therefore constitutes a potent delivery vehicle for antimalarials.

  16. A new sunscreen of the cinnamate class: synthesis and enzymatic hydrolysis evaluation of glyceryl esters of p-methoxycinnamic acid.

    PubMed

    de Freitas, Zaida Maria Faria; dos Santos, Elisabete Pereira; da Rocha, João Ferreira; Dellamora-Ortiz, Gisela Maria; Gonçalves, José Carlos Saraiva

    2005-05-01

    Glyceryl esters of p-methoxycinnamic acid, 1,3-dipalmitoyl-2-p-methoxycinnamoyl-1,2,3-propanetriol and 1,3-dioctanoyl-2-p-methoxycinnamoyl-1,2,3-propanetriol were synthesised in an attempt to increase substantivity and decrease eventual undesirable effects of sunscreens of this class. To assess if the glyceryl esters could present a higher stability towards hydrolysis by lipases in the stratum corneum, hydrolysis rates were determined in vitro using a commercial fungal lipase from Rhizomucor miehei. Results presented herein show that the glyceryl esters have similar lambda(max) and epsilon values to sunscreens of the cinnamate class. The ester 1,3-dipalmitoyl-2-p-methoxycinnamoyl-1,2,3-propanetriol presented a 2.8 times lower hydrolysis rate by lipase, in vitro, than the commercial sunscreen 2-ethylhexyl-p-methoxycinnamate (alkyl ester). This finding suggests that this triacylglycerol can possibly have a longer retention time in the skin and consequently promote a more intense and effective antisolar action than the commercial sunscreen.

  17. Preparation of multiparticulate vaginal tablet using glyceryl monooleate for sustained progesterone delivery.

    PubMed

    Biradar, Shailesh V; Dhumal, Ravindra S; Shah, Manish H; Paradkar, Anant R; Yamamura, Shigeo

    2009-01-01

    Most of the sustained release vaginal formulations are in the form of bioadhesive gels and tablets. Though proved efficient, their presence in the vagina for a longer time as a bulk produces discomfort and interference with body functioning including sexual activities. Hence, they lack complete patient compliance. In this study, multiparticulate vaginal tablets were prepared by utilizing progesterone (PRO) loaded dry powder precursor of cubic phase (DPPCP) of glyceryl monooleate (GMO). DPPCP were obtained by spray drying GMO with magnesium trisilicate (MTS) and have presented PRO sustained release in simulated vaginal fluid (SVF) for 14 hours. The effect of hydrophilic and hydrophobic tableting excipients on compression, phase, bioadhesion and drug release properties of prepared tablets was evaluated. The effervescent hydrophilic tablet (EHT) prepared with hydrophilic excipients showed rapid disintegration but, diminished sustaining ability owing to transformation into lamellar phase whereas the multiparticulate hydrophobic tablet (MHT) obtained from hydrophobic excipients presented both rapid disintegration and sustained release in SVF by virtue of cubic phase retention. During bioadhesivity testing, fast disintegration of MHT with formation of uniform and viscous bioadhesive layer on cow mucosa was observed even with a small volume of SVF. As MHT may not produce discomfort and interference, it will be preferred over bioadhesive gel or tablet.

  18. A novel method for the synthesis of glyceryl monocaffeate by the enzymatic transesterification and kinetic analysis.

    PubMed

    Sun, Shangde; Hu, Bingxue

    2017-01-01

    A novel enzymatic method for glyceryl monocaffeate (GMC) preparation by the transesterification of ethyl caffeate (EC) was investigated. The effects of reaction variables (reaction pressure, temperature, reaction time, enzyme load, and substrate ratio) on the enzymatic transesterification were studied and optimized using response surface methodology. HPLC-ESI-MS and HPLC-UV were used to monitor the transesterification. Thermodynamics, kinetic analyses and reaction mechanism were also evaluated. Results showed that, GMC can be successfully prepared by the enzymatic transesterification of EC with glycerol. Under the optimal conditions (enzyme load 22.54%, EC:glycerol=1:12.75 (mol/mol), 72.5°C, and 10.5h), EC conversion and GMC yield were 97.9±0.7% and 95.8±1.0%, respectively. The activation energies (Ea) for EC conversion and GMC formation were 44.23 and 46.51kJ/mol, respectively. The kinetic values for Vmax, Km(') and KIA were 2.18×10(-3)mol/(Lmin), 0.086mol/L, and 0.52mol/L, respectively. The transesterification mechanism with EC inhibition was also proposed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Liquid crystalline phases and their dispersions in aqueous mixtures of glycerol monooleate and glyceryl monooleyl ether.

    PubMed

    Popescu, Georgeta; Barauskas, Justas; Nylander, Tommy; Tiberg, Fredrik

    2007-01-16

    The aqueous phase behavior of mixtures of 1-glycerol monooleate (GMO) and its ether analogue, 1-glyceryl monooleyl ether (GME) has been investigated by a combination of polarized microscopy, X-ray diffraction, and NMR techniques. Three phase diagrams of the ternary GMO/GME/water system have been constructed at 25, 40, and 55 degrees C. The results demonstrate that the increasing amount of GME favors the formation of the reversed phases, evidenced by the transformation of the lamellar and bicontinuous cubic liquid crystalline phases of the binary GMO/water system into reversed micellar or reversed hexagonal phases. For a particular liquid crystalline phase, increasing the GME content has no effect on the structural characteristics and hydration properties, thus suggesting ideal mixing with GMO. Investigations of dispersed nanoparticle samples using shear and a polymeric stabilizer, Pluronic F127, show the possibility of forming two different kinds of bicontinuous cubic phase nanoparticles by simply changing the GMO/GME ratio. Also NMR self-diffusion measurements confirm that the block copolymer, Pluronic F127, used to facilitate dispersion formation, is associated with nanoparticles and provides steric stabilization.

  20. Genetic control of macrophage functions. I. Polygenic regulation of phagocytosis stimulation produced by Glyceryl Trioleate.

    PubMed

    Mouton, D; Bouthillier, Y; Feingold, N; Feingold, J; Decreusefond, C; Stiffel, C; Biozzi, G

    1975-02-01

    The phagocytic index K, established from the rate of blood clearance of colloidal carbon, measures the phagocytic activity of RE macrophages in contact with the circulating blood. The intravenous injection of glyceryl trioleate (triolein) produces a marked stimulation of the phagocytic activity of RE macrophages. This response is higher in the female than in the male mice. The phenotypic character "responsiveness of macrophage to triolein" presents large individual variants in population of random bred albinos mice. This character is submitted to polygenic regulation. Starting from a foundation population of 25 males and 25 females random bred albinos, mice, two lines were separated by selective breeding for the character "responsiveness to triolein": a "high" responder line, KTH, and a "low" responder line, KTL. After 26 consecutive generations of selective breeding, KTH mice present a very high response to triolein while KTL mice are almost irresponsive. The heritability of this character (h2) calculated from the interline divergence is of 12% plus or minus 1. This value of h2 indicates that the character investigated is determined by the cumulative effect of a group of about 27 independently segregating loci. The distribution of the character in (KTH plus KTL)F1 and their backcrosses with parental lines suggests that low responsiveness is dominant over high responsiveness. The genetic regulation of responsiveness to triolein is independent from the dose administered. These results are discussed in relation to the importance of genetic factors controlling macrophage functions involved in lipid metabolism and in the specific mechanisms of immunity.

  1. Genetic control of macrophage functions. I. Polygenic regulation of phagocytosis stimulation produced by Glyceryl Trioleate

    PubMed Central

    1975-01-01

    The phagocytic index K, established from the rate of blood clearance of colloidal carbon, measures the phagocytic activity of RE macrophages in contact with the circulating blood. The intravenous injection of glyceryl trioleate (triolein) produces a marked stimulation of the phagocytic activity of RE macrophages. This response is higher in the female than in the male mice. The phenotypic character "responsiveness of macrophage to triolein" presents large individual variants in population of random bred albinos mice. This character is submitted to polygenic regulation. Starting from a foundation population of 25 males and 25 females random bred albinos, mice, two lines were separated by selective breeding for the character "responsiveness to triolein": a "high" responder line, KTH, and a "low" responder line, KTL. After 26 consecutive generations of selective breeding, KTH mice present a very high response to triolein while KTL mice are almost irresponsive. The heritability of this character (h2) calculated from the interline divergence is of 12% plus or minus 1. This value of h2 indicates that the character investigated is determined by the cumulative effect of a group of about 27 independently segregating loci. The distribution of the character in (KTH plus KTL)F1 and their backcrosses with parental lines suggests that low responsiveness is dominant over high responsiveness. The genetic regulation of responsiveness to triolein is independent from the dose administered. These results are discussed in relation to the importance of genetic factors controlling macrophage functions involved in lipid metabolism and in the specific mechanisms of immunity. PMID:1113063

  2. Silymarin glyceryl monooleate/poloxamer 407 liquid crystalline matrices: physical characterization and enhanced oral bioavailability.

    PubMed

    Lian, Ruyue; Lu, Yi; Qi, Jianping; Tan, Yanan; Niu, Mengmeng; Guan, Peipei; Hu, Fuqiang; Wu, Wei

    2011-12-01

    Silymarin, a mixture of flavonolignans extracted from the seeds of milk thistle, is used clinically as a hepatoprotector to treat liver injuries and chronic hepatitis. However, its therapeutic effect is compromised by its poor oral bioavailability due to the poor solubility and low permeability across intestinal epithelia. The main purpose of this study was to prepare silymarin glyceryl monooleate/poloxamer 407 liquid crystalline matrices (GMO/P407 LCM) to improve the oral bioavailability of silymarin. GMO/P407 LCMs were prepared by a melting/congealing method. The isotropic phenomenon observed under polarized light microscope confirmed the liquid crystalline structure at the junction of LCM and water. Both differential scanning calorimetry and X-ray diffraction analysis confirmed disappearance of silymarin crystallinity after incorporation into the LCMs. In vitro release of silymarin from LCMs was limited, whereas LCMs were readily degraded by lipase and released silymarin quickly and completely. Pharmacokinetic study in beagle dogs showed significantly increased peak concentration for silymarin GMO/P407 LCM, and, most importantly, a 3.46-fold increase in oral bioavailability as compared with Legalon®, a commercial silymarin formulation.

  3. Formulation of a modified-release pregabalin tablet using hot-melt coating with glyceryl behenate.

    PubMed

    Jeong, Kyu Ho; Woo, Hye Seung; Kim, Chae Jin; Lee, Kyung Hwa; Jeon, Jun Young; Lee, Sang Young; Kang, Jae-Hoon; Lee, Sangkil; Choi, Young Wook

    2015-11-10

    A modified-release (MR) tablet of the anti-anxiety drug pregabalin (PRE) was prepared by hot-melt coating PRE with glyceryl behenate (GB) as a release retardant and compressing to form a matrix with microcrystalline cellulose (MCC) as a hydrophilic diluent. GB-coated PRE had a size in the range of 177-290 μm with good to acceptable flowability. Tablet hardness decreased slightly as GB content increased. PRE release from the tablet matrices was successfully modified by altering the ratio of MCC and GB, and it was found that dissolution- or diffusion-controlled release depended on the amount of GB used. Drug release was pH-independent. An accelerated stability test on the most promising MR tablet at 40°C and 75% relative humidity for 6 months showed no significant changes in PRE content, and the occurrence of total impurities--including PRE-lactam--was within acceptable limits. After oral administration of the selected MR tablet or a commercial IR capsule (Lyrica) to healthy human volunteers, pharmacokinetic parameters including Tmax, Cmax, AUC0-24, and T1/2 were compared. The confidence interval of AUC0-24 was within the adequate range, but that of Cmax was inadequate. This study demonstrated the potential use of GB for PRE-containing MR formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Cubic liquid crystalline glyceryl monooleate matrices for oral delivery of enzyme.

    PubMed

    Shah, Manish H; Paradkar, Anant

    2005-04-27

    In situ cubic phase transforming system of glyceryl monooleate (GMO) has been prepared which offers protection to the metaloenzyme, seratiopeptidase (STP), in gastric environment and provides delayed and controlled release with no initial burst after oral administration. Effect of magnesium trisilicate (MTS) on floating, proteolytic activity and drug release was studied. Gelucire 43/01 was incorporated in the system to provide prolonged lag time. The drug-loaded matrices required 100 mg of MTS to overcome floatability of GMO matrix. Plain GMO matrices showed 85.3% loss of proteolytic activity in acidic medium, whereas matrices containing MTS showed retention of activity (111.6%). The hydrophobic nature of MTS induced formation of cubic phase at faster rate and the existence of cubic phase was confirmed by polarizing light microscopy. Furthermore, MTS provided alkaline microenvironment, which prevented acid-catalyzed hydrolysis and protein unfolding. The magnesium ions restored the activity of STP. The release of STP was decreased with increasing amount of MTS in the matrix. Gelucire did not affect proteolytic activity. The water uptake of matrices with gelucire was decelerated due to formation of hexagonal phase. However, the rate of STP release from these matrices was very slow due to incorporation of gelucire into lipid bilayers, which provided resistance to movement of STP. Thus, microenvironment-controlled in situ cubic phase transforming GMO matrices provided protection to STP and controlled release.

  5. Development and evaluation of liquid embolic agents based on liquid crystalline material of glyceryl monooleate.

    PubMed

    Du, Ling-Ran; Lu, Xiao-Jing; Guan, Hai-Tao; Yang, Yong-Jie; Gu, Meng-Jie; Zheng, Zhuo-Zhao; Lv, Tian-Shi; Yan, Zi-Guang; Song, Li; Zou, Ying-Hua; Fu, Nai-Qi; Qi, Xian-Rong; Fan, Tian-Yuan

    2014-08-25

    New type of liquid embolic agents based on a liquid crystalline material of glyceryl monooleate (GMO) was developed and evaluated in this study. Ternary phase diagram of GMO, water and ethanol was constructed and three isotropic liquids (ILs, GMO:ethanol:water=49:21:30, 60:20:20 and 72:18:10 (w/w/w)) were selected as potential liquid embolic agents, which could spontaneously form viscous gel cast when contacting with water or physiological fluid. The ILs exhibited excellent microcatheter deliverability due to low viscosity, and were proved to successfully block the saline flow when performed in a device to simulate embolization in vitro. The ILs also showed good cytocompatibility on L929 mouse fibroblast cell line. The embolization of ILs to rabbit kidneys was performed successfully under monitoring of digital subtraction angiography (DSA), and embolic degree was affected by the initial formulation composition and used volume. At 5th week after embolization, DSA and computed tomography (CT) confirmed the renal arteries embolized with IL did not recanalize in follow-up period, and an obvious atrophy of the embolized kidney was observed. Therefore, the GMO-based liquid embolic agents showed feasible and effective to embolize, and potential use in clinical interventional embolization therapy.

  6. (GT)n Repeat Polymorphism in Heme Oxygenase-1 (HO-1) Correlates with Clinical Outcome after Myeloablative or Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Køllgaard, Tania; Kornblit, Brian; Petersen, Jesper; Klausen, Tobias Wirenfeldt; Mortensen, Bo Kok; Brændstrup, Peter; Sengeløv, Henrik; Høgdall, Estrid; Müller, Klaus; Vindeløv, Lars; Andersen, Mads Hald; thor Straten, Per

    2016-01-01

    Allogeneic hematopoietic cell transplantation (HCT) is a treatment for various hematologic diseases where efficacy of treatment is in part based on the graft versus tumour (GVT) activity of cells in the transplant. The cytoprotective enzyme heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation and it has been shown to exert anti-inflammatory functions. In humans a (GT)n repeat polymorphism regulates the expression of HO-1. We conducted fragment length analyses of the (GT)n repeat in the promotor region of the gene for HO-1 in DNA from donors and recipients receiving allogeneic myeloablative- (MA) (n = 110) or nonmyeloablative- (NMA-) (n = 250) HCT. Subsequently, we compared the length of the (GT)n repeat with clinical outcome after HCT. We demonstrated that transplants from a HO-1high donor after MA-conditioning (n = 13) is associated with higher relapse incidence at 3 years (p = 0.01, n = 110). In the NMA-conditioning setting transplantation of HO-1low donor cells into HO-1low recipients correlated significantly with decreased relapse related mortality (RRM) and longer progression free survival (PFS) (p = 0.03 and p = 0.008, respectively). Overall, our findings suggest that HO-1 may play a role for the induction of GVT effect after allogeneic HCT. PMID:27997582

  7. Spray dried glyceryl monooleate-magnesium trisilicate dry powder as cubic phase precursor.

    PubMed

    Shah, Manish H; Biradar, Shailesh V; Paradkar, Anant R

    2006-10-12

    Glyceryl monooleate (GMO) is a polar amphiphilic lipid, which forms different sequential lyotropic liquid crystals upon hydration. GMO has been utilized for various delivery systems and routes of administrations. Owing to sticky and waxy nature of GMO, preparation of oral solid dosage form utilizing GMO is still a challenge for pharmaceutical researchers. Therefore, the objective of the present work was to fabricate dry powder precursors using GMO, which upon hydration in situ forms cubic phase and can be wisely used for fabrication of oral solid dosage forms. In addition to this, dry powder precursor was evaluated for drug loading, in vitro release behavior and in vivo performance of model drug diclofenac sodium (DiNa). The dry powder precursor was obtained by spray-drying GMO with DiNa using magnesium trisilicate (MTS) as adsorbent. The percent drug entrapment of various batches of powder precursor was in the range of 84-93% indicating high content uniformity. SEM and image analysis showed that as the amount of MTS in powder precursor was increased, the particle size decreased. Furthermore, the viscosity of powder precursor was function of amount of MTS. The rate of water uptake of powder precursor was higher due to uniform layer of GMO on the MTS surface, which led to faster transformation of lamellar phase into cubic phase. The polarizing light microscopy confirmed that cubic phase was formed upon hydration of powder precursor. The drug released from powder precursor was initially governed by the cubic phase formed and in later stage it depends upon dynamic swelling behavior of hexagonally packed cylindrical aggregates. The drug loaded powder precursor was found to have more effective and prolonged anti-inflammatory and analgesic activity as compared to pure drug. Thus the dry powder precursor of cubic phase was prepared in which drug release was entirely governed by the mesophases formed.

  8. Chitosan and glyceryl monooleate nanostructures containing gemcitabine: potential delivery system for pancreatic cancer treatment.

    PubMed

    Trickler, William J; Khurana, Jatin; Nagvekar, Ankita A; Dash, Alekha K

    2010-03-01

    The objectives of this study are to enhance cellular accumulation of gemcitabine with chitosan/glyceryl monooleate (GMO) nanostructures, and to provide significant increase in cell death of human pancreatic cancer cells in vitro. The delivery system was prepared by a multiple emulsion solvent evaporation method. The nanostructure topography, size, and surface charge were determined by atomic force microscopy (AFM), and a zetameter. The cellular accumulation, cellular internalization and cytotoxicity of the nanostructures were evaluated by HPLC, confocal microscopy, or MTT assay in Mia PaCa-2 and BxPC-3 cells. The average particle diameter for 2% and 4% (w/w) drug loaded delivery system were 382.3 +/- 28.6 nm, and 385.2 +/- 16.1 nm, respectively with a surface charge of +21.94 +/- 4.37 and +21.23 +/- 1.46 mV. The MTT cytotoxicity dose-response studies revealed the placebo at/or below 1 mg/ml has no effect on MIA PaCa-2 or BxPC-3 cells. The delivery system demonstrated a significant decrease in the IC50 (3 to 4 log unit shift) in cell survival for gemcitabine nanostructures at 72 and 96 h post-treatment when compared with a solution of gemcitabine alone. The nanostructure reported here can be resuspended in an aqueous medium that demonstrate increased effective treatment compared with gemcitabine treatment alone in an in vitro model of human pancreatic cancer. The drug delivery system demonstrates capability to entrap both hydrophilic and hydrophobic compounds to potentially provide an effective treatment option in human pancreatic cancer.

  9. Effects of glyceryl polyethylene glycol ricinoleate on nutrient utilisation and performance of broiler chickens.

    PubMed

    Kaczmarek, Sebastian Andrzej; Bochenek, Maciej; Samuelsson, Anne-Cathrine; Rutkowski, Andrzej

    2015-01-01

    A completely randomised design study with a 2 × 2 factorial arrangement was conducted to observe effects of an emulsifier (glyceryl polyethylene glycol ricinoleate (GPR)) on nutrient utilisation and performance of broiler chickens. A total of 384 male broiler chickens were used to determine the influence of GPR (without addition or added at 0.04% of diet) and two levels of apparent metabolisable energy (AMEN) (according to standard requirements (Diets SE) or energy reduced by 0.4 MJ/kg diet (Diets LE)) on birds' performance and apparent total tract digestibility (ATTD). ATTD of ether extract (EE) and AMEN were measured on d 14 and 35, and ATTD of neutral detergent fibre (NDF) was measured on d 35. All diets were based on wheat-maize-soybean meal with rapeseed oil and lard (blend of 50:50) as fat sources. During the grower period and the whole trial, birds fed Diets supplemented with GPR were characterised by higher body weight gain (BWG) and lower feed conversion ratio (FCR) compared to chicken receiving diets without GPR (p < 0.05). At the end of experiment, birds fed Diet LE without GPR were characterised by lower BWG and higher FCR (p < 0.05). Supplementation with GPR caused a higher ATTD of EE for diets SE and LE at d 14 and 35 (p < 0.05). Moreover, the GPR addition to Diet LE improved ATTD of NDF at d 35 (p < 0.05). In conclusion, the findings suggest that GPR effects the digestion of a blend of animal fat/rapeseed oil positively, even in a practical maize-wheat-based broiler diet with decreased AMEN level.

  10. The Z′ = 12 superstructure of Λ-cobalt(III) sepulchrate trinitrate governed by C—H⋯O hydrogen bonds

    PubMed Central

    Dey, Somnath; Schönleber, Andreas; Mondal, Swastik; Prathapa, Siriyara Jagannatha; van Smaalen, Sander; Larsen, Finn Krebs

    2016-01-01

    Λ-Cobalt(III) sepulchrate trinitrate crystallizes in P6322 with Z = 2 (Z′ = 1/6) at room temperature. Slabs perpendicular to the hexagonal axis comprise molecules Co(sepulchrate) alternating with nitrate groups A and B. Coordinated by six sepulchrate molecules, highly disordered nitrate groups C are accommodated between the slabs. Here we report the fully ordered, low-temperature crystal structure of Co(sep)(NO3)3. It is found to be a high-Z′ structure with Z′ = 12 of the 12-fold superstructure with monoclinic symmetry P21 (c unique). Correlations between structural parameters are effectively removed by refinements within the superspace approach. Superstructure formation is governed by a densification of the packing in conjunction with ordering of nitrate group C, the latter assuming different orientations for each of the Z′ = 12 independent copies in the superstructure. The Co(sep) moiety exhibits small structural variations over its 12 independent copies, while orientations of nitrate groups A and B vary less than the orientations of the nitrate group C do. Molecular packing in the superstructure is found to be determined by short C—H⋯H—C contacts, with H⋯H distances of 2.2–2.3 Å, and by short C—H⋯O contacts, with H⋯O distances down to 2.2 Å. These contacts presumably represent weak C—H⋯O hydrogen bonds, but in any case they prevent further densification of the structure and strengthening of weak N—H⋯O hydrogen bonds with observed H⋯O distances of 2.4–2.6 Å. PMID:27240768

  11. Maintenance Therapy with Partially Hydrolyzed Guar Gum in the Conservative Treatment of Chronic Anal Fissure: Results of a Prospective, Randomized Study

    PubMed Central

    Izzo, Giuseppe; Di Martino, Natale; Renzi, Adolfo

    2014-01-01

    Purpose. This study was designed to evaluate the role of maintenance therapy with partially hydrolyzed guar gum (PHGG) after topical application of glyceryl trinitrate (GTN) in the conservative treatment of chronic anal fissure (CAF). Methods. From all the patients with CAF observed during the study period, 165 subjects with healed CAF after standard therapy with topical GTN 0.4% ointment were randomized to receive (group II) or not (group I) maintenance therapy with PHGG for 10 months. Clinical and manometric followup was carried out 6 and 12 months after treatment. Results. At six-month followup, median visual analogue scale score was significantly higher in group I if compared with group II. The success and recurrence rate at 12-month followup were, respectively, 38.3% (28/73) in group I versus 58.5% (41/70) in group II (P = 0.019; Fisher's exact test) and 30.2% (13/43) in group I versus 14.5% (7/48) in group II (P = 0.0047; Fisher's exact test). Conclusion. The maintenance therapy with PHGG in patients with healed CAF after chemical sphincterotomy by topical application of GTN 0.4% ointment seems associated with a significant reduction of recurrence rate and with a significant increase of success rate at 12-month followup. PMID:25089280

  12. Local L-NG-monomethyl-arginine attenuates the vasodilator action of bradykinin in the human forearm.

    PubMed Central

    O'Kane, K P; Webb, D J; Collier, J G; Vallance, P J

    1994-01-01

    1. Studies in animals indicate that bradykinin relaxes blood vessels directly through an action on smooth muscle and indirectly through the release of endothelium-derived mediators. Its precise mechanism of action in the human arterial circulation is not yet known. 2. In this study the effects of a specific inhibitor of nitric oxide synthase, L-NG-monomethyl-arginine (L-NMMA) and noradrenaline on the vasodilator responses to bradykinin were examined in the forearm arterial bed of healthy volunteers. Noradrenaline was used as a control for vasoconstriction by L-NMMA; glyceryl trinitrate (GTN) as a control vasodilator acting independently of the NO synthase enzyme. 3. L-NMMA (4 mumol min-1; 5 min) alone reduced resting forearm blood flow by 44% (P < 0.01; n = 6) confirming that nitric oxide plays an important role in regulating vascular tone. 4. Bradykinin (10 and 100 pmol min-1; 3 min each dose) and GTN (2 and 5 nmol min-1; 3 min each dose) increased forearm blood flow in a dose-dependent manner (percentage changes 171 +/- 17% and 398 +/- 35%, and 176 +/- 21% and 268 +/- 42%, respectively; n = 6). 5. The response to bradykinin, but not that to GTN, was attenuated by L-NMMA compared with noradrenaline (P < 0.05; n = 6), suggesting that bradykinin-induced vasodilatation in the forearm is mediated, at least in part, by stimulating release of nitric oxide. PMID:7833219

  13. Non-Invasive Vagus Nerve Stimulation as Treatment for Trigeminal Allodynia

    PubMed Central

    Oshinsky, Michael L.; Murphy, Angela L.; Hekierski, Hugh; Cooper, Marnie; Simon, Bruce J.

    2014-01-01

    Implanted vagus nerve stimulation (VNS) has been used to treat seizures and depression. In this study, we explore the mechanism of action of non-invasive vagus nerve stimulation (nVNS) for the treatment of trigeminal allodynia. Rats were repeatedly infused with inflammatory mediators directly onto the dura, which leads to chronic trigeminal allodynia. nVNS for 2min decreases periorbital sensitivity in rats with periorbital trigeminal allodynia for up to 3.5hr after stimulation. Using microdialysis, we quantified levels of extracellular neurotransmitters in the trigeminal nucleus caudalis (TNC). Allodynic rats showed a 7.7±0.9 fold increase in extracellular glutamate in the TNC following i.p. administration of the chemical headache trigger, glyceryl trinitrate (GTN; 0.1mg/kg). Allodynic rats, which received nVNS, had only a 2.3±0.4 fold increase in extracellular glutamate following GTN similar to the response in control naive rats. When nVNS was delayed until 120min after GTN treatment, the high levels of glutamate in the TNC were reversed following nVNS. The nVNS stimulation parameters used in this study did not produce significant changes in blood pressure or heart rate. These data suggest that nVNS may be used to treat trigeminal allodynia. PMID:24530613

  14. Ultrasound-assisted enzymatic transesterification of methyl benzoate and glycerol to 1-glyceryl benzoate in organic solvent.

    PubMed

    Ceni, Giovana; da Silva, Patrícia Costa; Lerin, Lindomar; Oliveira, J Vladimir; Toniazzo, Geciane; Treichel, Helen; Oestreicher, Enrique Guillermo; de Oliveira, Débora

    2011-02-08

    The aim of this work is to report the enzymatic transesterification production of 1-glyceryl benzoate under ultrasound irradiation, using a commercial immobilized lipase, Novozym 435. Firstly, a preliminary evaluation was carried out at 2, 4 and 6h, at constant temperature of 50 °C, methyl benzoate to glycerol molar ratio of 1:1 and 5.5 wt% of enzyme concentration. After analyzing the results obtained, the experimental design technique was used to evaluate the effects of temperature, substrates molar ratio, enzyme concentration, solvent volume and ultrasonic power on the 1-glyceryl benzoate production. The highest conversion, around 16%, was obtained at 65 °C, 1:1 of methyl benzoate to glycerol molar ratio, 15 wt% of enzyme concentration, 7 mL of solvent and 40% ultrasonic power in 4h of reaction. A preliminary kinetic experiment carried out varying the enzyme concentration (15 and 20 wt%) keeping fixed the temperature at 35 °C, 1:1 of substrates molar ratio, 3 mL of solvent and 40% of maximum ultrasonic power led to lower (around 15% after 12 h of reaction) conversions compared to that achieved in the experimental design. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Continuous twin screw melt granulation of glyceryl behenate: Development of controlled release tramadol hydrochloride tablets for improved safety.

    PubMed

    Keen, Justin M; Foley, Connor J; Hughey, Justin R; Bennett, Ryan C; Jannin, Vincent; Rosiaux, Yvonne; Marchaud, Delphine; McGinity, James W

    2015-06-20

    Interest in granulation processes using twin screw extrusion machines is rapidly growing. The primary objectives of this study were to develop a continuous granulation process for direct production of granules using this technique with glyceryl behenate as a binder, evaluate the properties of the resulting granules and develop controlled release tablets containing tramadol HCl. In addition, the granulation mechanism was probed and the polymorphic form of the lipid and drug release rate were evaluated on stability. Granules were prepared using a Leistritz NANO16 twin screw extruder operated without a constricting die. The solid state of the granules were characterized by differential scanning calorimetry and X-ray diffraction. Formulated tablets were studied in 0.1N HCl containing 0-40% ethanol to investigate propensity for alcohol induced dose dumping. The extrusion barrel temperature profile and feed rate were determined to be the primary factors influencing the particle size distribution. Granules were formed by a combination immersion/distribution mechanism, did not require subsequent milling, and were observed to contain desirable polymorphic forms of glyceryl behenate. Drug release from tablets was complete and controlled over 16 h and the tablets were determined to be resistant to alcohol induced dose dumping. The drug release rate from the tablets was found to be stable at 40°C and 75% relative humidity for the duration of a 3 month study.

  16. The effect of peroxynitrite decomposition catalyst MnTBAP on aldehyde dehydrogenase-2 nitration by organic nitrates: role in nitrate tolerance.

    PubMed

    Mollace, Vincenzo; Muscoli, Carolina; Dagostino, Concetta; Giancotti, Luigino Antonio; Gliozzi, Micaela; Sacco, Iolanda; Visalli, Valeria; Gratteri, Santo; Palma, Ernesto; Malara, Natalia; Musolino, Vincenzo; Carresi, Cristina; Muscoli, Saverio; Vitale, Cristiana; Salvemini, Daniela; Romeo, Francesco

    2014-11-01

    Bioconversion of glyceryl trinitrate (GTN) into nitric oxide (NO) by aldehyde dehydrogenase-2 (ALDH-2) is a crucial mechanism which drives vasodilatory and antiplatelet effect of organic nitrates in vitro and in vivo. Oxidative stress generated by overproduction of free radical species, mostly superoxide anions and NO-derived peroxynitrite, has been suggested to play a pivotal role in the development of nitrate tolerance, though the mechanism still remains unclear. Here we studied the free radical-dependent impairment of ALDH-2 in platelets as well as vascular tissues undergoing organic nitrate ester tolerance and potential benefit when using the selective peroxynitrite decomposition catalyst Mn(III) tetrakis (4-Benzoic acid) porphyrin (MnTBAP). Washed human platelets were made tolerant to nitrates via incubation with GTN for 4h. This was expressed by attenuation of platelet aggregation induced by thrombin (40U/mL), an effect accompanied by GTN-related induction of cGMP levels in platelets undergoing thrombin-induced aggregation. Both effects were associated to attenuated GTN-induced nitrite formation in platelets supernatants and to prominent nitration of ALDH-2, the GTN to NO metabolizing enzyme, suggesting that GTN tolerance was associated to reduced NO formation via impairment of ALDH-2. These effects were all antagonized by co-incubation of platelets with MnTBAP, which restored GTN-induced responses in tolerant platelets. Comparable effect was found under in in vivo settings. Indeed, MnTBAP (10mg/kg, i.p.) significantly restored the hypotensive effect of bolus injection of GTN in rats made tolerants to organic nitrates via chronic administration of isosorbide-5-mononitrate (IS-5-MN), thus confirming the role of peroxynitrite overproduction in the development of tolerance to vascular responses induced by organic nitrates. In conclusion, oxidative stress subsequent to prolonged use of organic nitrates, which occurs via nitration of ALDH-2, represents a key event

  17. Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2−/− mice

    PubMed Central

    Wenzel, P; Hink, U; Oelze, M; Seeling, A; Isse, T; Bruns, K; Steinhoff, L; Brandt, M; Kleschyov, A L; Schulz, E; Lange, K; Weiner, H; Lehmann, J; Lackner, K J; Kawamoto, T; Münzel, T; Daiber, A

    2007-01-01

    Background and purpose: Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator. Experimental approach: Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl trinitrate, GTN) and four (pentaerithrityl tetranitrate, PETN) nitrate groups were investigated. Vasodilatory potency was measured in isometric tension studies using isolated aortic segments of wild type (WT) and ALDH-2−/− mice. Activity of the cGMP-dependent kinase-I (reflected by levels of phosphorylated VAsodilator Stimulated Phosphoprotein, P-VASP) was quantified by Western blot analysis, mitochondrial dehydrogenase activity by HPLC. Following incubation of isolated mitochondria with PETN, PETriN-chromophore and PEDN, metabolites were quantified using chemiluminescence nitrogen detection and mass spectrometry. Key results: Compared to WT, vasorelaxation in response to PETN, PETriN and GTN was attenuated about 10fold in ALDH-2−/− mice, identical to WT vessels preincubated with inhibitors of ALDH-2. Reduced vasodilator potency correlated with reduced P-VASP formation and diminished biotransformation of the tetranitrate- and trinitrate-compounds. None of these findings were observed for PEDN, GDN and PEMN. Conclusions and implications: Our results support the crucial role of ALDH-2 in bioactivating highly reactive nitrates like GTN, PETN and PETriN. ALDH-2-mediated relaxation by organic nitrates therefore depends mainly on the number of nitrate groups. Less potent nitrates like PEDN, GDN and PEMN are apparently biotransformed by other pathways. PMID:17220910

  18. Temperature data acquired from the DOI/GTN-P Deep Borehole Array on the Arctic Slope of Alaska, 1973-2013

    NASA Astrophysics Data System (ADS)

    Clow, G. D.

    2014-05-01

    A homogeneous set of temperature measurements obtained from the DOI/GTN-P Deep Borehole Array between 1973 and 2013 is presented; DOI/GTN-P is the US Department of the Interior contribution to the Global Terrestrial Network for Permafrost (GTN-P). The 23-element array is located on the Arctic Slope of Alaska, a region of cold continuous permafrost. Most of the monitoring wells are situated on the Arctic coastal plain between the Brooks Range and the Arctic Ocean, while others are in the foothills to the south. The data represent the true temperatures in the wellbores and surrounding rocks at the time of the measurements; they have not been corrected to remove the thermal disturbance caused by drilling the wells. With a few exceptions, the drilling disturbance is estimated to have been on the order of 0.1 K or less by 1989. Thus, most of the temperature measurements acquired during the last 25 yr are little affected by the drilling disturbance. The data contribute to ongoing efforts to monitor changes in the thermal state of permafrost in both hemispheres by the Global Terrestrial Network for Permafrost, one of the primary subnetworks of the Global Terrestrial Observing System (GTOS). The data will also be useful for refining our basic understanding of the physical conditions in permafrost in Arctic Alaska, as well as providing important information for validating predictive models used for climate impact assessments. The processed data are available from the Advanced Cooperative Arctic Data and Information Service (ACADIS) repository at doi:10.5065/D6N014HK.

  19. Using ground data of the Global Terrestrial Network of Permafrost (GTN-P) for the evaluation of ESA Data User Element (DUE) Permafrost remote sensing derived products

    NASA Astrophysics Data System (ADS)

    Elger, K.; Heim, B.; Bartsch, A.; Paulik, Ch.; Duguay, C.; Hachem, S.; Soliman, A.; Boike, J.; Langer, M.; Lantuit, H.

    2012-04-01

    Permafrost is one of the essential climate variables addressed by the Global Terrestrial Observing System (GCOS). Remote sensing data provide area-wide monitoring of e.g. surface temperatures or soil surface status (frozen or thawed state) in the Arctic and Subarctic, where ground data collection is difficult and restricted to local measurements at few monitoring sites. The task of the ESA Data User Element (DUE) Permafrost project is to build-up an Earth observation service for northern high-latitudinal permafrost applications with extensive involvement of the international permafrost research community (www.ipf.tuwien.ac.at/permafrost). The satellite-derived DUE Permafrost products are Land Surface Temperature, Surface Soil Moisture, Surface Frozen and Thawed State, Digital Elevation Model (locally as remote sensing product and circumpolar as non-remote sensing product) and Subsidence, and Land Cover. Land Surface Temperature, Surface Soil Moisture, and Surface Frozen and Thawed State will be provided for the circumpolar permafrost area north of 55° N with 25 km spatial resolution. In addition, regional products with higher spatial resolution were developed for five case study regions in different permafrost zones of the tundra and taiga (Laptev Sea [RU], Central Yakutia [RU], Western Siberia [RU], Alaska N-S transect, [US] Mackenzie River and Valley [CA]). This study shows the evaluation of two DUE Permafrost regional products, Land Surface Temperature and Surface Frozen and Thawed State, using freely available ground truth data from the Global Terrestrial Network of Permafrost (GTN-P) and monitoring data from the Russian-German Samoylov research station in the Lena River Delta (Central Siberia, RU). The GTN-P permafrost monitoring sites with their position in different permafrost zones are highly qualified for the validation of DUE Permafrost remote sensing products. Air and surface temperatures with high-temporal resolution from eleven GTN-P sites in Alaska

  20. Worldwide glacier monitoring as part of policy-related climate observation: development and strategy of the Global Terrestrial Network for Glaciers (GTN-G)

    NASA Astrophysics Data System (ADS)

    Haeberli, W.; Zemp, M.

    2011-12-01

    Internationally coordinated observation of long-term glacier fluctuations as a key indication of global climate changes has a long tradition, starting already in 1894. With the development of the Global Climate Observing System in support of the United Nations Framework Convention on Climate Change, glaciers and ice caps became an Essential Climate Variable within the Global Terrestrial Observing System. A corresponding Global Terrestrial Network for Glaciers (GTN-G) was indeed established as a pilot project to this program. The basic principles followed by GTN-G and similar networks are to be relevant, feasible, comprehensive and understandable to a wider scientific community and the public. Following recommendations by the International Council for Sciences, a contribution should be made to free and unrestricted international sharing of high-quality, long-term and standardized data and information products. A tiered strategy was adopted in order to bridge the gap between detailed process studies at selected field sites with global coverage through satellite remote sensing. Efforts were also made to ensure continuity of long-term measurement series by combining traditional approaches with modern, future-oriented technologies. Today, the GTN-G is jointly run by three operational bodies in glacier monitoring, which are the World Glacier Monitoring Service, the US National Snow and Ice Data Center, and the Global Land Ice Measurements from Space initiative. With an online service, GTN-G provides fast access to regularly updated information on glacier fluctuation and inventory data. Currently, this includes global information from 100,000 glaciers mainly based on aerial photographs and outlines from 95,000 glaciers mainly based on satellite images, length change series from 1,800 glaciers, mass balance series from 250 glaciers, information on special events (e.g., hazards, surges, calving instabilities) from 130 glaciers, as well as 13,000 photographs from some 500

  1. Synthesis of Monoalkyl Glyceryl Ethers by Ring Opening of Glycidol with Alcohols in the Presence of Lewis Acids.

    PubMed

    Cucciniello, Raffaele; Ricciardi, Maria; Vitiello, Rosa; Di Serio, Martino; Proto, Antonio; Capacchione, Carmine

    2016-12-08

    The present work deals with the production of monoalkyl glyceryl ethers (MAGEs) through a new reaction pathway based on the reaction of glycidol and alcohols catalyzed by Lewis acid-based catalysts. Glycidol is quantitatively converted with high selectivity (99 %) into MAGEs under very mild reaction conditions (80 °C and 0.01 mol % catalyst loading) in only 1 h using Al(OTf)3 or Bi(OTf)3 as catalyst. The proposed method enhances the choice of possible green synthetic approaches for the production of value-added products such as MAGEs. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Mobility of molecules and diagram of the state of a glyceryl monooleate-water system according to NMR data

    NASA Astrophysics Data System (ADS)

    Sakharova, A. V.; Filippov, A. V.; Munavirov, B. V.; Skirda, V. D.

    2011-04-01

    Transverse relaxation and self-diffusion of molecules in a glyceryl monooleate (monoolein)-D2O system was studied using pulsed 1H NMR in a range of water concentrations from 10 to 30 wt % and a range of temperatures from 20 to 90°C. It was noted that self-diffusion is described by one or two self-diffusion coefficients, depending on the temperature and concentration of water, while NMR-relaxation has a complex form. It was determined that with a reduction in the transverse magnetization, a component that has a form similar to Gaussian and relaxation times of 70 to 250 μs is observed at certain temperatures and concentrations of water, confirming the formation of structures in which glyceryl monooleate molecules (GM) are characterized by anisotropic rotational mobility. It was demonstrated that the ranges of the concentrations of water and temperature in which this component is observed correspond to liquid-crystalline phase for lamellar and inverse hexagonal structural organizations of lipids, according to the state diagram obtained by X-ray diffraction. In the state diagram areas corresponding to micellar and cubic structures (characterized by the isotropic rotation of GM molecules in the time scale of NMR), multiexponential decays of magnetization with average relaxation times were noted in the range of 10 to 200 ms. A number of features were discovered with the use of NMR: specimens always contain structures with isotropic rotational mobility in the presence of structures characterized by anisotropic rotational mobility; a change in the fraction of the structures with anisotropic rotational mobility takes place slowly over 5-15 K, not abruptly. Our conclusions regarding the polymorphism of a GM-D2O system in the presence of anisotropic structures was confirmed by an analysis of the transverse NMR relaxation in an egg phosphatidylcholine-D2O system, for which the presence of only lamellar liquid-crystalline structure is confirmed by 31P NMR.

  3. ESA DUE Permafrost: Evaluation of remote sensing derived products using ground data from the Global Terrestrial Network of Permafrost (GTN-P)

    NASA Astrophysics Data System (ADS)

    Elger, K. K.; Heim, B.; Lantuit, H.; Boike, J.; Bartsch, A.; Paulik, C.; Duguay, C. R.; Hachem, S.; Soliman, A. S.

    2011-12-01

    The task of the ESA DUE Permafrost project is to build up an Earth observation service for high-latitudinal permafrost applications with extensive involvement of the permafrost research community. The DUE Permafrost products derived from remote sensing are land surface temperature (LST), surface soil moisture (SSM), surface frozen and thawed state (freeze/ thaw), terrain, land cover, and surface waters. Weekly and monthly averages for most of the DUE Permafrost products will be made available for the years 2007-2010. The DUE Permafrost products are provided for the circumpolar permafrost area (north of 55°N) with 25 km spatial resolution. In addition, regional products with higher spatial resolution (300-1000 m/ pixel) were developed for five case study regions. These regions are: (1) the Laptev Sea and Eastern Siberian Sea Region (RU, continuous very cold permafrost/ tundra), (2) the Yakutsk Region (RU, continuous cold permafrost/ taiga), (3) the Western Siberian transect including Yamal Peninsula and Ob Region (RU, continuous to discontinuous/ taiga-tundra), (4) the Alaska Highway Transect (US, continuous to discontinuous/ taiga-tundra), and (5) the Mackenzie Delta and Valley Transect (CA, continuous to discontinuous/ taiga-tundra). The challenge of the programme is to adapt remote sensing products that are well established and tested in agricultural low and mid-latitudinal areas for highly heterogeneous taiga/ tundra permafrost landscapes in arctic regions. Ground data is essential for the evaluation of DUE Permafrost products and is provided by user groups and global networks. A major part of the DUE Permafrost core user group is contributing to GTN-P, the Global Terrestrial Network of Permafrost. Its main programmes, the Circumpolar Active Layer Monitoring (CALM) and the Thermal State of Permafrost (TSP) have been thoroughly overhauled during the last International Polar Year (2007-2008). Their spatial coverage has been extended to provide a true circumpolar

  4. Synthesis and intravenous infusion into the rat of glyceryl bisacetoacetate, 1-acetoacetamido-2, 3-propane diol, and partially reduced glucosyl pentaacetoacetate.

    PubMed

    Birkhahn, R H; Clemens, R J; Hubbs, J C

    1997-07-01

    The efficacy of parenteral nutrition could be improved by finding a more effective energy source. Esters of short-chain fatty acids have exhibited some promise as alternatives to glucose. The present study reports on two new esters and one amide, each containing acetoacetate as the organic acid. The three compounds: glyceryl bisacetoacetate, N-2',3'-dihydroxypropyl-3-oxo-butanamide (1-acetoacetamido-2,3-propane diol), and partially reduced glucosyl pentaacetoacetate, were synthesized and then continuously infused into rats for 7 d. The infusion rate provided 50% of the rats' estimated metabolic energy requirements, and rats were fed with a reduced-energy oral diet that provided the remaining 50% of energy plus adequate protein. Rat groups for each compound were: (1) experimental-compound-infused and ad libitum-fed, (2) isoenergetic glucose-infused and pairfed, and (3) saline infused and pair-fed. Body-weight changes, N losses and N retention were measured daily. All rats died from partially reduced glucosyl pentaacetoacetate infusion at 100% and 50% of the intended rate. Rats infused with 1-acetoacetamido-2,3-propane diol failed to gain weight and to increase the plasma ketone-body concentration. Glyceryl bisacetoacetate produced hyperketonaemia, and weight gain and N variables that were similar to those for glucose-infused rats. It was concluded that only glyceryl bisacetoacetate would make a satisfactory parenteral nutrient.

  5. The involvement of the release of nitric oxide in the pharmacological activity of the new furoxan derivative CHF 2363.

    PubMed Central

    Civelli, M.; Giossi, M.; Caruso, P.; Razzetti, R.; Bergamaschi, M.; Bongrani, S.; Gasco, A.

    1996-01-01

    1. The mechanism of action and the pharmacological effects of the new furoxan derivative, CHF 2363 (4-ethoxy-3-phenylsulphonylfuroxan), were investigated. 2. Pre-incubation of CHF 2363 with human platelet-rich plasma produced a concentration-dependent inhibition of the platelet aggregation induced by collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). The test compound was about 5 times more potent than sodium nitroprusside. 3-Isobutyl-1-methyl-xanthine (IBMX) potentiated the antiaggregating effect of CHF 2363. 3. CHF 2363 was a potent inhibitor of rubbed endothelium rabbit aortic ring contraction induced by noradrenaline. Comparison of IC50 values showed that CHF 2363 was as potent as glyceryl trinitrate (GTN). 4. Increasing concentrations of CHF 2363 elevated platelet guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were unaffected. 5. Oxyhaemoglobin reduced all the pharmacological actions of the test compound. Moreover, CHF 2363 concentration-dependently released nitric oxide (NO) in platelet-rich plasma. The NO release was correlated to its ability to increase platelet cyclic GMP levels. 6. After exposure of rat aortic strips to supramaximal concentrations of GTN (550 microM), the vasorelaxant activity of CHF 2363 did not change, although that of GTN decreased about 55 fold. 7. It has been concluded that the new furoxan derivative CHF 2363 exerts a potent antiaggregating and vasorelaxant activity via NO release and increase of cyclic GMP levels. No in vitro cross tolerance between GTN and CHF 2363 was observed. PMID:8799563

  6. Short (GT)n microsatellite repeats in the heme oxygenase-1 gene promoter are associated with antioxidant and anti-inflammatory status in Mexican pediatric patients with sepsis.

    PubMed

    Vázquez-Armenta, Gabriela; González-Leal, Natalia; J Vázquez-de la Torre, Mayra; Muñoz-Valle, José Francisco; Ramos-Márquez, Martha E; Hernández-Cañaveral, Iván; Plascencia-Hernández, Arturo; Siller-López, Fernando

    2013-01-01

    An adequate immune and antioxidant response is a key to the resolution of sepsis. Heme oxygenase-1 (HMOX1) is a stress protein with a polymorphic (GT)n repeat in its gene promoter that regulates its expression in response to oxidative injury, such as that present in sepsis. HMOX1 is the rate-limiting enzyme of heme degradation, and the heme breakdown products, CO, Fe, and bilirubin, are considered to be biologically active metabolites with direct or indirect antioxidant and anti-inflammatory properties. In this study, we investigated the inflammatory and antioxidant response and the relationship with the HMOX1 levels and HMOX1 polymorphism in Mexican septic pediatric patients. In a case-control pilot study, we enrolled 64 septic patients and 72 hospitalized control patients without a diagnosis of sepsis. DNA extracted from buffy coat was genotyped for HMOX1 (GT)n polymorphism by PCR and markers of antioxidant and inflammatory status were quantified in plasma by analysis of the oxygen radical absorbance capacity (ORAC), protein carbonyl (PC), interleukin (IL) 6, IL10, and HMOX1 levels. In septic children, oxidative and inflammatory markers were elevated, and HMOX1 levels were positively correlated with IL10 levels. Genotypic and allelic distribution of HMOX1 polymorphism showed no difference between groups. HMOX1 short-allele septic carriers (< 25 GT repeats) presented favorable ORAC, PC and IL10 levels. This study confirms that an active response against pediatric sepsis involves the expression of HMOX1 and IL10, suggesting that the high antioxidant status associated with HMOX1 short-allele septic carriers might provide a beneficial environment for sepsis resolution.

  7. Global outlook from the Global Terrestrial Network for Permafrost (GTN-P): Changes in thermal state of permafrost and active layer thickness over the last decade

    NASA Astrophysics Data System (ADS)

    Streletskiy, D. A.; Biskaborn, B. K.; Romanovsky, V. E.; Smith, S. L.; Shiklomanov, N. I.; Nötzli, J.; Vieira, G.; Schoeneich, P.; Lanckman, J. P. F.; Lantuit, H.

    2016-12-01

    Long-term monitoring permafrost thermal state and active layer thickness (ALT) is critical in providing the baseline for assessment of climate change impacts in polar and high mountain regions, modeling of ecosystem processes and as an input for many engineering applications on permafrost among others. The Global Terrestrial Network for Permafrost (GTN-P) provides systematic long-term measurements of permafrost temperature and ALT, and is part of the Global Terrestrial Observing System (GTOS) of the Global Climate Observing System (GCOS). The GTN-P launched a sophisticated data management system (DMS), which allows automatic data submission, standardization, quality control, and processing. Presently 1250 permafrost boreholes and 250 active layers sites are registered within the DMS (gtnpdatabase.org), but the geographic distribution of sites and length of observations vary considerably among regions. Using DMS capabilities we selected sites with data available during the last International Polar Year (IPY) and in the recent 4 years and estimated changes in thermal state of permafrost and active layer thickness between the two reference periods. The results show that following air temperature trends, permafrost temperature has generally increased across permafrost domain, however, there is considerable spatial variability. The highest increases in permafrost temperature are found in Canadian High Arctic and are pronounced in regions with cold continuous permafrost such as Siberia and North America. In the sub-arctic, where permafrost temperatures are relatively high, the warming trend is less pronounced and permafrost temperature is similar to that of the IPY snapshot. In alpine permafrost areas, however, most measurement sites also show significant warming since 2009. ALT exhibits large interannual variability, but has generally increased in the majority of regions, especially in European Arctic sector where several sites experienced permafrost degradation. In

  8. Assessment of skin absorption and irritation potential of arachidonic acid and glyceryl arachidonate using in vitro diffusion cell techniques.

    PubMed

    Eppler, A R; Kraeling, M E K; Wickett, R R; Bronaugh, R L

    2007-11-01

    Arachidonic acid (AA), a precursor of pro-inflammatory mediators, and its glycerin ester, glyceryl arachidonate (GA), are reportedly used in cosmetic products. In vitro skin penetration of AA and GA and GA's ester hydrolysis was determined in flow-through diffusion cells. AA penetration with human and rat skin was 19.5% and 52.3% of the applied dose respectively, a substantial amount of which remained in the skin at 24h. Similar penetration results were obtained with GA in human skin. However, GA penetration through cultured skin (EpiDerm) was 51% of the applied dose, almost all of which appeared in the receptor fluid. At least 27.8% of GA penetrating skin was hydrolyzed to AA. In vitro methods were used to assess skin irritation in diffusion cells. Skin irritation of AA, sodium lauryl sulfate (SLS), and Tween 80 was determined by changes in transepidermal water loss (TEWL), skin viability (3-(4,5-dimethylthiaxol-2-yl)-2,5-diphenyltetrazolium bromide, MTT, formation), and cytokine release (IL-1alpha). SLS irritation was much less pronounced in an emulsion versus an aqueous vehicle. No significant irritation was observed in vitro from AA in an emulsion. This work predicts that AA would penetrate human skin in vivo and that it could be formed in skin from topically applied GA.

  9. V-Y advancement flap as first-line treatment for all chronic anal fissures.

    PubMed

    Chambers, William; Sajal, Rai; Dixon, Anthony

    2010-05-01

    It was suggested that anal advancement flap be used to treat patients with chronic anal fissures that have failed medical management and have a low-pressure sphincter complex. We wished to assess anal advancement flap as a treatment for all chronic anal fissures. All patients with chronic anal fissures regardless of their previous management underwent V-Y advancement flap. Patient demographics, symptom duration, previous treatments, short-term postoperative outcome and long-term follow-up were recorded. Fifty-four consecutive patients, median age 39 years (22-66), underwent a V-Y advancement flap over a 7-year period; 34 were men. Duration of symptoms ranged from 2 to 36 months with a median of 8 months. Forty-two patients (78%) had failed a previous therapy: glyceryl trinitrate (GTN) (25), GTN and diltiazem (16) and lateral sphincterotomy (one). Wound dehiscence occurred in three patients of which only one required a surgical intervention. On follow-up at 6 months, all but one patient had a healed wound and was asymptomatic. We have shown excellent rates of healing of chronic anal fissures treated with a V-Y advancement flap regardless of sphincter pressures, previous treatment and symptom chronicity. These results show the technique can be applied to all chronic fissures with success and used as a primary therapy.

  10. Macroangiopathy--does it play a role in young people?

    PubMed

    Donaghue, K C; Robinson, J; McCredie, R; Fung, A; Silink, M; Celermajer, D S

    1998-01-01

    Using a novel ultrasound method, brachial artery endothelial and smooth muscle physiology were studied in 20 adolescents with IDDM and in 20 nondiabetic subjects matched for age (13-22 years), gender and vessel size. Endothelium-dependent dilatation (EDD) was assessed in response to flow (EDD) and endothelium-independent vasodilatation after sublingual glyceryl trinitrate (GTN). Both EDD and GTN were reduced in those with IDDM compared with controls: 5 vs. 9%, (p = 0.0002) and 14 vs. 21% (p = 0.002). Abnormal EDD was found in 12 IDDM adolescents (diabetes duration 3.3-14.9 years). The mean urinary albumin excretion rate of the diabetic group with abnormal EDD was 5.76 +/- 2.82 vs. 8.05 +/- 4.88 microg/min in those with normal EDD (p = 0.25). In the diabetic adolescents there was no significant correlation observed between the test for early large vessel disease, HbAlc and tests for diabetic microangiopathy.

  11. St. John's wort reversal of meningeal nociception: a natural therapeutic perspective for migraine pain.

    PubMed

    Galeotti, N; Ghelardini, C

    2013-07-15

    Despite a number of antimigraine drugs belonging to different pharmacological classes are available, there is a huge unmet need for better migraine pharmacotherapy. We here demonstrated the capability of Hypericum perforatum, popularly called St. John's wort (SJW), to relieve meningeal nociception in an animal model induced by administration of the nitric oxide (NO) donors glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). GTN and SNP produced a delayed meningeal inflammation, as showed by the upregulation of interleukin (IL)-1β and inducible NO synthase (iNOS), and a prolonged cold allodynia and heat hyperalgesia with a time-course consistent with NO-induced migraine attacks. A single oral administration of a SJW dried extract (5mg/kg p.o.) counteracted the nociceptive behaviour and the overexpression of IL-1β and iNOS. To clarify the cellular pathways involved, the expression of protein kinase C (PKC) and downstream effectors was detected. NO donors increased expression and phosphorylation of PKCγ, PKCɛ and transcription factors, such as nuclear factor (NF)-κB, cyclic AMP response element binding protein (CREB), Signal Transducer and Activator of Transcription (STAT)-1. All these molecular events were prevented by SJW and hypericin, a SJW main component. In conclusion, SJW counteracted the NO donor-induced pain hypersensitivity and meningeal activation by blocking PKC-mediated pathways involving NF-κB, CREB, STAT1. These results might suggest SJW as an innovative and safe perspective for migraine pain.

  12. Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate.

    PubMed

    Koenig, Andreas; Lange, Kathrin; Konter, Joerg; Daiber, Andreas; Stalleicken, Dirk; Glusa, Erika; Lehmann, Jochen

    2007-07-01

    Neither therapeutic dosage of nitrovasodilators nor the development of tolerance correlates with nitrate groups in these molecules. Clinically, low dosages of glyceryl trinitrate (GTN) develop tolerance, but 100-fold higher dosages of pentaerythrityl tetranitrate (PETN) do not. Vasorelaxation was studied on prostaglandian F2alpha (PGF2alpha)-precontracted porcine pulmonary arteries in organ bath procedure. In vitro tolerance was induced by incubating the arteries with different nitrate concentrations and thereafter concentration-response curves were repeated. Furthermore, 14 mg/kg PETN were daily administered to rats by gavage; PETN and metabolites were measured in feces and blood. In vitro, the vasodilator potencies increased from mononitrates to tetranitrates (pD2: 4.14 to 8.18); PETN was the most potent vasodilator. In vitro tolerance was found with PETN and trinitrates but not with dinitrates and mononitrates. Thus, in vitro tolerance correlated with the in vitro potency of nitrates but not with the vasodilator potency of NO donors in general, because S-nitroso-N-aectyl-D-penicillamine and N-phenylpiperazin-NONOate were more potent than GTN but did not induce tolerance. After feeding of rats with PETN, pentaerythrityl dinitrate (PEdiN) and mononitrate (PEmonoN) but neither PETN nor PEtriN (both detected in feces) were found in the blood. The missing systemic bioavailability of PETN and PEtriN may explain the discrepancy between in vitro and in vivo findings. We conclude that the partially denitrated metabolites PEdiN and PEmonoN contribute to the moderate and tolerance-devoid clinical activity of PETN.

  13. Efficacy of transdermal nitroglycerine in idiopathic pre-term labour.

    PubMed

    Shaikh, Shahida; Shaikh, Abdul Hameed; Akhter, Saleem; Isran, Basma

    2012-01-01

    To determine the efficacy of transdermal Nitroglycerine patch in idiopathic pre-term labour and foetomaternal outcome. This quasi-experimental study was conducted at the Obstetrics Unit-II of Shaikh Zayed Hospital for Women, Chandka Medical College, Shaheed Mohtarma Benazir Bhutto Medical University, Larkana, from Jan 1 to June 30, 2010. Sixtyfive pregnant women at 28-34 weeks of gestation were recruited after they met the selection criteria based on non-probability consecutive sampling. Initially, 73 patients were selected, but 65 of them completed the treatment, while 8 patients refused to continue. Patients diagnosed with pre-term labour were given glyceryl trinitrate (GTN) 5 mg/12 hours transdermal patch which was applied on the anterior abdominal wall. The second patch of same dose was given after 12 hours. Arrest of labour, prolongation of pregnancy in days or weeks along with side effects of the agent were monitored. Patients were followed till delivery to know the foeto-maternal outcome. Dramatic effects were seen in around 60 (92.3%), of the total patients who had felt relief from premature labour pains within the first hour and only 5 (7.6%) patients could not go beyond 24 hours, as among them 3 (4.61%) had previous uterine scar and 2 (3.07%) developed ruptured membranes after 12 hours of admission and their babies also could not survive. Mean pregnancy prolongation was 15.35 +/- 9.45 days (min: 4 max: 35), so delivery was deferred up to 48 hours, 3 to 7 days and more than 7 days in 4 (6.15%), 6 (9.23%) and 50 (76.92%) respectively. Glyceryl trinitrate, trans dermal patch is effective and safe tocolytic in idiopathic preterm labour. By prolonging pregnancy it improves neonatal outcome.

  14. Pharmacokinetics and enhanced oral bioavailability in beagle dogs of cyclosporine A encapsulated in glyceryl monooleate/poloxamer 407 cubic nanoparticles

    PubMed Central

    Lai, Jie; Lu, Yi; Yin, Zongning; Hu, Fuqiang; Wu, Wei

    2010-01-01

    Efforts to improve the oral bioavailability of cyclosporine A (CyA) remains a challenge in the field of drug delivery. In this study, glyceryl monooleate (GMO)/poloxamer 407 cubic nanoparticles were evaluated as potential vehicles to improve the oral bioavailability of CyA. Cubic nanoparticles were prepared via the fragmentation of a bulk GMO/poloxamer 407 cubic phase gel by sonication and homogenization. The cubic inner structure formed was verified using Cryo-TEM. The mean diameters of the nanoparticles were about 180 nm, and the entrapment efficiency of these particles for CyA was over 85%. The in vitro release of CyA from these nanoparticles was less than 5% at 12 h. The results of a pharmacokinetic study in beagle dogs showed improved absorption of CyA from cubic nanoparticles as compared to microemulsion-based Neoral®; higher Cmax (1371.18 ± 37.34 vs 969.68 ± 176.3 ng mL−1), higher AUC0–t (7757.21 ± 1093.64 vs 4739.52 ± 806.30 ng h mL−1) and AUC0–∞ (9004.77 ± 1090.38 vs 5462.31 ± 930.76 ng h mL−1). The relative oral bioavailability of CyA cubic nanoparticles calculated on the basis of AUC0–∞ was about 178% as compared to Neoral®. The enhanced bioavailability of CyA is likely due to facilitated absorption by cubic nanoparticles rather than improved release. PMID:20161984

  15. Pharmacokinetics and enhanced oral bioavailability in beagle dogs of cyclosporine A encapsulated in glyceryl monooleate/poloxamer 407 cubic nanoparticles.

    PubMed

    Lai, Jie; Lu, Yi; Yin, Zongning; Hu, Fuqiang; Wu, Wei

    2010-02-02

    Efforts to improve the oral bioavailability of cyclosporine A (CyA) remains a challenge in the field of drug delivery. In this study, glyceryl monooleate (GMO)/poloxamer 407 cubic nanoparticles were evaluated as potential vehicles to improve the oral bioavailability of CyA. Cubic nanoparticles were prepared via the fragmentation of a bulk GMO/poloxamer 407 cubic phase gel by sonication and homogenization. The cubic inner structure formed was verified using Cryo-TEM. The mean diameters of the nanoparticles were about 180 nm, and the entrapment efficiency of these particles for CyA was over 85%. The in vitro release of CyA from these nanoparticles was less than 5% at 12 h. The results of a pharmacokinetic study in beagle dogs showed improved absorption of CyA from cubic nanoparticles as compared to microemulsion-based Neoral((R)); higher C(max) (1371.18 +/- 37.34 vs 969.68 +/- 176.3 ng mL(-1)), higher AUC(0-t) (7757.21 +/- 1093.64 vs 4739.52 +/- 806.30 ng h mL(-1)) and AUC(0-infinity) (9004.77 +/- 1090.38 vs 5462.31 +/- 930.76 ng h mL(-1)). The relative oral bioavailability of CyA cubic nanoparticles calculated on the basis of AUC(0-infinity) was about 178% as compared to Neoral((R)). The enhanced bioavailability of CyA is likely due to facilitated absorption by cubic nanoparticles rather than improved release.

  16. DOI/GTN-P climate and active-layer data acquired in the National Petroleum Reserve: Alaska and the Arctic National Wildlife Refuge, 1998-2011

    USGS Publications Warehouse

    Urban, Frank E.; Clow, Gary D.

    2014-01-01

    This report provides data collected by the climate monitoring array of the U.S. Department of the Interior on Federal lands in Arctic Alaska over the period August 1998 to July 2011; this array is part of the Global Terrestrial Network for Permafrost, (DOI/GTN-P). In addition to presenting data, this report also describes monitoring, data collection, and quality-control methodology. This array of 16 monitoring stations spans lat 68.5°N. to 70.5°N. and long 142.5°W. to 161°W., an area of approximately 150,000 square kilometers. Climate summaries are presented along with quality-controlled data. Data collection is ongoing and includes the following climate- and permafrost-related variables: air temperature, wind speed and direction, ground temperature and soil moisture, snow depth, rainfall, up- and downwelling shortwave radiation, and atmospheric pressure. These data were collected by the U.S. Geological Survey in close collaboration with the Bureau of Land Management and the U.S. Fish and Wildlife Service.

  17. DOI/GTN-P climate and active-layer data acquired in the National Petroleum Reserve-Alaska and the Arctic National Wildlife Refuge

    USGS Publications Warehouse

    Urban, Frank E.; Clow, Gary D.

    2014-01-01

    This report provides data collected by the climate monitoring array of the U.S. Department of the Interior on Federal lands in Arctic Alaska over the period August 1998 to July 2013; this array is part of the Global Terrestrial Network for Permafrost, (DOI/GTN-P). In addition to presenting data, this report also describes monitoring, data collection, and quality-control methods. This array of 16 monitoring stations spans lat 68.5°N. to 70.5°N. and long 142.5°W. to 161°W., an area of approximately 150,000 square kilometers. Climate summaries are presented along with quality-controlled data. Data collection is ongoing and includes the following climate- and permafrost-related variables: air temperature, wind speed and direction, ground temperature, soil moisture, snow depth, rainfall totals, up- and downwelling shortwave radiation, and atmospheric pressure. These data were collected by the U.S. Geological Survey in close collaboration with the Bureau of Land Management and the U.S. Fish and Wildlife Service.

  18. DOI/GTN-P Climate and active-layer data acquired in the National Petroleum Reserve–Alaska and the Arctic National Wildlife Refuge, 1998–2015

    USGS Publications Warehouse

    Urban, Frank E.; Clow, Gary D.

    2017-02-06

    This report provides data collected by the climate monitoring array of the U.S. Department of the Interior on Federal lands in Arctic Alaska over the period August 1998 to July 2015; this array is part of the Global Terrestrial Network for Permafrost (DOI/GTN-P). In addition to presenting data, this report also describes monitoring, data collection, and quality-control methods. The array of 16 monitoring stations spans lat 68.5°N. to 70.5°N. and long 142.5°W. to 161°W., an area of approximately 150,000 square kilometers. Climate summaries are presented along with quality-controlled data. Data collection is ongoing and includes the following climate- and permafrost-related variables: air temperature, wind speed and direction, ground temperature, soil moisture, snow depth, rainfall totals, up- and downwelling shortwave radiation, and atmospheric pressure. These data were collected by the U.S. Geological Survey in close collaboration with the Bureau of Land Management and the U.S. Fish and Wildlife Service.

  19. DOI/GTN-P Climate and active-layer data acquired in the National Petroleum Reserve–Alaska and the Arctic National Wildlife Refuge, 1998–2014

    USGS Publications Warehouse

    Urban, Frank E.; Clow, Gary D.

    2016-03-04

    This report provides data collected by the climate monitoring array of the U.S. Department of the Interior on Federal lands in Arctic Alaska over the period August 1998 to July 2014; this array is part of the Global Terrestrial Network for Permafrost (DOI/GTN-P). In addition to presenting data, this report also describes monitoring, data collection, and quality-control methods. The array of 16 monitoring stations spans lat 68.5°N. to 70.5°N. and long 142.5°W. to 161°W., an area of approximately 150,000 square kilometers. Climate summaries are presented along with quality-controlled data. Data collection is ongoing and includes the following climate- and permafrost-related variables: air temperature, wind speed and direction, ground temperature, soil moisture, snow depth, rainfall totals, up- and downwelling shortwave radiation, and atmospheric pressure. These data were collected by the U.S. Geological Survey in close collaboration with the Bureau of Land Management and the U.S. Fish and Wildlife Service.

  20. Study on the cyclic GMP-dependency of relaxations to endogenous and exogenous nitric oxide in the mouse gastrointestinal tract.

    PubMed

    De Man, J G; De Winter, B Y; Herman, A G; Pelckmans, P A

    2007-01-01

    cGMP mediates nitrergic relaxations of intestinal smooth muscle, but several studies have indicated that cGMP-independent mechanisms may also be involved. We addressed this contention by studying the effect of ODQ and ns2028, specific inhibitors of soluble guanylate cyclase, on nitrergic relaxations of the mouse gut. Mouse gastric fundus and small intestinal muscle preparations were mounted in organ baths to study relaxations to exogenous NO, NO donors and electrical field stimulation (EFS) of enteric nerves. In gastric fundus longitudinal muscle strips, ODQ and NS2028 abolished the L-nitroarginine-sensitive relaxations to EFS and the relaxations to NO and NO donors, glyceryl trinitrate (GTN), SIN-1 and sodium nitroprusside (SNP). EFS of intestinal segments and muscle strips showed L-nitroarginine-resistant relaxations, which were abolished by the purinoceptor blocker suramin. In the presence of suramin, ODQ and NS2028 abolished all relaxations to EFS in intestinal segments and strips. ODQ and NS2028 abolished the relaxations to exogenous NO and to the NO donors GTN, SIN-1 and SNP in circular and longitudinal intestinal muscle strips. Intestinal segments showed residual relaxations to NO and GTN. Our results indicate that relaxations to endogenous NO in the mouse gastric fundus and small intestine are completely dependent on cGMP. ODQ and NS2028 incompletely blocked nitrergic relaxations to exogenous NO in intact intestinal segments. However, it is unlikely that this is due to the involvement of cGMP-independent pathways because ODQ and NS2028 abolished all relaxations to endogenous and exogenous NO in intestinal muscle strips.

  1. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells.

    PubMed

    Barsoum, Ivraym B; Smallwood, Chelsea A; Siemens, D Robert; Graham, Charles H

    2014-02-01

    Immune escape is a fundamental trait of cancer in which mechanistic knowledge is incomplete. Here, we describe a novel mechanism by which hypoxia contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL). Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1α (HIF-1α). In vivo studies also demonstrated cellular colocalization of HIF-1α and PD-L1 in tumors. Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1α accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN attenuated tumor growth in mice. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells. This increase in apoptosis was prevented by blocking the interaction of PD-L1 with PD-1, the PD-L1 receptor on T cells, or by addition of GTN. Our findings point to a role for hypoxia/HIF-1 in driving immune escape from CTL, and they suggest a novel cancer immunotherapy to block PD-L1 expression in hypoxic-tumor cells by administering NO mimetics.

  2. 6D.03: FLOW-MEDIATED DILATATION (FMD) AND ENDOTHELIUM-INDEPENDENT DILATATION (EID) IN PATIENTS WITH MULTIFOCAL FIBROMUSCULAR DYSPLASIA: A CROSS-SECTIONAL STUDY.

    PubMed

    Khettab, H; Lorthior, A; Niarra, R; Chambon, Y; Jeunemaitre, X; Plouin, P F; Laurent, S; Boutouyrie, P; Azizi, M

    2015-06-01

    Fibromuscular dysplasia (FD) is a rare idiopathic, segmental, non-atherosclerotic non-inflammatory vascular disease. We previously showed that FD is a general arterial disease with focal exacerbation of the trait. However, whether endothelial dysfunction may be involved in the pathophysiology of FD is unclear. In a cross sectional study, we compared the endothelial function between 50 patients with multifocal FD of renal/carotid arteries confirmed by CT-angiography, 50 essential hypertensive (EH) patients matched for age, sex, ethnicity and BP and 50 healthy subjects (HS) matched for age, sex and ethnicity. Exclusion criteria were: tobacco consumption, hypercholesterolemia, diabetes, aspirin or statin treatment. Brachial artery (BA) FMD after release of hand ischemia and glyceryl trinitrate (GTN)-induced EID was measured using a high-resolution radiofrequency-based echotracking system blind to the diagnosis. FD, EH and HS were well matched (52yrs, 85% women, 80% caucasian). SBP was higher in FD (125 ± 15mmHg) and EH (121 ± 12mmHg) than EH (113 ± 10mmHg) despite antihypertensive treatments. BA external diameter was significantly lower in FD than in both HS and EH before, during and after hand ischemia and after GTN. BA intima media thickness (IMT), internal diameter did not differ between the 3 groups. FMD (%) or EID (%) did not significantly differ between the 3 groups. BA flow velocity did not significantly differ in any experimental condition.(Figure is included in full-text article.) : In conclusion, despite showing similar acute vasodilatory responses to flow and GTN, FD patients differed from EH and HS in terms of arterial morphology with smaller BA diameter associated with similar IMT. This paradoxical remodeling may suggest a chronic defect in the endothelium-dependent pathways involved in arterial remodeling in FD patients.

  3. Exercise training improves conduit vessel function in patients with coronary artery disease.

    PubMed

    Walsh, Jennifer H; Bilsborough, William; Maiorana, Andrew; Best, Matthew; O'Driscoll, Gerard J; Taylor, Roger R; Green, Daniel J

    2003-07-01

    It is well established that endothelial dysfunction is present in coronary artery disease (CAD), although few studies have determined the effect of training on peripheral conduit vessel function in patients with CAD. A randomized, crossover design determined the effect of 8 wk of predominantly lower limb, combined aerobic and resistance training, in 10 patients with treated CAD. Endothelium-dependent dilation of the brachial artery was determined, by using high-resolution vascular ultrasonography, from flow-mediated vasodilation (FMD) after ischemia. Endothelium-independent vasodilation was measured after administration of glyceryl trinitrate (GTN). Baseline function was compared with that of 10 control subjects. Compared with matched healthy control subjects, FMD and GTN responses were significantly impaired in the untrained CAD patients [3.0 +/- 0.8 (SE) vs. 5.8 +/- 0.8% and 14.5 +/- 1.9 vs. 20.4 +/- 1.5%, respectively; both P < 0.05]. Training significantly improved FMD in the CAD patients (from 3.0 +/- 0.8 to 5.7 +/- 1.1%; P < 0.05) but not responsiveness to GTN (14.5 +/- 1.9 vs. 12.1 +/- 1.4%; P = not significant). Exercise training improves endothelium-dependent conduit vessel dilation in subjects with CAD, and the effect, evident in the brachial artery, appears to be generalized rather than limited to vessels of exercising muscle beds. These results provide evidence for the benefit of exercise training, as an adjunct to routine therapy, in patients with a history of CAD.

  4. Phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained-release oral drug delivery systems for poorly water soluble drugs I. Phase behaviour in physiologically-relevant media.

    PubMed

    Nguyen, Tri-Hung; Hanley, Tracey; Porter, Christopher J H; Larson, Ian; Boyd, Ben J

    2010-07-01

    The potential utility of liquid crystalline lipid-based formulations in oral drug delivery is expected to depend critically on their structure formation and stability in gastrointestinal fluids. The phase behaviour of lipid-based liquid crystals formed by phytantriol and glyceryl monooleate, known to form a bicontinuous cubic phase in excess water, was therefore assessed in physiologically-relevant simulated gastrointestinal media. Fixed composition phase studies, crossed polarised light microscopy (CPLM) and small angle X-ray scattering (SAXS) were used to determine the phase structures formed in phosphate-buffered saline, simulated gastric and intestinal fluids in the presence of model poorly water soluble drugs cinnarizine, diazepam and vitamin E acetate. The phase behaviour of phytantriol in phosphate-buffered saline was very similar to that in water. Increasing concentrations of bile components (bile salts and phospholipids) caused an increase in the lattice parameter of the cubic phase structure for both lipids. Incorporation of cinnarizine and diazepam did not influence the phase behaviour of the phytantriol- or glyceryl monooleate-based systems at physiological temperatures; however, an inverse hexagonal phase formed on incorporation of vitamin E acetate. Phytantriol and glyceryl monooleate have the potential to form stable cubic phase liquid crystalline delivery systems in the gastrointestinal tract. In-vivo studies to assess their sustained-release behaviour are warranted.

  5. Analysis of curing of a sustained release coating formulation by application of NIR spectroscopy to monitor changes associated with glyceryl monostearate.

    PubMed

    Howland, Harris; Fahmy, Raafat; Hoag, Stephen W

    2015-01-01

    For controlled release, latex or pseudolatex coatings to function as designed, it must be cured at temperatures at or slightly above the polymer's glass transition temperature. The focus of this study is to develop an understanding of the curing process and to develop near infrared spectroscopy as a tool for monitoring curing. Differential scanning calorimetry studies were used to determine how the thermal properties of glyceryl monostearate (GMS) and its polymorphic forms relate to the extent of Eudragit® polymer coat curing at different curing temperatures. The different GMS melting endotherms were used to monitor the extent of curing and as references for model development. The calculated melting peak areas for the GMS were plotted versus time and found to be dependent on time and temperature used for curing. Principal component analysis and parallel factor analysis were used to investigate the effect of curing on the films and showed that spectral changes could be could be directly related to the changes associated with the GMS during curing. Partial least square models developed could predict the extent of curing and the final state of GMS post curing.

  6. Ocular delivery of cyclosporine A based on glyceryl monooleate/poloxamer 407 liquid crystalline nanoparticles: preparation, characterization, in vitro corneal penetration and ocular irritation.

    PubMed

    Chen, Yan; Lu, Yi; Zhong, Yanqiang; Wang, Qingping; Wu, Wei; Gao, Shen

    2012-12-01

    The purpose of this study was to develop an ophthalmic drug delivery system for cyclosporine A (CsA) based on glyceryl monooleate (GMO)/poloxamer 407 liquid crystalline nanoparticles with reduced ocular irritancy and improved corneal penetration. CsA-loaded liquid crystalline nanoparticles were prepared via fragmentation of a bulk GMO/poloxamer 407 cubic phase gel by high-pressure homogenization and characterized. Corneal permeation and retention was evaluated using modified Franz diffusing cells. Intra-corneal transportation was investigated with fluorescein isothiocyanate (FITC)-labeled liquid crystalline nanoparticles. Ocular irritation was then evaluated using the Draize method. The mean particle size of liquid crystalline nanoparticles was 193.5 nm and the entrapment efficiency was 95.11 ± 0.67%. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray diffraction (SAXD) analysis. A 1.52-fold increase in J(s) and a 2.2-fold increase in corneal retention was achieved by liquid crystalline nanoparticles compared with oil solution. In vitro corneal permeation investigated with FITC-labeled liquid crystalline nanoparticles revealed that CsA penetrated across the cornea under the transportation of liquid crystalline nanoparticles. Liquid crystalline nanoparticles exhibited excellent ocular tolerance in the ocular irritation test. This low-irritant vehicle based on liquid crystalline nanoparticles might be a promising system for effective ocular CsA delivery.

  7. Glyceryl monooleate/poloxamer 407 cubic nanoparticles as oral drug delivery systems: I. In vitro evaluation and enhanced oral bioavailability of the poorly water-soluble drug simvastatin.

    PubMed

    Lai, Jie; Chen, Jianming; Lu, Yi; Sun, Jing; Hu, Fuqiang; Yin, Zongning; Wu, Wei

    2009-01-01

    Glyceryl monooleate (GMO)/poloxamer 407 cubic nanoparticles were investigated as potential oral drug delivery systems to enhance the bioavailability of the water-insoluble model drug simvastatin. The simvastatin-loaded cubic nanoparticles were prepared through fragmentation of the GMO/poloxamer 407 bulk cubic-phase gel using high-pressure homogenization. The internal structure of the cubic nanoparticles was identified by cryo-transmission electron microscopy. The mean diameter of the cubic nanoparticles varied within the range of 100-150 nm, and both GMO/poloxamer 407 ratio and theoretical drug loading had no significant effect on particle size and distribution. Almost complete entrapment with efficiency over 98% was achieved due to the high affinity of simvastatin to the hydrophobic regions of the cubic phase. Release of simvastatin from the cubic nanoparticles was limited both in 0.1 M hydrochloride solution containing 0.2% sodium lauryl sulfate and fasted-state simulated intestinal fluid with a total release of <3.0% at 10 h. Pharmacokinetic profiles in beagle dogs showed sustained plasma levels of simvastatin for cubic nanoparticles over 12 h. The relative oral bioavailability of simvastatin cubic nanoparticles calculated on the basis of area under the curve was 241% compared to simvastatin crystal powder. The enhancement of simvastatin bioavailability was possibly attributable to facilitated absorption by lipids in the formulation rather than improved release.

  8. Glyceryl Tribenzoate: A Flavoring Ingredient, Inhibits the Adoptive Transfer of Experimental Allergic Encephalomyelitis via TGF-β: Implications for Multiple Sclerosis Therapy

    PubMed Central

    Mondal, Susanta; Dasarathi, Sridevi; Pahan, Kalipada

    2017-01-01

    Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS). Here, we have explored a novel use of glyceryl tribenzoate (GTB), a flavoring ingredient, in ameliorating the disease process of experimental allergic encephalomyelitis (EAE), an animal model of MS, via TGF-β. Oral feeding of GTB suppressed clinical symptoms of adoptively-transferred relapsing-remitting (RR) EAE in recipient mice and suppressed the generation of encephalitogenic T cells in donor mice. GTB also attenuated clinical symptoms of RR-EAE in PLP-TCR transgenic mice and chronic EAE in male C57/BL6 mice. Accordingly, GTB also suppressed perivascular cuffing, preserved the integrity of blood-brain barrier and blood-spinal cord barrier, inhibited inflammation, and stopped demyelination in the CNS of EAE mice. Interestingly, GTB treatment upregulated TGF-β and enriched regulatory T cells (Tregs) in splenocytes as well as in vivo in EAE mice. Blocking TGF-β by neutralizing antibodies abrogated GTB-mediated enrichment of Tregs and protection of EAE. These results suggest that oral GTB may be considered as a possible therapy for MS patients. PMID:28367355

  9. A new class of furoxan derivatives as NO donors: mechanism of action and biological activity.

    PubMed Central

    Ferioli, R; Folco, G C; Ferretti, C; Gasco, A M; Medana, C; Fruttero, R; Civelli, M; Gasco, A

    1995-01-01

    1. The mechanism of action and biological activity of a series of R-substituted and di-R-substituted phenylfuroxans is reported. 2. Maximal potency as vasodilators on rabbit aortic rings, precontracted with noradrenaline (1 microM), was shown by phenyl-cyano isomers and by the 3,4-dicyanofuroxan, characterized by a potency ratio 3-10 fold higher than glyceryl trinitrate (GTN). This effect was reduced upon coincubation with methylene blue or oxyhaemoglobin (10 microM). 3. The furoxan derivatives showing maximal potency as vasodilators were also able to inhibit collagen-induced platelet aggregation, with IC50 values in the sub-micromolar range. 4. The furoxan derivatives were able to stimulate partially purified, rat lung soluble guanylate cyclase; among the most active compounds, the 3-R-substituted isomers displayed a higher level of stimulatory effect than the 4-R analogues. 5. Solutions (0.1 mM) of all the tested furoxans, prepared using 50 mM phosphate buffer, pH 7.4, (diluting 10 mM DMSO stock solutions) did not release nitric oxide (NO) spontaneously; however in presence of 5 mM L-cysteine, a significant NO-releasing capacity was observed, which correlated significantly with their stimulation of the guanylate cyclase activity. PMID:7773542

  10. Synthesis and characterization of a novel organic nitrate NDHP: Role of xanthine oxidoreductase-mediated nitric oxide formation.

    PubMed

    Zhuge, Zhengbing; Paulo, Luciano L; Jahandideh, Arghavan; Brandão, Maria C R; Athayde-Filho, Petrônio F; Lundberg, Jon O; Braga, Valdir A; Carlström, Mattias; Montenegro, Marcelo F

    2017-10-01

    In this report, we describe the synthesis and characterization of 1,3-bis(hexyloxy)propan-2-yl nitrate (NDHP), a novel organic mono nitrate. Using purified xanthine oxidoreductase (XOR), chemiluminescence and electron paramagnetic resonance (EPR) spectroscopy, we found that XOR catalyzes nitric oxide (NO) generation from NDHP under anaerobic conditions, and that thiols are not involved or required in this process. Further mechanistic studies revealed that NDHP could be reduced to NO at both the FAD and the molybdenum sites of XOR, but that the FAD site required an unoccupied molybdenum site. Conversely, the molybdenum site was able to reduce NDHP independently of an active FAD site. Moreover, using isolated vessels in a myograph, we demonstrate that NDHP dilates pre-constricted mesenteric arteries from rats and mice. These effects were diminished when XOR was blocked using the selective inhibitor febuxostat. Finally, we demonstrate that NDHP, in contrast to glyceryl trinitrate (GTN), is not subject to development of tolerance in isolated mesenteric arteries. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Folate supplementation fails to affect vascular function and carotid artery intima media thickness in cyclosporin A-treated renal transplant recipients.

    PubMed

    Austen, S K; Fassett, R G; Geraghty, D P; Coombes, J S

    2006-11-01

    Cyclosporin A (CsA)-treated renal transplant recipients (RTR) exhibit relative hyperhomocystinemia and vascular dysfunction. Folate supplementation lowers homocysteine and has been shown to improve vascular function in healthy subjects and patients with coronary artery disease. The aim of this study was to assess the effects of 3 months of folate supplementation (5 mg/day) on vascular function and structure in RTR. A double-blind, placebo-controlled crossover study was conducted in 10 CsA-treated RTR. Vascular structure was measured as carotid artery intima media thickness (IMT) and function was assessed as changes in brachial artery diameter during reactive hyperemia (RH) and in response to glyceryl trinitrate (GTN). Function data were analyzed as absolute and percent change from baseline and area under the diameter/time curve. Blood samples were collected before and after supplementation and analyzed for total plasma homocysteine, folate, vitamin B12 and asymmetric dimethyl arginine (ADMA) in addition to regular measures of hemoglobin, hematocrit, mean corpuscular volume (MCV) and serum creatinine. Folate supplementation significantly increased plasma folate by 687% (p < 0.005) and decreased homocysteine by 37% (p < 0.05) with no changes (p > 0.05) in vitamin B12 or ADMA. There were no significant (p > 0.05) changes in vascular structure or function during the placebo or the folate supplementation phases; IMT; placebo pre mean +/- SD, 0.52 +/- 0.12, post 0.50 +/- 0.11; folate pre 0.55 +/- 0.17, post 0.49 +/- 0.20 mm, 5% change in brachial artery diameter (RH, placebo pre 10 +/- 8, post 6 +/- 5; folate pre 9 +/- 7, post 7 +/- 5; GTN, placebo pre 18 +/- 10, post 17 +/- 9, folate pre 16 +/- 9, post-supplementation 18 +/- 8). Three months of folate supplementation decreases plasma homocysteine but has no effect on endothelial function or carotid artery IMT in RTR.

  12. Inhibitory effects of calcium antagonists on alpha-adrenoceptor-mediated contraction in the human internal mammary artery.

    PubMed Central

    He, G W; Acuff, T E; Ryan, W H; Yang, C Q; Douthit, M B; Bowman, R T; Mack, M J

    1994-01-01

    1. The internal mammary artery has become a preferred coronary bypass graft. Sympathomimetic amines are spasmogens for vasospasm and calcium antagonists are frequently administered drugs perioperatively. The effect of calcium antagonists on alpha-adrenoceptor-mediated contraction depends on the subtype of alpha-adrenoceptor and the type of origin of vascular smooth muscle. This study was designed to investigate the effect of calcium antagonists on alpha-adrenoceptor-mediated contraction in the IMA. 2. Human IMA segments taken from 22 patients undergoing IMA--coronary artery bypass grafting were mounted in an organ bath under the physiological pressure determined from their own length-tension curves. 3. Three ring segments were allocated into three groups. One served as a control and the others were treated with clinically related concentrations of nifedipine (20 or 200 nM) for 25 min before concentration-contraction curves to alpha 1-adrenoceptor agonist methoxamine (MO) or full alpha-adrenoceptor agonist noradrenaline (NA) were established. 4. In separate experiments, the concentration-relaxation curves to nifedipine were established in the IMA rings precontracted with MO (30 microM) or NA (10 microM). Glyceryl trinitrate (GTN, 3 microM) was added to further relax the vessels. 5. Pretreatment with nifedipine (200 nM) only slightly inhibited the MO- (1.74 +/- 0.32 vs 2.88 +/- 0.56 g) or NA- (2.43 +/- 0.66 vs 3.60 +/- 0.82 g) induced contraction without statistical significance (P > 0.05). 6. On the other hand, nifedipine only caused 34.49% relaxation in the MO-precontracted and 24.39% relaxation in the NA-precontracted IMAs. In contrast, GTN caused 76.16% (against MO, P < 0.05) or 92.22% (against NA, P < 0.0001) relaxation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7910471

  13. Fenofibrate effects on arterial endothelial function in adults with type 2 diabetes mellitus: A FIELD substudy.

    PubMed

    Harmer, Jason A; Keech, Anthony C; Veillard, Anne-Sophie; Skilton, Michael R; Marwick, Thomas H; Watts, Gerald F; Meredith, Ian T; Celermajer, David S

    2015-09-01

    Dislipidaemia in type 2 diabetes mellitus contributes to arterial endothelial dysfunction and an increased risk of cardiovascular disease. Fenofibrate, a lipid-regulating peroxisome proliferator-activated receptor-α (PPARα) agonist, has been shown to reduce vascular complications in adults with type 2 diabetes. However, the mechanisms for such benefit are not well understood. We examined the effects of fenofibrate on brachial artery endothelial function in adults with type 2 diabetes. In a prospectively designed substudy of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, we assessed arterial flow-mediated dilatation (FMD; endothelium-dependent dilatation) and dilator responses to glyceryl trinitrate (GTN, an endothelium-independent dilator) in a subset of 193 representative adults. Traditional risk factors were assessed at baseline, 4 months and 2 years after randomised treatment allocation to fenofibrate (200 mg daily) or placebo. The prespecified primary study endpoint was the difference in FMD between treatment groups at 4 months. Fenofibrate was associated with a significant improvement at 4 months compared with placebo (+1.05% (absolute); P=0.03); GTN-dilator responses were unchanged (P=0.77). After 2 years, FMD was similar in both groups (P=0.46). In multivariable models, none of the fenofibrate-related changes in lipoproteins and lipids were significantly associated with improved FMD on fenofibrate at 4 months. Treatment with fenofibrate significantly improved arterial endothelial function after 4 months. However, the effect was no longer apparent after 2 years. The long-term beneficial vascular effects of fenofibrate in type 2 diabetes are likely to be mediated via mechanisms other than improvement in endothelium-dependent dilatation of conduit arteries, and may differ for the microcirculation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Brachial artery adaptation to lower limb exercise training: role of shear stress.

    PubMed

    Birk, Gurpreet K; Dawson, Ellen A; Atkinson, Ceri; Haynes, Andrew; Cable, N Timothy; Thijssen, Dick H J; Green, Daniel J

    2012-05-01

    Lower limb exercise increases upper limb conduit artery blood flow and shear stress, and leg exercise training can enhance upper limb vascular function. We therefore examined the contribution of shear stress to changes in vascular function in the nonexercising upper limbs in response to lower limb cycling exercise training. Initially, five male subjects underwent bilateral brachial artery duplex ultrasound to measure blood flow and shear responses to 30-min cycling exercise at 80% of maximal heart rate. Responses in one forearm were significantly (P < 0.05) attenuated via cuff inflation throughout the exercise bout. An additional 11 subjects participated in an 8-wk cycle training study undertaken at a similar intensity, with unilateral cuff inflation around the forearm during each exercise bout. Bilateral brachial artery flow-mediated dilation responses to a 5-min ischemic stimulus (FMD%), an ischemic handgrip exercise stimulus (iEX), and endothelium-independent NO donor administration [glyceryl trinitrate (GTN)] were measured at 2, 4, and 8 wk. Cycle training increased FMD% in the noncuffed limb at week 2, after which time responses returned toward baseline levels (5.8 ± 4.1, 8.6 ± 3.8, 7.4 ± 3.5, 6.0 ± 2.3 at 0, 2, 4 and 8 wk, respectively; ANOVA: P = 0.04). No changes in FMD% were observed in the cuffed arm. No changes were evident in response to iEX or GTN in either the cuffed or noncuffed arms (P > 0.05) across the 8-wk intervention period. Our data suggest that lower limb cycle training induces a transient increase in upper limb vascular function in healthy young humans, which is, at least partly, mediated via shear stress.

  15. Nitric oxide modulation of ophthalmic artery blood flow velocity waveform morphology in healthy volunteers.

    PubMed

    Lockhart, Christopher J; Gamble, Andrew J; Rea, Derrick; Hughes, Sinead; McGivern, R Canice; Wolsley, Clive; Stevenson, Michael; Harbinson, Mark T; Plumb, Richard D; McVeigh, Gary E

    2006-07-01

    Quantitative analysis of the arterial pressure pulse waveform recorded by applanation tonometry of the radial artery can track NO (nitric oxide)-mediated modulation of arterial smooth muscle tone. The changes in pressure pulse waveform morphology result from pulse wave reflection arising predominantly from smaller arteries and arterioles. Employing Doppler ultrasound to record the spectral flow velocity waveform in the ophthalmic artery, we studied the effects of NO modulation on waveforms recorded in the proximity of the terminal ocular microcirculatory bed. In healthy young men (n=10; age 18-26 years), recordings were made at baseline, following 300 mug of sublingual GTN (glyceryl trinitrate) and during the intravenous infusion of 0.25 and 0.5 mg/kg of L-NAME (N(G)-nitro-L-arginine methyl ester). Peaks (P1, P2 and P3) and nodes (N1, N2 and N3) on the arterial flow velocity waveform were identified during the cardiac cycle and employed to quantify wave shape change in response to the haemodynamic actions of the pharmacological interventions. The administration of GTN resulted in a significant (P<0.05) increase in heart rate without significant alteration in blood pressure. At the doses employed, L-NAME did not significantly alter systemic haemodynamics. With the exception of peak Doppler systolic velocity, all other peaks and nodes decreased significantly in response to GTN (P<0.05 for all points compared with baseline). In response to the administration of L-NAME, all peaks and nodes decreased significantly (P<0.05 for all points compared with baseline). The resistive index, a ratio calculated from the peak and trough flow velocities employed to assess change in flow resistance, increased significantly in response to GTN (0.77 at baseline compared with 0.85; P<0.05). Quantification of changes in the flow velocity spectral waveform during the cardiac cycle sensitively identified NO modulation of smooth muscle tone prior to alteration in systemic haemodynamics

  16. Impaired vasodilator response to organic nitrates in isolated basilar arteries

    PubMed Central

    Martens, Dorothee; Kojda, Georg

    2001-01-01

    The differential responsiveness of various sections and regions in the vascular system to the vasodilator activity of organic nitrates is important for the beneficial antiischaemic effects of these drugs. In this study we examined the vasodilator activity of organic nitrates in cerebral arteries, where vasodilation causes substantial nitrate induced headache. Isolated porcine basilar and coronary arteries were subjected to increasing concentrations of glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN). S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and endothelium-dependent vasodilation was investigated for comparison purpose. The vasodilator potency (halfmaximal effective concentration in −logM) of GTN (4.33±0.1, n=8), ISMN (1.61±0.07, n=7) and PETN (>10 μM, n=7) in basilar arteries was more than 100 fold lower than that of GTN (6.52±0.06, n=12), ISMN (3.66±0.08, n=10) and PETN (6.3±0.13, n=8) observed in coronary arteries. In striking contrast, the vasodilator potency of SNAP (halfmaximal effective concentration in −logM) was almost similar in basilar (7.76±0.05, n=7) and coronary arteries (7.59±0.05, n=9). Likewise, no difference in endothelium dependent relaxation was observed. Denudation of the endothelium resulted in a small increase of the vasodilator potency (halfmaximal effective concentration in −logM) of GTN (4.84±0.09, n=7, P<0.03) in basilar arteries and similar results were obtained in the presence of the NO-synthase inhibitor Nω-nitro-L-arginine (4.59±0.05, n=9, P<0.03). These results suggest that cerebral conductance blood vessels such as porcine basilar arteries seems to have a reduced expression and/or activity of certain cellular enzymatic electron transport systems such as cytochrome P450 enzymes, which are necessary to bioconvert organic nitrates to NO. PMID:11156558

  17. Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model.

    PubMed

    Madhavarao, C N; Arun, P; Anikster, Y; Mog, S R; Staretz-Chacham, O; Moffett, J R; Grunberg, N E; Gahl, W A; Namboodiri, A M A

    2009-10-01

    Canavan disease (CD) is a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. Here we tested tolerability of a potent acetate precursor, glyceryl triacetate (GTA), at low doses in two infants diagnosed with CD, aged 8 and 13 months. Much higher doses of GTA were evaluated for toxicity in the tremor rat model of CD. GTA was given orally to the infants for up to 4.5 and 6 months, starting at 25 mg/kg twice daily, doubling the dose weekly until a maximum of 250 mg/kg reached. Wild-type and tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 through 14, and at 5.8 g/kg from day 15 through 23, and thereafter in food (7.5%) and water (5%). At the end of the trial (approximately 90 to 120 days) sera and tissues from rats were analysed for changes in blood chemistry and histopathology. GTA treatment caused no detectable toxicity and the patients showed no deterioration in clinical status. In the high-dose animal studies, no significant differences in the mean blood chemistry values occurred between treated and untreated groups, and no lesions indicating toxicity were detectable in any of the tissues examined. Lack of GTA toxicity in two CD patients in low-dose trials, as well as in high-dose animal studies, suggests that higher, effective dose studies in human CD patients are warranted.

  18. Progress toward acetate supplementation therapy for Canavan disease: glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain.

    PubMed

    Mathew, Raji; Arun, Peethambaran; Madhavarao, Chikkathur N; Moffett, John R; Namboodiri, M A Aryan

    2005-10-01

    Canavan disease (CD) is a fatal genetic neurodegenerative disorder caused by mutations in the gene for aspartoacylase, an enzyme that hydrolyzes N-acetylaspartate (NAA) into L-aspartate and acetate. Because aspartoacylase is localized in oligodendrocytes, and NAA-derived acetate is incorporated into myelin lipids, we hypothesize that an acetate deficiency in oligodendrocytes is responsible for the pathology in CD, and we propose acetate supplementation as a possible therapy. In our preclinical efforts toward this goal, we studied the effectiveness of orally administered glyceryl triacetate (GTA) and calcium acetate for increasing acetate levels in the murine brain. The concentrations of brain acetate and NAA were determined simultaneously after intragastric administration of GTA. We found that the acetate levels in brain were increased in a dose- and time-dependent manner, with a 17-fold increase observed at 1 to 2 h in 20- to 21-day-old mice at a dose of 5.8 g/kg GTA. NAA levels in the brain were not significantly increased under these conditions. Studies using mice at varying stages of development showed that the dose of GTA required to maintain similarly elevated acetate levels in the brain increased with age. Also, GTA was significantly more effective as an acetate source than calcium acetate. Chronic administration of GTA up to 25 days of age did not result in any overt pathology in the mice. Based on these results and the current Food and Drug Administration-approved use of GTA as a food additive, we propose that it is a potential candidate for use in acetate supplementation therapy for CD.

  19. Final amended report on the safety assessment of Ammonium Thioglycolate, Butyl Thioglycolate, Calcium Thioglycolate, Ethanolamine Thioglycolate, Ethyl Thioglycolate, Glyceryl Thioglycolate, Isooctyl Thioglycolate, Isopropyl Thioglycolate, Magnesium Thioglycolate, Methyl Thioglycolate, Potassium Thioglycolate, Sodium Thioglycolate, and Thioglycolic Acid.

    PubMed

    Burnett, Christina L; Bergfeld, Wilma F; Belsito, Donald V; Klaassen, Curtis D; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2009-01-01

    This safety assessment includes Ammonium and Glyceryl Thioglycolate and Thioglycolic Acid Butyl, Calcium, Ethanolamine, Ethyl, Isooctyl, Isopropyl, Magnesium, Methyl, Potassium, and Sodium Thioglycolate, as used in cosmetics. Thioglycolates penetrate skin and distribute to the kidneys, lungs, small intestine, and spleen; excretion is primarily in urine. Thioglycolates were slightly toxic in rat acute oral toxicity studies. Thioglycolates are minimal to severe ocular irritants. Thioglycolates can be skin irritants in animal and in vitro tests, and can be sensitizers. A no-observable-adverse-effect level for reproductive and developmental toxicity of 100 mg/kg per day was determined using rats. Thioglycolates were not mutagenic, and there was no evidence of carcinogenicity. Thioglycolates were skin irritants in some clinical tests. Clinically significant adverse reactions to these ingredients used in depilatories are not commonly seen, suggesting current products are formulated to be practically nonirritating under conditions of recommended use. Formulators should take steps necessary to assure that current practices are followed.

  20. Outcome Of 0.2% Glyceryltrinitrate Cream Versus 2% Diltiazem Cream In The Treatment Of Chronic Anal Fissure.

    PubMed

    Khan, Muhammad Siddique; Akbar, Ismail; Zeb, Junaid; Ahmad, Salman; Khan, Ajmal

    2017-01-01

    Anal fissure is a linear tear in the distal anal canal resulting from persistent hypertonia and spasm of the internal sphincter which results in mucosal ischemia. We have conducted a study in order to compare the outcome of 0.2% glyceryl trinitrate cream versus 2% diltiazem cream in the treatment of chronic anal fissure. This randomized controlled trial (RCT) was carried out in the Department of Surgical "B" unit, at Ayub Teaching Hospital, Abbottabad, Pakistan from 15th June 2012 to 15th May 2015. One hundred and eighty-four patients who visited the outpatient department for the treatment of chronic anal fissure were included in the study. They were divided into two groups with 92 patients in each group. Patients in group "A" included those patients receiving topical glyceryl trinitrate and group "B" patients were those receiving topical diltiazem cream. Out of 184 patients 66.3% were males, 33.7% were females. Mean age of the patients was 43.84±7.976 and mean duration of symptoms was 10.55±2.524. Overall outcome in terms of healing was 71.2%, among which 80.4% were from diltiazem group while 62% in glyceryl trinitrate group. Complete relief of pain was observed in 67.9%, 26.1% complained of mild pain and 5.4% complained of moderate pain. Only one patient in glyceryl trinitrate group complained with severe pain with no healing after one month of follow up. No statistical association was found between healing outcome and gender as well as age of the patients (p>0.05) although an association was found between healing outcome and duration of symptoms (p<0.05). This study shows that diltiazem has better outcome in terms of healing of chronic anal fissure and reductions in symptoms, i.e., pain compared with glyceryl trinitrate.

  1. Assessment of endothelial dysfunction by flow-mediated dilatation in men on long-term androgen deprivation therapy for prostate cancer.

    PubMed

    Gilbert, Stephen E; Tew, Garry A; Bourke, Liam; Winter, Edward M; Rosario, Derek J

    2013-09-01

    What is the central question of this study? Androgen deprivation therapy (ADT) for prostate cancer has been linked with increased cardiovascular risk, but the mechanisms are unclear. Is there evidence that endothelial dysfunction, as evidenced by reduced flow-mediated dilatation (FMD), is associated with ADT? What is the main finding and its importance? Reduction in FMD with preservation of glyceryl trinitrate-mediated dilatation indicates endothelial dysfunction in men with prostate cancer on long-term ADT compared with well-matched control subjects. Vascular endothelial dysfunction associated with long-term ADT for prostate cancer might explain the observed epidemiological increases in adverse cardiovascular events. Assessment of FMD may be useful in the monitoring of cardiovascular risk in men with prostate cancer on ADT. Androgen deprivation therapy (ADT) in men with prostate cancer has been linked to an increased incidence of cardiovascular events and mortality, but the underpinning mechanisms are unclear. Endothelial dysfunction is considered a precursor for cardiovascular disease. Previous studies have reported variably on the association between ADT and endothelial function. This blinded case-control study examined endothelial function, using high-resolution ultrasound to measure flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-mediated-dilatation in the brachial artery, in 20 men with prostate cancer (69 ± 7 years old) treated by ADT (median duration 22 months, range 6-133 months) and 20 men without prostate cancer (69 ± 5 years old) matched for age, physical activity, coexistent cardiovascular disease and body mass index. The magnitude of dilatation was calculated traditionally and allometrically scaled, adjusting for baseline diameter. There were no differences between groups for resting vascular measures (means ± SD). Flow-mediated dilatation was lower in men on ADT than in control subjects (3.9 ± 2.1 versus 5.9 ± 3.8% for traditional

  2. Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans.

    PubMed

    Arif, Sayqa; Borgognone, Alessandra; Lin, Erica Lai-Sze; O'Sullivan, Aine G; Sharma, Vishal; Drury, Nigel E; Menon, Ashvini; Nightingale, Peter; Mascaro, Jorge; Bonser, Robert S; Horowitz, John D; Feelisch, Martin; Frenneaux, Michael P; Madhani, Melanie

    2015-07-01

    Hypoxic conditions favour the reduction of nitrite to nitric oxide (NO) to elicit vasodilatation, but the mechanism(s) responsible for bioconversion remains ill defined. In the present study, we assess the role of aldehyde dehydrogenase 2 (ALDH2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature. The role of ALDH2 in vascular responses to nitrite was studied using rat thoracic aorta and gluteal subcutaneous fat resistance vessels from patients with heart failure (HF; 16 patients) in vitro and by measurement of changes in forearm blood flow (FBF) during intra-arterial nitrite infusion (21 patients) in vivo. Specifically, we investigated the effects of (i) ALDH2 inhibition by cyanamide or propionaldehyde and the (ii) tolerance-independent inactivation of ALDH2 by glyceryl trinitrate (GTN) on the vasodilator activity of nitrite. In each setting, nitrite effects were measured via evaluation of the concentration-response relationship under normoxic and hypoxic conditions in the absence or presence of ALDH2 inhibitors. Both in rat aorta and human resistance vessels, dilatation to nitrite was diminished following ALDH2 inhibition, in particular under hypoxia. In humans there was a non-significant trend towards attenuation of nitrite-mediated increases in FBF. In human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with HF in vivo, the role of this enzyme in nitrite bioactivation is at the most, modest, suggesting the involvement of other more important mechanisms. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  3. The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache.

    PubMed

    Olesen, Jes

    2008-11-01

    The most important primary headaches (i.e. independent disorders that are not caused by another disease) are migraine, tension-type headache and cluster headache. All primary headaches are in need of better treatments. Migraine has a prevalence of 10% in the general population and its societal costs are high. Although the precise mechanisms underlying the pathophysiology of migraine are still elusive, the last decades have witnessed some progress (e.g. involvement of serotonin, calcitonin gene-related peptide, nitric oxide, etc). Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-NMMA effectively treats attacks of migraine without aura. Similar results have been obtained for chronic tension-type headache and cluster headache. Inhibition of the breakdown of cGMP also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Several relationships exist between NO, calcitonin gene-related peptide and other molecules important in migraine. Also ion channels, particularly the K(ATP) channels, are important for the action of NO. In conclusion, inhibition of NO production or blockade of steps in the NO-cGMP pathway or scavenging of NO may be targets for new drugs for treating migraine and other headaches. Indeed, selective n-NOS and i-NOS inhibitors are already in early clinical development.

  4. Final report on the safety assessment of Ricinus Communis (Castor) Seed Oil, Hydrogenated Castor Oil, Glyceryl Ricinoleate, Glyceryl Ricinoleate SE, Ricinoleic Acid, Potassium Ricinoleate, Sodium Ricinoleate, Zinc Ricinoleate, Cetyl Ricinoleate, Ethyl Ricinoleate, Glycol Ricinoleate, Isopropyl Ricinoleate, Methyl Ricinoleate, and Octyldodecyl Ricinoleate.

    PubMed

    2007-01-01

    The oil derived from the seed of the Ricinus communis plant and its primary constituent, Ricinoleic Acid, along with certain of its salts and esters function primarily as skin-conditioning agents, emulsion stabilizers, and surfactants in cosmetics, although other functions are described. Ricinus Communis (Castor) Seed Oil is the naming convention for castor oil used in cosmetics. It is produced by cold pressing the seeds and subsequent clarification of the oil by heat. Castor oil does not contain ricin because ricin does not partition into the oil. Castor oil and Glyceryl Ricinoleate absorb ultraviolet (UV) light, with a maximum absorbance at 270 nm. Castor oil and Hydrogenated Castor Oil reportedly were used in 769 and 202 cosmetic products, respectively, in 2002; fewer uses were reported for the other ingredients in this group. The highest reported use concentration (81%) for castor oil is associated with lipstick. Castor oil is classified by Food and Drug Administration (FDA) as generally recognized as safe and effective for use as a stimulant laxative. The Joint Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives established an acceptable daily castor oil intake (for man) of 0 to 0.7 mg/kg body weight. Castor oil is hydrolyzed in the small intestine by pancreatic enzymes, leading to the release of glycerol and Ricinoleic Acid, although 3,6-epoxyoctanedioic acid, 3,6-epoxydecanedioic acid, and 3,6-epoxydodecanedioic acid also appear to be metabolites. Castor oil and Ricinoleic Acid can enhance the transdermal penetration of other chemicals. Although chemically similar to prostaglandin E(1), Ricinoleic Acid did not have the same physiological properties. These ingredients are not acute toxicants, and a National Toxicology Program (NTP) subchronic oral toxicity study using castor oil at concentrations up to 10% in the diet of rats was not toxic. Other subchronic studies of castor oil produced similar findings

  5. Midodrine: a role in the management of neurocardiogenic syncope

    PubMed Central

    Ward, C; Gray, J; Gilroy, J; Kenny, R

    1998-01-01

    Objective—To determine the benefit of midodrine, an α agonist, on symptom frequency and haemodynamic responses during head up tilt in patients with neurocardiogenic syncope.
Setting—Cardiovascular investigation unit (a secondary and tertiary referral centre for the investigation and management of syncope).
Patients—16 outpatients (mean (SD) age 56 (18) years; five men) with frequent hypotensive symptoms (more than two syncopal episodes and fewer than 20 symptom free days per month), and reproducible syncope with glyceryl trinitrate (GTN) during head up tilt.
Design and intervention—Randomised double blind placebo controlled study. Patients were randomised to receive either placebo or midodrine for one month. Symptom events were recorded during each study month. At the end of each study month patients completed a quality of life scoring scale (Short Form 36) and a global assessment of therapeutic response. They received GTN with head up tilt for measurement of heart rate (electrocardiography), phasic blood pressure (digital photoplethysmography), and thoracic fluid index (transthoracic impedance plethysmography) during symptom provocation.
Results—Patients administered midodrine had an average of 7.3 more symptom free days than those who received placebo (95% confidence interval (CI) 4.6 to 9; p < 0.0001). Eleven patients reported a positive therapeutic response with midodrine (p = 0.002). All domains of quality of life showed improvement with midodrine, in particular physical function (8.1; 95% CI 3.7 to 12.2), energy and vitality (14.6; 95% CI 7.3 to 22.1), and change in health status (22.2; 95% CI 11 to 33.4 ). Fourteen patients who were given placebo had tilt induced syncope compared with six given midodrine (p = 0.01). Baseline supine systolic blood pressure was higher and heart rate lower in patients who received midodrine than in those who were given placebo ( p < 0.05). A lower thoracic fluid index in patients administered

  6. Relationship of levels of Vitamin D with flow-mediated dilatation of brachial artery in patients of myocardial infarction and healthy control: A case–control study

    PubMed Central

    Malik, Sarthak; Giri, Subhash; Madhu, S. V.; Rathi, Vinita; Banerjee, B. D.; Gupta, Nikhil

    2016-01-01

    Background: Cardiovascular diseases (CVD) remain the leading cause of death worldwide. Vitamin D deficiency has been linked to increased risk of adverse CV events. Vitamin D deficiency may be responsible for endothelial dysfunction which in turn affects the onset and progression of coronary artery disease and its risk factors, directly or indirectly through various mechanisms. Materials and Methods: It was case–control study. A total of 50 cases of acute myocardial infarction (AMI) (aged 40–60 years), admitted to medicine emergency/CCU, were taken as per ACC/AHA 2007 guidelines. An equal number of age- and sex-matched controls were also taken. Risk factors of AMI, flow-mediated dilatation (FMD), and 25(OH)D levels were studied in all cases and controls. Correlation was also studied between FMD and 25(OH)D. Results: The mean values of FMD were 18.86 ± 5.39% and 10.35 ± 4.90% in controls and cases, respectively (P < 0.05). The endothelial dilatation after glyceryl trinitrate (GTN) was also studied and was found to be 26.175 ± 4.25% and 18.80 ± 5.72% in controls and cases, respectively (P < 0.05). The mean levels of 25(OH)D in controls and cases were 25.45 ± 12.17 and 14.53 ± 8.28 ng/ml, respectively. In this study, 56% of subjects were Vitamin D deficient, 25% were Vitamin D insufficient, and only 19% had Vitamin D in normal range. A positive correlation coefficient was found between FMD and 25(OH) Vitamin D levels (r = 0.841, P < 0.01). In this study, a positive correlation coefficient was also found between endothelial dilatation after GTN and 25(OH)D levels (r = 0.743, P < 0.01). Conclusion: In this study, it was found that FMD was markedly impaired in patients of AMI when compared to controls. It was also found that majority of the study population was Vitamin D deficient; however, the deficiency was more severe in patients of AMI. We also found out that FMD was positively correlated (r = 0.841) to the deficiency state of Vitamin D in all the study

  7. Hypoxic potentiation of nitrite effects in human vessels and platelets.

    PubMed

    Dautov, Rustem F; Stafford, Irene; Liu, Saifei; Cullen, Hugh; Madhani, M; Chirkov, Yuliy Y; Horowitz, John D

    2014-08-31

    Previous studies in non-human blood vessels and in platelets have demonstrated that under hypoxic conditions release of NO from nitrite (NO2(-)) is potentiated by deoxyhaemoglobin. In the current study, we characterized hypoxic potentiation of NO2(-) effects in human vasculature and platelets in vitro, addressing underlying mechanisms. The vasodilator efficacy of NO2(-), in comparison with glyceryl trinitrate (GTN), was evaluated in vitro, using segments of human saphenous vein. Under hypoxic conditions, there was a leftward shift of the NO2(-) concentration-response curve (EC50: 22 μM in hyperoxia vs 3.5 μM in hypoxia; p<0.01), but no significant potentiation of GTN effect. In the presence of red blood cells, hypoxic potentiation of NO2(-) vasodilator effect was accentuated. In whole blood samples and platelet-rich plasma (PRP) we assessed inhibition of platelet aggregation by NO2(-) (1mM), in comparison with that of sodium nitroprusside (SNP, 10 μM). In individual subjects (n=37), there was a strong correlation (r=0.75, p<0.0001) between anti-aggregatory effects of NO2(-) and SNP in whole blood, signifying that resultant sGC activation underlies biological effect and responses to NO2(-) are diminished in the presence of NO resistance. In PRP, the effects of NO2(-) were less pronounced than in whole blood (p=0.0001), suggesting an important role of Hb (within RBCs) in the bioconversion of NO2(-) to NO. Inhibition of platelet aggregation by NO2(-) was almost 3-fold greater in venous than in arterial blood (p<0.0001), and deoxyHb concentration directly correlated (r=0.69, p=0.013) with anti-aggregatory response. Incremental hypoxia applied to venous blood samples (in hypoxic chamber) caused a progressive increase in both deoxyHb level and anti-aggregatory effect of NO2(-). When subjects inhaled a 12% O2 mixture for 20 min, there was a 3-fold rise in blood deoxyHb fraction (p<0.01). In PRP, response to NO2(-) also increased under hypoxia, and was further enhanced

  8. Influence of nitrovasodilators and endothelin-1 on rheology of human blood in vitro.

    PubMed

    Walter, R; Mark, M; Gaudenz, R; Harris, L G; Reinhart, W H

    1999-10-01

    1. The shear stress of flowing blood profoundly influences the release of endothelium-dependent vasodilative and constrictive factors. Conversely, the influence of these mediators such as nitric oxide (NO) or endothelin-1 (ET-1) on blood rheology remains elusive. In the present study the influence of nitrovasodilators and ET-1 on red blood cell (RBC) shape and whole blood viscosity were investigated. 2. Incubation of whole blood with sodium-nitroprusside (SNP, 10-5 - 10-2 M), glyceryl trinitrate (GTN, 0.0001 - 0.1 mg mL-1), S-nitroso-N-acetylpenicillamine (SNAP, 10-6 - 10-3 M), and the active metabolite of molsidomine (SIN-1, 10-6 - 10-3 M), but not molsidomine (10-6 - 10-3 M), resulted in significantly increased amounts of methaemoglobin, indicating a relevant interaction with RBCs. Treatment with SNP at 10-2 M induced a marked echinocytosis (morphological index: 2.23+/-0.98 vs -0.17+/-0.10; P<0.001) and increased blood viscosity (haematocrit 45%) at a high shear rate of 94.5 s-1 (6.46+/-0.60 vs 5.07+/-0.35 mPa.s; P<0.01) and a low shear rate of 0.1 s-1 (88.6+/-36.8 vs 42.1+/-11.7 mPa.s; P<0.01). Echinocytosis was probably due to cyanide accumulation. SIN-1 at 10-3 M slightly decreased high shear viscosity (4.88+/-0.28 vs 4. 95+/-0.30 mPa.s; P<0.05). SNAP at 10-3 M slightly increased both high (5.14+/-0.23 vs 5.05+/-0.24 mPa.s; P<0.01) and low shear (53.9+/-7.2 vs 51.2+/-5.9 mPa.s; P<0.05) viscosity. Molsidomine and GTN failed to influence whole blood viscosity. ET-1 (10-9 - 10-6 M) had no effect on RBC shape and viscosity. 3. We conclude that the most important modulators of vascular tone, NO and ET-1, do not affect RBC shape and blood viscosity, which is important from both a physiological and a pharmacological point of view.

  9. Ambulatory blood pressure monitoring and endothelium-dependent vasodilation in the elderly athletes.

    PubMed

    Galetta, F; Franzoni, F; Plantinga, Y; Ghiadoni, L; Rossi, M; Prattichizzo, F; Carpi, A; Taddei, S; Santoro, G

    2006-09-01

    Regular exercise is a key component of cardiovascular risk prevention strategies, because it is associated with a variety of beneficial metabolic and vascular effects that reduce mortality and the incidence of cardiovascular adverse events. Endothelium plays an important role in the local regulation of vascular tone and structure, mainly by nitric oxide (NO) synthesis and action. Aim of the present study was to evaluate in elderly athletes the effect of regular aerobic exercise on arterial blood pressure (BP) and on endothelium-dependent flow-mediated dilation (FMD) of the brachial artery. The study population included 30 male subjects (mean age 65.6+/-5.6 years), who had practiced endurance running at a competitive level for at least 40 years, and 28 age- and sex-matched subjects (mean age 64.5+/-4.5 years) with sedentary lifestyle and free of cardiovascular disease. Athletes and control subjects underwent standard 12-lead ECG, clinic BP, 24-h ambulatory BP monitoring and endothelium-dependent FMD and endothelium-independent response to glyceryl trinitrate (GTN), 400 microg, in the brachial artery by high-resolution ultrasonography. Systolic clinic and ambulatory 24-h BP were significantly lower in the athletes, than in the controls (P<0.001, respectively). Systolic and diastolic 24-h BP variability, when assessed either by the standard deviation (S.D.), or by the coefficient of variation (CV), were also significantly lower in the athletes (P<0.01). The athletes also had a lower 24-h, day-time and night-time heart rate (HR) (P<0.01), as well as a lower HR variability (P<0.01). As regards circadian BP change, the %Delta was statistically significant greater in athletes (P<0.05). Elderly athletes showed higher FMD than elderly sedentary subjects (P<0.001), whereas no differences were shown in the response to GTN. Our results, suggest that long-term physical activity can counteract the age-related endothelial dysfunction that characterizes sedentary aging, preserving

  10. Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humans

    PubMed Central

    Rathod, Krishnaraj S.; Kapil, Vikas; Velmurugan, Shanti; Khambata, Rayomand S.; Siddique, Umme; Khan, Saima; Van Eijl, Sven; Bansal, Jascharanpreet; Pitrola, Kavi; Shaw, Christopher; D’Acquisto, Fulvio; Colas, Romain A.; Marelli-Berg, Federica

    2016-01-01

    BACKGROUND. Cardiovascular disease occurs at lower incidence in premenopausal females compared with age-matched males. This variation may be linked to sex differences in inflammation. We prospectively investigated whether inflammation and components of the inflammatory response are altered in females compared with males. METHODS. We performed 2 clinical studies in healthy volunteers. In 12 men and 12 women, we assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD). In a further 8 volunteers of each sex, we assessed FMD response to glyceryl trinitrate (GTN) at baseline and at 8 hours and 32 hours after typhoid vaccine. In a separate study in 16 men and 16 women, we measured inflammatory exudate mediators and cellular recruitment in cantharidin-induced skin blisters at 24 and 72 hours. RESULTS. Typhoid vaccine induced mild systemic inflammation at 8 hours, reflected by increased white cell count in both sexes. Although neutrophil numbers at baseline and 8 hours were greater in females, the neutrophils were less activated. Systemic inflammation caused a decrease in FMD in males, but an increase in females, at 8 hours. In contrast, GTN response was not altered in either sex after vaccine. At 24 hours, cantharidin formed blisters of similar volume in both sexes; however, at 72 hours, blisters had only resolved in females. Monocyte and leukocyte counts were reduced, and the activation state of all major leukocytes was lower, in blisters of females. This was associated with enhanced levels of the resolving lipids, particularly D-resolvin. CONCLUSIONS. Our findings suggest that female sex protects against systemic inflammation-induced endothelial dysfunction. This effect is likely due to accelerated resolution of inflammation compared with males, specifically via neutrophils, mediated by an elevation of the D-resolvin pathway. TRIAL REGISTRATION. ClinicalTrials.gov NCT01582321 and NRES: City Road and Hampstead Ethics

  11. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial

    PubMed Central

    2015-01-01

    Summary Background High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to lower their blood pressure. Methods In our multicentre, partial-factorial trial, we randomly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure (systolic 140–220 mm Hg) to 7 days of transdermal glyceryl trinitrate (5 mg per day), started within 48 h of stroke onset, or to no glyceryl trinitrate (control group). A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. The primary outcome was function, assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment. This study is registered, number ISRCTN99414122. Findings Between July 20, 2001, and Oct 14, 2013, we enrolled 4011 patients. Mean blood pressure was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16–37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls (difference −7·0 [95% CI −8·5 to −5·6] mm Hg/–3·5 [–4·4 to −2·6] mm Hg; both p<0·0001), and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients randomised to stop them (difference −9·5 [95% CI −11·8 to −7·2] mm Hg/–5·0 [–6·4 to −3·7] mm Hg; both p<0·0001). Functional outcome at day 90 did not differ in either treatment comparison—the adjusted common odds ratio (OR) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 (95% CI 0·91–1·13; p=0·83), and with continue versus stop antihypertensive drugs OR was 1·05 (0·90–1·22; p=0·55). Interpretation

  12. The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation

    PubMed Central

    Buces, Elena; Pion, Marjorie; Sánchez-Hernández, Noemí; Martín-Antonio, Beatriz; Guillem, Vicent; Bosch-Vizcaya, Anna; Bento, Leyre; González-Rivera, Milagros; Balsalobre, Pascual; Kwon, Mi; Serrano, David; Gayoso, Jorge; de la Cámara, Rafael; Brunet, Salut; Rojas-Contreras, Rafael; Nieto, José B.; Martínez, Carmen; Gónzalez, Marcos; Espigado, Ildefonso; Vallejo, Juan C.; Sampol, Antonia; Jiménez-Velasco, Antonio; Urbano-Ispizua, Alvaro; Solano, Carlos; Gallardo, David; Díez-Martín, José L.; Buño, Ismael

    2015-01-01

    The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08–0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients. PMID:26473355

  13. The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

    PubMed

    Noriega, Víctor; Martínez-Laperche, Carolina; Buces, Elena; Pion, Marjorie; Sánchez-Hernández, Noemí; Martín-Antonio, Beatriz; Guillem, Vicent; Bosch-Vizcaya, Anna; Bento, Leyre; González-Rivera, Milagros; Balsalobre, Pascual; Kwon, Mi; Serrano, David; Gayoso, Jorge; de la Cámara, Rafael; Brunet, Salut; Rojas-Contreras, Rafael; Nieto, José B; Martínez, Carmen; Gónzalez, Marcos; Espigado, Ildefonso; Vallejo, Juan C; Sampol, Antonia; Jiménez-Velasco, Antonio; Urbano-Ispizua, Alvaro; Solano, Carlos; Gallardo, David; Díez-Martín, José L; Buño, Ismael

    2015-01-01

    The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients.

  14. 21 CFR 184.1323 - Glyceryl monooleate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...(n)(3) of this chapter; chewing gum as defined in § 170.3(n)(6) of this chapter; and meat products as...) The ingredient must be of a purity suitable for its intended use. (c) In accordance with § 184.1(b)(1), the ingredient is used in food with no limitation other than current good manufacturing practice. The...

  15. 21 CFR 184.1323 - Glyceryl monooleate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...(n)(3) of this chapter; chewing gum as defined in § 170.3(n)(6) of this chapter; and meat products as...) The ingredient must be of a purity suitable for its intended use. (c) In accordance with § 184.1(b)(1), the ingredient is used in food with no limitation other than current good manufacturing practice. The...

  16. 21 CFR 184.1328 - Glyceryl behenate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... acid made from glycerin and behenic acid (a saturated C22 fatty acid). The mixture contains... monoglyceride, 47 to 59 percent diglyceride, 26 to 38 percent triglyceride, and not more than 2.5 percent free fatty acids. (2) Behenic acid. Between 80 and 90 percent of the total fatty acid content. (3) Acid value...

  17. 21 CFR 172.811 - Glyceryl tristearate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... glycerol content: Not to exceed 0.5 percent. Unsaponifiable matter: Not to exceed 0.5 percent. Melting point (Class II): 69 °C-73 °C. (c) The additive is used or intended for use as follows when standards of...

  18. 21 CFR 172.811 - Glyceryl tristearate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... glycerol content: Not to exceed 0.5 percent. Unsaponifiable matter: Not to exceed 0.5 percent. Melting point (Class II): 69 °C-73 °C. (c) The additive is used or intended for use as follows when standards of...

  19. 21 CFR 172.811 - Glyceryl tristearate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... glycerol content: Not to exceed 0.5 percent. Unsaponifiable matter: Not to exceed 0.5 percent. Melting point (Class II): 69 °C-73 °C. (c) The additive is used or intended for use as follows when standards of...

  20. 21 CFR 172.811 - Glyceryl tristearate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... reacting stearic acid with glycerol in the presence of a suitable catalyst. (b) The food additive meets the... number: 186-192. Hydroxyl number: Not to exceed 5.0. Free glycerol content: Not to exceed 0.5...

  1. In vitro suppression of drug-induced methaemoglobin formation by Intralipid(®) in whole human blood: observations relevant to the 'lipid sink theory'.

    PubMed

    Samuels, T L; Willers, J W; Uncles, D R; Monteiro, R; Halloran, C; Dai, H

    2012-01-01

    To provide further evidence for the lipid sink theory, we have developed an in vitro model to assess the effect of Intralipid® 20% on methaemoglobin formation by drugs of varying lipid solubility. Progressively increasing Intralipid concentrations from 4 to 24 mg.ml⁻¹ suppressed methaemoglobin formation by the lipid soluble drug glyceryl trinitrate in a dose-dependent manner (p < 0.001). Both dose and timing of administration of Intralipid to blood previously incubated with glyceryl trinitrate for 10 and 40 min resulted in significant suppression of methaemoglobin formation (p < 0.0001 and p < 0.05, respectively). Mathematical modelling demonstrated that the entire process of methaemoglobin formation by glyceryl trinitrate was slowed down in the presence of Intralipid. Intralipid did not significantly suppress methaemoglobin formation induced by 2-amino-5-hydroxytoluene (partially lipid soluble) or sodium nitrite (lipid insoluble; both p > 0.5). This work may assist determination of the suitability of drugs taken in overdose for which Intralipid might be deployed.

  2. A systematic review and meta-analysis of the treatment of anal fissure.

    PubMed

    Nelson, R L; Manuel, D; Gumienny, C; Spencer, B; Patel, K; Schmitt, K; Castillo, D; Bravo, A; Yeboah-Sampong, A

    2017-08-09

    Anal fissure has a very large number of treatment options. The choice is difficult. In an effort to assist in that, choice presented here is a systematic review and meta-analysis of all published treatments for anal fissure that have been studied in randomized controlled trials. Randomized trials were sought in the Cochrane Controlled Trials Register, Medline, EMBASE and the trials registry sites clinicaltrials.gov and who/int/ictrp/search/en. Abstracts were screened, full-text studies chosen, and finally eligible studies selected and abstracted. The review was then divided into those studies that compared two or more surgical procedures and those that had at least one arm that was non-surgical. Studies were further categorized by the specific interventions and comparisons. The outcome assessed was treatment failure. Negative effects of treatment assessed were headache and anal incontinence. Risk of bias was assessed for each study, and the strength of the evidence of each comparison was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. One hundred and forty-eight eligible trials were found and assessed, 31 in the surgical group and 117 in the non-surgical group. There were 14 different operations described in the surgical group and 29 different non-surgical treatments in the non-surgical group along with partial lateral internal sphincterotomy (LIS). There were 61 different comparisons. Of these, 47 were reported in 2 or fewer studies, usually with quite small patient samples. The largest single comparison was glyceryl trinitrate (GTN) versus control with 19 studies. GTN was more effective than control in sustained cure (OR 0.68; 95% CI 0.63-0.77), but the quality of evidence was very poor because of severe heterogeneity, and risk of bias due to inadequate clinical follow-up. The only comparison to have a GRADE quality of evidence of high was a subgroup analysis of LIS versus any medical therapy (OR 0.12; CI 0

  3. Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation

    PubMed Central

    Lewis, Nia C S; Bailey, Damian M; duManoir, Gregory R; Messinger, Laura; Lucas, Samuel J E; Cotter, James D; Donnelly, Joseph; McEneny, Jane; Young, Ian S; Stembridge, Mike; Burgess, Keith R; Basnet, Aparna S; Ainslie, Philip N

    2014-01-01

    Research detailing the normal vascular adaptions to high altitude is minimal and often confounded by pathology (e.g. chronic mountain sickness) and methodological issues. We examined vascular function and structure in: (1) healthy lowlanders during acute hypoxia and prolonged (∼2 weeks) exposure to high altitude, and (2) high-altitude natives at 5050 m (highlanders). In 12 healthy lowlanders (aged 32 ± 7 years) and 12 highlanders (Sherpa; 33 ± 14 years) we assessed brachial endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent dilatation (via glyceryl trinitrate; GTN), common carotid intima–media thickness (CIMT) and diameter (ultrasound), and arterial stiffness via pulse wave velocity (PWV; applanation tonometry). Cephalic venous biomarkers of free radical-mediated lipid peroxidation (lipid hydroperoxides, LOOH), nitrite (NO2–) and lipid soluble antioxidants were also obtained at rest. In lowlanders, measurements were performed at sea level (334 m) and between days 3–4 (acute high altitude) and 12–14 (chronic high altitude) following arrival to 5050 m. Highlanders were assessed once at 5050 m. Compared with sea level, acute high altitude reduced lowlanders’ FMD (7.9 ± 0.4 vs. 6.8 ± 0.4%; P = 0.004) and GTN-induced dilatation (16.6 ± 0.9 vs. 14.5 ± 0.8%; P = 0.006), and raised central PWV (6.0 ± 0.2 vs. 6.6 ± 0.3 m s−1; P = 0.001). These changes persisted at days 12–14, and after allometrically scaling FMD to adjust for altered baseline diameter. Compared to lowlanders at sea level and high altitude, highlanders had a lower carotid wall:lumen ratio (∼19%, P ≤ 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO2– increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (n = 11, r = −0.53) and chronic (n = 7, r = −0.69; P

  4. Pharmacodynamic action and mechanism of Du Liang soft capsule, a traditional Chinese medicine capsule, on treating nitroglycerin-induced migraine.

    PubMed

    Hou, Min; Tang, Qing; Xue, Qiang; Zhang, Xiaona; Liu, Yang; Yang, Sheng; Chen, Liechun; Xu, Xiaoyu

    2017-01-04

    Du Liang soft capsule (DL) is a traditional Chinese medicine for treating migraines; it is made from two Chinese herbs, including LigusticumstriatumDC., root; Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., root. In the present study, we aimed to elucidate the pharmacodynamic action of DL and its mechanism in an animal model of migraines induced by glyceryl trinitrate (GTN). Sixty rats were randomly divided into six groups, including a normal control group, model control group, positive group (Sumatriptan 0.006gkg(-1)), and three DL groups (0.44, 1.31 and 3.93gkg(-1)). All rats were intragastrically treated with the corresponding treatment for 7 consecutive days, and they were subcutaneously injected with GTN (10mgkg(-1)) 30min after the last treatment, except in the normal control group. After model establishment, the behaviors of all rats, including head scratching, cage climbing, and the development of red ears were observed continuously by digital camera every 30min for 3h. Four hours after GTN treatment, all rats were anaesthetized and the blood and tissue samples were collected. Plasma calcitonin gene related to peptide (CGRP) and endothelin (ET) levels were measured using the radioimmunoassay method, and serum NO was determined by the colorimetric method. Afterwards, the brainstem tissues were dissected and washed with physiological saline, and divided evenly into two parts. One part was used to test the monoamine levels, including levels of 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA), by the fluorometric method, and the other part was used to determine the nuclear factor kappaB (NF-κB) p65, nuclear c-fos, inducible nitric oxide synthase (iNOS), interleukin (IL)-1β (IL-1β), and cyclooxygenase-2 (COX-2) levels by Western blot analysis. In the pharmacodynamic action assay, DL (1.31 and 3.93gkg(-1)) greatly improved the abnormal behaviors of migraine rats, including head scratching and cage climbing, and the development

  5. Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation.

    PubMed

    Lewis, Nia C S; Bailey, Damian M; Dumanoir, Gregory R; Messinger, Laura; Lucas, Samuel J E; Cotter, James D; Donnelly, Joseph; McEneny, Jane; Young, Ian S; Stembridge, Mike; Burgess, Keith R; Basnet, Aparna S; Ainslie, Philip N

    2014-03-01

    Research detailing the normal vascular adaptions to high altitude is minimal and often confounded by pathology (e.g., chronic mountain sickness) and methodological issues. We examined vascular function and structure in: (1) healthy lowlanders during acute hypoxia and prolonged (∼2 weeks) exposure to high altitude, and (2) high-altitude natives at 5050 m (highlanders). In 12 healthy lowlanders (aged 32 ± 7 years) and 12 highlanders (Sherpa; 33 ± 14 years) we assessed brachial endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent dilatation (via glyceryl trinitrate; GTN), common carotid intima-media thickness (CIMT) and diameter (ultrasound), and arterial stiffness via pulse wave velocity (PWV; applanation tonometry). Cephalic venous biomarkers of free radical-mediated lipid peroxidation (lipid hydroperoxides, LOOH), nitrite (NO2-) and lipid soluble antioxidants were also obtained at rest. In lowlanders, measurements were performed at sea level (334 m) and between days 3-4 (acute high altitude) and 12-14 (chronic high altitude) following arrival to 5050 m. Highlanders were assessed once at 5050 m. Compared with sea level, acute high altitude reduced lowlanders' FMD (7.9 ± 0.4 vs. 6.8 ± 0.4%; P = 0.004) and GTN-induced dilatation (16.6 ± 0.9 vs. 14.5 ± 0.8%; P = 0.006), and raised central PWV (6.0 ± 0.2 vs. 6.6 ± 0.3 m s(-1); P = 0.001). These changes persisted at days 12-14, and after allometrically scaling FMD to adjust for altered baseline diameter. Compared to lowlanders at sea level and high altitude, highlanders had a lower carotid wall:lumen ratio (∼19%, P ≤ 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO2- increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (n = 11, r = -0.53) and chronic (n = 7, r = -0.69; P ≤ 0.01) exposure to 5050 m. In a follow-up, placebo-controlled experiment (n = 11 healthy lowlanders

  6. Biodegradation of explosives by transgenic plants expressing pentaerythritol tetranitrate reductase.

    PubMed

    French, C E; Rosser, S J; Davies, G J; Nicklin, S; Bruce, N C

    1999-05-01

    Plants offer many advantages over bacteria as agents for bioremediation; however, they typically lack the degradative capabilities of specially selected bacterial strains. Transgenic plants expressing microbial degradative enzymes could combine the advantages of both systems. To investigate this possibility in the context of bioremediation of explosive residues, we generated transgenic tobacco plants expressing pentaerythritol tetranitrate reductase, an enzyme derived from an explosive-degrading bacterium that enables degradation of nitrate ester and nitroaromatic explosives. Seeds from transgenic plants were able to germinate and grow in the presence of 1 mM glycerol trinitrate (GTN) or 0.05 mM trinitrotoluene, at concentrations that inhibited germination and growth of wild-type seeds. Transgenic seedlings grown in liquid medium with 1 mM GTN showed more rapid and complete denitration of GTN than wild-type seedlings. This example suggests that transgenic plants expressing microbial degradative genes may provide a generally applicable strategy for bioremediation of organic pollutants in soil.

  7. The effect of a national quality improvement collaborative on prehospital care for acute myocardial infarction and stroke in England.

    PubMed

    Siriwardena, Aloysius Niroshan; Shaw, Deborah; Essam, Nadya; Togher, Fiona Jayne; Davy, Zowie; Spaight, Anne; Dewey, Michael

    2014-01-23

    Previous studies have shown wide variations in prehospital ambulance care for acute myocardial infarction (AMI) and stroke. We aimed to evaluate the effectiveness of implementing a Quality Improvement Collaborative (QIC) for improving ambulance care for AMI and stroke. We used an interrupted time series design to investigate the effect of a national QIC on change in delivery of care bundles for AMI (aspirin, glyceryl trinitrate [GTN], pain assessment and analgesia) and stroke (face-arm-speech test, blood pressure and blood glucose recording) in all English ambulance services between January 2010 and February 2012. Key strategies for change included local quality improvement (QI) teams in each ambulance service supported by a national coordinating expert group that conducted workshops educating staff in QI methods to improve AMI and stroke care. Expertise and ideas were shared between QI teams who met together at three national workshops, between QI leads through monthly teleconferences, and between the expert group and participants. Feedback was provided to services using annotated control charts. We analyzed change over time using logistic regression with three predictor variables: time, gender, and age. There were statistically significant improvements in care bundles in nine (of 12) participating trusts for AMI (OR 1.04, 95% CI 1.04, 1.04), nine for stroke (OR 1.06, 95% CI 1.05, 1.07), 11 for either AMI or stroke, and seven for both conditions. Overall care bundle performance for AMI increased in England from 43 to 79% and for stroke from 83 to 96%. Successful services all introduced provider prompts and individualized or team feedback. Other determinants of success included engagement with front-line clinicians, feedback using annotated control charts, expert support, and shared learning between participants and organizations. This first national prehospital QIC led to significant improvements in ambulance care for AMI and stroke in England. The use of care

  8. Glyceryl 1,3-Dipalmitate Produced from Lactobacillus paracasei subspecies. paracasei NTU 101 Inhibits Oxygen-Glucose Deprivation and Reperfusion-Induced Oxidative Stress via Upregulation of Peroxisome Proliferator-Activated Receptor γ in Neuronal SH-SY5Y Cells.

    PubMed

    Cheng, Meng-Chun; Pan, Tzu-Ming

    2017-09-13

    Glyceryl 1,3-dipalmitate (GD) purified from Lactobacillus paracasei subsp. paracasei NTU 101-fermented products has been demonstrated to possess neuroprotective properties. We determined the effect of GD on oxygen-glucose deprivation and reperfusion (OGD/R)-induced SH-SY5Y neuroblastoma cell death. GD ameliorated OGD/R-induced apoptosis by elevating the protein expression of nuclear peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby attenuating reactive oxygen species (ROS) generation. Pretreatment with GD reduced nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) expression from 1.54 ± 0.27 to 0.84 ± 0.46, thereby attenuating the induction of pro-inflammatory mediators, and increased the plasma membrane Ca(2+) ATPase (PMCA) levels from 0.81 ± 0.02 to 1.08 ± 0.06, thus reducing the levels of cytosolic Ca(2+); this also correlated with reduced cell death. We conclude that GD prevents SH-SY5Y cells from injury after OGD/R insult, possibly by modulating oxidative stress and inflammatory response.

  9. Acute Dermal Toxicity of Trimethylolethane Trinitrate (TMETN) in Rabbits

    DTIC Science & Technology

    1989-07-01

    and lateral sections of the animals (surface area approximately 300 cm 2 ) were close-clipped with electric clippers (Oster® Model A5, Size 40 blade...13 Nov 84 Cause: Unknown Syndrome : None Gross Comments: All lesions including the liver lesion were considered as incidental findings and not

  10. Morbidity associated with treatment of chronic anal fissure

    PubMed Central

    Latif, Ansar; Ansar, Anila; Butt, Muhammad Qasim

    2013-01-01

    diagnosis were excluded. Sixty six patients i.e. 51% were those who directly reported to surgical OPD and had no previous treatment. With surgical treatment, pain, bleeding per rectum and constipation showed significant improvement as compared to GTN ointment application. Fissure healing was 100% in surgical group as compared to 74% in medical group. Complications were recorded and were found to be headache with medical treatment; while the most feared complication with surgical treatment i.e. permanent incontinence was not encountered in our study. Conclusion: Topical glyceryl trinitrate is economical, has a good healing rate, and faecal incontinence has not been reported. Its effectiveness, however, depends on patients’ compliance which may be poor in view of associated headaches and a local burning sensation. It is first line of treatment for anal fissure but lateral internal sphincterotomy is superior, more effective and curative than the chemical sphincterotomy. Surgery is reserved for people with anal fissure who have tried medical therapy for at least one to three months but failed. PMID:24353726

  11. Bioactivation of pentaerythrityl tetranitrate by mitochondrial aldehyde dehydrogenase.

    PubMed

    Griesberger, Martina; Kollau, Alexander; Wölkart, Gerald; Wenzl, M Verena; Beretta, Matteo; Russwurm, Michael; Koesling, Doris; Schmidt, Kurt; Gorren, Antonius C F; Mayer, Bernd

    2011-03-01

    Mitochondrial aldehyde dehydrogenase (ALDH2) contributes to vascular bioactivation of the antianginal drugs nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN), resulting in cGMP-mediated vasodilation. Although continuous treatment with GTN results in the loss of efficacy that is presumably caused by inactivation of ALDH2, PETN does not induce vascular tolerance. To clarify the mechanisms underlying the distinct pharmacological profiles of GTN and PETN, bioactivation of the nitrates was studied with aortas isolated from ALDH2-deficient and nitrate-tolerant mice, isolated mitochondria, and purified ALDH2. Pharmacological inhibition or gene deletion of ALDH2 attenuated vasodilation to both GTN and PETN to virtually the same degree as long-term treatment with GTN, whereas treatment with PETN did not cause tolerance. Purified ALDH2 catalyzed bioactivation of PETN, assayed as activation of soluble guanylate cyclase (sGC) and formation of nitric oxide (NO). The EC(50) value of PETN for sGC activation was 2.2 ± 0.5 μM. Denitration of PETN to pentaerythrityl trinitrate was catalyzed by ALDH2 with a specific activity of 9.6 ± 0.8 nmol · min(-1) · mg(-1) and a very low apparent affinity of 94.7 ± 7.4 μM. In contrast to GTN, PETN did not cause significant inactivation of ALDH2. Our data suggest that ALDH2 catalyzes bioconversion of PETN in two distinct reactions. Besides the major denitration pathway, which occurs only at high PETN concentrations, a minor high-affinity pathway may reflect vascular bioactivation of the nitrate yielding NO. The very low rate of ALDH2 inactivation, presumably as a result of low affinity of the denitration pathway, may at least partially explain why PETN does not induce vascular tolerance.

  12. Effect of Tityus serrulatus scorpion venom on the rabbit isolated corpus cavernosum and the involvement of NANC nitrergic nerve fibres

    PubMed Central

    Teixeira, Cleber E; Bento, Antonio C; Lopes-Martins, Rodrigo A B; Teixeira, Simone A; von Eickestedt, Vera; Muscará, Marcelo N; Arantes, Eliane C; Giglio, Jose R; Antunes, Edson; de Nucci, Gilberto

    1998-01-01

    The effect of Tityus serrulatus scorpion venom and its toxin components on the rabbit isolated corpus cavernosum was investigated by use of a bioassay cascade. Tityus serrulatus venom (3–100 μg), acetylcholine (ACh; 0.3–30 nmol) and glyceryl trinitrate (GTN; 0.5–10 nmol) dose-dependently relaxed rabbit isolated corpus cavernosum preparations precontracted with noradrenaline (3 μM). The selective soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-alquinoxalin-1-one] (ODQ; 30 μM) increased the basal tone of the rabbit isolated corpus cavernosum and abolished the relaxations induced by the agents mentioned above. Methylene blue (30 μM) also inhibited the relaxations induced by Tityus serrulatus venom but, in contrast to ODQ, the inhibition was irreversible. The non-selective NO synthase (NOS) inhibitors NΩ-nitro-L-arginine methyl ester (L-NAME; 10 μM) and NG-iminoethyl-L-ornithine (L-NIO; 30 μM) also increased the tone of the rabbit isolated corpus cavernosum and markedly reduced both ACh- and Tityus serrulatus venom-induced relaxations without affecting those evoked by GTN. The inhibitory effect was reversed by infusion of L-arginine (300 μM), but not D-arginine (300 μM). The neuronal NOS inhibitor 1-(2-trifluoromethylphenyl) imidazole (TRIM, 100 μM) did not affect either the tone of the rabbit isolated corpus cavernosum or the relaxations induced by ACh, bradykinin (Bk), Tityus serrulatus venom and GTN. TRIM was approximately 1,000 times less potent than L-NAME in inhibiting rabbit cerebellar NOS in vitro, as measured by the conversion of [3H]-L-arginine to [3H]-L-citrulline. The protease inhibitor aprotinin (Trasylol; 10 μg ml−1) and the bradykinin B2 receptor antagonist Hoe 140 (D-Arg-[Hyp3,Thi5,D-Tic7, Oic8]-BK; 50 nM) did not affect the rabbit isolated corpus cavernosum relaxations induced by Tityus serrulatus venom. The ATP-dependent K+ channel antagonist glibenclamide (10 μM) and the Ca2+-activated

  13. Topical nitric oxide application in the treatment of chronic extensor tendinosis at the elbow: a randomized, double-blinded, placebo-controlled clinical trial.

    PubMed

    Paoloni, Justin A; Appleyard, Richard C; Nelson, Janis; Murrell, George A C

    2003-01-01

    Extensor tendinosis ("tennis elbow") is a degenerative overuse tendinopathy of the wrist extensors at their attachment to the lateral humeral epicondyle. No treatment has been universally successful. Topical application of nitric oxide has been used effectively to treat fractures and cutaneous wounds in animal models, presumably by stimulation of collagen synthesis in fibroblasts. To determine whether topical nitric oxide can improve outcome of patients with extensor tendinosis. Prospective, randomized, double-blinded clinical trial. Eighty-six patients with extensor tendinosis were randomized into two equal groups; both were instructed to perform a standard tendon rehabilitation program. One group received an active glyceryl trinitrate transdermal patch, and the other group received a placebo patch. Patients in the glyceryl trinitrate group had significantly reduced elbow pain with activity at 2 weeks, reduced epicondylar tenderness at 6 and 12 weeks, and an increase in wrist extensor mean peak force and total work at 24 weeks. At 6 months, 81% of treated patients were asymptomatic during activities of daily living, compared with 60% of patients who had tendon rehabilitation alone. Application of topical nitric oxide improved early pain with activity, late functional measures, and outcomes of patients with extensor tendinosis.

  14. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.

    PubMed Central

    Clarkson, P; Adams, M R; Powe, A J; Donald, A E; McCredie, R; Robinson, J; McCarthy, S N; Keech, A; Celermajer, D S; Deanfield, J E

    1996-01-01

    In hypercholesterolemic rabbits, oral L-arginine (the substrate for endothelium derived nitric oxide) attenuates endothelial dysfunction and atheroma formation, but the effect in hypercholesterolemic humans is unknown. Using high resolution external ultrasound, we studied arterial physiology in 27 hypercholesterolemic subjects aged 29+/-5 (19-40) years, with known endothelial dysfunction and LDL-cholesterol levels of 238+/-43 mg/dl. Each subject was studied before and after 4 wk of L-arginine (7 grams x 3/day) or placebo powder, with 4 wk washout, in a randomized double-blind crossover study. Brachial artery diameter was measured at rest, during increased flow (causing endothelium-dependent dilation, EDD) and after sublingual glyceryl trinitrate (causing endothelium-independent dilation). After oral L-arginine, plasma L-arginine levels rose from 115+/-103 to 231+/-125 micromol/liter (P<0.001), and EDD improved from 1.7+/-1.3 to 5.6+/-3.0% (P<0.001). In contrast there was no significant change in response to glyceryl trinitrate. After placebo there were no changes in endothelium-dependent or independent vascular responses. Lipid levels were unchanged after L-arginine and placebo. Dietary supplementation with L-arginine significantly improves EDD in hypercholesterolemic young adults, and this may impact favorably on the atherogenic process. PMID:8621785

  15. Effects of buccal nitrate on left ventricular haemodynamics and volume at rest and during exercise-induced angina.

    PubMed Central

    Silke, B; Verma, S P; Frais, M A; Hafizullah, M; Taylor, S H

    1985-01-01

    A novel approach has been employed to characterize the effects of a cardioactive drug on left ventricular haemodynamics and volume by simultaneously determining cardiac stroke volume (thermodilution) and left ventricular ejection fraction (nuclear probe). The effects of glyceryl trinitrate were evaluated in 12 patients with angiographically proven coronary artery disease at rest and 3, 7, 15 and 30 min following 10 mg buccal nitroglycerin (Suscard) administration. The impact of the drug on left ventricular haemodynamics and volume during exercise-induced angina was determined by repeating exercise 30 min following drug administration, at the workload that reliably induced angina during control exercise. At rest buccal nitroglycerin reduced systemic arterial pressure, cardiac and stroke volume indices, and increased heart rate. The left ventricular ejection fraction (E.F.) increased; its filling pressure together with end-diastolic and end-systolic volumes were significantly reduced. Compared with control supine-bicycle exercise, the drug reduced mean systemic arterial pressure and left ventricular filling pressure without change in cardiac and stroke volume indices. There was a smaller increase in left ventricular volume during exercise, and the fall in E.F. was attenuated. These data demonstrated differential actions of glyceryl trinitrate on left ventricular function related to the physiological state in obstructive coronary artery disease. These techniques appear to hold promise in the evaluation of the effects of other therapies on left ventricular volume in coronary artery disease. PMID:3935147

  16. Effect of nitric oxide on spinal evoked potentials and survival rate in rats with decompression sickness.

    PubMed

    Randsoe, T; Meehan, C F; Broholm, H; Hyldegaard, O

    2015-01-01

    Nitric oxide (NO) releasing agents have, in experimental settings, been shown to decrease intravascular nitrogen bubble formation and to increase the survival rate during decompression sickness (DCS) from diving. The effect has been ascribed to a possible removal of preexisting micronuclei or an increased nitrogen washout on decompression through augmented blood flow rate. The present experiments were conducted to investigate whether a short- or long-acting NO donor [glycerol trinitrate (GTN) or isosorbide-5-mononitrate (ISMN), respectively] would offer the same protection against spinal cord DCS evaluated by means of spinal evoked potentials (SEPs). Anesthetized rats were decompressed from a 1-h hyperbaric air dive at 506.6 kPa (40 m of seawater) for 3 min and 17 s, and spinal cord conduction was studied by measurements of SEPs. Histological samples of the spinal cord were analyzed for lesions of DCS. In total, 58 rats were divided into 6 different treatment groups. The first three received either saline (group 1), 300 mg/kg iv ISMN (group 2), or 10 mg/kg ip GTN (group 3) before compression. The last three received either 300 mg/kg iv ISMN (group 4), 1 mg/kg iv GTN (group 5), or 75 μg/kg iv GTN (group 6) during the dive, before decompression. In all groups, decompression caused considerable intravascular bubble formation. The ISMN groups showed no difference compared with the control group, whereas the GTN groups showed a tendency toward faster SEP disappearance and shorter survival times. In conclusion, neither a short- nor long-acting NO donor had any protective effect against fatal DCS by intravenous bubble formation. This effect is most likely due to a fast ascent rate overriding the protective effects of NO, rather than the total inert tissue gas load. Copyright © 2015 the American Physiological Society.

  17. Regional distribution and kinetics of [18F]6-flurodopamine as a measure of cardiac sympathetic activity in humans.

    PubMed Central

    Coates, G.; Chirakal, R.; Fallen, E. L.; Firnau, G.; Garnett, E. S.; Kamath, M. V.; Scheffel, A.; Nahmias, C.

    1996-01-01

    OBJECTIVES--To determine whether an increase in cardiac sympathetic activity produced by exercise or sublingual glyceryl trinitrate causes an increased rate of loss of fluorine-18 from the myocardium after intravenous [18F]6-fluorodopamine ([18F]F-DA) in normal volunteers. In addition, to determine the contribution of non-specific uptake of [18F]F-DA in the myocardium in patients with recent heart transplant. PROTOCOL--[18F]F was prepared by direct electrophilic fluorination of dopamine. Nine healthy volunteers each received 1.85 x 10(8) Bq (168-250 micrograms) [18F]F-DA over a period of 3 min and were scanned for 2 h in an ECAT 953/31 tomograph. Three controls were scanned before and after vigorous cycle exercise and two were scanned before and after sublingual glyceryl trinitrate. In addition, two patients (1 and 2 years post-heart transplant) underwent a myocardial perfusion study with ammonia labelled with nitrogen-13 followed by an [18F]F-DA study. RESULTS--There was intense uniform uptake of [18F]F-DA throughout the myocardium in the healthy volunteers. The time course of 18F in the myocardium under resting conditions fitted a biexponential function with mean half-times of 8.0 and 109 min. Vigorous exercise produced a three to fivefold increase in the rate of loss of 18F compared with that when resting. After glyceryl trinitrate, one control had a profound reduction in blood pressure (23%) and twofold increase in the rate of loss of myocardial 18F. The other control had no physiologically significant change in blood pressure, heart rate, or rate of loss of myocardial 18F. Uptake of [18F]F-DA in the two posttransplant patients was confined to a small anterobasal region adjacent to the atrioventricular groove, while blood flow, as measured with [13N] ammonia, was uniformly distributed throughout the myocardium. Partial reinnervation of the myocardium was confirmed by the presence of distinct low frequency spectral peaks of the heart rate power spectrum in both

  18. Application of a shear-modified GTN model to incremental sheet forming

    NASA Astrophysics Data System (ADS)

    Smith, Jacob; Malhotra, Rajiv; Liu, W. K.; Cao, Jian

    2013-12-01

    This paper investigates the effects of using a shear-modified Gurson-Tvergaard-Needleman model, which is based on the mechanics of voids, for simulating material behavior in the incremental forming process. The problem chosen for analysis is a simplified version of the NUMISHEET 2014 incremental forming benchmark test. The implications of the shear-modification of the model specifically for incremental sheet forming processes are confirmed using finite element analysis. It is shown that including the shear term has a significant effect on fracture timing in incremental forming, which is not well reflected in the observed tensile test simulations for calibration. The numerical implementation and the need for comprehensive calibration of the model are briefly discussed.

  19. An overview of drugs and ancillary equipment for the dentist's emergency kit.

    PubMed

    Chapman, P J

    2003-06-01

    The concept of a basic (i.e., essential) medical emergency kit suitable for a general dental practitioner varies somewhat between different authorities. A practitioner's choice is also dependant on the proximity of medical aid and the nature of the dental practice. Over recent years the trend has been to restrict the items to a minimum, in the interest of both common sense and safety, for example, just oxygen, adrenaline 1:1000, an oral carbohydrate source, glyceryl trinitrate and aspirin as first options. Ancillary equipment should include an oxygen therapy facemask, a pocket mask and a set of oral (Guedel) airways. Two further medication options for consideration are an aerosol bronchodilator and, in certain circumstances, an injectable antihypoglycaemic agent. This paper provides a selective overview of the subject. An absolute necessity is for dentists to be competent in Basic Life Support skills, and to maintain a complete and current medical history for all patients.

  20. Sphincter of Oddi Function and Risk Factors for Dysfunction.

    PubMed

    Afghani, Elham; Lo, Simon K; Covington, Paul S; Cash, Brooks D; Pandol, Stephen J

    2017-01-01

    The sphincter of Oddi (SO) is a smooth muscle valve regulating the flow of biliary and pancreatic secretions into the duodenum, initially described in 1887 by the Italian anatomist, Ruggero Oddi. SO dysfunction (SOD) is a broad term referring to numerous biliary, pancreatic, and hepatic disorders resulting from spasms, strictures, and relaxation of this valve at inappropriate times. This review brings attention to various factors that may increase the risk of SOD, including but not limited to: cholecystectomy, opiates, and alcohol. Lack of proper recognition and treatment of SOD may be associated with clinical events, including pancreatitis and biliary symptoms with hepatic enzyme elevation. Pharmacologic and non-pharmacologic approaches are discussed to help recognize, prevent, and treat SOD. Future studies are needed to assess the treatment benefit of agents such as calcium-channel blockers, glyceryl trinitrate, or tricyclic antidepressants in patients with SOD.

  1. Three-dimensional solubility parameters and their use in characterising the permeation of drugs through the skin.

    PubMed

    Groning, R; Braun, F J

    1996-05-01

    The physico-chemical properties of drug substances are major determinants of their transdermal absorption. In the present study the concept of the three-dimensional solubility parameters of Hansen was applied in conjunction with the Bagley projection to describe the permeation of drugs and model substances through the skin. Drug permeation data from the literature were compared with the calculated solubility parameters of the drugs. It was demonstrated that the permeation of drugs can be estimated by their position in the Bagley diagram. There is a linear correlation between the logarithm of the skin permeation of drugs and the exchange cohesive energy for the steroids testosterone, progesterone, hydrocortisone acetate, corticosterone, cortisone, and dexamethasone. A linear correlation can be confirmed for the permeation of glyceryl trinitrate, digitoxin, oestradiol, scopolamine, atropine, diethylcarbamazine, fentanyl, and chlorpheniramine. In the case of morphine, codeine, sufentanil, meperidine and hydromorphone there is a linear relationship, too.

  2. Sphincter of Oddi Function and Risk Factors for Dysfunction

    PubMed Central

    Afghani, Elham; Lo, Simon K.; Covington, Paul S.; Cash, Brooks D.; Pandol, Stephen J.

    2017-01-01

    The sphincter of Oddi (SO) is a smooth muscle valve regulating the flow of biliary and pancreatic secretions into the duodenum, initially described in 1887 by the Italian anatomist, Ruggero Oddi. SO dysfunction (SOD) is a broad term referring to numerous biliary, pancreatic, and hepatic disorders resulting from spasms, strictures, and relaxation of this valve at inappropriate times. This review brings attention to various factors that may increase the risk of SOD, including but not limited to: cholecystectomy, opiates, and alcohol. Lack of proper recognition and treatment of SOD may be associated with clinical events, including pancreatitis and biliary symptoms with hepatic enzyme elevation. Pharmacologic and non-pharmacologic approaches are discussed to help recognize, prevent, and treat SOD. Future studies are needed to assess the treatment benefit of agents such as calcium-channel blockers, glyceryl trinitrate, or tricyclic antidepressants in patients with SOD. PMID:28194398

  3. Biological denitration of propylene glycol dinitrate by Bacillus sp. ATCC 51912.

    PubMed

    Sun, W Q; Meng, M; Kumar, G; Geelhaar, L A; Payne, G F; Speedie, M K; Stacy, J R

    1996-05-01

    In previous studies, bacterial cultures were isolated that had the ability to degrade the nitrate ester glyceryl trinitrate (i.e., nitroglycerin). The goal of the present study was to examine the ability of resting cells and cell-free extracts of the isolate Bacillus sp. ATCC 51912 to degrade the more recalcitrant nitrate ester propylene glycol dinitrate (PGDN). It was observed that the PGDN-denitrating activity was expressed during growth even when cells were cultured in the absence of nitrate esters. This indicates that nitrate esters are not required for expression of denitration activity. Using cell-free extracts, PGDN was observed to be sequentially denitrated to propylene glycol mononitrate (PGMN) and propylene glycol with the second denitration step proceeding more slowly than the first. Also it was observed that dialysis of the cell-free extracts did not affect denitration activity indicating that regenerable cofactors [e.g., NAD(P)H or ATP] are not required for denitration.

  4. Nitric oxide is negatively correlated to pain during acute inflammation

    PubMed Central

    2010-01-01

    Background The role that nitric oxide (NO) plays in modulating pain in the periphery is unclear. We show here, the results of two independent clinical studies (microdialysis and gene expression studies) and a pilot dose finding study (glyceryl trinitrate study), to study the role of NO in the early phase of acute inflammatory pain following oral surgery. The effect of ketorolac on NO production and nitric oxide synthase (NOS) gene expression was also studied. Results Microdialysis samples showed significantly higher levels of NO at the first 100 min compared to the last 80 minutes in the placebo treated group. In the ketorolac group, on the other hand, NO levels gradually decreased over the first 60 min but were similar to placebo over the later 100-180 min, with no significant change in NO level over time. The levels of NO were negatively correlated to pain intensity scores. Local infusion of the NO donor glyceryl trinitrate at the site of surgery, showed a small analgesic effect that did not reach statistical significance in the sample size used. While the gene expression of iNOS and eNOS were not up-regulated, 3 hours after surgery, nNOS was downregulated in both treatment groups and eNOS gene expression was significantly lower in the ketorolac group compared to the placebo group. Further, there was a positive correlation between the change in gene expression of nNOS and eNOS in the placebo goup but not in the ketorolac group. Conclusion We suggest that at this early stage of inflammatory pain in man, NO is analgesic in the periphery. Further, ketorolac down-regulates eNOS gene expression. PMID:20843331

  5. A randomized trial of oral vs. topical diltiazem for chronic anal fissures.

    PubMed

    Jonas, M; Neal, K R; Abercrombie, J F; Scholefield, J H

    2001-08-01

    Chemical sphincterotomy has proved effective in treating chronic anal fissure. Glyceryl trinitrate is the most widely used agent, and topical 0.2 percent glyceryl trinitrate ointment heals up to two thirds of chronic anal fissures. Unfortunately, however, many patients experience troublesome headaches as a side effect of this treatment. This study assessed the effectiveness of oral and topical diltiazem in healing chronic fissures. Fifty consecutive patients with chronic anal fissures were randomly assigned to receive oral (60 mg) or topical (2 percent gel) diltiazem twice daily for up to eight weeks. Anal manometry was performed before and after the first dose, and blood pressure was recorded at 15-minute intervals. Patients were reviewed fortnightly, pain was expressed with a visual linear analog scale, blood pressure was recorded, fissure healing was assessed, and side effects were noted. Twenty-four patients received oral diltiazem, and 26 received topical diltiazem. Mean (+/- standard error of the mean) maximum resting anal pressures fell by 15 and 23 percent from 95 +/- 4 to 81 +/- 4 and from 102 +/- 5 to 79 +/- 5 cm H2O in the two groups, respectively. There was no significant reduction in blood pressure during the study or at follow-up in either group. Fissure healing was complete in 9 patients (38 percent) receiving oral diltiazem and 15 (65 percent) on topical treatment by eight weeks. Oral diltiazem caused side effects in eight patients (rash, two; headaches, two; nausea or vomiting, three; reduced smell and taste, one), whereas no side effects were seen in those receiving topical therapy (P = 0.001). Oral and topical diltiazem heal chronic anal fissures. Topical diltiazem is more effective, achieving healing rates comparable to those reported with topical nitrates, with significantly fewer side effects.

  6. Regulation of Human Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Activity by Electrophiles in Vitro*

    PubMed Central

    Oelze, Matthias; Knorr, Maike; Schell, Richard; Kamuf, Jens; Pautz, Andrea; Art, Julia; Wenzel, Philip; Münzel, Thomas; Kleinert, Hartmut; Daiber, Andreas

    2011-01-01

    Recently, mitochondrial aldehyde dehydrogenase (ALDH-2) was reported to reduce ischemic damage in an experimental myocardial infarction model. ALDH-2 activity is redox-sensitive. Therefore, we here compared effects of various electrophiles (organic nitrates, reactive fatty acid metabolites, or oxidants) on the activity of ALDH-2 with special emphasis on organic nitrate-induced inactivation of the enzyme, the biochemical correlate of nitrate tolerance. Recombinant human ALDH-2 was overexpressed in Escherichia coli; activity was determined with an HPLC-based assay, and reactive oxygen and nitrogen species formation was determined by chemiluminescence, fluorescence, protein tyrosine nitration, and diaminonaphthalene nitrosation. The organic nitrate glyceryl trinitrate caused a severe concentration-dependent decrease in enzyme activity, whereas incubation with pentaerythritol tetranitrate had only minor effects. 4-Hydroxynonenal, an oxidized prostaglandin J2, and 9- or 10-nitrooleate caused a significant inhibition of ALDH-2 activity, which was improved in the presence of Mg2+ and Ca2+. Hydrogen peroxide and NO generation caused only minor inhibition of ALDH-2 activity, whereas peroxynitrite generation or bolus additions lead to severe impairment of the enzymatic activity, which was prevented by the thioredoxin/thioredoxin reductase (Trx/TrxR) system. In the presence of glyceryl trinitrate and to a lesser extent pentaerythritol tetranitrate, ALDH-2 may be switched to a peroxynitrite synthase. Electrophiles of different nature potently regulate the enzymatic activity of ALDH-2 and thereby may influence the resistance to ischemic damage in response to myocardial infarction. The Trx/TrxR system may play an important role in this process because it not only prevents inhibition of ALDH-2 but is also inhibited by the ALDH-2 substrate 4-hydroxynonenal. PMID:21252222

  7. Synthesis of some novel organic nitrates and comparative in vitro study of their vasodilator profile.

    PubMed

    Chegaev, Konstantin; Lazzarato, Loretta; Marcarino, Paolo; Di Stilo, Antonella; Fruttero, Roberta; Vanthuyne, Nicolas; Roussel, Christian; Gasco, Alberto

    2009-07-09

    Synthesis and structural characterization of the 4-phenylbutane-1,2-diyl dinitrate and of the erythro and threo diastereoisomers of 4-phenylbutane-1,2,3-triyl trinitrate as well as the HPLC chiral separation of the corresponding racemic mixtures are reported. Vasodilator activity of the single enantiomers of these products, of 4-phenylbutyl nitrate, and of the previously described phenylpropyl analogues were assessed on rat aorta strips precontracted with phenylephrine. The compounds were able to relax the contracted tissue in a concentration dependent manner. In the couples of antipodes, a complete lack of enantioselectivity was observed as far as the vasodilator potency is concerned. The concentration response curves of the products, with the exception of those of all the trinitrooxy substituted models, were rightward shifted in the presence of ALDH-2 inhibitors. Mono and dinitrates, but not trinitrates, displayed in vitro cross-tolerance with GTN. This new series of nitric acid esters is an interesting tool that can help to shed light on the unresolved puzzle of nitrate pharmacology. Selected members are worthy of additional study as potential drugs.

  8. Treatment of Xerosis with a Topical Formulation Containing Glyceryl Glucoside, Natural Moisturizing Factors, and Ceramide

    PubMed Central

    Kausch, Martina; Rippke, Frank; Schoelermann, Andrea M.; Filbry, Alexander W.

    2012-01-01

    Objective: To assess the effects of Light Formulation, an oil-in-water emulsion, and Rich Formulation, a water-in-oil emulsion, for the treatment of xerosis. Design: Two double-blind, vehicle-controlled trials (both formulations); a double-blind, randomized regression study (Rich Formulation); and a single-blind tolerability study (Light Formulation). The two formulations were applied twice daily for two weeks, for five days in the regression study, and twice daily for two weeks in the tolerability study. Setting: Studies were conducted during winter in Hamburg, Germany. Participants: A total of 169 subjects were enrolled and 154 completed the studies. The majority were between 50 and 80 years of age, women, all with very dry skin. One withdrew because of an incompatibility reaction that reoccurred with the subject's own body lotion after sun exposure. Measurements: Skin hydration and skin barrier function with both formulations over two weeks, long-term moisturization effect after discontinuation of Rich Formulation, and symptom improvement and skin tolerability with Light Formulation. Results: Vehicle-controlled studies of Light and Rich Formulations demonstrated significantly improved hydration at Weeks 1 and 2 versus the untreated site and vehicles, and significantly reduced transepidermal water loss versus untreated site and basic vehicle. Both products significantly decreased visible dryness and tactile roughness. In the regression study, Rich Formulation maintained significant moisturization six days after treatment discontinuation. Light Formulation reduced symptoms of itching, burning, tightness, tingling, and feeling of dryness. Conclusion: These formulations represent a new approach for the treatment of xerosis by addressing multiple key deficiencies in skin hydration. PMID:22916312

  9. In-vivo evaluation of clindamycin release from glyceryl monooleate-alginate microspheres by NIR spectroscopy.

    PubMed

    Mohamed, Amir Ibrahim; Ahmed, Osama A A; Amin, Suzan; Elkadi, Omar Anwar; Kassem, Mohamed A

    2015-10-15

    The purpose of this study was to use near-infrared (NIR) transmission spectroscopic technique to determine clindamycin plasma concentration after oral administration of clindamycin loaded GMO-alginate microspheres using rabbits as animal models. Lyophilized clindamycin-plasma standard samples at a concentration range of 0.001-10 μg/ml were prepared and analyzed by NIR and HPLC as a reference method. NIR calibration model was developed with partial least square (PLS) regression analysis. Then, a single dose in-vivo evaluation was carried out and clindamycin-plasma concentration was estimated by NIR. Over 24 h time period, the pharmacokinetic parameters of clindamycin were calculated for the clindamycin loaded GMO-alginate microspheres (F3) and alginate microspheres (F2), and compared with the plain drug (F1). PLS calibration model with 7-principal components (PC), and 8000-9200 cm(-1) spectral range shows a good correlation between HPLC and NIR values with root mean square error of cross validation (RMSECV), root mean square error of prediction (RMSEP), and calibration coefficient (R(2)) values of 0.245, 1.164, and 0.9753, respectively, which suggests that NIR transmission technique can be used for drug-plasma analysis without any extraction procedure. F3 microspheres exhibited controlled and prolonged absorption Tmax of 4.0 vs. 1.0 and 0.5 h; Cmax of 2.37±0.3 vs. 3.81±0.8 and 5.43±0.7 μg/ml for F2 and F1, respectively. These results suggest that the combination of GMO and alginate (1:4 w/w) could be successfully employed for once daily clindamycin microspheres formulation which confirmed by low Cmax and high Tmax values.

  10. A safety trial of high dose glyceryl triacetate for Canavan disease.

    PubMed

    Segel, Reeval; Anikster, Yair; Zevin, Shoshana; Steinberg, Avraham; Gahl, William A; Fisher, Drora; Staretz-Chacham, Orna; Zimran, Ari; Altarescu, Gheona

    2011-07-01

    Canavan disease (CD MIM#271900) is a rare autosomal recessive neurodegenerative disorder presenting in early infancy. The course of the disease is variable, but it is always fatal. CD is caused by mutations in the ASPA gene, which codes for the enzyme aspartoacylase (ASPA), which breaks down N-acetylaspartate (NAA) to acetate and aspartic acid. The lack of NAA-degrading enzyme activity leads to excess accumulation of NAA in the brain and deficiency of acetate, which is necessary for myelin lipid synthesis. Glyceryltriacetate (GTA) is a short-chain triglyceride with three acetate moieties on a glycerol backbone and has proven an effective acetate precursor. Intragastric administration of GTA to tremor mice results in greatly increased brain acetate levels, and improved motor functions. GTA given to infants with CD at a low dose (up to 0.25 g/kg/d) resulted in no improvement in their clinical status, but also no detectable toxicity. We present for the first time the safety profile of high dose GTA (4.5 g/kg/d) in 2 patients with CD. We treated 2 infants with CD at ages 8 months and 1 year with high dose GTA, for 4.5 and 6 months respectively. No significant side effects and no toxicity were observed. Although the treatment resulted in no motor improvement, it was well tolerated. The lack of clinical improvement might be explained mainly by the late onset of treatment, when significant brain damage was already present. Further larger studies of CD patients below age 3 months are required in order to test the long-term efficacy of this drug.

  11. Problem Definition Study on the Health Effects of Diethyleneglycol Dinitrate, Triethylenegycol Dinitrate, and Trimethylolethane Trinitrate and Their Respective Combustion Products

    DTIC Science & Technology

    1983-04-01

    erythritol tetranitrate by glutathione. J. Biol. Chem. 183:129-138. Hosko, M.J. 1970. The effect of carbon monoxide on the visual evoked response in man...and erythritol tetranitrate by glutathione. J. Biol. Chem. 183:129-138. 79 -4 Jones, R.A., J.A. Strickland, and J. Siegel. 1972. Toxicity of pro- pylene

  12. Calcium channel blockers for inhibiting preterm labour and birth.

    PubMed

    Flenady, Vicki; Wojcieszek, Aleena M; Papatsonis, Dimitri N M; Stock, Owen M; Murray, Linda; Jardine, Luke A; Carbonne, Bruno

    2014-06-05

    with placebo or no treatment showed a significant reduction in birth less than 48 hours after trial entry (RR 0.30, 95% CI 0.21 to 0.43) and an increase in maternal adverse effects (RR 49.89, 95% CI 3.13 to 795.02, one trial of 89 women). Due to substantial heterogeneity, outcome data for preterm birth (less than 37 weeks) were not combined; one placebo controlled trial showed no difference (RR 0.96, 95% CI 0.89 to 1.03) while the other (non-placebo controlled trial) reported a reduction (RR 0.44, 95% CI 0.31 to 0.62). No other outcomes were reported.Comparing CCBs (mainly nifedipine) with other tocolytics by type (including betamimetics, glyceryl trinitrate (GTN) patch, non-steriodal anti inflammatories (NSAID), magnesium sulphate and ORAs), no significant reductions were shown in primary outcome measures of birth within 48 hours of treatment or perinatal mortality.Comparing CCBs with betamimetics, there were fewer maternal adverse effects (average RR 0.36, 95% CI 0.24 to 0.53) and fewer maternal adverse effects requiring discontinuation of therapy (average RR 0.22, 95% CI 0.10 to 0.48). Calcium channel blockers resulted in an increase in the interval between trial entry and birth (average MD 4.38 days, 95% CI 0.25 to 8.52) and gestational age (MD 0.71 weeks, 95% CI 0.34 to 1.09), while decreasing preterm and very preterm birth (RR 0.89, 95% CI 0.80 to 0.98 and RR 0.78, 95% CI 0.66 to 0.93); respiratory distress syndrome (RR 0.64, 95% CI 0.48 to 0.86); necrotising enterocolitis (RR 0.21, 95% CI 0.05 to 0.96); intraventricular haemorrhage (RR 0.53, 95% CI 0.34 to 0.84); neonatal jaundice (RR 0.72, 95% CI 0.57 to 0.92); and admissions to neonatal intensive care unit (NICU) (average RR 0.74, 95% CI 0.63 to 0.87). No difference was shown in one trial of outcomes at nine to twelve years of age.Comparing CCBs with ORA, data from one study (which did blind the intervention) showed an increase in gestational age at birth (MD 1.20 completed weeks, 95% CI 0.25 to 2.15) and

  13. Arterial pressure suffices to increase liver stiffness.

    PubMed

    Piecha, Felix; Peccerella, Teresa; Bruckner, Tom; Seitz, Helmut-Karl; Rausch, Vanessa; Mueller, Sebastian

    2016-11-01

    Noninvasive measurement of liver stiffness (LS) has been established to screen for liver fibrosis. Since LS is also elevated in response to pressure-related conditions such as liver congestion, this study was undertaken to learn more about the role of arterial pressure on LS. LS was measured by transient elastography (μFibroscan platform, Echosens, Paris, France) during single intravenous injections of catecholamines in anesthetized rats with and without thioacetamide (TAA)-induced fibrosis. The effect of vasodilating glycerol trinitrate (GTN) on LS was also studied. Pressures in the abdominal aorta and caval and portal veins were measured in real time with the PowerLab device (AD Instruments, Dunedin, New Zealand). Baseline LS values in all rats (3.8 ± 0.5 kPa, n = 25) did not significantly differ from those in humans. Epinephrine and norepinephrine drastically increased mean arterial pressure (MAP) from 82 to 173 and 156 mmHg. Concomitantly, LS almost doubled from 4 to 8 kPa, while central venous pressure remained unchanged. Likewise, portal pressure only showed a slight and delayed increase. In the TAA-induced fibrosis model, LS increased from 9.5 ± 1.0 to 25.6 ± 14.7 kPa upon epinephrine injection and could efficiently be decreased by GTN. We finally show a direct association in humans in a physiological setting of elevated cardiac output and MAP. During continuous spinning at 200 W, MAP increased from 84 ± 8 to 99 ± 11 mmHg while LS significantly increased from 4.4 ± 1.8 to 6.7 ± 2.1 kPa. In conclusion, our data show that arterial pressure suffices to increase LS. Moreover, lowering MAP efficiently decreases LS in fibrotic livers that are predominantly supplied by arterial blood. Copyright © 2016 the American Physiological Society.

  14. Effect of sublingual nitrate on respiratory reflexes arising from stimulation of juxta-pulmonary capillary (J) receptors by i.v. lobeline and short duration exercise.

    PubMed

    Anand, Ashima; Srivastava, Niraj; Raj, Hans

    2012-05-31

    Juxta-pulmonary capillary (J or pulmonary C fiber) receptors are stimulated by an increase in pulmonary blood flow and give rise to respiratory acceleration and related sensations and inhibit exercise. However, the reverse, i.e., the effect of reducing pulmonary blood flow on their reflexes, is as yet not known. This was investigated by carrying out a placebo-controlled study on the acute effects of a single dose (0.4 mg) of sublingual glyceryl nitrate (GTN), known to shift blood from the central to the peripheral circulation, on the respiratory parameters of exercising healthy subjects and on their responses to i.v. lobeline. In 10 subjects, GTN use delayed the first appearance of respiratory sensations from 9.08 ± 0.9 min to 11 min (P=0.002), reduced the increase in minute ventilation by the end of 10 min of exercise (P=0.003) and increased its duration by 1-4s and doubled it in the remaining one subject. In a majority of 8 of them, the effect of GTN on i.v. lobeline-induced respiratory reflexes and sensations was a significant increase in the dose required (P=0.006) for producing threshold effects and in the latency of their appearance (P=0.003). The latter feature points to a reduction in blood flow in the lung parenchyma where these receptors are located and to which they are sensitive. As this would have led to a reduced stimulation of these receptors, it would account for the delayed appearance of respiratory symptoms, a reduction in ventilatory increase and prolongation of exercise duration. We demonstrated a mechanism of reducing the stimulus level of J receptors by reducing pulmonary blood flow by means of pharmacological sequestration with GTN use, which then led to a reduction in the magnitude of respiratory and viscerosomatic reflexes, while noting at the same time that changes in blood flow in the pulmonary bed do not directly influence limb muscles, tendons and joints which also determine exercise output.

  15. Nanoassemblies containing a fluorouracil/zidovudine glyceryl prodrug with phospholipase A2-triggered drug release for cancer treatment.

    PubMed

    Jin, Yiguang; Yang, Fang; Du, Lina

    2013-12-01

    Secretory phospholipase A2 (sPLA2), which is overexpressed in many tumors, cleaves ester bonds at the sn-2 position of phospholipids. A PLA2-sensitive amphiphilic prodrug, 1-O-octadecyl-2-(5-fluorouracil)-N-acetyl-3-zidovudine-phosphorylglycerol (OFZG), was synthesized and used to prepare nanoassemblies through the injection of a mixture of OFZG/cholesterol/Tween 80 (2:1:0.1, mol:mol:mol) into water. Cholesterol and Tween 80 was incorporated into the OFZG monolayers at the air/water interface to yield nanoassemblies. The resulting nanoassemblies exhibited a narrow size distribution with a mean size of 77.8nm and were stable due to their high surface charges. The in vitro experiments showed that PLA2 degraded OFZG. The nanoassemblies exhibited higher anticancer activity than the parent drug 5-fluorouracil (5-FU) in COLO205, HT-28, and HCT-116 cells. The intravenous (i.v.) administration of the nanoassemblies into mice resulted in the rapid elimination of OFZG from the circulation and its distribution mainly in the liver, lung, spleen, and kidney. After their injection into tumor-bearing mice, the nanoassemblies exhibited anticancer efficiency comparable to that of 5-FU, even though the nanoassemblies contained concentrations of only 1/10 of the molar amount of 5-FU. The lessons learned from the study and methods for the design of PLA2-sensitive amphiphilic prodrugs are also discussed. Enzyme-sensitive amphiphilic combinatorial prodrugs and prodrug-loaded nanoassemblies may represent a new strategy for anticancer drug design. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. 1-O-alkenyl-sn-glyceryl-3-phosphorylcholine may be a novel posttranslational modification used by the placenta.

    PubMed

    Lowry, Philip

    2011-01-01

    Neurokinin B (NKB) secreted by the placenta was previously found to be raised in preeclampsia and most of the symptoms in this disease appeared to be through progressive activation of the three neurokinin receptors. Further characterization of placental NKB revealed that placental NKB eluted in the approximate position of a 13mer and this was confirmed by TOF mass spectrometry which gave a mass of 1580. Although this is consistent with dimethylated NKB-Gly-Lys-Arg, further characterization (immunological and mass spectrometric fragment analysis) suggested a novel posttranslational modification containing phosphocholine (PC) with some evidence for glycerol and a coordinated alkene. The structure that fits all the data is that a form of platelet activating factor is attached to the aspartyl side chain at position 4 of NKB and thus now implicates placental NKB in the platelet pathology seen in preeclampsia. As it has been reported that it is the PC group per se attached to certain proteins secreted by filarial nematodes imparts them with immune inhibitory properties and thus survival in the host over long periods, attaching PC to placental secretory peptide hormones (also be found on the placental precursors of CRF, ACTH, and activin) may result in a similar situation.

  17. Enhanced topical delivery of finasteride using glyceryl monooleate-based liquid crystalline nanoparticles stabilized by cremophor surfactants.

    PubMed

    Madheswaran, Thiagarajan; Baskaran, Rengarajan; Yong, Chul Soon; Yoo, Bong Kyu

    2014-02-01

    The aim of this study was to investigate the capability of two surfactants, Cremophor RH 40 (RH) and Cremophor EL (EL), to prepare liquid crystalline nanoparticles (LCN) and to study its influence on the topical delivery of finasteride (FNS). FNS-loaded LCN was formulated with the two surfactants and characterized for size distribution, morphology, entrapment efficiency, in vitro drug release, and skin permeation/retention. Influence of FNS-loaded LCN on the conformational changes on porcine skin was also studied using attenuated total reflectance Fourier-transform infrared spectroscopy. Transmission electron microscopical image confirmed the formation of LCN. The average particle size of formulations was in the range of 165.1-208.6 and 153.7-243.0 nm, respectively. The formulations prepared with higher surfactant concentrations showed faster release and significantly increased skin permeation. Specifically, LCN prepared with RH 2.5% presented higher permeation flux (0.100 ± 0.005 μgcm(-2)h(-1)) compared with lower concentration (0.029 ± 0.007 μgcm(-2)h(-1)). Typical spectral bands of lipid matrix of porcine skin were shifted to higher wavenumber, indicating increased degree of disorder of the lipid acyl chains which might cause fluidity increase of stratum corneum. Taken together, Cremophor surfactants exhibited a promising potential to stabilize the LCN and significantly augmented the skin permeation of FNS.

  18. Effect of ethylcellulose and propylene glycol on the controlled-release performance of glyceryl monooleate-mertronidazole periodontal gel.

    PubMed

    Sallam, Al-Sayed; Hamudi, Firas Falih; Khalil, Enam Ayoub

    2015-03-01

    Controlled-release metronidazole, mucoadhesive gel proposed as a drug-delivery system for periodontal application was developed and characterized. The system was based on a mixture of glycerylmonooleate (GMO) and ethylcellulose (EC). The mechanism of release depends: firstly, on the ability of GMO to form a viscous liquid crystalline mesophases and secondly on the solubilized EC to form a hydrophobic network when the mixture comes into contact with water resulting in sustaining the release of the drug. Ethylcellulose dissolved in GMO had a profound influence on the rate of drug release, reduced the initial drug release and prolonged the sustained release of metronidazole. Propylene glycol (PG) was added to increase the solubility of the drug and water was added with PG to control the viscosity. A controlled release formulation containing w/w, 20% metronidazole, 10% PG, 5% water and 65% GMO that contains 7% EC was found to be mucoadhesive, easily injectable at room temperature, and to follow Fickian diffusion release mechanism. When the drug loading was increased the drug release was accelerated, and the mechanism followed anomalous controlled-release mechanism. Stability studies indicated that the formulation should be stored at 4 °C in a dark place.

  19. Rapid and sensitive measurements of nitrate ester explosives using microchip electrophoresis with electrochemical detection.

    PubMed

    Piccin, Evandro; Dossi, Nicolò; Cagan, Avi; Carrilho, Emanuel; Wang, Joseph

    2009-03-01

    This article describes an effective microchip protocol based on electrophoretic-separation and electrochemical detection for highly sensitive and rapid measurements of nitrate ester explosives, including ethylene glycol dinitrate (EGDN), pentaerythritol tetranitrate (PETN), propylene glycol dinitrate (PGDN) and glyceryl trinitrate (nitroglycerin, NG). Factors influencing the separation and detection processes were examined and optimized. Under the optimal separation conditions obtained using a 15 mM borate buffer (pH 9.2) containing 20 mM SDS, and applying a separation voltage of 1500 V, the four nitrate ester explosives were separated within less than 3 min. The glassy-carbon amperometric detector (operated at -0.9 V vs. Ag/AgCl) offers convenient cathodic detection down to the picogram level, with detection limits of 0.5 ppm and 0.3 ppm for PGDN and for NG, respectively, along with good repeatability (RSD of 1.8-2.3%; n = 6) and linearity (over the 10-60 ppm range). Such effective microchip operation offers great promise for field screening of nitrate ester explosives and for supporting various counter-terrorism surveillance activities.

  20. Vasoactive drugs inhibit oxygen radical production of neutrophils.

    PubMed

    Weiss, M; Schneider, E M; Liebert, S; Mettler, S; Lemoine, H

    1997-05-01

    A concentration response study was performed to clarify whether vasoactive drugs, routinely used in intensive care patients, inhibit oxygen radical production of neutrophils. Moreover, in a cell-free system, it was investigated whether these drugs exert free radical scavenging properties. Vasoactive agents were incubated with neutrophils from healthy human volunteers, which were stimulated by N-formyl-methionyl-leucyl-phenylalanine (FMLP) and by opsonized zymosan to produce oxygen radicals, detected by chemiluminescence measurements. Sympathomimetics (epinephrine greater than norepinephrine, dopamine and dobutamine) as well as phosphodiesterase-inhibitors (amrinone and enoximone) inhibited FMLP-induced and zymosan-induced oxygen radical production of neutrophils in a concentration-dependent and drug-specific fashion. With the exception of amrinone, FMLP-induced chemiluminescence of neutrophils was impaired nearly 10-fold more markedly than zymosan-induced chemiluminescence. Glyceryl trinitrate, nifedipine and prostacyclin had no effect on oxygen radical production of neutrophils. In the cell-free system, epinephrine, norepinephrine, dopamine, amrinone and enoximone demonstrated oxygen free radical scavenging properties. This study shows that vasoactive drugs, frequently used in the clinical setting, may suppress oxidative burst after FMLP-receptor stimulation. As demonstrated in the cell-free system, this suppression was, at least in part, due to oxygen radical scavenging.

  1. Angioplasty of forearm arteries as a finger salvage procedure for patient with end-stage renal failure

    PubMed Central

    Law, Yuk; Chan, Yiu Che; Cheng, Stephen Wing-Keung

    2016-01-01

    Due to the relatively low metabolic demand and extensive collaterals of the upper limb, peripheral arterial disease seldom leads to tissue loss, except in patients with end-stage renal failure (ESRF), rheumatologic diseases, Raynaud’s disease, frostbites, or distal emboli. We report a case of a 51-year-old lady with ESRF who presented to our tertiary referral vascular center with infected gangrene of her right ring finger. Duplex ultrasound showed that her forearm arteries were severely diseased. Digital subtraction angiogram showed severe multilevel stenoses/occlusions in her forearm radial and ulnar arteries. These lesions were successfully angioplastized with 2 mm × 25 mm angioplasty balloon. Completion angiogram showed good radiological results with some post-dilatation spasm which improved with intra-arterial glyceryl trinitrate. The sepsis improved after revascularization, and the distal phalanx was allowed to self-demarcate with dressings and autoamputate with good clinical results. Our case illustrated that even in delayed setting, patients could still benefit from specialist vascular care with a combination of expert care and angioplasty of forearm arteries, with successful salvage of her finger. PMID:27143949

  2. [Recent findings on nitrates: their action, bioactivation and development of tolerance].

    PubMed

    Münzel, T

    2008-10-01

    Organic nitrates still are one of the most important drug classes used in the treatment of an acute coronary syndrome and stable coronary artery disease as well as acute and chronic congestive heart failure. The mechanism of vasodilatation comprises the release of nitric oxide, which in turn activates soluble guanylate cyclase and lowers the intracellular calcium content leading to relaxation of vascular smooth muscle. Recent research has demonstrated that highly reactive nitrates, such as nitroglycerin (or glyceryl trinitrate) and pentaerthrityl tetranitrate (PETN) are bioactivated by aldehyde dehydrogenase 2 (ALDH-2), an enzyme located in mitochondria. The enzyme, which bioactivates mono- and dinitrates is not yet identified. Despite being effective in the acute treatment of patients, its long-term efficacy is limited by the development of tolerance to nitrates and of endothelial dysfunction. Both of these side effects of nitrate therapy are due to increased production of reactive oxygen species. This review focuses on new aspects of the process of bioactivation of organic nitrates, the conception of oxidative stress of endothelial dysfunction and of the development of tolerance and their therapeutic consequences. Also discussed are more recent findings on nitric oxide donors such as molsidomine, PETN and the combination treatment of isosorbide dinitrate and hydralazine of patients with coronary artery disease and chronic heart failure.

  3. Non-hemodynamic effects of organic nitrates and the distinctive characteristics of pentaerithrityl tetranitrate.

    PubMed

    Gori, Tommaso; Daiber, Andreas

    2009-01-01

    Organic nitrates are among the oldest and yet most commonly employed drugs in the long-term therapy of coronary artery disease and congestive heart failure. While they have long been used in clinical practice, our understanding of their mechanism of action and side effects remains incomplete. For instance, recent findings provide evidence of previously unanticipated, non-hemodynamic properties that include potentially beneficial mechanisms (such as the induction of a protective phenotype that mimics ischemic preconditioning), but also toxic effects (such as endothelial and autonomic dysfunction, rebound angina, tolerance). To date, the most commonly employed organic nitrates are isosorbide mononitrate, isosorbide dinitrate, and nitroglycerin (glyceryl trinitrate). Another organic nitrate, pentaerithrityl tetranitrate (PETN), has long been employed in eastern European countries and is currently being reintroduced in Western countries. In light of their wide use, and of the (re)introduction of PETN in Western markets, the present review focuses on the novel effects of organic nitrates, describing their potential clinical implications and discussing differences among different compounds. We believe that these recent findings have important clinical implications. Since the side effects of organic nitrates such as nitroglycerin and isosorbides appear to be mediated by reactive oxygen species, care should be taken that drugs with antioxidant properties are co-administered. On the other hand, efforts should be made to clinically exploit the preconditioning effects of these drugs.

  4. Sensitivity analysis of near-infrared functional lymphatic imaging

    NASA Astrophysics Data System (ADS)

    Weiler, Michael; Kassis, Timothy; Dixon, J. Brandon

    2012-06-01

    Near-infrared imaging of lymphatic drainage of injected indocyanine green (ICG) has emerged as a new technology for clinical imaging of lymphatic architecture and quantification of vessel function, yet the imaging capabilities of this approach have yet to be quantitatively characterized. We seek to quantify its capabilities as a diagnostic tool for lymphatic disease. Imaging is performed in a tissue phantom for sensitivity analysis and in hairless rats for in vivo testing. To demonstrate the efficacy of this imaging approach to quantifying immediate functional changes in lymphatics, we investigate the effects of a topically applied nitric oxide (NO) donor glyceryl trinitrate ointment. Premixing ICG with albumin induces greater fluorescence intensity, with the ideal concentration being 150 μg/mL ICG and 60 g/L albumin. ICG fluorescence can be detected at a concentration of 150 μg/mL as deep as 6 mm with our system, but spatial resolution deteriorates below 3 mm, skewing measurements of vessel geometry. NO treatment slows lymphatic transport, which is reflected in increased transport time, reduced packet frequency, reduced packet velocity, and reduced effective contraction length. NIR imaging may be an alternative to invasive procedures measuring lymphatic function in vivo in real time.

  5. Can migraine aura be provoked experimentally? A systematic review of potential methods for the provocation of migraine aura.

    PubMed

    Lindblad, Marianne; Hougaard, Anders; Amin, Faisal Mohammad; Ashina, Messoud

    2017-01-01

    Background The nature of the migraine aura and its role in migraine pathophysiology is incompletely understood. In particular, the mechanisms underlying aura initiation and the causal relation between aura and headache are unknown. The scientific investigation of aura in patients is only possible if aura can be triggered. This paper reviews potential methods for the experimental provocation of migraine aura. Methods We systematically searched PubMed for studies of experimental migraine provocation, including case reports of patients with aura and reports of the occurrence of aura following exposure to any kind of suspected trigger. Results We identified 21 provocation studies, using 13 different prospective provocation methods, and 34 case reports. In the prospective studies, aura were reported following the administration of intravenous and sublingual glyceryl trinitrate, visual stimulation, physical activity, calcitonin gene-related peptide infusion, chocolate ingestion, and the intravenous injection of insulin. In addition, carotid artery puncture has consistently been reported as a trigger of aura. Conclusions No safe and efficient method for aura provocation exists at present, but several approaches could prove useful for this purpose.

  6. A mimicry of an acute coronary syndrome.

    PubMed

    Teo, Bervin

    2009-01-01

    A 79-year-old woman was out in the garden having lunch on a hot summer day. She developed stabbing chest pains, more severe on her left side, associated with radiation down her left arm. Severity was 7 out of 10. There was no relief of pain with glyceryl trinitrate spray. Risk factors for ischaemic heart disease include hyperlipidaemia, being an ex-smoker (40 years), no history of diabetes or hypertension. There was a family history of her father having a myocardial infarction at the age of 54. Echocardiogram (ECG) revealed widespread deep symmetrical T-wave inversion in the chest leads and lateral limb leads. The patient's serum creatine kinase level was 180 IU/litre (normal range 30-135), troponin I level was 6.56 g/litre (normal range 0-0.10), D-dimer was negative and random serum cholesterol level was 5.3 mmol/litre (3.8-5.2). Significant coronary stenoses were excluded. A left ventriculogram revealed a hyperkinetic base and a dyskinetic apical region of the left ventricle. Echocardiography showed normal valves, basal septal hypertrophy and a dilated akinetic apex, with the region of akinesia spanning more than the arterial territory. Takotsubo cardiomyopathy. Treatment with aspirin, angiotensin-converting enzyme (ACE) inhibitor, β blocker and a statin.

  7. A mimicry of an acute coronary syndrome.

    PubMed

    Teo, Bervin

    2007-04-01

    A 79-year-old woman was out in the garden having lunch on a hot summer's day. She developed stabbing chest pains more severe on her left side, associated with radiation down her left arm. Severity was 7 out of 10. There was no relief of pain with glyceryl trinitrate spray. Risk factors for ischaemic heart disease include hyperlipidaemia, being an ex-smoker 40 years ago, no history of diabetes or hypertension. There was a family history of her father having a myocardial infarction at the age of 54. ECG revealed widespread deep symmetrical T-wave inversion in the chest leads and lateral limb leads. The patient's serum creatine kinase level was 180 IU/l (normaL range 30-135), troponin I level was 6.56 g/l (normal range 0-0.10), D-dimer was negative and random serum cholesterol level was 5.3 mmol/l (3.8-5.2). Significant coronary stenoses were excluded. A left ventriculogram revealed a hyperkinetic base and a dyskinetic apical region of the left ventricle. Echocardiography showed normal valves, basal septal hypertrophy and a dilated akinetic apex, with the region of akinesia spanning more than the arterial territory. Takotsubo cardiomyopathy. Treatment with aspirin, ACE inhibitor, beta blocker and a statin.

  8. Lateral epicondylalgia: midlife crisis of a tendon.

    PubMed

    Luk, James K H; Tsang, Raymond C C; Leung, H B

    2014-04-01

    The pathogenesis and management of lateral epicondylalgia, or tennis elbow, a common ailment affecting middle-aged subjects of both genders continue to provoke controversy. Currently it is thought to be due to local tendon pathology, pain system changes, and motor system impairment. Its diagnosis is usually clinical, based on a classical history, as well as symptoms and signs. In selected cases, additional imaging (X-rays, ultrasound, and magnetic resonance imaging) can help to confirm the diagnosis. Different treatment modalities have been described, including the use of orthotics, non-steroidal anti-inflammatory drugs, steroid injections, topical glyceryl trinitrate, exercise therapy, manual therapy, ultrasound therapy, laser therapy, extracorporeal shockwave therapy, acupuncture, taping, platelet-rich plasma injections, hyaluronan gel injections, botulinum toxin injections, and surgery. Nevertheless, evidence to select the best treatment is lacking and the choice of therapy depends on the experience of the management team, availability of the equipment and expertise, and patient response. This article provides a snapshot of current medical practice for lateral epicondylalgia management.

  9. Neuromyogenic properties of the internal anal sphincter: therapeutic rationale for anal fissures.

    PubMed

    Bhardwaj, R; Vaizey, C J; Boulos, P B; Hoyle, C H

    2000-06-01

    Lateral sphincterotomy diminishes internal anal sphincter hypertonia and thereby reduces anal canal pressure. This improves anal mucosal blood flow and promotes the healing of anal fissures. However, sphincterotomy can be associated with long term disturbances of sphincter function. The optimal treatment for an anal fissure is to induce a temporary reduction of anal canal resting pressure to allow healing of the fissure without permanently disrupting normal sphincter function. Broader understanding of the intrinsic mechanisms controlling smooth muscle contraction has allowed pharmacological manipulation of anal sphincter tone. We performed an initial Medline literature search to identify all articles concerning "internal anal sphincter" and "anal fissures". This review is based on these articles and on additional publications obtained by manual cross referencing. Internal anal smooth muscle relaxation can be inhibited by stimulation of non-adrenergic non-cholinergic enteric neurones, parasympathetic muscarinic receptors, or sympathetic beta adrenoceptors, and by inhibition of calcium entry into the cell. Sphincter contraction depends on an increase in cytoplasmic calcium and is enhanced by sympathetic adrenergic stimulation. Currently, the most commonly used pharmacological agent in the treatment of anal fissures is topical glyceryl trinitrate, a nitric oxide donor. Alternative agents that exhibit a similar effect via membrane Ca2+ channels, muscarinic receptors, and alpha or beta adrenoceptors are also likely to have a therapeutic potential in treating anal fissures.

  10. Collaboration: a solution to the challenge of conducting nursing research in cardiac rehabilitation.

    PubMed

    Gallagher, Robyn; Sadler, Leonie; Kirkness, Ann; Belshaw, Julie; Roach, Kellie; Warrington, Darrell

    2013-01-01

    Clinical nurse leaders such as clinical nurse consultants are required to conduct research and incorporate outcomes of this research into their every day practice. However, undertaking research presents issues for cardiac rehabilitation clinical nurse consultants because they may have competing demands, difficulty with finding replacements and may be relatively isolated from other researchers. The solution to this situation is the formation of a collaborative research team with other cardiac rehabilitation clinical nurse consultants, with the inclusion of an experienced university academic as a mentor for the cardiac rehabilitation clinical nurse consultants working in an Area Health Service encompassing both rural and metropolitan hospitals in New South Wales, Australia. The related research project aimed to evaluate and improve the clients' knowledge and practices related to the use of sublingual glyceryl trinitrate. The team's experiences and suggestions for clinical nurse Leaders are presented in this paper. Essential team characteristics include having shared motivation, good communication practices, flexibility and tolerance, an effective team size, achieving success, willingness to accept challenges and an experienced mentor. The benefits of developing a collaborative team for research led by clinical nurse consultants in cardiac rehabilitation by far outweigh the time and effort involved in the process.

  11. Adrenoceptor hyporeactivity is responsible for Escherichia coli endotoxin-induced acute vascular dysfunction in humans.

    PubMed

    Pleiner, Johannes; Heere-Ress, Elisabeth; Langenberger, Herbert; Sieder, Anna E; Bayerle-Eder, Michaela; Mittermayer, Fritz; Fuchsjäger-Mayrl, Gabriele; Böhm, Johannes; Jansen, Burkhard; Wolzt, Michael

    2002-01-01

    Impaired response to catecholamines contributes to the altered hemodynamics in sepsis, which has been attributed to excessive NO formation. We have studied the systemic hemodynamic and local forearm responses and inducible NO synthase (iNOS) expression during experimental endotoxemia in humans. Escherichia coli endotoxin (lipopolysaccharide [LPS]) was administered at doses of 1 or 2 ng/kg to healthy volunteers. In 10 subjects, the systemic pressor effect of phenylephrine was assessed before and after the administration of LPS. In 9 further subjects, forearm blood flow responses to intra-arterial noradrenaline, acetylcholine, glyceryl trinitrate, and N(G)-monomethyl-L-arginine (L-NMMA) were studied at baseline and after LPS administration. Peripheral blood was collected and analyzed for iNOS mRNA and protein. Four hours after LPS, the response of systolic blood pressure (P<0.0005) and heart rate (P<0.05) to phenylephrine was significantly reduced. In the forearm, noradrenaline-induced vasoconstriction was also reduced by approximately 50% (P<0.01), but L-NMMA responsiveness was unchanged. iNOS mRNA or protein was not increased. Marked vascular adrenoceptor hyporeactivity is detectable in the absence of increased NO activity or iNOS expression in endotoxemia, arguing against major involvement of vascular iNOS activity in the acute systemic vasodilation to LPS.

  12. Modifying the Interagency Emergency Health Kit to include treatment for non-communicable diseases in natural disasters and complex emergencies

    PubMed Central

    Tonelli, Marcello; Nadler, Brian; Darzi, Ara; Rasheed, Shahnawaz

    2016-01-01

    The Interagency Emergency Health Kit (IEHK) provides a standard package of medicines and simple medical devices for aid agencies to use in emergencies such as disasters and armed conflicts. Despite the increasing burden of non-communicable diseases (NCDs) in such settings, the IEHK includes few drugs and devices for management of NCDs. Using published data to model the population burden of acute and chronic presentations of NCDs in emergency-prone regions, we estimated the quantity of medications and devices that should be included in the IEHK. NCDs considered were cardiovascular diseases, diabetes, hypertension and chronic respiratory disease. In scenario 1 (the primary scenario), we assumed that resources in the IEHK would only include those needed to manage acute life-threatening conditions. In scenario 2, we included resources required to manage both acute and chronic presentations of NCDs. Drugs and devices that might be required included amlodipine, aspirin, atenolol, beclomethasone, dextrose 50%, enalapril, furosemide, glibenclamide, glyceryl trinitrate, heparin, hydralazine, hydrochlorothiazide, insulin, metformin, prednisone, salbutamol and simvastatin. For scenario 1, the number of units required ranged from 12 (phials of hydralazine) to ∼15 000 (tablets of enalapril). Space and weight requirements were modest and total cost for all drugs and devices was approximately US$2078. As expected, resources required for scenario 2 were much greater. Space and cost requirements increased proportionately: estimated total cost of scenario 2 was $22 208. The resources required to treat acute NCD presentations appear modest, and their inclusion in the IEHK seems feasible. PMID:28588970

  13. Calcitonin gene-related peptide antagonism and cluster headache: an emerging new treatment.

    PubMed

    Ashina, Håkan; Newman, Lawrence; Ashina, Sait

    2017-08-30

    Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov . The search term used was "cluster headache and calcitonin gene related peptide" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play an important role in cluster headache pathophysiology. More refined human studies are warranted with regard to assay validation and using larger sample sizes. The results from RCTs may reveal the therapeutic potential of CGRP monoclonal antibodies and antagonists for cluster headache treatment.

  14. Randomized controlled trial using bosentan to enhance the impact of exercise training in subjects with type 2 diabetes mellitus.

    PubMed

    Schreuder, Tim H A; Duncker, Dirk J; Hopman, Maria T E; Thijssen, Dick H J

    2014-11-01

    In type 2 diabetes patients, endothelin (ET) receptor blockade may enhance blood flow responses to exercise training. The combination of exercise training and ET receptor blockade may represent a more potent stimulus than training alone to improve vascular function, physical fitness and glucose homeostasis. We assessed the effect of an 8 week exercise training programme combined with either ET blockade or placebo on vasculature, fitness and glucose homeostasis in people with type 2 diabetes. In a double-blind randomized controlled trial, brachial endothelium-dependent and ‑independent dilatation (using flow-mediated dilatation and glyceryl trinitrate, respectively), glucose homeostasis (using Homeostasis Model Assessment for Insulin Resistance (HOMA-IR)) and physical fitness (maximal cycling test) were assessed in 18 men with type 2 diabetes (60 ± 6 years old). Subjects underwent an 8 week exercise training programme, with half of the subjects receiving ET receptor blockade (bosentan) and the other half a placebo, followed by reassessment of the tests above. Exercise training improved physical fitness to a similar extent in both groups, but we did not detect changes in vascular function in either group. This study suggests that there is no adaptation in brachial and femoral artery endothelial function after 8 weeks of training in type 2 diabetes patients. Endothelin receptor blockade combined with exercise training does not additionally alter conduit artery endothelial function or physical fitness in type 2 diabetes.

  15. Pharmacological interventions for the treatment of Achilles tendinopathy: a systematic review of randomized controlled trials.

    PubMed

    Maffulli, Nicola; Papalia, Rocco; D'Adamio, Stefano; Diaz Balzani, Lorenzo; Denaro, Vincenzo

    2015-03-01

    Several pharmacological interventions have been proposed for the management of Achilles tendinopathy, with no agreement on which is the overall best option available. This systematic review investigates the efficacy and safety of different local pharmacological treatments for Achilles tendinopathy. We included only randomized controlled studies (RCTs) focusing on clinical and functional outcomes of therapies consisting in injection of a substance or local application. Assessment of the methodological quality was performed using a modified version of the Coleman methodology score (CMS) to determine possible risks of bias. Thirteen RCTs were included with a total of 528 studied patients. Eleven studies reported the outcomes of injection therapies. Two studies examined the outcomes of patients who applied glyceryl trinitrate patch. The mean modified CMS was 70.6 out of 90. There was no significant evidence of remarkable benefits provided by any of the therapies studied. There is not univocal evidence to advise any particular pharmacological treatment as the best advisable non-operative option for Achilles tendinopathy as equivalent alternative to the most commonly used eccentric loading rehabilitation program. However, potential was shown by the combination of different substances administered with physical therapy. There is a need for more long-term investigations, studying large enough cohort with standardized scores and evaluations shared by all the investigations to confirm the healing potential, and provide a stronger statistical comparison of the available treatments. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Patellar Tendinopathy.

    PubMed

    Schwartz, Aaron; Watson, Jonathan N; Hutchinson, Mark R

    2015-01-01

    Patellar tendinopathy is a common condition. There are a wide variety of treatment options available, the majority of which are nonoperative. No consensus exists on the optimal method of treatment. PubMed spanning 1962-2014. Clinical review. Level 4. The majority of cases resolve with nonoperative therapy: rest, physical therapy with eccentric exercises, cryotherapy, anti-inflammatories, corticosteroid injections, extracorporeal shockwave therapy, glyceryl trinitrate, platelet-rich plasma injections, and ultrasound-guided sclerosis. Refractory cases may require either open or arthroscopic debridement of the patellar tendon. Corticosteroid injections provide short-term pain relief but increase risk of tendon rupture. Anti-inflammatories and injectable agents have shown mixed results. Surgical treatment is effective in many refractory cases unresponsive to nonoperative modalities. Physical therapy with an eccentric exercise program is the mainstay of treatment for patellar tendinopathy. Platelet-rich plasma has demonstrated mixed results; evidence-based recommendations on its efficacy cannot be made. In the event that nonoperative treatment fails, surgical intervention has produced good to excellent outcomes in the majority of patients. © 2015 The Author(s).

  17. Sensitivity analysis of near-infrared functional lymphatic imaging

    PubMed Central

    Weiler, Michael; Kassis, Timothy

    2012-01-01

    Abstract. Near-infrared imaging of lymphatic drainage of injected indocyanine green (ICG) has emerged as a new technology for clinical imaging of lymphatic architecture and quantification of vessel function, yet the imaging capabilities of this approach have yet to be quantitatively characterized. We seek to quantify its capabilities as a diagnostic tool for lymphatic disease. Imaging is performed in a tissue phantom for sensitivity analysis and in hairless rats for in vivo testing. To demonstrate the efficacy of this imaging approach to quantifying immediate functional changes in lymphatics, we investigate the effects of a topically applied nitric oxide (NO) donor glyceryl trinitrate ointment. Premixing ICG with albumin induces greater fluorescence intensity, with the ideal concentration being 150  μg/mL ICG and 60  g/L albumin. ICG fluorescence can be detected at a concentration of 150  μg/mL as deep as 6 mm with our system, but spatial resolution deteriorates below 3 mm, skewing measurements of vessel geometry. NO treatment slows lymphatic transport, which is reflected in increased transport time, reduced packet frequency, reduced packet velocity, and reduced effective contraction length. NIR imaging may be an alternative to invasive procedures measuring lymphatic function in vivo in real time. PMID:22734775

  18. Exercise-induced improvement in endothelial dysfunction is not mediated by changes in CV risk factors: pooled analysis of diverse patient populations.

    PubMed

    Green, Daniel J; Walsh, Jennifer H; Maiorana, Andrew; Best, Matthew J; Taylor, Roger R; O'Driscoll, J Gerard

    2003-12-01

    We have pooled data from a series of our exercise training studies undertaken in groups with a broad range of vascular (dys) function to the examine the hypothesis that exercise-induced improvements in the conduit and/or resistance vessel function are related to improvements in risk factors for cardiovascular (CV) disease. Endothelium-dependent and -independent conduit vessel function were assessed by using wall tracking of high-resolution ultrasound images of the brachial artery response to flow-mediated dilation (FMD) and glyceryl trinitrate. Resistance vessel function was assessed using intrabrachial administration of acetylcholine (ACh), sodium nitroprusside, and NG-monomethyl-l-arginine. Randomized cross-over studies of 8-wk exercise training were undertaken in untreated hypercholesterolemic (n = 11), treated hypercholesterolemic (n = 11), coronary artery disease (n = 10), chronic heart failure (n = 12), Type 2 diabetic (n = 15), and healthy control subjects (n = 16). Exercise training did not significantly alter plasma lipids, blood pressure, blood glucose, waist-to-hip ratio, or body mass index values, despite significant improvement in both FMD and ACh responses. There were no correlations between changes in any risk factor variables and indexes of either resistance or conduit vessel function. We conclude that, in these subjects with antecedent vascular dysfunction, the beneficial effects of relatively short-term exercise training on vascular function are not solely mediated by the effects of exercise on CV risk factors.

  19. Patellar Tendinopathy

    PubMed Central

    Schwartz, Aaron; Watson, Jonathan N.; Hutchinson, Mark R.

    2015-01-01

    Context: Patellar tendinopathy is a common condition. There are a wide variety of treatment options available, the majority of which are nonoperative. No consensus exists on the optimal method of treatment. Evidence Acquisition: PubMed spanning 1962-2014. Study Design: Clinical review. Level of Evidence: Level 4. Results: The majority of cases resolve with nonoperative therapy: rest, physical therapy with eccentric exercises, cryotherapy, anti-inflammatories, corticosteroid injections, extracorporeal shockwave therapy, glyceryl trinitrate, platelet-rich plasma injections, and ultrasound-guided sclerosis. Refractory cases may require either open or arthroscopic debridement of the patellar tendon. Corticosteroid injections provide short-term pain relief but increase risk of tendon rupture. Anti-inflammatories and injectable agents have shown mixed results. Surgical treatment is effective in many refractory cases unresponsive to nonoperative modalities. Conclusion: Physical therapy with an eccentric exercise program is the mainstay of treatment for patellar tendinopathy. Platelet-rich plasma has demonstrated mixed results; evidence-based recommendations on its efficacy cannot be made. In the event that nonoperative treatment fails, surgical intervention has produced good to excellent outcomes in the majority of patients. PMID:26502416

  20. The chick chorioallantoic membrane imaging method as a platform to evaluate vasoactivity and assess irritancy of compounds.

    PubMed

    Tay, Stephanie L M; Heng, Paul W S; Chan, Lai Wah

    2012-08-01

    To determine if the chick chorioallantoic membrane (CAM) is a potential alternative that is capable of screening test substances for vasoactivity in terms of vessel diameter changes. The CAM was also evaluated as a tool for irritancy screening. Visual assessment of the CAM for irritancy after the application of the test substance or solvent to its surface was made. An imaging based-in-vivo CAM model was developed by imaging CAM blood vessels in a pre-defined area using a semi-automatic image processing and analysis technique to measure blood vessel diameters. Solvents and drugs such as 70% v/v ethanol, normal saline, 5% w/v glucose monohydrate, glycerin, glucagon, N-methylpyrrolidone, nicotine, glyceryl trinitrate, glucagon, propranolol and caffeine were tested on the CAM. Propranolol, nicotine and glycerin were irritants on CAM. Changes in the diameters of fine blood vessels were accurately measured by high resolution image analysis. Vasoconstriction was seen with 70% v/v ethanol while vasodilation was displayed with glucagon and caffeine. The results reflected expected trends with evidence of feedback mechanisms ensuring homeostasis. The CAM model can be applied to assess pharmaceutical and cosmetic formulations in early development work to gain useful insights to potential irritancy and biological effects of components and formulations. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

  1. Temperature data acquired from the DOI/GTN-P Deep Borehole Array on the Arctic Slope of Alaska, 1973-2013

    USGS Publications Warehouse

    Clow, Gary D.

    2014-01-01

    System (GTOS). The data will also be useful for refining our basic understanding of the physical conditions in permafrost in Arctic Alaska, as well as providing important information for validating predictive models used for climate impact assessments. The processed data are available from the Advanced Cooperative Arctic Data and Information Service (ACADIS) repository at doi:10.5065/D6N014HK.

  2. Test for Chemical Induction of Chromosome Aberrations in Cultured Chinese Hamster (CHO) Cells With and Without Metabolic Activation. Test Article. Diethylene triamine trinitrate (DETN)

    DTIC Science & Technology

    2010-02-25

    metabolic activation mixture was prepared by SITEK Research Laboratories and it consisted of phenobarbital -S,6-Benzoflavone (phenobarbitallB-naphthoflavone... Phenobarbital -S,6-Benzoflavone <-70°C May 21, 2011 Detailed infonnation about the S-9 batch used in the Assay is provided in Appendix N. 13 SITEK Study No

  3. Crystal structure of tri-hydrogen bis-{[1,1,1-tris-(2-oxido-ethyl-amino-meth-yl)ethane]-cobalt(III)} trinitrate.

    PubMed

    Sethi, Waqas; Johannesen, Heini V; Morsing, Thorbjørn J; Piligkos, Stergios; Weihe, Høgni

    2015-12-01

    The title compound, [Co2(L)2](3+)·3NO3 (-) [where L = CH3C(CH2NHCH2CH2OH1/2)3], has been synthesized from the ligand 1,1,1-tris-(2-hy-droxy-ethyl-amino-meth-yl)ethane. The cobalt(III) dimer has an inter-esting and uncommon O-H⋯O hydrogen-bonding motif with the three bridging hy-droxy H atoms each being equally disordered over two positions. In the dimeric trication, the octa-hedrally coordinated Co(III) atoms and the capping C atoms lie on a threefold rotation axis. The N atoms of two crystallographically independent nitrate anions also lie on threefold rotation axes. N-H⋯O hydrogen bonding between the complex cations and nitrate anions leads to the formation of a three-dimensional network structure. The compound is a racemic conglomerate of crystals containing either d or l mol-ecules. The crystal used for this study is a d crystal.

  4. In Vivo Test for Chemical Induction of Micronucleated Polychromatic Erythrocytes for Mouse bone Marrow Cells, Test Article, Diethylene Triamine Trinitrate (DETN)

    DTIC Science & Technology

    2010-02-25

    marrow cytogenetics tests : Micronucleus Assay. Revised July 1, 2002, (1). OECD Guideline for Testing of Chemicals, No. 474. Mammalian Erythrocyte... Micronucleus Test . Adopted July 21, 1997, (2). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals...in the Range Finding Test . Five male and five female mice per dose group per harvest time were used in the Micronucleus Assay. The Range Finding Test

  5. The Structure of Glycerol Trinitrate Reductase NerA from Agrobacterium radiobacter Reveals the Molecular Reason for Nitro- and Ene-Reductase Activity in OYE Homologues

    PubMed Central

    Oberdorfer, Gustav; Binter, Alexandra; Wallner, Silvia; Durchschein, Katharina; Hall, Mélanie; Faber, Kurt; Macheroux, Peter; Gruber, Karl

    2013-01-01

    In recent years, Old Yellow Enzymes (OYEs) and their homologues have found broad application in the efficient asymmetric hydrogenation of activated C=C bonds with high selectivities and yields. Members of this class of enzymes have been found in many different organisms and are rather diverse on the sequence level, with pairwise identities as low as 20 %, but they exhibit significant structural similarities with the adoption of a conserved (αβ)8-barrel fold. Some OYEs have been shown not only to reduce C=C double bonds, but also to be capable of reducing nitro groups in both saturated and unsaturated substrates. In order to understand this dual activity we determined and analyzed X-ray crystal structures of NerA from Agrobacterium radiobacter, both in its apo form and in complex with 4-hydroxybenzaldehyde and with 1-nitro-2-phenylpropene. These structures, together with spectroscopic studies of substrate binding to several OYEs, indicate that nitro-containing substrates can bind to OYEs in different binding modes, one of which leads to C=C double bond reduction and the other to nitro group reduction. PMID:23606302

  6. Choline alphoscerate (alpha-glyceryl-phosphoryl-choline) an old choline- containing phospholipid with a still interesting profile as cognition enhancing agent.

    PubMed

    Traini, Enea; Bramanti, Vincenzo; Amenta, Francesco

    2013-12-01

    Cholinergic precursors have represented the first approach to counter cognitive impairment occurring in adultonset dementia disorders. These compounds were early leaved because their clinical efficacy was not clearly demonstrated. This is probably not true for some choline-containing phospholipids including choline alphoscerate. Choline alphoscerate increases the release of acetylcholine in rat hippocampus, facilitates learning and memory in experimental animals, improves brain transduction mechanisms and decreases age-dependent structural changes occurring in rat brain areas involved in learning and memory. The compound exerts neuroprotective effects in models of altered cholinergic neurotransmission and of brain vascular injury. In clinical studies choline alphoscerate improved memory and attention impairment, as well as affective and somatic symptoms in dementia disorders. An ongoing trial indicates that association between the acetylcholinesterase inhibitor donepezil and choline alphoscerate is accompanied by an improvement in several cognitive tests superior to that induced by donepezil alone. It is suggested that this association may represent a therapeutic option to prolong beneficial effects of cholinergic therapies in Alzheimer's disease patients with concomitant ischemic cerebrovascular disorders. In summary, choline alphoscerate has significant effects on cognitive function with a good safety profile and tolerability. Although limited both in terms of size of the samples investigated and of the length of treatment, preclinical and clinical results presented suggest that cognitive enhancing capabilities of choline alphoscerate merit of being further investigated in appropriate trials.

  7. Self-management of coronary heart disease in older patients after elective percutaneous transluminal coronary angioplasty

    PubMed Central

    Dawkes, Susan; Smith, Graeme D; Elliott, Lawrie; Raeside, Robert; Donaldson, Jayne H

    2016-01-01

    Objective To explore how older patients self-manage their coronary heart disease (CHD) after undergoing elective percutaneous transluminal coronary angioplasty (PTCA). Methods This mixed methods study used a sequential, explanatory design and recruited a convenience sample of patients (n = 93) approximately three months after elective PTCA. The study was conducted in two phases. Quantitative data collected in Phase 1 by means of a self-administered survey were subject to univariate and bivariate analysis. Phase 1 findings informed the purposive sampling for Phase 2 where ten participants were selected from the original sample for an in-depth interview. Qualitative data were analysed using thematic analysis. This paper will primarily report the findings from a sub-group of older participants (n = 47) classified as 65 years of age or older. Results 78.7% (n = 37) of participants indicated that they would manage recurring angina symptoms by taking glyceryl trinitrate and 34% (n = 16) thought that resting would help. Regardless of the duration or severity of the symptoms 40.5% (n = 19) would call their general practitioner or an emergency ambulance for assistance during any recurrence of angina symptoms. Older participants weighed less (P = 0.02) and smoked less (P = 0.01) than their younger counterparts in the study. Age did not seem to affect PTCA patients' likelihood of altering dietary factors such as fruit, vegetable and saturated fat consumption (P = 0.237). Conclusions The findings suggest that older people in the study were less likely to know how to correctly manage any recurring angina symptoms than their younger counterparts but they had fewer risk factors for CHD. Age was not a factor that influenced participants' likelihood to alter lifestyle factors. PMID:27594866

  8. Effectiveness of interventions of specific complaints of the arm, neck, or shoulder (CANS): musculoskeletal disorders of the hand.

    PubMed

    van Middelkoop, Marienke; Huisstede, Bionka M A; Glerum, Suzanne; Koes, Bart W

    2009-01-01

    The aim of this study was to provide an evidence-based overview of the effectiveness of (conservative and surgical) interventions for the 4 specific pain disorders of the hand: trigger finger, primary Raynaud's phenomenon, Dupuytren disease, and De Quervain's disease. This information can help clinicians in the selection of interventions in daily practice, and may give direction to future research. Relevant review publications and randomized clinical trials (RCTs) in PubMed were searched. Data extraction and quality assessment were performed. To summarize the results of the included reviews and RCTs, a best-evidence synthesis was used. For primary Raynaud's phenomenon (1 review, 20 RCTs), we found strong evidence for calcium channel blockers and moderate evidence for laser therapy. Limited evidence was found for Ketanserin, Prozasin, Buflomedil, transdermal glyceryl trinitrate patches, Ginkgo biloba, and behavioral treatment with temperature feedback. Other interventions did not show clear favorable treatment effects. For Trigger finger one very small RCT was found that showed limited evidence for steroid injection. For Dupuytren disease (4 RCTs) limited evidence was found in favor of use of staples versus sutures in the Dupuytren's surgery, and for intermittent compression on the postoperative hand after surgery. For other interventions no clear positive effects could be demonstrated. For De Quervain's disease (2 RCTs), we found no efficacy of Nimesulide as addition to a Triamcinolone injection, and no clear differences between a corticosteroid injection and a splint in pregnant patients or patients breast-feeding. Well-designed and well-conducted RCTs are clearly needed in this field.

  9. Improved analysis of brachial artery ultrasound using a novel edge-detection software system.

    PubMed

    Woodman, R J; Playford, D A; Watts, G F; Cheetham, C; Reed, C; Taylor, R R; Puddey, I B; Beilin, L J; Burke, V; Mori, T A; Green, D

    2001-08-01

    Brachial artery ultrasound is commonly employed for noninvasive assessment of endothelial function. However, analysis is observer dependent and susceptible to errors. We describe studies on a computerized edge-detection and wall-tracking software program to allow more accurate and reproducible measurement. In study 1, three purpose-built Perspex phantom arteries, 3.00, 4.00, and 6.00 mm in diameter, were measured with the software. There was a mean bias of 11 microm (P < 0.001 at each level) between known and measured values; the mean resolving power of the software was estimated as 8.3 microm. In study 2, the mean intraobserver coefficient of variation of repeated measures of flow-mediated dilation (FMD) using the software (6.7%) was significantly lower than that for traditional manual measurements using the intima-lumen interfaces (24.8%, P < 0.05) and intima-media interfaces (32.5%, P < 0.05). In study 3, 24 healthy volunteers underwent repeat testing twice within 1 wk; the coefficients of variation for between-visit reproducibility of FMD and response to glyceryl trinitrate using the software were 14.7 and 17.6%, respectively. Assuming 80% power and an alpha of 0.05, eight subjects with matched controls would be required, in a parallel designed study, to detect an absolute 2.5% change in FMD. In summary, we have developed a semiautomated computerized vascular ultrasound analysis system that will improve the power of clinical intervention studies to detect small changes in arterial diameter.

  10. Direct and reflex effects of nitroglycerin on coronary and left ventricular dynamics in conscious dogs

    PubMed Central

    Vatner, Stephen F.; Higgins, Charles B.; Millard, Ronald W.; Franklin, Dean

    1972-01-01

    The effects of intravenous and sublingual glyceryl trinitrate (nitroglycerin), 40 μg/kg, were studied on coronary blood flow and resistance, left ventricular (LV) pressures (P) and diameters (D), rate of change of pressure (dP/dt), (dP/dt)/P, and on the velocity (V) of myocardial fiber shortening in conscious dogs. Nitroglycerin i.v. caused substantial coronary vasodilatation prior to any changes in systemic hemodynamics. Mean coronary flow increased by a maximum of 47 ml/min and coronary sinus Po2 rose from 16 to 26 mm Hg while pressure and diameter began to fall, and heart rate began to rise. After the maximal fall in mean arterial pressure (—26 mm Hg), a secondary peak in coronary flow occurred which was associated with increases in heart rate (100 beats/min), (dP/dt)/P (22%), and isolength V (12%). Beta blockade prevented the reflex increases in contractility but only a part of the reflex tachycardia; the remainder was prevented by cholinergic blockade. Maintaining heart rate constant minimized the decreases in LV D and increases in contractility. When the reflex inotropic and chronotropic effects were prevented by a combination of atrial pacing and beta blockade the early coronary vasodilatation was unaltered, but the later coronary vasodilatation was minimized. Thus i.v. nitroglycerin in the conscious dog exerts a potent direct coronary vasodilating action and also a secondary coronary vasodilation caused by reflex increases in contractility and heart rate. The decreases in diameter are largely the result of tachycardia. Sublingual nitroglycerin produced directionally similar, but quantitatively lesser effects on coronary flow and resistance, LV D, LV P, and contractility. Images PMID:4404139

  11. Topical analgesics in the management of acute and chronic pain.

    PubMed

    Argoff, Charles E

    2013-02-01

    Oral analgesics are commonly prescribed for the treatment of acute and chronic pain, but these agents often produce adverse systemic effects, which sometimes are severe. Topical analgesics offer the potential to provide the same analgesic relief provided by oral analgesics but with minimal adverse systemic effects. This article describes the results of a systematic review of the efficacy of topical analgesics in the management of acute and chronic pain conditions. A literature search of MEDLINE/PubMed was conducted using the keywords topical analgesic AND chronic pain OR acute pain OR neuropathic pain and focused only on individual clinical trials published in English-language journals. The search identified 92 articles, of which 65 were eligible for inclusion in the review. The most commonly studied topical analgesics were nonsteroidal anti-inflammatory drugs (n=27), followed by lidocaine (n=9), capsaicin (n=6), amitriptyline (n=5), glyceryl trinitrate (n=3), opioids (n=2), menthol (n=2), pimecrolimus (n=2), and phenytoin (n=2). The most common indications were acute soft tissue injuries (n=18), followed by neuropathic pain (n=17), experimental pain (n=6), osteoarthritis and other chronic joint-related conditions (n=5), skin or leg ulcers (n=5), and chronic knee pain (n=2). Strong evidence was identified for the use of topical diclofenac and topical ibuprofen in the treatment of acute soft tissue injuries or chronic joint-related conditions, such as osteoarthritis. Evidence also supports the use of topical lidocaine in the treatment of postherpetic neuralgia and diabetic neuropathy. Currently, limited evidence is available to support the use of other topical analgesics in acute and chronic pain.

  12. Erosive Hand Osteoarthritis is Associated with Subclinical Atherosclerosis and Endothelial Dysfunction

    PubMed Central

    Koutroumpas, Athanasios; Giannoukas, Athanasios; Zintzaras, Elias; Exarchou, Ekaterini; Baliakos, Aris; Makaritsis, Konstantinos; Sakkas, Lazaros I.

    2013-01-01

    Chronic inflammatory disorders have been associated with accelerated atherosclerosis and increased cardiovascular (CV) risk. Recent evidence suggests that erosive hand osteoarthritis (EOA) has considerable inflammation; therefore, we examined the presence of subclinical atherosclerosis and endothelial dysfunction in EOA. Twenty-four patients with EOA and 24 age- and sex-matched healthy individuals without clinical OA were included in the study. No subject had a history of CV disease. Intima-media thickness (IMT) and atheromatous plaques in the common carotid and common femoral arteries were measured by Doppler ultrasonography. The endothelium-dependent, flow-mediated dilatation (FMD) and endothelium-independent, sublingual glyceryl trinitrate (NTG)-induced dilatation (NMD) of the brachial artery were assessed. The EOA patients had significantly elevated systolic and diastolic blood pressure (p<0.001 for both). The 10-year risk of general CV disease, as predicted with the Framingham Risk Score, was similar in patients and controls (p=0.18). IMT of both common carotid and common femoral artery were increased in EOA (p=0.01 and p<0.01, respectively), but the frequency of atherosclerotic plaques was not increased. There was no difference in FMD and NMD between the two groups, but the difference between FMD and NMD was increased in EOA. In conclusion, this small controlled study showed an association between EOA and subclinical atherosclerosis that cannot be fully attributed to traditional CV risk factors, as assessed by the Framingham score. These results suggest that chronic, low-grade inflammation is implicated in atherosclerosis in EOA. PMID:24711757

  13. Increased vascular eNOS and cystathionine-γ-lyase protein after 6 weeks oral administration of 3, 5, 7, 3', 4'-pentamethoxyflavone to middle-aged male rats.

    PubMed

    Yorsin, Somruedee; Kanokwiroon, Kanyanatt; Radenahmad, Nisaudah; Jansakul, Chaweewan

    2016-11-01

    Effects of treatment of middle-aged male rats with 3, 5, 7, 3', 4'-pentamethoxyflavone (PMF) on vascular and perivascular adipose tissue (PVAT) functions and blood chemistry were investigated. Rats received PMF (22 mg/kg), orally or vehicle, twice a day for 6 weeks. The PMF-treated rats had lower serum glucose, higher HDL-C levels, but no change in other parameters. Thoracic aortic and mesenteric rings of PMF treated rats produced lower maximal contraction to phenylephrine that was normalized by N(G)-nitro-L-arginine (L-NA) or endothelial removal. The aortic- and mesenteric rings of the PMF treated rats showed improved relaxation to acetylcholine, but not to glyceryl trinitrate, and had higher eNOS protein. DL-propargylglycine (PAG) caused greater increase in the baseline tension of the PMF-treated aortic ring and higher contraction to low concentrations of phenylephrine. PVAT lowered the contractile response of the L-NA pretreated aortic rings to phenylephrine for both groups, but PAG had no effect. The cystathionine-γ-lyase (CSE) protein of the thoracic rings, but not of the PVAT, shows increased expression after PMF treatment. Overall, PMF treatment of middle aged rats appeared to increase production of NO and H2S from the blood vessels by upregulating the expression of eNOS and CSE. PMF also decreased fasting serum glucose and increased HDL-C levels, with no toxicity to liver and kidney functions. Thus, PMF is a novel compound for possible use as a health product to prevent and/or to reduce the development of diabetes type II and/or cardiovascular disease.

  14. Relaxant mechanisms of 3, 5, 7, 3', 4'-pentamethoxyflavone on isolated human cavernosum.

    PubMed

    Jansakul, Chaweewan; Tachanaparuksa, Kuldej; Mulvany, Michael J; Sukpondma, Youwapa

    2012-09-15

    We have investigated effects and mechanisms responsible for the activity of 3, 5, 7, 3', 4'-pentamethoxyflavone (PMF) on isolated human cavernosum. PMF is the major flavone isolated from Kaempferia parviflora claimed to act as an aphrodisiac. PMF caused relaxation of phenylephrine precontracted human cavernosal strips, and this effect was slightly inhibited by N(G)-nitro-l-arginine, a nitric oxide synthase inhibitor, but not by ODQ (soluble guanylate cyclase inhibitor), TEA (tetraethylammonium, blocker of voltage-dependent K(+) channels) or glybenclamide (blocker of ATP-dependent K(+) channels). PMF did not significantly inhibit the relaxant activity of glyceryltrinitrate or acetylcholine on human cavernosal strips precontracted with phenylephrine. In contrast, sildenafil (phosphodiesterase inhibitor) potentiated the relaxant activity of glyceryl trinitrate but not of acetylcholine. In normal Krebs solution with nifedipine (blocker of l-type Ca(2+) channels), or in Ca(2+)-free Krebs solution, PMF caused a further inhibition of human cavernosum contracted with phenylephrine. In human cavernosum treated with thapsigargin (inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase) in Ca(2+)-free medium, PMF suppressed the concentration-response curve of human cavernosum to phenylephrine and a further suppression was found when SKF-96365 (a blocker of store-operated Ca(2+) channels and Y-27632 (inhibitor of Rho-kinase)), but not nifedipine, were added sequentially. Thus, PMF had only a weak effect on the release of nitric oxide, and had no effect as a K(ATP)- or K(Ca) channel opener, a phosphodiesterase inhibitor, a store-operated Ca(2+) channel blocker or a Rho-kinase inhibitor. Therefore, these studies suggest that PMF causes relaxation of human cavernosum through voltage-dependent Ca(2+) channels and other mechanisms associated with calcium mobilization. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. A picosecond laser FAIMS analyzer for detecting ultralow quantities of explosives

    NASA Astrophysics Data System (ADS)

    Chistyakov, Alexander A.; Kotkovskii, Gennadii E.; Sychev, Alexey V.; Odulo, Ivan P.; Bogdanov, Artem S.; Perederiy, Anatoly N.; Spitsyn, Evgeny M.; Shestakov, Alexander V.

    2014-10-01

    A method for detecting ultralow quantities of explosives in air and explosive traces using a state-of-the-art picosecond chip Nd3+:YAG laser has been elaborated. The method combines field asymmetric ion mobility spectrometry (FAIMS) with laser ionization of air samples and laser desorption of analyzed molecules from examined surfaces. Radiation of the fourth harmonic (λ = 266 nm, τpulse = 300 ps, Epulse = 20-150 μJ, ν = 20-300 Hz) was used. The ionization efficiencies for trinitrotoluene (TNT), cyclotrimethylenetrinitramine (RDX), and glyceryl trinitrate (NG) were investigated. The dependences on frequency, pulse energy, peak intensity, and average power for TNT and RDX were determined. It was shown that the optimal peak intensity should be no less than 2•106 W/cm2; at lower peak intensities, the increase of the average laser power in the interval 5-15 mW enhanced the ion signal. The results of detection of TNT, RDX, and NG vapors under these conditions were compared with the results obtained using nanosecond laser excitation. The detected ion signals for all explosives were shown to be two- to threefold higher in the case of picosecond excitation. The FAIMS laser desorption regime was developed where a laser beam exiting the detector after removal of a special plug was used. The results of TNT and RDX detection are presented. The chip Nd3+:YAG laser has a small emitter and a consumed electric power of 25 W. The estimated detection threshold of the prototype picosecond laser FAIMS analyzer of explosives is (1-3)•10-15g/cm3 for TNT vapors.

  16. Near-Infrared Spectroscopy in Adult Cardiac Surgery Patients: A Systematic Review and Meta-Analysis.

    PubMed

    Chan, Matthew J; Chung, Tricia; Glassford, Neil J; Bellomo, Rinaldo

    2017-08-01

    To identify the normal baseline preoperative range of cerebral tissue oxygen saturation (SctO2) derived using near-infrared spectroscopy (NIRS) and the efficacy of perioperative interventions designed to modulate SctO2 in cardiac surgical patients. Systematic review and meta-analysis of relevant randomized controlled trials (RCTs) extracted from the Medline, Embase, and Cochrane Central Register of Controlled Trials databases. Hospitals performing cardiac surgery. The study comprised 953 participants from 11 RCTs. Interventions included the following: (1) SctO2 monitoring protocol compared with no monitoring; (2) use of cardiopulmonary bypass (CPB) compared with no CPB; (3) normothermic CPB compared with hypothermic CPB; (4) glyceryl trinitrate during surgery compared with placebo; (5) midazolam during induction of anesthesia compared with propofol; (6) sevoflurane anesthesia compared with total intravenous anesthesia; (7) sevoflurane anesthesia compared with propofol-based anesthesia; and (8) norepinephrine during CPB compared with phenylephrine. Eleven RCTs with 953 participants measured baseline preoperative SctO2 using NIRS. The pooled mean baseline SctO2 was 66.4% (95% CI 65.0-67.7), generating a reference range of 51.0% to 81.8%. Four interventions (1, 3, 4, and 6 described in the Interventions section above) increased intraoperative SctO2 across the majority of reported time points. Postoperative follow-up of SctO2 occurred in only 1 study, and postoperative cognitive assessment correlating SctO2 with cognitive function was applied in only 4 studies using variable methodology. The authors have established that reference values for baseline NIRS-derived SctO2 in cardiac surgery patients are varied and have identified interventions that modulate SctO2. This information opens the door to standardized research and interventional studies in this field. Copyright © 2017. Published by Elsevier Inc.

  17. Raynaud's phenomenon (secondary)

    PubMed Central

    2008-01-01

    Introduction Raynaud’s phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes. It presents as episodic colour changes of the digits, usually in response to cold exposure or stress. The classic triphasic colour change is white (ischaemia), then blue (deoxygenation), then red (reperfusion). Raynaud’s phenomenon can be primary (idiopathic) or secondary to several different conditions and causes. This review deals with secondary Raynaud’s phenomenon. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of self-help measures for secondary Raynaud’s phenomenon? What are the effects of drug treatments for secondary Raynaud’s phenomenon? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alpha-blockers; angiotensin-converting enzyme (ACE) inhibitors; angiotensin II receptor antagonists; antithrombotics/inhibitors of platelet aggregation; biofeedback; calcium channel blockers; endothelin-1 receptor antagonists; glyceryl trinitrate (transdermal); hand exercises; inositol nicotinate; moxisylyte; naftidrofuryl oxylate; phosphodiesterase inhibitors; prostaglandins (oral, intravenous); relaxation therapy

  18. Does metformin improve vascular heath in children with type 1 diabetes? Protocol for a one year, double blind, randomised, placebo controlled trial

    PubMed Central

    2013-01-01

    Background Cardiovascular disease is the leading cause of mortality in Type 1 diabetes (T1D). Vascular dysfunction is an early and critical event in the development of cardiovascular disease. Children with T1D have vascular dysfunction therefore early interventions to improve vascular health are essential to reduce cardiovascular mortality in T1D. Metformin is an insulin sensitising agent which is known to improve vascular health outcomes in type 2 diabetes (T2D) and other individuals with insulin resistance. It has been used safely in children and adolescents with T2D for over 10 years. This study aims to assess the effect of metformin on vascular health in children with T1D. Methods/Design This study is a 12 month, double blind, randomised, placebo controlled trial to determine the effect of metformin on vascular health in children (age 8–18) with T1D. The sample size is 76 with 38 children in the metformin group and 38 children in the placebo group. Vascular health and biochemical markers will be measured at baseline, 3, 6 and 12 months. Vascular function will be measured using flow mediated dilatation and glyceryl trinitrate mediated dilatation of the brachial artery and vascular structure will be measured with carotid and aortic intima media thickness, using standardised protocols. Discussion This study will be the first to investigate the effect of metformin on vascular health in children with T1D. It will provide important information on a potential intervention to improve cardiovascular morbidity and mortality in this population at high risk from cardiovascular disease. Trial registration Australia New Zealand Clinical Trials Registry ACTRN12611000148976 PMID:23865839

  19. Intrathecal Clonidine Pump Failure Causing Acute Withdrawal Syndrome With 'Stress-Induced' Cardiomyopathy.

    PubMed

    Lee, Hwee Min D; Ruggoo, Varuna; Graudins, Andis

    2016-03-01

    Clonidine is a central alpha(2)-agonist antihypertensive used widely for opioid/alcohol withdrawal, attention deficit hyperactivity disorder and chronic pain management. We describe a case of clonidine withdrawal causing life-threatening hypertensive crisis and stress-induced cardiomyopathy. A 47-year-old man with chronic back pain, treated with clonidine for many years via intrathecal pump (550 mcg/24 h), presented following a collapse and complaining of sudden worsening of back pain, severe headache, diaphoresis, nausea and vomiting. A few hours prior to presentation, his subcutaneous pump malfunctioned. On presentation, vital signs included pulse 100 bpm, BP 176/103 mmHg, temperature 37.8 °C and O2 saturation 100 % (room air). Acute clonidine withdrawal with hypertensive crisis was suspected. Intravenous clonidine loading dose and a 50 mcg/h infusion were commenced. Five hours later, severe chest pain, dyspnoea, tachycardia, hypoxia, with BP 180/120 mmHg and pulmonary edema ensued. ECG showed sinus tachycardia with no ST elevation. Repeated intravenous clonidine doses were given (25 mcg every 5-10 min), with ongoing clonidine infusion to control blood pressure. Glyceryl trinitrate infusion, positive pressure ventilation and intravenous benzodiazepines were added. Bedside echocardiogram showed stress-induced cardiomyopathy pattern. Serum troponin-I was markedly elevated. His coronary angiography showed minor irregularities in the major vessels. Over the next 3 days in the ICU, drug infusions were weaned. Discharge was 12 days later on oral clonidine, metoprolol, perindopril, aspirin and oxycodone-SR. Two months later, his echocardiogram was normal. The intrathecal pump was removed. We report a case of stress-induced cardiomyopathy resulting from the sudden cessation of long-term intrathecal clonidine. This was managed by re-institution of clonidine and targeted organ-specific therapies.

  20. A NOS3 polymorphism determines endothelial response to folate in children with type 1 diabetes or obesity.

    PubMed

    Wiltshire, Esko J; Peña, Alexia S; MacKenzie, Karen; Bose-Sundernathan, Tulika; Gent, Roger; Couper, Jennifer J

    2015-02-01

    To determine the effect of polymorphisms in NOS3 and folate pathway enzymes on vascular function and folate status and endothelial response to folate in children with diabetes or obesity. A total of 244 subjects (age 13.8 ± 2.8 years, 125 males) were studied for NOS3 and/or folate pathway polymorphisms using polymerase chain reaction/restriction fragment length polymorphism, including at baseline: 139 with type 1 diabetes; 58 with obesity; and 47 controls. The effect of NOS3 genotype on endothelial response to folate (5 mg) was assessed in 85 subjects with diabetes and 28 obese subjects who received active treatment during intervention trials. Vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate-mediated dilatation), clinical, and biochemical measurements were assessed at baseline and 8 weeks in folate intervention studies. Folate pathway enzyme and NOS3 polymorphisms did not significantly affect baseline vascular function. The polymorphism in intron 4 of endothelial nitric oxide synthase altered endothelial response to folate significantly: in subjects with diabetes FMD improved by 6.4 ± 5% (insertion carriers) vs 2.3 ± 6.6% (deletion carriers), P = .01; in obese subjects FMD improved by 1.8 ± 5.4% (insertion carriers) and deteriorated by -3.2 ± 7.2% (deletion carriers), P = .05. More subjects carrying the insertion normalized FMD after folate supplementation (insertion 64% vs deletion 28%, χ(2) = 10.14, P = .001). A NOS3 polymorphism predicts endothelial response to folate in children with diabetes or obesity, with implications for vascular risk and folate intervention studies. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Evidence that cranberry juice may improve augmentation index in overweight men.

    PubMed

    Ruel, Guillaume; Lapointe, Annie; Pomerleau, Sonia; Couture, Patrick; Lemieux, Simone; Lamarche, Benoît; Couillard, Charles

    2013-01-01

    The stiffening of arteries is a key step in atherogenesis leading to cardiovascular disease. It has been suggested that dietary polyphenols may be cardioprotective through possible favorable effects on oxidative stress and vascular function. The present study was undertaken in order to examine the effect of consuming low-calorie cranberry juice cocktail (CJC), a source of polyphenols, on arterial stiffness in abdominally obese men. We hypothesize that regular CJC consumption will reduce circulating oxidized low-density lipoproteins concentrations and have a beneficial impact on endothelial function. Thirty-five men (mean age ± SD: 45 ± 10 years) were randomly assigned to drink 500 mL CJC/day (27% juice) or 500 mL placebo juice (PJ)/day for 4 weeks in a double-blind crossover design. Augmentation index (AIx), an index of arterial stiffness, was measured by applanation tonometry of the radial artery and the cardiometabolic profile was assessed in each participant before and after each phase of the study. We found no significant difference in AIx changes between men who consumed CJC or PJ for 4 weeks (P = .5820). Furthermore, there was no between-treatment difference in changes in AIx responses to salbutamol (P = .6303) and glyceryl trinitrate (P = .4224). No significant difference was noted in other cardiometabolic variables between men consuming PJ or CJC. However, a significant within group decrease in AIx (mean decrease ± SE; -14.0 ± 5.8%, P = .019) was noted following the consumption of 500 mL CJC/day for 4 weeks. Our results indicate that the effect of chronic consumption of CJC on AIx was not significantly different from changes associated with the consumption of PJ. However, the significant within-group decrease in AIx following CJC consumption in abdominally obese men may deserve further investigation.

  2. Minimally invasive method for determining the effective lymphatic pumping pressure in rats using near-infrared imaging

    PubMed Central

    Nelson, Tyler S.; Akin, Ryan E.; Weiler, Michael J.; Kassis, Timothy; Kornuta, Jeffrey A.

    2014-01-01

    The ability to quantify collecting vessel function in a minimally invasive fashion is crucial to the study of lymphatic physiology and the role of lymphatic pump function in disease progression. Therefore, we developed a highly sensitive, minimally invasive research platform for quantifying the pumping capacity of collecting lymphatic vessels in the rodent tail and forelimb. To achieve this, we have integrated a near-infrared lymphatic imaging system with a feedback-controlled pressure cuff to modulate lymph flow. After occluding lymphatic flow by inflating a pressure cuff on the limb or tail, we gradually deflate the cuff while imaging flow restoration proximal to the cuff. Using prescribed pressure applications and automated image processing of fluorescence intensity levels in the vessels, we were able to noninvasively quantify the effective pumping pressure (Peff, pressure at which flow is restored after occlusion) and vessel emptying rate (rate of fluorescence clearance during flow occlusion) of lymphatics in the rat. To demonstrate the sensitivity of this system to changes in lymphatic function, a nitric oxide (NO) donor cream, glyceryl trinitrate ointment (GTNO), was applied to the tails. GTNO decreased Peff of the vessels by nearly 50% and the average emptying rate by more than 60%. We also demonstrate the suitability of this approach for acquiring measurements on the rat forelimb. Thus, this novel research platform provides the first minimally invasive measurements of Peff and emptying rate in rodents. This experimental platform holds strong potential for future in vivo studies that seek to evaluate changes in lymphatic health and disease. PMID:24430884

  3. Current Chemotherapeutic Management of Patients with Gestational Trophoblastic Neoplasia

    PubMed Central

    May, Taymaa; Goldstein, Donald P.; Berkowitz, Ross S.

    2011-01-01

    Gestational trophoblastic neoplasia (GTN) describes a heterogeneous group of interrelated lesions that arise from abnormal proliferation of placental trophoblasts. GTN lesions are histologically distinct, malignant lesions that include invasive hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). GTN tumors are generally highly responsive to chemotherapy. Early stage GTN disease is often cured with single-agent chemotherapy. In contrast, advanced stage disease requires multiagent combination chemotherapeutic regimens to achieve a cure. Various adjuvant surgical procedures can be helpful to treat women with GTN. Patients require careful followup after completing treatment and recurrent disease should be aggressively managed. Women with a history of GTN are at increased risk of subsequent GTN, hence future pregnancies require careful monitoring to ensure normal gestational development. This article will review the workup, management and followup of women with all stages of GTN as well as with recurrent disease. PMID:22312558

  4. Joint Deployment and Redeployment Operations

    DTIC Science & Technology

    2007-11-02

    GCCS, GCSS, and GTN development efforts. To provide full functionality, these planning and execution systems must have a modeling and simulation...development and integration of the global transportation network ( GTN ) into the Global Command and Control System (GCCS) and the Global Combat Support...ongoing movements in the DTS through GTN . GTN provides the central data base for all scheduled transportation movements. The central data base for all

  5. Evaluation of a Test Article in the Salmonella typhimurium/Ecscherichia coli Plate Incorporation Mutation Assay in the Presence and Absence of Induced Rat Liver S-9. Test Article - Diethylene triamine trinitrate (DETN)

    DTIC Science & Technology

    2010-02-25

    the culture is required in order to be metabolized prior to plating . The Pre-Incubation method of treatment is perfonned at the request ofthe...Kalamazoo, Michigan. CULTURE CONDITIONS The cells were grown in Oxoid Nutrient Broth No.2 (Oxoid LTD, Hampshire, England) in a shaker incubator... aseptically placed in the center of the agar overlay. Ten ilL of a 1.0 mg/mL crystal violet solution was then added to the disc. The plates were

  6. Crystal structure of tri­hydrogen bis­{[1,1,1-tris­(2-oxido­ethyl­amino­meth­yl)ethane]­cobalt(III)} trinitrate

    PubMed Central

    Sethi, Waqas; Johannesen, Heini V.; Morsing, Thorbjørn J.; Piligkos, Stergios; Weihe, Høgni

    2015-01-01

    The title compound, [Co2(L)2]3+·3NO3 − [where L = CH3C(CH2NHCH2CH2OH1/2)3], has been synthesized from the ligand 1,1,1-tris­(2-hy­droxy­ethyl­amino­meth­yl)ethane. The cobalt(III) dimer has an inter­esting and uncommon O—H⋯O hydrogen-bonding motif with the three bridging hy­droxy H atoms each being equally disordered over two positions. In the dimeric trication, the octa­hedrally coordinated CoIII atoms and the capping C atoms lie on a threefold rotation axis. The N atoms of two crystallographically independent nitrate anions also lie on threefold rotation axes. N—H⋯O hydrogen bonding between the complex cations and nitrate anions leads to the formation of a three-dimensional network structure. The compound is a racemic conglomerate of crystals containing either d or l mol­ecules. The crystal used for this study is a d crystal. PMID:26870462

  7. Safety of air travel following acute myocardial infarction.

    PubMed

    Roby, Howard; Lee, Anna; Hopkins, Andrew

    2002-02-01

    A randomized, single-blind, controlled trial was carried out to: 1) examine the safety of patients flying on commercial airlines 2 wk after a myocardial infarction; 2) determine whether or not the use of supplemental oxygen was associated with a reduced risk of in-flight adverse events; and 3) determine the need for a medical escort. There were 38 patients who were prospectively and randomly assigned supplemental continuous oxygen therapy (2 L x min(-1) via nasal prongs; n = 19) or no oxygen (n = 19) during the flight. Prior to flying, an escorting doctor completed a medical questionnaire for each patient. Both groups underwent Holter monitoring throughout the flight. The major end-point was the development of inflight myocardial ischemia, as detected by Holter monitoring. Minor end-points included patients complaining of chest pain or dyspnea; the detection of bigeminy or trigeminy by Holter monitoring; or oxygen desaturation to less than 90%, as measured by pulse oximetry. Of the 38 patients enrolled, there was only 1 major end-point. This patient had a brief, self-limiting, asymptomatic episode of myocardial ischemia diagnosed by Holter monitoring. Minor end-points occurred in 13 (34%) patients. One patient had asymptomatic evidence of S-T depression on a transport monitor, but not on the Holter. Five patients had transient low (<90%) oxygen saturations, two complained of chest pain, and five had complex ventricular ectopic beats or periods of transient ventricular tachycardia. None of the minor end-points were associated with Holter evidence of myocardial ischemia. Of the 30 patients with completed questionnaires and Holter results, there was no difference in the incidence of minor end-points between the oxygen (5/13) and no oxygen groups (6/15) (p = 0.93). Intervention by the medical escort consisted of commencing oxygen therapy on those patients with low oxygen saturations and those with chest pain. Use of an already dispensed glyceryl trinitrate spray was

  8. Soluble guanylyl cyclase (sGC) degradation and impairment of nitric oxide-mediated responses in urethra from obese mice: reversal by the sGC activator BAY 60-2770.

    PubMed

    Alexandre, Eduardo C; Leiria, Luiz O; Silva, Fábio H; Mendes-Silvério, Camila B; Calmasini, Fabiano B; Davel, Ana Paula C; Mónica, Fabíola Z; De Nucci, Gilberto; Antunes, Edson

    2014-04-01

    Obesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesity-induced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase (sGC) activation with BAY 60-2770 [acid 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4-(trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} methyl) benzoic] rescues the urethral reactivity through improvement of sGC-cGMP (cyclic guanosine monophosphate) signaling. Male C57BL/6 mice were fed for 12 weeks with a high-fat diet to induce obesity. Separate groups of animals were treated with BAY 60-2770 (1 mg/kg per day for 2 weeks). Functional assays and measurements of cGMP, reactive-oxygen species (ROS), and sGC protein expression in USM were determined. USM relaxations induced by NO (acidified sodium nitrite), NO donors (S-nitrosoglutathione and glyceryl trinitrate), and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] (sGC stimulator) were markedly reduced in obese compared with lean mice. In contrast, USM relaxations induced by BAY 60-2770 (sGC activator) were 43% greater in obese mice (P < 0.05), which was accompanied by increases in cGMP levels. Oxidation of sGC with ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one] (10 μM) potentiated BAY 60-2770-induced USM responses in the lean group. Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactive-oxygen species (ROS) production was enhanced, but protein expression of β1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral

  9. Pharmaceutical excipients. Adverse effects associated with inactive ingredients in drug products (Part I).

    PubMed

    Golightly, L K; Smolinske, S S; Bennett, M L; Sutherland, E W; Rumack, B H

    1988-01-01

    Excipient reactions have resulted from the use of clearly toxic substances (e.g. diethyleneglycol), the use of certain excipients in a susceptible group (e.g. very low birthweight neonates, patients with large surface area burns, patients with a history of asthma or contact dermatitis), the alteration of an excipient mixture resulting in altered bioavailability (e.g. phenytoin), and the deliberate or inadvertent extradural administration of preserved medications intended for intravenous use. Inadvertent excipient overdose has also occurred when unusually large doses of a drug containing a preservative were used [chlorbutol in morphine, ethanol in glyceryl trinitrate (nitroglycerin)]. Most excipient problems are preventable with knowledge of the currently available formulation. Government drug regulatory agencies have largely prevented introduction of a new toxic excipient; however, the new use of previously approved (but not adequately studied) excipients continues to result in unfortunate tragedies (e.g. the E-ferol incident). Populations at risk should be monitored carefully. Very low birthweight infants (less than 100g) have a well-demonstrated intolerance to many excipients, particularly during the first 2 weeks of life. Research should be directed toward development of non-preserved medications and safer diluents for this population. Drugs and excipients which have previously been demonstrated to be safer in other populations (e.g. doxapram) should be meticulously studied in this age group before widespread use is recommended. Asthmatic patients comprise another population that are frequently sensitive to excipient toxicity. In some cases, as in sulphiting agents, which are ubiquitous in foods as well as in medications, total avoidance may not be possible and prophylactic therapy may be beneficial. Inactive ingredients are clearly not consistently inert in their biological activity and therefore should not be listed as such. A more useful and concise term is

  10. [Arterial rigidity and endothelial dysfunction in obese children].

    PubMed

    Aggoun, Y; Tounian, P; Dabbas-Tyan, M; Massih, T Abdel; Girardet, J P; Ricour, C; Sidi, D; Bonnet, D

    2002-01-01

    Obesity is a cardiovascular risk factor in adults. Poorly is known about effect of obesity on cardiovascular system in children. Mechanical properties of a great elastic trunk, the common carotid artery (CCA) and endothelium function of the brachial artery were studied in 130 obese children (age: 12 +/- 3 years, body mass index (BMI): 29 +/- 5.5 kg/m2, without hypertension (115 +/- 19/58 +/- 8 mmHg). These patients had a vascular high resolution echographical analysis. Cross sectional compliance (CSC), cross sectional distensibility (CSD) and incremental elastic modulus (Einc) were analysed at the CCA site. The brachial artery dilation was measured after hyperthemia (flow mediated dilation, FMD), an endothelium dependent function and after sublingually glyceryl trinitrate (GTNMD), an independent endothelium function. Fat mass composition and distribution were assessed by dual-energy X-ray absorptiometry in 70 patients. In 50 obese patients an oral glucose tolerance test was done to determine insulin resistance. The obese children had significantly lower CSC and CSD than the healthy controls (respectively 0.12 +/- 0.04 vs 0.14 +/- 0.05 mm2.mmHg-1; p < 0.05 and 0.5 +/- 0.2 vs 0.8 +/- 0.4 mmHg(-1).10(-2); p < 0.001). Obese children had higher value than the controls for Einc (2.4 +/- 0.4 vs 1 +/- 0.24 mmHg.10(3); p < 0.001) that correlated poorly with fasting insulin concentrations (r = 0.34; p < 0.06) and BMI (r = 0.34; p < 0.01). FMD was significantly lower in obese children than in controls (6 +/- 3 vs 8 +/- 4%, p < 0.01) without modification of GTNMD (17 +/- 6 vs 18 +/- 7%, NS). These two parameters were respectively correlated with the android fat distribution (r = 0.36; p < 0.01; r = 0.49; p < 0.001). The CCA stiffness of obese children is linked to the amount of the overweight and to insulin resistance. The android fat distribution is related to endothelium dysfunction.

  11. Role of plasma S-nitrosothiols in regulation of blood pressure in anesthetized rabbits with special references to hypotensive effects of acetylcholine and nitrovasodilators.

    PubMed

    Ishibashi, Takaharu; Miwa, Tomoko; Nishizawa, Naoki; Shinkawa, Ikumi; Yoshida, Junko; Kawada, Tomie; Nishio, Matomo

    2011-01-01

    The regulatory role of plasma nitrosothiols (R-SNOs) under steady-state conditions and their possible contribution to pharmacological vasodilation were systematically examined in anesthetized rabbits. Nitrosocystein (Cys-NO), S-nitrosoglutathione (G-SNO), and S-nitrosoalbumin (Alb-SNO) were determined by HPLC-Saville's method with respective sensitivities of 1, 1, and 5 nM. These R-SNOs were not detected under steady-state conditions even in the presence of N-ethylmaleimide, a thiol protective agent used to prevent transnitrosation of R-SNOs. Development of plasma Alb-SNO below 300 nM was observed after intravenous injection (i.v.) of nitric oxide (NO) solution (0.1 to 3 ml/g), NOC7 (an NO releasing agent, above 1 µg/kg), and a low dose of Alb-SNO (10 nmol/kg). However, blood pressure was not significantly reduced by NO solution or Alb-SNO. Intravenous injection of a high dose of Alb-SNO (300 nmol/kg) significantly reduced blood pressure with the appearance not only Alb-SNO in micromolar level in plasma, but also G-SNO in lesser degree. Conversely, the hypotensive effect of Cys-NO (300 nmol/kg, i.v.) and G-SNO (300 nmol/kg, i.v.) accompanied development of Alb-SNO (micromolar level), but not Cys-NO or G-SNO in plasma. R-SNOs were not found in plasma during profound hypotension induced by acetylcholine (10 and 30 µg/kg/min, continuous i.v.), glyceryl trinitrate (100 µg/kg, i.v.), sodium nitroprusside (100 µg/kg, i.v.), and isosorbide dinitrate (300 µg/kg, i.v.). These results indicate that R-SNOs do not play an important role under unstimulated condition. In addition, plasma R-SNOs may not be involved in pharmacological vasodilation where contributions of NO or R-SNOs are suggested.

  12. Dietary supplement with vitamin C prevents nitrate tolerance.

    PubMed Central

    Bassenge, E; Fink, N; Skatchkov, M; Fink, B

    1998-01-01

    Enhanced formation of superoxide radicals has been proposed to play a major role in the development of nitrate tolerance in humans. We tested the effects of vitamin C (Vit-C) supplementation on glyceroltrinitrate (GTN)-induced hemodynamic effects during 3-d nonintermittent transdermal administration of GTN (0.4 mg/h) in nine healthy subjects. Tolerance development was monitored by changes in arterial pressure, dicrotic digital pulse pressure, and heart rate. Studies with GTN, Vit-C, or GTN/Vit-C were successively carried out at random in three different series in the same subjects. GTN treatment caused an immediate rise in arterial conductivity (a/b ratio of dicrotic pulse), but within 2 d of initiating GTN, the a/b ratio progressively decreased and reached basal levels. In addition, there was a progressive loss of the orthostatic decrease in blood pressure. However, coadministration of Vit-C and GTN fully maintained the GTN-induced changes in the orthostatic blood pressure, and the rise of a/b ratio was augmented by 310% for the duration of the test period. Changes in vascular tolerance in GTN-treated subjects were paralleled by upregulation of the activity of isolated platelets, which was also reversed by Vit-C administration. These findings demonstrate that dietary supplementation with Vit-C eliminates vascular tolerance and concomitant upregulation of ex vivo-washed platelet activity during long-term nonintermittent administration of GTN in humans. PMID:9649558

  13. Final report on the safety assessment of Glycyrrhetinic Acid, Potassium Glycyrrhetinate, Disodium Succinoyl Glycyrrhetinate, Glyceryl Glycyrrhetinate, Glycyrrhetinyl Stearate, Stearyl Glycyrrhetinate, Glycyrrhizic Acid, Ammonium Glycyrrhizate, Dipotassium Glycyrrhizate, Disodium Glycyrrhizate, Trisodium Glycyrrhizate, Methyl Glycyrrhizate, and Potassium Glycyrrhizinate.

    PubMed

    2007-01-01

    Glycyrrhetinic Acid and its salts and esters and Glycyrrhizic Acid and its salts and esters are cosmetic ingredients that function as flavoring agents or skin-conditioning agents - miscellaneous or both. These chemicals may be isolated from licorice plants. Glycyrrhetinc Acid is described as at least 98% pure, with 0.6% 24-OH-Glycyrrhetinic Acid, not more than 20 mu g/g of heavy metals and not more than 2 mu g/g of arsenic. Ammonium Glycyrrhizate has been found to be at least 98% pure and Dipotassium Glycyrrhizate has been found to be at least 95% pure. Glycyrrhetinic Acid is used in cosmetics at concentrations of up to 2%; Stearyl Glycyrrhetinate, up to 1%; Glycyrrhizic Acid, up to 0.1%; Ammonium Glycyrrhizate, up to 5%; Dipotassium Glycyrrhizate, up to 1%; and Potassium Glycyrretinate, up to 1%. Although Glycyrrhizic Acid is poorly absorbed by the intestinal tract, it may be hydrolyzed to Glycyrrhetinic Acid by a beta -glucuronidase produced by intestinal bacteria. Glycyrrhetinic Acid and Glycyrrhizic Acid bind to rat and human albumin, but do not absorb well into tissues. Glycyrrhetinic Acid and Glycyrrhizic Acid and metabolites are mostly excreted in the bile, with very little excreted in urine. Dipotassium Glycyrrhizate was undetectable in the receptor chamber when tested for transepidermal permeation through pig skin. Glycyrrhizic Acid increased the dermal penetration of diclofenac sodium in rat skin. Dipotassium Glycyrrhizate increased the intestinal absorption of calcitonin in rats. In humans, Glycyrrhetinic Acid potentiated the effects of hydrocortisone in the skin. Moderate chronic or high acute exposure to Glycyrrhizic Acid, Ammonium Glycyrrhizate, and their metabolites have been demonstrated to cause transient systemic alterations, including increased potassium excretion, sodium and water retention, body weight gain, alkalosis, suppression of the renin-angiotensis-aldosterone system, hypertension, and muscular paralysis; possibly through inhibition of 11beta -hydroxysteroid dehydrogenase-2 (11beta -OHSD2) in the kidney. Glycyrrhetinic Acid and its derivatives block gap junction intracellular communication in a dose-dependent manner in animal and human cells, including epithelial cells, fibroblasts, osteoblasts, hepatocytes, and astrocytes; at high concentrations, it is cytotoxic. Glycyrrhetinic Acid and Glycyrrhizic Acid protect liver tissue from carbon tetrachloride. Glycyrrhizic Acid has been used to treat chronic hepatitis, inhibiting the penetration of the hepatitis A virus into hepatocytes. Glycyrrhetinic Acid and Glycyrrhizic Acid have anti-inflammatory effects in rats and mice. The acute intraperitoneal LD(50) for Glycyrrhetinic Acid in mice was 308 mg/kg and the oral LD(50) was > 610 mg/kg. The oral LD(50) in rats was reported to be 610 mg/kg. Higher LD(50) values were generally reported for salts. Little short-term, subchronic, or chronic toxicity was seen in rats given ammonium, dipotassium, or disodium salts of Glycyrrhizic Acid. Glycyrrhetinic Acid was not irritating to shaved rabbit skin, but was considered slightly irritating in an in vitro test. Glycyrrhetinic Acid inhibited the mutagenic activity of benzo[a]pyrene and inhibited tumor initiation and promotion by other agents in mice. Glycyrrhizic Acid inhibited tumor initiation by another agent, but did not prevent tumor promotion in mice. Glycyrrhizic Acid delayed mortality in mice injected with Erlich ascites tumor cells, but did not reduce the mortality rate. Ammonium Glycyrrhizate was not genotoxic in in vivo and in vitro cytogenetics assays, the dominant lethal assay, an Ames assay, and heritable translocation tests, except for possible increase in dominant lethal mutations in rats given 2000 mg/kg day(-1) in their diet. Disodium Glycyrrhizate was not carcinogenic in mice in a drinking water study at exposure levels up to 12.2 mg/kg day(-1) for 96 weeks. Glycyrrhizate salts produced no reproductive or developmental toxicity in rats, mice, golden hamsters, or Dutch-belted rabbits, except for a dose-dependent increase (at 238.8 and 679.9 mg/kg day(-1)) in sternebral variants in a study using rats. Sedation, hypnosis, hypothermia, and respiratory depression were seen in mice given 1250 mg/kg Glycyrrhetinic Acid intraperitoneally. Rats fed a powdered diet containing up to 4% Ammonium Glycyrrhizate had no treatment related effects in motor function tests, but active avoidance was facilitated at 4%, unaffected at 3%, and depressed at 2%. In a study of 39 healthy volunteers, a no effect level of 2 mg/kg/day was determined for Glycyrrhizic Acid given orally for 8 weeks. Clinical tests in seven normal individuals given oral Ammonium Glycyrrhizate at 6 g/day for 3 days revealed reduced renal and thermal sweat excretion of Na+ and K+, but carbohydrate and protein metabolism were not affected. Glycyrrhetinic Acid at concentrations up to 6% was not a skin irritant or a sensitizer in clinical tests. Neither Glycyrrhizic Acid, Ammonium Glycyrrhizate, nor Dipotassium Glycyrrhizate at 5% were phototoxic agents or photosensitizers. Birth weight and maternal blood pressure were unrelated to the level of consumption of Glycyrrhizic Acid in 1049 Finnish women with infants, but babies whose mother consumed > 500 mg/wk were more likely to be born before 38 weeks. The Cosmetic Ingredient Review (CIR) Expert Panel noted that the ingredients in this safety assessment are not plant extracts, powders, or juices, but rather are specific chemical species that may be isolated from the licorice plant. Because these chemicals may be isolated from plant sources, however, steps should be taken to assure that pesticide and toxic metal residues are below acceptable levels. The Panel advised the industry that total polychlorobiphenyl (PCB)/pesticide contamination should be limited to not more than 40 ppm, with not more than 10 ppm for any specific residue, and that toxic metal levels must not contain more than 3 mg/kg of arsenic (as As), not more than 0.002% heavy metals, and not more than 1 mg/kg of lead (as Pb). Although the Panel noted that Glycyrrhizic Acid is cytotoxic at high doses and ingestion can have physiological effects, there is little acute, short-term, subchronic, or chronic toxicity and it is expected that these ingredients would be poorly absorbed through the skin. These ingredients are not considered to be irritants, sensitizers, phototoxic agents, or photosensitizers at the current maximum concentration of use. Accordingly, the CIR Expert Panel concluded that these ingredients are safe in the current practices of use and concentration. The Panel recognizes that certain ingredients in this group are reportedly used in a given product category, but the concentration of use is not available. For other ingredients in this group, information regarding use concentration for specific product categories is provided, but the number of such products is not known. In still other cases, an ingredient is not in current use, but may be used in the future. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used and at what concentration indicate a pattern of use. Within this overall pattern of use, the Expert Panel considers all ingredients in this group to be safe.

  14. MNE5 Coalition Logistics Information Sharing (NATO IR Decomposition Methodology)

    DTIC Science & Technology

    2008-07-16

    Populate IR: The name of the Authoritative Data Source Example: Global Transportation Network ( GTN ) • Link to Source / Systems: The connecting link...best chance possible to locate it. Additionally, if there is a document that could be modified to support exchanging this information list it and...COMMERCI AL BILL OF LADING FROM WHICH THE FREIGHT- LADING- BILL WAS Nation al, CTF GTN GTN.doc 18 UNCLASSIFIED –APPROVED FOR PUBLIC RELEASE

  15. MNE 5 Coalition Logistics Information Sharing (NATO IR Decomposition Methodology)

    DTIC Science & Technology

    2008-07-16

    Populate IR: The name of the Authoritative Data Source Example: Global Transportation Network ( GTN ) • Link to Source / Systems: The connecting...the best chance possible to locate it. Additionally, if there is a document that could be modified to support exchanging this information list it...THE COMMERCI AL BILL OF LADING FROM WHICH THE FREIGHT- LADING- BILL WAS Nation al, CTF GTN GTN.doc 18 UNCLASSIFIED –APPROVED FOR PUBLIC

  16. Joint Tactics, Techniques, and Procedures for Foreign Humanitarian Assistance

    DTIC Science & Technology

    2007-11-02

    Transition Model ..................................................................................... IV-23 V-1 Types of Training...DALIS for its basic design. II-14 Chapter II JP 3-07.6 • Global Transportation Network ( GTN ). GTN is a standardized DOD system that provides access to...transportation data inputs from a wide variety of in-transit visibility systems. Users can query the GTN database to track cargo and passengers from

  17. Nitroglycerin Tolerance in Caveolin-1 Deficient Mice

    PubMed Central

    Mao, Mao; Varadarajan, Sudhahar; Fukai, Tohru; Bakhshi, Farnaz R.; Chernaya, Olga; Dudley, Samuel C.; Minshall, Richard D.; Bonini, Marcelo G.

    2014-01-01

    Nitrate tolerance developed after persistent nitroglycerin (GTN) exposure limits its clinical utility. Previously, we have shown that the vasodilatory action of GTN is dependent on endothelial nitric oxide synthase (eNOS/NOS3) activity. Caveolin-1 (Cav-1) is known to interact with NOS3 on the cytoplasmic side of cholesterol-enriched plasma membrane microdomains (caveolae) and to inhibit NOS3 activity. Loss of Cav-1 expression results in NOS3 hyperactivation and uncoupling, converting NOS3 into a source of superoxide radicals, peroxynitrite, and oxidative stress. Therefore, we hypothesized that nitrate tolerance induced by persistent GTN treatment results from NOS3 dysfunction and vascular toxicity. Exposure to GTN for 48–72 h resulted in nitrosation and depletion (>50%) of Cav-1, NOS3 uncoupling as measured by an increase in peroxynitrite production (>100%), and endothelial toxicity in cultured cells. In the Cav-1 deficient mice, NOS3 dysfunction was accompanied by GTN tolerance (>50% dilation inhibition at low GTN concentrations). In conclusion, GTN tolerance results from Cav-1 modification and depletion by GTN that causes persistent NOS3 activation and uncoupling, preventing it from participating in GTN-medicated vasodilation. PMID:25158065

  18. The Effects of Platelet-Activating Factor (PAF) and a PAF Antagonist (CV-3988) on Smoke Inhalation Injury in an Ovine Model,

    DTIC Science & Technology

    1992-03-01

    decyl-2-acetyl-sn-glyceryl-3- phosphorylcholine ) has following PAF injection. In models of endotoxin shock, been reported to be one of the principal...instillation of 1-0-octadecyl-2- 25. Traber DL, Herndon DN, Stein MD, et al: The pulmonary lesion acetyl-sn-glyceryl-3- phosphorylcholine or of native platelet-ac...glyceryl ether phosphorylcholine infusion in the change (abstr). Proceedings of the American Burn Association rabbit. Am Rev Respir Dis 124:416, 1981 22nd

  19. 5-HIAA urine test

    MedlinePlus

    HIAA; 5-hydroxyindole acetic acid; Serotonin metabolite ... interfere with the test. Medicines that can increase 5-HIAA measurements include acetaminophen (Tylenol), acetanilide, phenacetin, glyceryl ...

  20. Formation of Nitric Oxide by Aldehyde Dehydrogenase-2 Is Necessary and Sufficient for Vascular Bioactivation of Nitroglycerin*

    PubMed Central

    Opelt, Marissa; Eroglu, Emrah; Waldeck-Weiermair, Markus; Russwurm, Michael; Koesling, Doris; Malli, Roland; Graier, Wolfgang F.; Fassett, John T.; Schrammel, Astrid; Mayer, Bernd

    2016-01-01

    Aldehyde dehydrogenase-2 (ALDH2) catalyzes vascular bioactivation of the antianginal drug nitroglycerin (GTN), resulting in activation of soluble guanylate cyclase (sGC) and cGMP-mediated vasodilation. We have previously shown that a minor reaction of ALDH2-catalyzed GTN bioconversion, accounting for about 5% of the main clearance-based turnover yielding inorganic nitrite, results in direct NO formation and concluded that this minor pathway could provide the link between vascular GTN metabolism and activation of sGC. However, lack of detectable NO at therapeutically relevant GTN concentrations (≤1 μm) in vascular tissue called into question the biological significance of NO formation by purified ALDH2. We addressed this issue and used a novel, highly sensitive genetically encoded fluorescent NO probe (geNOp) to visualize intracellular NO formation at low GTN concentrations (≤1 μm) in cultured vascular smooth muscle cells (VSMC) expressing an ALDH2 mutant that reduces GTN to NO but lacks clearance-based GTN denitration activity. NO formation was compared with GTN-induced activation of sGC. The addition of 1 μm GTN to VSMC expressing either wild-type or C301S/C303S ALDH2 resulted in pronounced intracellular NO elevation, with maximal concentrations of 7 and 17 nm, respectively. Formation of GTN-derived NO correlated well with activation of purified sGC in VSMC lysates and cGMP accumulation in intact porcine aortic endothelial cells infected with wild-type or mutant ALDH2. Formation of NO and cGMP accumulation were inhibited by ALDH inhibitors chloral hydrate and daidzin. The present study demonstrates that ALDH2-catalyzed NO formation is necessary and sufficient for GTN bioactivation in VSMC. PMID:27679490

  1. The anti-inflammatory and analgesic action of transdermal glyceryltrinitrate in the treatment of infusion-related thrombophlebitis.

    PubMed

    Berrazueta, J R; Poveda, J J; Ochoteco, J; Amado, J A; Puebla, F; Salas, E; Sarabia, M

    1993-01-01

    We have carried out a prospective double-blind randomized study in 40 patients with infusion-related thrombophlebitis. Twenty-two patients were included in the glyceryltrinitrate (GTN) ointment group and 18 patients in the control heparinoid group. Pain was assessed by an analogue scale. At 48 hours the analgesic index was 84.6 +/- 18 units with GTN and 49 +/- 45 units with heparinoid ointment (P < 0.01). Faster relief of oedema was also observed in the GTN-treated group. All signs of thrombophlebitis were relieved in less than 4 days in the GTN group compared with 9 days in the controls (P < 0.005). We conclude that transdermal GTN is useful therapy for infusion-related thrombophlebitis showing evidence of anti-inflammatory and analgesic effect.

  2. The anti-inflammatory and analgesic action of transdermal glyceryltrinitrate in the treatment of infusion-related thrombophlebitis.

    PubMed Central

    Berrazueta, J. R.; Poveda, J. J.; Ochoteco, J.; Amado, J. A.; Puebla, F.; Salas, E.; Sarabia, M.

    1993-01-01

    We have carried out a prospective double-blind randomized study in 40 patients with infusion-related thrombophlebitis. Twenty-two patients were included in the glyceryltrinitrate (GTN) ointment group and 18 patients in the control heparinoid group. Pain was assessed by an analogue scale. At 48 hours the analgesic index was 84.6 +/- 18 units with GTN and 49 +/- 45 units with heparinoid ointment (P < 0.01). Faster relief of oedema was also observed in the GTN-treated group. All signs of thrombophlebitis were relieved in less than 4 days in the GTN group compared with 9 days in the controls (P < 0.005). We conclude that transdermal GTN is useful therapy for infusion-related thrombophlebitis showing evidence of anti-inflammatory and analgesic effect. PMID:8383319

  3. 21 CFR 172.832 - Monoglyceride citrate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN... glyceryl monooleate and its citric acid monoester manufactured by the reaction of glyceryl monooleate with... addition to oils and fats whereby the additive does not exceed 200 parts per million of the combined...

  4. Gestational trophoblastic neoplasia after achieving a nondetectable serum human chorionic gonadotrophin level.

    PubMed

    Gueye, M; Kane-Gueye, S M; Ndiaye-Gueye, M D; Mbaye, M; Diouf, A A; Niang, M M; Diallo, M; Moreau, J C

    2014-10-01

    To determine the risk of recurrent trophoblastic disease after normalisation of human chorionic gonadotrophin (hCG) levels in women with hydatidiform mole. A retrospective review of data from a national gestational trophoblastic disease centre. The Trophoblastic Disease Unit, Dakar, Senegal. Women with pregnancies affected by hydatidiform mole registered between 2006 and 2012. The women were followed up in accordance with the hospital protocol 'Score de Dakar'. For women who progressed to gestational trophoblastic neoplasia (GTN) the time to onset of GTN, treatment and evolution were evaluated. The rate of evolution to GTN after normalisation of hCG was determined. Rate of occurrence of GTN after chemotherapy for hydatidiform mole. Five hundred and thirty-one women were diagnosed to have molar pregnancies. According to the hospital's protocol, 107 (20.2%) of these had chemotherapy and 224 (42.2%) had prophylactic chemotherapy. Five hundred and thirteen women (96.4%; 95% confidence interval [95% CI] 95.05-98.14%) achieved remission. Eighteen women (3.4%; 95% CI 1.86-4.94%) developed GTN (11 before remission and seven after remission). Seven women out of the 18 developed GTN after hCG normalisation (1.3%). Five of these seven were diagnosed beyond the recommended period of follow up. The mean interval to diagnosis of GTN was 18.7 months. These seven women underwent combination chemotherapy: five achieved complete remission whereas two died from GTN. Cytotoxic therapy for hydatidiform mole does not prevent GTN, it delays its diagnosis and promotes GTN after normalisation of hCG. © 2014 Royal College of Obstetricians and Gynaecologists.

  5. Involvement of phorbol-12-myristate-13-acetate-induced protein 1 in goniothalamin-induced TP53-dependent and -independent apoptosis in hepatocellular carcinoma-derived cells

    SciTech Connect

    Kuo, Kung-Kai; Chen, Yi-Ling; Chen, Lih-Ren; Li, Chien-Feng; Lan, Yu-Hsuan; Chang, Fang-Rong; Wu, Yang-Chang; Shiue, Yow-Ling

    2011-10-01

    The objective was to investigate the upstream apoptotic mechanisms that were triggered by a styrylpyrone derivative, goniothalamin (GTN), in tumor protein p53 (TP53)-positive and -negative hepatocellular carcinoma (HCC)-derived cells. Effects of GTN were evaluated by the flow cytometry, alkaline comet assay, immunocytochemistry, small-hairpin RNA interference, mitochondria/cytosol fractionation, quantitative reverse transcription-polymerase chain reaction, immunoblotting analysis and caspase 3 activity assays in two HCC-derived cell lines. Results indicated that GTN triggered phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA)-mediated apoptosis via TP53-dependent and -independent pathways. In TP53-positive SK-Hep1 cells, GTN furthermore induced TP53 transcription-dependent and -independent apoptosis. After GTN treatment, accumulation of reactive oxygen species, formation of DNA double-strand breaks, transactivation of TP53 and/or PMAIP1 gene, translocation of TP53 and/or PMAIP1 proteins to mitochondria, release of cytochrome c from mitochondria, cleavage of caspases and induction of apoptosis in both cell lines were sustained. GTN might represent a novel class of anticancer drug that induces apoptosis in HCC-derived cells through PMAIP1 transactivation regardless of the status of TP53 gene. - Highlights: > Goniothalamin (GTN) induced apoptosis in hepatocellular carcinomas-derived cells. > The apoptosis induced by GTN is PMAIP1-dependent, regardless of TP53 status. > The apoptosis induced by GTN might be TP53 transcription-dependent or -independent. > GTN-induced apoptosis is mitochondria- and caspases-mediated.

  6. [Therapy with NO donors-antiatherogenic and antioxidant actions].

    PubMed

    Grosser, Nina; Schröder, Henning

    2004-02-01

    Nitric acid esters such as glyceryl trinitrate were introduced into therapy more than a century ago and are still widely used for the treatment of myocardial ischemia and its main symptom angina pectoris. The basic mechanisms responsible for the vasodilatory and anti-ischemic action of organic nitrates involve bioactivation of, and nitric oxide (NO) release from, these compounds which have therefore been termed NO donors. The organic nitrate pentaerythritol tetranitrate (PETN) is known to possess antioxidant properties that are thought to be the underlying cause for its specific pharmacological profile. In contrast to other long-acting nitrates, PETN induces tolerance- free vasodilation in humans and was reported to prevent endothelial dysfunction as well as atherogenesis in cholesterol- fed rabbits. However, the exact nature of the vasoprotective signaling pathways triggered by PETN has remained obscure. The present study demonstrates that the active PETN metabolite PETriN stimulates protein expression of the antioxidant defense protein heme oxygenase-1 (HO-1; Figures 1 and 2). Additionally, PETriN enhanced the enzymatic activity of HO-1 measured as formation of the HO-1 metabolites bilirubin (Figure 3) and carbon monoxide (Figure 4) in lysates from endothelial cells. HO-1 induction subsequently led to a marked increase in protein expression of a second antioxidant protein, ferritin, via the HO-1-dependent release of free iron from endogenous heme sources (Figures 1 and 5). Pretreatment of endothelial cells with PETriN was followed by increased cellular resistance to oxidant injury mediated by hydrogen peroxide (Figure 6). Endothelial protection by PETriN was mimicked by exogenous bilirubin which led to an almost complete reversal of hydrogen peroxide-induced toxicity (Figure 8). Increased HO-1 and ferritin expression as well as endothelial protection occurred at micromolar concentrations of PETriN which are well within the range of plasma or tissue levels that

  7. Effects of Kaempferia parviflora rhizomes dichloromethane extract on vascular functions in middle-aged male rat.

    PubMed

    Yorsin, Somruedee; Kanokwiroon, Kanyanatt; Radenahmad, Nisaudah; Jansakul, Chaweewan

    2014-10-28

    In Thai traditional medicine, rhizomes of Kaempferia parviflora (KP) have been used for treating hypertension and for the promotion of longevity with good health and well being. Ageing is one of the most important risk factors for development of cardiovascular disease. To investigate whether a 6 weeks oral administration of a dichloromethane extract of fresh rhizomes of Kaempferia parviflora (KPD) had any effects on vascular functions, on the accumulation of lipid, as well as on any signs of gross organ toxicity in middle-aged rats. Fresh rhizomes of Kaempferia parviflora were first macerated twice with 95% ethanol to remove the dark color before extracting three times with 100% dichloromethane. The dichloromethane extract was evaporated under reduced pressure to obtain the dried Kaempferia parviflora dichloromethane extract (KPD). The rats were orally administered with the KPD at a dosage of 100mg/kg body weight, or with the same volume of the vehicle (tween 80, 0.2g: carboxy-methylcellulose sodium, 0.2g: distilled water 10 ml) once or twice a day for 6 weeks. Vascular functions were studied on isolated thoracic aorta and the mesenteric artery. The vascular eNOS enzyme was measured by Western blot analysis. Blood chemistry was measured by enzymatic methods. Liver cell lipid accumulation was measured using oil red O staining. A 6 weeks treatment of KPD once a day had no significant effects on any of the studied parameters. When the KPD was given twice a day, the contractile responses to phenylephrine of the thoracic aorta and mesenteric artery were lower than the vehicle control group, and this effect was abolished by N(G)-nitro-l-arginine or by removal of the vascular endothelium. Vasorelaxation to acetylcholine, but not to glyceryl trinitrate, by the thoracic aortic and mesenteric ring precontracted with phenylephrine was higher from the KPD treated rats than those from the vehicle control groups. Western blot analysis showed a higher quantity of thoracic- and

  8. Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Trophoblastic Disease Center.

    PubMed

    Vargas, Roberto; Barroilhet, Lisa M; Esselen, Katharine; Diver, Elisabeth; Bernstein, Marilyn; Goldstein, Donald P; Berkowitz, Ross S

    2014-01-01

    To review and update the subsequent reproductive outcomes in patients with complete, partial, and recurrent hydatidiform moles, as well as gestational trophoblastic neoplasia (GTN) at the New England Trophoblastic Disease Center. Patients with complete and partial hydatidiform mole, recurrent hydatidiform mole, and GTN were identified from the Donald P. Goldstein, M.D., Trophoblastic Tumor Registry. Questionnaires regarding subsequent pregnancies were mailed to patients with current mailing addresses available. Additional patient data was obtained from electronic medical records. A total of 2,432 subsequent pregnancies have been reported since 1965. Of those, 1,388 pregnancies were after complete mole, 357 after partial mole, and 667 after GTN. The subsequent reproductive outcomes in patients with complete and partial molar pregnancies and persistent GTN remain similar to those in the general population. However, approximately 1.7% of patients with a prior molar pregnancy had a molar pregnancy in a later gestation. Furthermore, after successful chemotherapy for GTN the incidence of stillbirth was slightly increased to 1.3% in later pregnancies. Patients with molar pregnancies and GTN should expect similar reproductive outcomes as compared to the general population. However, patients receiving chemotherapy for GTN have a slightly increased risk stillbirth in subsequent pregnancies.

  9. Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates.

    PubMed

    Wenzel, Philip; Oelze, Matthias; Coldewey, Meike; Hortmann, Marcus; Seeling, Andreas; Hink, Ulrich; Mollnau, Hanke; Stalleicken, Dirk; Weiner, Henry; Lehmann, Jochen; Li, Huige; Förstermann, Ulrich; Münzel, Thomas; Daiber, Andreas

    2007-08-01

    Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance. Wistar rats were treated with PETN or GTN (10.5 or 6.6 microg/kg/min for 4 days). In contrast to GTN, PETN did not induce nitrate tolerance or cross-tolerance as assessed by isometric tension recordings in isolated aortic rings. Vascular protein and mRNA expression of HO-1 and ferritin were increased in response to PETN but not GTN. In contrast to GTN therapy, NO signaling, ROS formation, and the activity of ALDH-2 (as assessed by an high-performance liquid chromatography-based method) were not significantly influenced by PETN. Inhibition of HO-1 expression by apigenin induced "tolerance" to PETN whereas HO-1 gene induction by hemin prevented tolerance in GTN treated rats. HO-1 expression and activity appear to play a key role in the development of nitrate tolerance and might represent an intrinsic antioxidative mechanism of therapeutic interest.

  10. Differential effects of pentaerythritol tetranitrate and nitroglycerin on the development of tolerance and evidence of lipid peroxidation: a human in vivo study.

    PubMed

    Jurt, U; Gori, T; Ravandi, A; Babaei, S; Zeman, P; Parker, J D

    2001-09-01

    We investigated the development of nitrate tolerance after continuous exposure to nitroglycerin (GTN) as compared with pentaerythritol tetranitrate (PETN) in humans. Sustained therapy with GTN causes tolerance and has been associated with increased production of free oxygen radicals by the endothelium. Pentaerythritol tetranitrate is an organic nitrate that has been used in the therapy of angina. There have been no investigations concerning the development of tolerance to PETN in humans. Animal investigations suggested that continuous therapy with PETN does not cause increased free radical production or hemodynamic tolerance. We randomized 30 healthy volunteers to continuous GTN (0.6 mg/h/24 h), long-acting PETN (60 mg orally three times a day) or no treatment (control group) for seven days. We studied systemic blood pressure responses and venous volume responses to GTN with strain-gauge plethysmography. The levels of cytotoxic aldehydes and isoprostanes were measured as markers of free radical-mediated lipid peroxidation. Tolerance, as demonstrated by blood pressure and forearm plethysmography, developed in the GTN group and was absent in the PETN group (p < 0.05). Therapy with GTN was associated with a significant increase in plasma markers of lipid peroxidation. This response was not observed in those treated with PETN (isoprostanes: control: 38 +/- 5; GTN: 59 +/- 6; PETN: 38 +/- 3 microg/ml; p < 0.005). Treatment with PETN does not cause tolerance and is not associated with evidence of increased free radical production.

  11. 5-Acetyl goniothalamin suppresses proliferation of breast cancer cells via Wnt/β-catenin signaling.

    PubMed

    Boonmuen, Nittaya; Thongon, Natthakan; Chairoungdua, Arthit; Suksen, Kanoknetr; Pompimon, Wilart; Tuchinda, Patoomratana; Reutrakul, Vichai; Piyachaturawat, Pawinee

    2016-11-15

    Styryl lactones are plant-derived compounds from genus Goniothalamus with promising anti-proliferation and anticancer properties. However, the exact mechanism and the target for their activities remained unclear. In the present study, we investigated the effect of 5-acetyl goniothalamin (5GTN) from Goniothalamus marcanii on Wnt/β-catenin signaling pathway which is a key regulator in controlling cell proliferation in breast cancer cells (MCF-7 and MDA-MB-231). 5GTN, a naturally occurring derivative of goniothalamin (GTN) mediated the toxicity to MCF-7 and MDA-MB-231 cells in a dose- and time- related manner, and was more potent than that of GTN. 5GTN strongly inhibited cell proliferation and markedly suppressed transcriptional activity induced by β-catenin in luciferase reporter gene assay. In consistent with this view, the expression of Wnt/β-catenin signaling target genes including c-Myc, cyclin D1 and Axin2 in MCF-7 and MDA-MB-231 cells were suppressed after treatment with 5GTN. It was concomitant with cell cycle arrest at G1 phase and cell apoptosis in MCF-7 cells. In addition, 5GTN enhanced glycogen synthase kinase (GSK-3β) activity and therefore reduced the expression of active form of β-catenin protein in MCF-7 and MDA-MB-231 cells. Taken together, 5GTN exhibited a promising anticancer effect against breast cancer cells through an inhibition of Wnt/β-catenin signaling. This pathway may be served as a potential chemotherapeutic target for breast cancer by 5GTN.

  12. A 10-Year Clinical Experience of Gestational Trophoblastic Disease at Rajavithi Hospital, 2001-2010.

    PubMed

    Yanaranop, Marut; Potikul, Chalermrat; Tuipae, Suphet

    2016-02-01

    Gestational trophoblastic disease (GTD) develops from abnormal cellular proliferation of trophoblasts following fertilization and is categorized as either an hydatidiform mole (HM) or a gestational trophoblastic neoplasia (GTN). To analyze the clinical characteristics, incidence and treatment outcomes of GTD at Rajavithi Hospital. Medical records of women diagnosed with GTD at Rajavithi Hospital from January 1, 2001 to December 31, 2010 were retrospectively reviewed. Disease diagnosis, treatment and follow-up data were analyzed. A total of 329 cases of GTD were reviewed. HM was diagnosed in 167 patients (incidence 2.32 per 1,000 deliveries); 26 patients were lost to follow-up; and 49 of the remaining 141 patients (34.8%) developed post-molar GTN. In multivariable analysis, uterus >16 week size and pre-treatment human chorionic gonadotropin (hCG) level >250,000 mIU/mL were the significant risk factors for developing post-molar GTN. Of 162 patients with GTN (incidence 2.25 per 1,000 deliveries), 15 patients were lost to follow-up, and 116 patients, 29 patients and 2 patients were classified as having low-risk GTN, high-risk GTN and placental site trophoblastic disease respectively. The overall survival rate in the low-risk group was 100% whereas in the high-risk group it was 86.2%. A modified WHO prognostic score of more than five was the significant risk factor for developing resistant GTN. GTD treatment at Rajavithi Hospital showed excellent clinical outcomes. Uterus >16 weeks size and pre- treatment hCG > 250,000 mIU/mL were the significant risk factors for developing post-molar GTN in HM patients. Classifying GTN patients into low- and high-risk groups was useful in planning treatment and counseling.

  13. Solid lipid extrusion of sustained release dosage forms.

    PubMed

    Reitz, Claudia; Kleinebudde, Peter

    2007-09-01

    The applicability of the solid lipid extrusion process as preparations method for sustained release dosage forms was investigated in this study. Two lipids with similar melting ranges but of different composition, glyceryl palmitostearate (Precirol ATO 5) and glyceryl trimyristate (Dynasan 114), and mixtures of each lipid with 50% or 75% theophylline were extruded at temperatures below their melting ranges. Extrudates were analyzed using differential scanning calorimetry, scanning electron microscopy, porosity measurements and in vitro drug dissolution studies. The possibility of processing lipids by softening instead of complete melting and without subsequent formation of low-melting, metastable polymorphs could be demonstrated. Extrudates based on formulations of glyceryl palmitostearate/theophylline (50:50) and glyceryl trimyristate/theophylline (50:50) showed sustained release properties. An influence of extrusion conditions on the matrix structure was shown for extrudates based on a mixture of glyceryl trimyristate and theophylline (50:50). Glyceryl trimyristate tended to solidify in porous structures after melting. Exceeding a material temperature of 50.5 degrees C led to porous extrudate matrices with a faster drug release. The production of novel, non porous sustained release matrices was possible at a material temperature of 49.5 degrees C. Extrudates based on glyceryl trimyristate/theophylline (50:50) only slight changes in melting enthalpy and stable drug release profiles.

  14. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia.

    PubMed

    Lurain, John R

    2011-01-01

    Gestational trophoblastic neoplasia (GTN) includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. The overall cure rate in treating these tumors is currently >90%. Thorough evaluation and staging allow selection of appropriate therapy that maximizes chances for cure while minimizing toxicity. Nonmetastatic (stage I) and low-risk metastatic (stages II and III, score <7) GTN can be treated with single-agent chemotherapy resulting in a survival rate approaching 100%. High-risk GTN (stages II-IV, score ≥7) requires initial multiagent chemotherapy with or without adjuvant radiation and surgery to achieve a survival rate of 80-90%. Copyright © 2011 Mosby, Inc. All rights reserved.

  15. Enabling the Interoperability of Large-Scale Legacy Systems

    DTIC Science & Technology

    2008-01-01

    with two schemas to evaluate IMT on the mapping task: (1) the WPS- GTN schema and (2) the Master Model schema (see Table 1). This task...focuses on mapping WPS- GTN to the Master Model , which has 12,383 fields. This pair of schemas has 10,302,656 1:1 possible field mappings. USTRANSCOM...provided 597 of the 832 mappings from WPS- GTN to the Master Model , which we used as the Gold Standard for our investigation. There were no mappings

  16. 76 FR 5796 - Gas Transmission Northwest Corporation; Notice of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-02

    ... Energy Regulatory Commission Gas Transmission Northwest Corporation; Notice of Application January 26, 2011. Take notice that on January 14, 2011, Gas Transmission Northwest Corporation (GTN), 717 Texas..., Manager, Project Determinations & Regulatory Administration, Gas Transmission Northwest Corporation,...

  17. Management of Chemoresistant and Quiescent Gestational Trophoblastic Disease.

    PubMed

    Ngu, Siew-Fei; Chan, Karen K L

    2014-01-01

    Gestational trophoblastic neoplasia (GTN) is highly chemosensitive and has a high cure rate. Since the introduction of chemotherapy, reliable measurement of human chorionic gonadotropin (hCG) levels, and individualised risk-based therapy into the management of GTN, almost all low-risk and more than 80 % of high-risk GTN cases are curable. However, approximately 25 % of high-risk GTN developed resistance to chemotherapy or relapsed after completion of initial therapy, which often necessitate salvage combination chemotherapy. On the other end of the spectrum, a proportion of patients with gestational trophoblastic disease (GTD) have persistently low levels of hCG, without clinical or radiological evidence of disease, a condition called quiescent GTD. Recently, measurement of hyperglycosylated hCG has been proposed for the management of patients with quiescent GTD. Although representing a small proportion of GTD cases, the management of patients with chemoresistant and quiescent GTD often poses challenges to medical practitioners.

  18. Methotrexate on a 21-day cycle for low-risk gestational trophoblastic neoplasia.

    PubMed

    Diaz, Juan; Thomas, M Bijoy; Paz-Pabon, Charlotte; Hernandez, Enrique

    2012-01-01

    To perform an outcome analysis of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with a 5-day intramuscular methotrexate (MTX) regimen on a 21-day cycle. A retrospective review of 31 patients with low-risk GTN treated with a 5-day MTX regimen. A total of 31 patients with low-risk GTN (WHO score < 7) received single-agent MTX at a dose of 0.4 mg/kg daily for 5 days every 21 days (mean number of cycles, 3; 83% remission). The only significant toxicity encountered was grade 2 stomatitis in 8 (26%) patients. A 5-day MTX regimen given every 21 days is convenient, well-tolerated and effective for patients with low-risk GTN.

  19. Human Chorionic Gonadotropin (hCG) Regression Curve for Predicting Response to EMA/CO (Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide and Vincristine) Regimen in Gestational Trophoblastic Neoplasia.

    PubMed

    Rattanaburi, Athithan; Boonyapipat, Sathana; Supasinth, Yuthasak

    2015-01-01

    An hCG regression curve has been used to predict the natural history and response to chemotherapy in gestational trophoblastic disease. We constructed hCG regression curves in high-risk gestational trophoblastic neoplasia (GTN) treated with EMA/CO and identified an optimal hCG level to detect EMA/CO resistance in GTN. Eighty-one women with GTN treated with EMA/CO were classified as primary high-risk GTN (n=65) and single agent-resistance GTN (n=16). The hCG levels prior to each course of chemotherapy were plotted in the 10th, 50th, and 90th percentiles to construct the hCG regression curves. Diagnostic performance was evaluated for an optimal cut-off value. The median hCG levels were 264,482 mIU/mL mIU/mL and 495.5 mIU/mL mIU/mL for primary high-risk GTN and single agent-resistance GTN, respectively. The 50th percentile of the hCG level in primary high-risk GTN and single agent-resistance turned to normal before the 4th and the 2nd course of chemotherapy, respectively. The 90th percentile of the hCG level in primary high-risk GTN and single agent-resistance turned to normal before the 9th and the 2nd course of chemotherapy, respectively. The hCG level of ≥118.6 mIU/mL mIU/mL at the 5thcourse of EMA/CO predicted the EMA/CO resistance in primary high-risk GTN patients with a sensitivity of 85.7% and a specificity of 100%. EMA/CO resistance in primary high-risk GTN can be predicted by using an hCG regression curve in combination with the cut-off value of 118.6 mIU/mL at the 5thcourse of chemotherapy.

  20. Rate-Dependent Homogenization Based Continuum Plasticity Damage Model for Dendritic Cast Aluminum Alloys

    DTIC Science & Technology

    2011-01-01

    The overall framework of this rate-dependent HCPD model follows the structure of the anisotropic Gursen- Tvergaard-Needleman( GTN ) type elasto...with evolving porosity. The HCPD model follows the Gurson-Tvergaard-Needleman or GTN models framework established in [14, 15, 16, 17] that account for...this method. In [32, 33] the VCFEM model has been extended for rate-dependent elastic- viscoplastic porous ductile material. Micromechanical analysis

  1. Expeditionary Border Security Operations: Eliminating the Seams

    DTIC Science & Technology

    2008-05-22

    CTC model as they actively and passively support TCO and GTN activity. Al Qaeda has operated training camps in the Sudan in the past and conducted...threat model and demonstrate the danger to US national security interests. The rise of TCOs and GTNs as a result of the rapid globalization of the...Initiative TCO- Transnational Criminal Organization GTN - Global Terrorist Network GSPC- Groupe Salafiste pour la Predication et le Combat AQIM

  2. Clinical characteristics and prognosis of ultra high-risk gestational trophoblastic neoplasia patients: A retrospective cohort study.

    PubMed

    Kong, Yujia; Yang, Junjun; Jiang, Fang; Zhao, Jun; Ren, Tong; Li, Jie; Wang, Xiaoyu; Feng, Fengzhi; Wan, Xirun; Xiang, Yang

    2017-07-01

    The gestational trophoblastic neoplasia (GTN) patients with the International Federation of Gynecology and Obstetrics (FIGO) score≥12 are defined as ultra high-risk GTN. This study aims to investigate the clinical characteristics, the treatment efficiency, and the prognosis of ultra high-risk GTN patients. Between January 2002 and December 2015, medical record data of 143 GTN patients with FIGO score≥12 at Peking Union Medical College Hospital (PUMCH) were reviewed. Ratios were compared using chi-square test, and prognostic risk factors were analyzed by univariate analysis and multivariate analysis. Among the 143 ultra high-risk GTN patients, 94 (65.7%) patients had achieved complete remission and 15.9% (15/94) patients relapsed after complete remission. The 5-year overall survival (OS) rate of the entire cohort approached 67.9%. The results of the multivariate analysis revealed that non-molar antecedent pregnancy [Relative risk (RR) 4.689, 95% CI 1.448-15.189, P=0.010], brain metastases (RR 2.280, 95% CI 1.248-4.163, P=0.007), previous failed multiagent chemotherapy (RR 5.345, 95% CI 2.222-12.857, P=0.000) and surgery (RR 0.336, 95% CI 0.177-0.641, P=0.001) all had influence on the prognosis of ultra high-risk GTN patients. GTN patients with FIGO score≥12 have a poor prognosis. More emphasis should be placed on non-molar antecedent pregnancy, brain metastases, and previous multiagent chemotherapy failure. Moreover, salvage surgery may improve the prognosis. Floxuridine-based multiagent chemotherapy is effective with manageable toxicity for ultra high-risk GTN patients. Copyright © 2017. Published by Elsevier Inc.

  3. 21 CFR 184.1903 - Tributyrin.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... known as butyrin or glyceryl tributyrate, is the triester of glycerin and butyric acid. It is prepared by esterification of glycerin with excess butyric acid. (b) The ingredient meets the specification of...

  4. 21 CFR 184.1903 - Tributyrin.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... known as butyrin or glyceryl tributyrate, is the triester of glycerin and butyric acid. It is prepared by esterification of glycerin with excess butyric acid. (b) The ingredient meets the specification of...

  5. 21 CFR 184.1903 - Tributyrin.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... known as butyrin or glyceryl tributyrate, is the triester of glycerin and butyric acid. It is prepared by esterification of glycerin with excess butyric acid. (b) The ingredient meets the specification of...

  6. 21 CFR 184.1903 - Tributyrin.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... known as butyrin or glyceryl tributyrate, is the triester of glycerin and butyric acid. It is prepared by esterification of glycerin with excess butyric acid. (b) The ingredient meets the specification of...

  7. Lipstick dermatitis due to C18 aliphatic compounds.

    PubMed

    Hayakawa, R; Matsunaga, K; Suzuki, M; Arima, Y; Ohkido, Y

    1987-04-01

    An 18-year-old girl developed cheilitis. She had a past history of lip cream dermatitis, but the cause was not found. Patch tests with 2 lipsticks were strongly positive. Tests with the ingredients were positive to 2 aliphatic compounds, glyceryl diisostearate and diisostearyl malate. Impurities in the materials were suspected as the cause. Analysis by gas chromatography detected 3 chemicals in glyceryl diisostearate and 1 in diisostearyl malate as impurities. Patch testing with the impurities and glyceryl monoisostearate 0.01% pet in glyceryl diisostearate and isostearyl alcohol 0.25% pet in diisostearyl malate were strongly positive. The characteristics common to the 2 chemicals were liquidity at room temperature, branched C18 aliphatic compound and primary alcohol. Chemicals lacking any of the above 3 features did not react.

  8. Effect of permeation enhancers on the in vitro percutaneous absorption of pentazocine.

    PubMed

    Furuishi, Takayuki; Oda, Sachiko; Saito, Hiroaki; Fukami, Toshiro; Suzuki, Toyofumi; Tomono, Kazuo

    2007-07-01

    The effect of permeation enhancers on the percutaneous absorption of pentazocine (PTZ) was investigated in excised hairless mice using Franz diffusion cells in vitro. The enhancing effect on the percutaneous absorption of PTZ from the isopropyl myristate (IPM) solution system was improved with glyceryl monocaprylate (GEFA-C(8)), which is a kind of glycerol ester of fatty acid (GEFA). The flux of PTZ through the skin was ca. 4 times higher compared with IPM alone, while a less enhancing effect of glyceryl dicaprylate (GEFA-DiC(8)) and glyceryl tricaprylate (GEFA-TriC(8)) on the skin permeation of PTZ was found. Moreover, maximum enhancement of PTZ flux was observed with glyceryl monocaproate (GEFA-C(6)) among various alkyl chains (C(2)-C(18)) of monoglycerides. These results indicated that the IPM solution system combination with GEFA may be used to develop a transdermal formulation with improved skin permeation of PTZ.

  9. Circulating Cell Free DNA in the Diagnosis of Trophoblastic Tumors

    PubMed Central

    Openshaw, Mark R.; Harvey, Richard A.; Sebire, Neil J.; Kaur, Baljeet; Sarwar, Naveed; Seckl, Michael J.; Fisher, Rosemary A.

    2015-01-01

    Gestational trophoblastic neoplasia (GTN) represents a group of diseases characterized by production of human chorionic gonadotropin (hCG). Since non-gestational tumors may occasionally secrete hCG, histopathological diagnosis is important for appropriate clinical management. However, a histopathological diagnosis is not always available. We therefore investigated the feasibility of extracting cell free DNA (cfDNA) from the plasma of women with GTN for use as a “liquid biopsy” in patients without histopathological diagnosis. cfDNA was prepared from the plasma of 20 women with a diagnosis of GTN and five with hCG-secreting tumors of unknown origin. Genotyping of cfDNA from the patient, genomic DNA from her and her partner and DNA from the tumor tissue identified circulating tumor DNA (ctDNA) (from 9% to 53% of total cfDNA) in 12 of 20 patients with GTN. In one case without a tissue diagnosis, ctDNA enabled a diagnosis of GTN originating in a non-molar conception and in another a diagnosis of non-gestational tumor, based on the high degree of allelic instability and loss of heterozygosity in the ctDNA. In summary ctDNA can be detected in the plasma of women with GTN and can facilitate the diagnosis of both gestational and non-gestational trophoblastic tumors in cases without histopathological diagnosis. PMID:26981554

  10. Styryl-lactone goniothalamin inhibits TNF-α-induced NF-κB activation.

    PubMed

    Orlikova, Barbora; Schumacher, Marc; Juncker, Tom; Yan, Choo Chee; Inayat-Hussain, Salmaan H; Hajjouli, Shéhérazade; Cerella, Claudia; Dicato, Mario; Diederich, Marc

    2013-09-01

    (R)-(+)-Goniothalamin (GTN), a styryl-lactone isolated from the medicinal plant Goniothalamus macrophyllus, exhibits pharmacological activities including cytotoxic and anti-inflammatory effects. In this study, GTN modulated TNF-α induced NF-κB activation. GTN concentrations up to 20 μM showed low cytotoxic effects in K562 chronic myelogenous leukemia and in Jurkat T cells. Importantly, at these concentrations, no cytotoxicity was observed in healthy peripheral blood mononuclear cells. Our results confirmed that GTN inhibited tumor necrosis factor-α (TNF-α)-induced NF-κB activation in Jurkat and K562 leukemia cells at concentrations as low as 5 μM as shown by reporter gene assays and western blots. Moreover, GTN down-regulated translocation of the p50/p65 heterodimer to the nucleus, prevented binding of NF-κB to its DNA response element and reduced TNF-α-activated interleukin-8 (IL-8) expression. In conclusion, GTN inhibits TNF-α-induced NF-κB activation at non-apoptogenic concentrations in different leukemia cell models without presenting toxicity towards healthy blood cells underlining the anti-leukemic potential of this natural compound.

  11. Circulating Cell Free DNA in the Diagnosis of Trophoblastic Tumors.

    PubMed

    Openshaw, Mark R; Harvey, Richard A; Sebire, Neil J; Kaur, Baljeet; Sarwar, Naveed; Seckl, Michael J; Fisher, Rosemary A

    2016-02-01

    Gestational trophoblastic neoplasia (GTN) represents a group of diseases characterized by production of human chorionic gonadotropin (hCG). Since non-gestational tumors may occasionally secrete hCG, histopathological diagnosis is important for appropriate clinical management. However, a histopathological diagnosis is not always available. We therefore investigated the feasibility of extracting cell free DNA (cfDNA) from the plasma of women with GTN for use as a "liquid biopsy" in patients without histopathological diagnosis. cfDNA was prepared from the plasma of 20 women with a diagnosis of GTN and five with hCG-secreting tumors of unknown origin. Genotyping of cfDNA from the patient, genomic DNA from her and her partner and DNA from the tumor tissue identified circulating tumor DNA (ctDNA) (from 9% to 53% of total cfDNA) in 12 of 20 patients with GTN. In one case without a tissue diagnosis, ctDNA enabled a diagnosis of GTN originating in a non-molar conception and in another a diagnosis of non-gestational tumor, based on the high degree of allelic instability and loss of heterozygosity in the ctDNA. In summary ctDNA can be detected in the plasma of women with GTN and can facilitate the diagnosis of both gestational and non-gestational trophoblastic tumors in cases without histopathological diagnosis.

  12. Gastroprotective effects of goniothalamin against ethanol and indomethacin-induced gastric lesions in rats: Role of prostaglandins, nitric oxide and sulfhydryl compounds.

    PubMed

    Vendramini-Costa, Débora Barbosa; Monteiro, Karin Maia; Iwamoto, Leilane Hespporte; Jorge, Michelle Pedroza; Tinti, Sirlene Valério; Pilli, Ronaldo Aloise; de Carvalho, João Ernesto

    2014-12-05

    Goniothalamin (GTN), a styryl-lactone, is a secondary metabolite naturally found in its enantiomeric form (R) in plants of the genus Goniothalamus (Annonaceae). The antiproliferative activity against human tumor cell lines reported in several studies suggest that the α,β-unsaturated δ-lactone moiety emerges as a key Michael acceptor for cysteine residues or other nucleophilic biological molecules. Our group reported on the in vivo activity of (R)- and (S)-GTN as well as its racemic form (rac-GTN) in both Ehrlich solid tumor and carrageenan-induced paw edema in mice, without side effects in the effective doses. Despite the rich body of data on the in vitro GTN biological activity, much less is known about its in vivo pharmacological action. Herein we describe the gastroprotective activity of rac-GTN on chemical-induced gastric ulcers models in rats. GTN has a potent gastroprotective effect on ethanol-induced ulcers (effective dose50=18mg/kg) and this activity is dependent on sulfhydryl compounds and prostaglandins generation, but independent of nitric oxide (NO), gastric secretion and mucus production. We hypothesize that goniothalamin may act as a mild irritant, inducing the production of sulfhydryl compounds and prostaglandins, in a process known as adaptive cytoprotection. This hypothesis is supported by the fact that Michael acceptors are the most potent inducers of antioxidant response (as activation of Nrf2 pathway) through generation of mild oxidative stress and that gastroprotective activity of goniothalamin is inhibited after pre-treatment with NEM (N-ethylmaleimide) and NSAID (non-steroidal anti-inflammatory drugs), highlighting the importance of sulfhydryl compounds and prostaglandins on GTN activity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. Advances in the clinical laboratory detection of gestational trophoblastic disease.

    PubMed

    Seki, Katsuyoshi; Matsui, Hideo; Sekiya, Souei

    2004-11-01

    Gestational trophoblastic disease (GTD) consists of a spectrum of disorders that are characterized by an abnormal proliferation of trophoblastic tissue. Gestational trophoblastic neoplasia (GTN) refers to a subset of GTD with a persistently elevated serum hCG in the absence of a normal pregnancy and with a history of normal or abnormal pregnancy. Although previously a lethal disease, GTN is considered today the most curable gynecologic cancer. However, a delay in the diagnosis may increase the patient's risk of developing malignant GTN, and therefore the prompt identification of GTN is important. hCG test is essential for detection of GTN. It has emerged that there are problems with hCG tests. In addition to regular hCG, at least five major variants of hCG are present in serum samples. False-positive hCG (phantom hCG) can occur in the absence of GTN. Low-level real hCG may occasionally persist in the absence of clinical evidence of pregnancy or GTD. Alternatively, low-level real hCG may be due to pituitary hCG. Other placental hormones, human placental lactogen (hPL), inhibin and activin, and progesterone have also been evaluated as tumor markers for GTD. hCG has high diagnostic sensitivity, approaching 100% sensitivity, for managing the treatment of GTN and for detecting recurrences of disease. It is recommended to use hCG test that recognizes all forms of the hCG molecule. In cases where low-level hCG persists, it must be differentiated whether it is real or false. Real-hCG may be due to quiescent gestational trophoblastic disease or pituitary hCG. It has not yet been established whether measurement of markers other than hCG (hPL, inhibin, activin, and progesterone) is useful in the detection and follow-up of GTD.

  14. Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/- mice

    PubMed Central

    Mollnau, Hanke; Wenzel, Philip; Oelze, Matthias; Treiber, Nicolai; Pautz, Andrea; Schulz, Eberhard; Schuhmacher, Swenja; Reifenberg, Kurt; Stalleicken, Dirk; Scharffetter-Kochanek, Karin; Kleinert, Hartmut; Münzel, Thomas; Daiber, Andreas

    2006-01-01

    Background Chronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance. Methods Tolerance was induced by infusion of wild type (WT) and heterozygous manganese superoxide dismutase mice (Mn-SOD+/-) with ethanolic solution of GTN (12.5 μg/min/kg for 4 d). For comparison, the tolerance-free pentaerithrityl tetranitrate (PETN, 17.5 μg/min/kg for 4 d) was infused in DMSO. Vascular reactivity was measured by isometric tension studies of isolated aortic rings. ROS formation and aldehyde dehydrogenase (ALDH-2) activity was measured in isolated heart mitochondria. Results Chronic GTN infusion lead to impaired vascular responses to GTN and acetylcholine (ACh), increased the ROS formation in mitochondria and decreased ALDH-2 activity in Mn-SOD+/- mice. In contrast, PETN infusion did not increase mitochondrial ROS formation, did not decrease ALDH-2 activity and accordingly did not lead to tolerance and cross-tolerance in Mn-SOD+/- mice. PETN but not GTN increased heme oxygenase-1 mRNA in EA.hy 926 cells and bilirubin efficiently scavenged GTN-derived ROS. Conclusion Chronic GTN infusion stimulates mitochondrial ROS production which is an important mechanism leading to tolerance and cross-tolerance. The tetranitrate PETN is devoid of mitochondrial oxidative stress induction and according to the present animal study as well as numerous previous clinical studies can be used without limitations due to tolerance and cross-tolerance. PMID:17092343

  15. Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line.

    PubMed

    Vendramini-Costa, Débora Barbosa; Alcaide, Antonio; Pelizzaro-Rocha, Karin Juliane; Talero, Elena; Ávila-Román, Javier; Garcia-Mauriño, Sofia; Pilli, Ronaldo Aloise; de Carvalho, João Ernesto; Motilva, Virginia

    2016-06-01

    Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects. As inflammation is a well-known tumor promoter, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on chemically induced and spontaneous colitis, as well as the cytotoxic effects of GTN on a human colon tumor cell line (HT-29). GTN treatments inhibited TNBS-induced acute and chronic colitis development in Wistar rats, reducing myeloperoxidase levels and inflammatory cells infiltration in the mucosa. In spontaneous-colitis using IL-10 deficient mice (C57BL/6 background), GTN prevented colitis development through downregulation of TNF-α, upregulation of SIRT-1 and inhibition of proliferation (PCNA index), without signs of toxicity after three months of treatment. In HT-29 cells, treatment with 10μM of GTN induced apoptosis by increasing BAX/BCL2, p-JNK1/JNK1, p-P38/P38 ratios as well as through ROS generation. Caspase 8, 9 and 3 activation also occurred, suggesting caspase-dependent apoptotic pathway, culminating in PARP-1 cleavage. Together with previous data, these results show the importance of GTN as a pro-apoptotic, preventive and therapeutic agent for IBD and highlight its potential as a chemopreventive agent for colon cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Postmolar gestational trophoblastic neoplasia: beyond the traditional risk factors.

    PubMed

    Bakhtiyari, Mahmood; Mirzamoradi, Masoumeh; Kimyaiee, Parichehr; Aghaie, Abbas; Mansournia, Mohammd Ali; Ashrafi-Vand, Sepideh; Sarfjoo, Fatemeh Sadat

    2015-09-01

    To investigate the slope of linear regression of postevacuation serum hCG as an independent risk factor for postmolar gestational trophoblastic neoplasia (GTN). Multicenter retrospective cohort study. Academic referral health care centers. All subjects with confirmed hydatidiform mole and at least four measurements of β-hCG titer. None. Type and magnitude of the relationship between the slope of linear regression of β-hCG as a new risk factor and GTN using Bayesian logistic regression with penalized log-likelihood estimation. Among the high-risk and low-risk molar pregnancy cases, 11 (18.6%) and 19 cases (13.3%) had GTN, respectively. No significant relationship was found between the components of a high-risk pregnancy and GTN. The β-hCG return slope was higher in the spontaneous cure group. However, the initial level of this hormone in the first measurement was higher in the GTN group compared with in the spontaneous recovery group. The average time for diagnosing GTN in the high-risk molar pregnancy group was 2 weeks less than that of the low-risk molar pregnancy group. In addition to slope of linear regression of β-hCG (odds ratio [OR], 12.74, confidence interval [CI], 5.42-29.2), abortion history (OR, 2.53; 95% CI, 1.27-5.04) and large uterine height for gestational age (OR, 1.26; CI, 1.04-1.54) had the maximum effects on GTN outcome, respectively. The slope of linear regression of β-hCG was introduced as an independent risk factor, which could be used for clinical decision making based on records of β-hCG titer and subsequent prevention program. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  17. Effect of ethacrynic acid, a glutathione-S-transferase inhibitor, on nitroglycerin-mediated cGMP elevation and vasorelaxation of rabbit aortic strips.

    PubMed

    Kenkare, S R; Benet, L Z

    1993-07-20

    The effects of ethacrynic acid (ECA), an inhibitor of glutathione-S-transferase, on both the pharmacologic and biochemical responses of aortic tissue to nitroglycerin (GTN) were evaluated. Using the rabbit aortic strip model, relaxation responses to 0.6 microM GTN were measured with and without ECA (0.2 mM) pretreatment. These same strips were frozen, and the concentrations of cGMP in the strips were measured using a 3H-labeled radioimmunoassay. Both the relaxation response and the increase in cGMP upon GTN treatment were reduced significantly by pretreatment of the strips with ECA. A correlation was observed between the decreases in the pharmacodynamic and biochemical responses upon ECA pretreatment. cGMP levels in strips treated with sodium nitroprusside, which generates nitric oxide by mechanisms distinct from that for organic nitrates, were not decreased by ECA pretreatment. These observations suggest that the mechanism of GTN action involves a glutathione-S-transferase-mediated metabolic step for GTN and that the isozyme(s) involved in this activation process may be inhibited by ECA.

  18. Prognosis of Patients with Gestational Trophoblastic Neoplasia and Obstetric Outcomes of Those Conceiving After Chemotherapy.

    PubMed

    Gadducci, Angiolo; Cosio, Stefania; Fanucchi, Antonio; Tana, Roberta; Manacorda, Simona; Pistolesi, Sabina; Strigini, Francesca Letizia

    2016-07-01

    To assess prognosis of gestational trophoblastic neoplasia (GTN) and obstetric outcome after chemotherapy. Sixty-six patients had diagnosis of hydatiform mole on curettage and 18 developed GTN. Two patients were referred with pathological diagnosis of GTN. Chemotherapy was tailored according to International Federation of Gynecology and Obstetrics risk scoring system. All patients with GTN but one, were recovered by chemotherapy and had no evidence of disease after a median follow-up of 80 months. Only the patient with epithelioid trophoblastic tumor died of disease. Seven out of the eight women who tried to conceive after chemotherapy became pregnant. Ten conceptions occurred, resulting in no molar pregnancy, three miscarriages and seven term-live healthy births (70.0%). All seven babies showed normal development and growth after a median follow-up of 38 months. The prognosis of women with GTN is very good, and obstetric outcomes of those who conceive after chemotherapy are similar to those of the general population. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  19. The roles of surgery and EMA/CO chemotherapy regimen in primary refractory and non-refractory gestational trophoblastic neoplasia.

    PubMed

    Aydiner, Adnan; Keskin, Serkan; Berkman, Sinan; Bengisu, Ergin; Ilhan, Huseyin Ridvan; Tas, Faruk; Topuz, Erkan

    2012-06-01

    To determine the characteristics and outcome of patients with refractory gestational trophoblastic neoplasia (GTN) after primary chemotherapy (CTx). The outcome of low- and high-risk patients with refractory GTN (n = 14, 37%) was compared to those with non-refractory GTN (n = 24, 63%). Methotrexate treatment was used for patients with low-risk disease and EMA/CO for patients with high-risk disease. Median follow-up time was 53 months (range 1-173 months). All non-refractory patients and 11 refractory patients (79%) survived (p = 0.015). Factors related to resistance to primary CTx was age (p = 0.012), duration between causal pregnancy and initial treatment (p = 0.003), surgery (p = 0.014), hCG level before CTx (p = 0.09) and half-life of hCG (p = 0.061). Six out of 10 low-risk refractory patients treated with EMA/CO regimen in the second-line setting had been followed by no evidence of disease. Nine of 38 (24%) patients underwent surgery (TAH ± BSO) for GTN. All of the patients treated with surgery were in the non-refractory group, but none of refractory patients underwent surgery (p = 0.014). Surgery and EMA/CO regimen are one of the main factors that play a role in the management of refractory low-risk GTN.

  20. The recipient's heme oxygenase-1 promoter region polymorphism is associated with cardiac allograft vasculopathy.

    PubMed

    Freystaetter, Kathrin; Andreas, Martin; Bilban, Martin; Perkmann, Thomas; Kaider, Alexandra; Masetti, Marco; Kocher, Alfred; Wolzt, Michael; Zuckermann, Andreas

    2017-02-10

    Heme oxygenase-1 (HO-1) catalyses the degradation of heme to biliverdin, free iron, and carbon monoxide. The promoter region contains a highly polymorphic (GT)n repeat, where shorter (GT)n repeat sequences are linked to higher transcriptional activity, which was shown to correlate with a cytoprotective effect. Higher HO-1 levels may protect from cardiac allograft vasculopathy. Cardiac allograft recipients transplanted between 1988 and 2012 were analyzed for the HO-1 (GT)n repeat polymorphism using PCR and DNA fragment analysis with capillary electrophoresis. A relation to cardiac allograft vasculopathy (CAV) was analyzed using Cox regression including common risk factors for CAV and the occurrence of rejection episodes as explanatory variables. A total of 344 patients were analyzed, of which 127 patients were positive for CAV (36.9%). In our multivariable Cox regression analysis, the short homozygous HO-1 (GT)n genotype with <27 repeats (S/S) revealed a higher risk for CAV (P = 0.032). Donor age (P = 0.001) and donor weight (P = 0.005) were significant predictors for CAV. A potential risk for CAV was associated with rejection episodes (P = 0.058) and history of smoking (P = 0.06). The recipient HO-1 (GT)n genotype may contribute to CAV development. This finding has to be evaluated in larger series including studies targeting the underlying disease mechanism.

  1. Dissolution of solid lipid extrudates in biorelevant media.

    PubMed

    Witzleb, R; Müllertz, A; Kanikanti, V-R; Hamann, H-J; Kleinebudde, P

    2012-01-17

    Solid lipid extrudates with the model drug praziquantel were produced with chemically diverse lipids and investigated regarding their dissolution behaviour in different media. The lipids used in this study were glyceryl tripalmitate, glyceryl dibehenate, glyceryl monostearate, cetyl palmitate and solid paraffin. Thermoanalytical and dissolution behaviour was investigated directly after extrusion and after 3 and 6 months open storage at 40°C/75% RH. Dissolution studies were conducted in hydrochloric acid (HCl) pH 1.2 with different levels of polysorbate 20 and with a biorelevant medium containing pancreatic lipase, bile salts and phospholipids. Furthermore, the impact of lipid digestion on drug release was studied using in vitro lipolysis. The release of praziquantel from cetyl palmitate and glyceryl monostearate in the biorelevant medium was much faster than in HCl, whereas there was hardly any difference for the other lipids. It was shown that drug release from glyceryl monostearate matrices is driven by both solubilisation and enzymatic degradation of the lipid, whereas dissolution from cetyl palmitate extrudates is dependent only on solubilisation by surfactants in the medium. Moreover, storage influenced the appearance of the extrudate surface and the dissolution rate for all lipids except solid paraffin. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Application of Gurson–Tvergaard–Needleman Constitutive Model to the Tensile Behavior of Reinforcing Bars with Corrosion Pits

    PubMed Central

    Xu, Yidong; Qian, Chunxiang

    2013-01-01

    Based on meso-damage mechanics and finite element analysis, the aim of this paper is to describe the feasibility of the Gurson–Tvergaard–Needleman (GTN) constitutive model in describing the tensile behavior of corroded reinforcing bars. The orthogonal test results showed that different fracture pattern and the related damage evolution process can be simulated by choosing different material parameters of GTN constitutive model. Compared with failure parameters, the two constitutive parameters are significant factors affecting the tensile strength. Both the nominal yield and ultimate tensile strength decrease markedly with the increase of constitutive parameters. Combining with the latest data and trial-and-error method, the suitable material parameters of GTN constitutive model were adopted to simulate the tensile behavior of corroded reinforcing bars in concrete under carbonation environment attack. The numerical predictions can not only agree very well with experimental measurements, but also simplify the finite element modeling process. PMID:23342140

  3. Gestational trophoblastic disease: an overview.

    PubMed

    Monchek, Ruth; Wiedaseck, Susan

    2012-01-01

    This article reviews the different disease entities that fall under the classification of gestational trophoblastic disease (GTD). The conditions included range from molar pregnancy to the malignant forms of gestational trophoblastic neoplasm (GTN). These disorders all arise from abnormal placental trophoblastic development. The different types of GTD, symptomatology, and diagnostic modalities are examined. The various methods of treatment are reviewed. Although the management of GTD and GTN falls outside the scope of midwifery practice, midwives need to be aware of the incidence, risk factors, and symptoms for specific types of GTD in order to be able to diagnose and refer for treatment in a timely manner. Psychosocial aspects that affect the woman who has not only had a pregnancy loss but also may be faced with a life-threatening illness are examined. The role of the midwife in the management, counseling, and follow-up of GTD and GTN is discussed. © 2012 by the American College of Nurse-Midwives.

  4. Application of Gurson-Tvergaard-Needleman constitutive model to the tensile behavior of reinforcing bars with corrosion pits.

    PubMed

    Xu, Yidong; Qian, Chunxiang

    2013-01-01

    Based on meso-damage mechanics and finite element analysis, the aim of this paper is to describe the feasibility of the Gurson-Tvergaard-Needleman (GTN) constitutive model in describing the tensile behavior of corroded reinforcing bars. The orthogonal test results showed that different fracture pattern and the related damage evolution process can be simulated by choosing different material parameters of GTN constitutive model. Compared with failure parameters, the two constitutive parameters are significant factors affecting the tensile strength. Both the nominal yield and ultimate tensile strength decrease markedly with the increase of constitutive parameters. Combining with the latest data and trial-and-error method, the suitable material parameters of GTN constitutive model were adopted to simulate the tensile behavior of corroded reinforcing bars in concrete under carbonation environment attack. The numerical predictions can not only agree very well with experimental measurements, but also simplify the finite element modeling process.

  5. Antihypertensive withdrawal for the prevention of cognitive decline.

    PubMed

    Jongstra, Susan; Harrison, Jennifer K; Quinn, Terry J; Richard, Edo

    2016-11-01

    9.5 mmHg higher in the intervention compared to the control group (95% CI 7.43 to 11.57; 2095 participants) and diastolic blood pressure was 5.1 mmHg higher (95% CI 3.86 to 6.34; 2095 participants). This evidence was low quality, downgraded due to indirectness, because the data must be interpreted in the context of the wider study looking at glyceryl trinitrate administration or not, and evidence from a single study. In the other study, systolic blood pressure increased by 7.4 mmHg in the withdrawal group compared to the control group (95% CI 7.08 to 7.72; 356 participants) and diastolic blood pressure increased by 2.6 mmHg (95% CI 2.42 to 2.78; 356 participants). This was moderate quality evidence, downgraded as evidence was from a single study. We combined data for mortality and cardiovascular events. There was no clear evidence that antihypertensive medication withdrawal affected adverse events, although there was a possible trend to increased cardiovascular events in the large post-stroke study (pooled mortality risk ratio 0.88, 95% CI 0.72 to 1.08; 2485 participants; and cardiovascular events risk ratio 1.29, 95% CI 0.96 to 1.72). Certain prespecified outcomes of interest (falls, hospitalisation) were not reported. The effects of withdrawing antihypertensive medications on cognition or prevention of dementia are uncertain. There was a signal of a positive effect in one study looking at withdrawal after acute stroke but these results are unlikely to be generalisable to non-stroke settings and were not a primary outcome of the study. Withdrawing antihypertensive drugs was associated with increased blood pressure. It is unlikely to increase mortality at three to four months' follow-up, although there was a signal from one large study looking at withdrawal after stroke that withdrawal was associated an increase in cardiovascular events.

  6. The added value of hysterectomy in the management of gestational trophoblastic neoplasia.

    PubMed

    Eysbouts, Y K; Massuger, L F A G; IntHout, J; Lok, C A R; Sweep, F C G J; Ottevanger, P B

    2017-06-01

    Despite the undoubted effectiveness of chemotherapeutic treatment in gestational trophoblastic neoplasia (GTN), problems related to toxicity of chemotherapy and chemo-resistant disease have led to reconsideration of the use of hysterectomy. Aim of the present study was to evaluate indications for and outcome of hysterectomy in patients with GTN in a nation-wide cohort. Between 1977 and 2012, we identified all patients diagnosed with GTN and treated with hysterectomy from the Dutch national databases. Demographics, clinical characteristics and follow-up were recorded retrospectively. One hundred and nine patients (16.5% of all registered patients with GTN) underwent hysterectomy as part of their management for GTN. The majority of patients was classified as low-risk disease (74.3%), post-molar GTN (73.5%) and disease confined to the uterus (65.1%). After hysterectomy, complete remission was achieved in 66.2% of patients with localized disease and in 15.8% of patients with metastatic disease. For patients with localized disease, treated with primary hysterectomy, treatment duration was significantly shorter (mean 3.2weeks and 8.0weeks respectively, p=0.01) with lower number of administered chemotherapy cycles (mean 1.5 and 5.8 respectively, p<0.01) than patients in a matched control group. In selected cases, a hysterectomy may be an effective means to either reduce or eliminate tumor bulk. Primary hysterectomy should mainly be considered in older patients with localized disease and no desire to preserve fertility, whereas patients with chemotherapy-resistant disease may benefit from additional hysterectomy, especially when disease is localized. For patients with widespread metastatic disease, the benefit of hysterectomy lies in the removal of chemotherapy-resistant tumor bulk with subsequent effect on survival. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Salvage chemotherapy for gestational trophoblastic neoplasia: Utility or futility?

    PubMed

    Essel, Kathleen G; Bruegl, Amanda; Gershenson, David M; Ramondetta, Lois M; Naumann, R Wendel; Brown, Jubilee

    2017-07-01

    To determine the efficacy of chemotherapy after failed initial treatment in patients with high risk gestational trophoblastic neoplasia (GTN). We performed a retrospective IRB-approved chart review of all patients with GTN seen at a single institution from 1985 to 2015, including all patients who failed initial treatment. We summarized clinical characteristics with descriptive statistics and estimated progression-free survival (PFS) and overall survival (OS) with the Kaplan-Meier method. Of 68 identified patients, 38 required >2 chemotherapy regimens. Patients were treated for GTN (n=53), including choriocarcinoma, persistent GTN, and invasive mole; for placental site trophoblastic tumor (PSTT) (n=5); and for intermediate trophoblastic tumor (ITT) (n=10). Patients with GTN had a median of 2 salvage regimens, median PFS of 4.0months, and median OS was not reached at median follow-up of 71.2months. Active regimens included EMACO, MAC, BEP, platinum- and etoposide-based combination therapies, and ICE; 8 of 53 patients died of disease (DOD). Patients with PSTT had a median of 3 salvage regimens, median PFS of 2.8months, and median OS of 38.8months. Active regimens included ICE and EMA-EP; 4 of 5 patients DOD. Patients with ITT had a median of 3 salvage regimens, median PFS of 4.1months, and median OS of 38.2months. Active regimens included liposomal doxorubicin, platinum-containing regimens, EMA-CO, and EMA-EP; 7 of 10 patients DOD. Several salvage chemotherapy regimens demonstrate activity in high risk GTN. Multiple regimens may be required and cure is not universal. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Fatal Cases of Gestational Trophoblastic Neoplasia in a National Trophoblastic Disease Reference Center in Dakar Senegal.

    PubMed

    Gueye, Mamour; Ndiaye-Gueye, Mame Diarra; Kane Gueye, Serigne Modou; Moreau, Jean Charles

    2016-01-01

    The objectives of this study were to analyze deaths after gestational trophoblastic neoplasia and to determine the factors of treatment failure. This is a retrospective study in Aristide Le Dantec teaching Hospital in Dakar, Senegal, between 1 January 2006 and 31 December 2014. We took into account socio-epidemiological characteristics of patients, initial diagnosis, time between uterine evacuation and admission, time to onset of gestational trophoblastic neoplasia (GTN), treatment received (deadlines, protocols), difficulties experienced in the diagnosis and the initiation of treatment and survival. In total, 1044 patients were admitted during the study period; 164 cases of GTN were diagnosed (15.7%); and 21 deaths occurred leading to a specific lethality of 12.8%. The average age was 30 years. Almost all patients (n = 18; 85.7%) had low income or no income. Eight out of 21 patients (38.1%) were seen in our department after GTN onset. The mean time to onset of GTN of all patients was 22.1 weeks. For 66.6%, histology was not available; the diagnosis of hydatidiform mole was made on the clinical history and sonographic features and GTN on human chorionic gonadotrophin (hCG) evolution and ultrasound findings. None of the patients had regular chemotherapy due to financial reasons. Patients who died within 3 months after diagnosis had metastatic tumors (7 of 21). All these women had resistance to treatment or progressed after three courses of chemotherapy. Ten of the 12 women with high-risk GTN were not treated with multi-agent chemotherapy (EMA-CO) for purely financial reasons. The high incidence and mortality require a profound reorganization of our health system and a high awareness of practitioners to refer to time or to declare all suspected cases of hydatidiform mole or gestational trophoblastic neoplasia.

  9. Changing presentation of complete hydatidiform mole at the New England Trophoblastic Disease Center over the past three decades: does early diagnosis alter risk for gestational trophoblastic neoplasia?

    PubMed

    Sun, Sue Yazaki; Melamed, Alexander; Goldstein, Donald P; Bernstein, Marilyn R; Horowitz, Neil S; Moron, Antonio Fernandes; Maestá, Izildinha; Braga, Antonio; Berkowitz, Ross S

    2015-07-01

    To compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among recent (1994-2013) and historical (1988-1993) cases of complete hydatidiform mole (CHM). This study included two non-concurrent cohorts (1988-1993 versus 1994-2013) of patients from the New England Trophoblastic Disease Center (NETDC). Clinical and pathologic reports of patients diagnosed with CHM between 1994 and 2013 were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin (hCG) levels, and the rate of progression to GTN were compared. In the current cohort (1994 to 2013) the median gestational age at diagnosis continued to decline compared to our prior cohort (1988-1993) (9weeks versus 12weeks). Patients from the current cohort were significantly more likely to be diagnosed prior to the 11th week of gestation (56 versus 41%, p=0.04). Patients in the current cohort were also significantly less likely to present with vaginal bleeding (46 versus 84%, p<0.001). Earlier diagnosis of complete mole did not result in a decrease in the rate of postmolar GTN. The frequencies of postmolar GTN in the current (1994-2013) and prior (1988-1993) cohorts were 19 and 23%, respectively. In the current cohort, even diagnosis prior to ten weeks gestation did not decrease the risk of developing GTN. This study indicates that complete mole continues to be diagnosed progressively earlier resulting in a further decrease in some classical presenting symptoms. However, despite earlier detection, the risk of development of postmolar GTN has not been affected. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Gestational Trophoblastic Neoplasia Treatment at the Butaro Cancer Center of Excellence in Rwanda

    PubMed Central

    Nzayisenga, Ignace; Segal, Roanne; Pritchett, Natalie; Xu, Mary J.; Park, Paul H.; Mpanumusingo, Edgie V.; Umuhizi, Denis G.; Goldstein, Donald P.; Berkowitz, Ross S.; Hategekimana, Vedaste; Muhayimana, Clemence; Rubagumya, Fidel; Fadelu, Temidayo; Tapela, Neo; Mpunga, Tharcisse

    2016-01-01

    Purpose Gestational trophoblastic neoplasia (GTN) is a highly treatable disease, most often affecting young women of childbearing age. This study reviewed patients managed for GTN at the Butaro Cancer Center of Excellence (BCCOE) in Rwanda to determine initial program outcomes. Patients and Methods A retrospective medical record review was performed for 35 patients with GTN assessed or treated between May 1, 2012, and November 30, 2014. Stage, risk score, and low or high GTN risk category were based on International Federation of Gynecology and Obstetrics staging and the WHO scoring system and determined by beta human chorionic gonadotropin level, chest x-ray, and ultrasound per protocol guidelines for resource-limited settings. Pathology reports and computed tomography scans were assessed when possible. Treatment was based on a predetermined protocol stratified by risk status. Results Of the 35 patients (mean age, 32 years), 26 (74%) had high-risk and nine (26%) had low-risk disease. Nineteen patients (54%) had undergone dilation and curettage and 11 (31%) had undergone hysterectomy before evaluation at BCCOE. Pathology reports were available in 48% of the molar pregnancy surgical cases. Systemic chemotherapy was initiated in 30 of the initial 35 patients: 13 (43%) received single-agent oral methotrexate, 15 (50%) received EMACO (etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine), and two (7%) received alternate regimens. Of the 13 patients initiating methotrexate, three had their treatment intensified to EMACO. Four patients experienced treatment delays because of medication stockouts. At a median follow-up of 7.8 months, the survival probability for low-risk patients was 1.00; for high-risk patients, it was 0.63. Conclusion This experience demonstrates the feasibility of GTN treatment in rural, resource-limited settings. GTN is a curable disease and can be treated following the BCCOE model of cancer care. PMID:28717722

  11. Pentaerythrityl tetranitrate and nitroglycerin, but not isosorbide mononitrate, prevent endothelial dysfunction induced by ischemia and reperfusion.

    PubMed

    Dragoni, Saverio; Gori, Tommaso; Lisi, Monica; Di Stolfo, Giuseppe; Pautz, Andrea; Kleinert, Hartmut; Parker, John D

    2007-09-01

    Short term exposure to nitroglycerin (GTN) has protective properties that are similar to ischemic preconditioning. Whether other organic nitrates such as pentaerithrityl tetranitrate (PETN) and isosorbide mononitrate (ISMN) have similar protective effects has not been explored. In a randomized, parallel, double blind, controlled trial, 37 healthy young volunteers received no therapy (n=10), transdermal GTN 1.2 mg for 2 hours (n=9), PETN 80 mg (n=9), or ISMN 40 mg (n=9). Twenty-four hours later, endothelium-dependent flow-mediated vasodilation (FMD) was measured before and after local exposure to ischemia and reperfusion (IR). In the no therapy group, IR blunted FMD (FMD after IR: 1.9+/-0.6%, P<0.05), an effect that was prevented by GTN (FMD after IR: 5.3+/-1.4%, P<0.05 compared with no therapy). PETN had the same protective effect (FMD after IR: 8.1+/-1.3%, P<0.05 compared with no therapy), whereas ISMN had no significant pharmacological preconditioning effect (FMD after-IR: 3.6+/-0.8%, P=ns compared with no therapy). While it blocked the effect of GTN, Vitamin C (n=8) did not modify PETN preconditioning (FMD after IR: 6.3+/-0.9%, P=ns compared with before IR), showing that this phenomenon is not mediated by oxygen free radical production. In an effort to identify the mechanism of PETN preconditioning, isolated human endothelial cells were incubated with PETN, GTN, or ISMN. Only PETN induced expression of the genes encoding for heme oxygenase and ferritin, which have been involved in ischemic and pharmacological preconditioning. We show important differences among organic nitrates in their capacity to prevent IR-induced endothelial dysfunction. GTN and PETN, but not ISMN, have this preconditioning effect. The potential clinical implications of these data warrant further investigation.

  12. Effect of heme oxygenase-1 gene promoter polymorphism on cancer risk by histological subtype: A prospective study in arseniasis-endemic areas in Taiwan.

    PubMed

    Wu, Meei-Maan; Lee, Chih-Hung; Hsu, Ling-I; Cheng, Wen-Fang; Lee, Te-Chang; Wang, Yuang-Hung; Chiou, Hung-Yi; Chen, Chien-Jen

    2016-04-15

    Heme oxygenase (HO)-1 is upregulated by many stressful stimuli, including arsenic. A GT-repeat ((GT)n) polymorphism in the HO-1 gene promoter inversely modulates the levels of HO-1 induction. Previous HO-1 (GT)n polymorphism studies in relation to cancer risk have shown disparate results. We prospectively investigated the associations between HO-1 (GT)n polymorphism and cancer risk related to arsenic from drinking water. Totally, 1,013 participants from community-based cohorts of arseniasis-endemic areas in Taiwan were followed for 13 years. Allelic polymorphisms were classified into long (L, ≥ 27 (GT)n) and short (S, <27 (GT)n). Newly developed cases were identified through linkage with National Cancer Registry of Taiwan. Multivariate Cox proportional hazard methods were used to evaluate effects of the HO-1 polymorphism alone or combined with arsenic exposure. Results showed that participants with the S/S genotype had an increased risk of Bowen's disease (HR = 10.49; 95% CI: 2.77-39.7), invasive skin cancer (HR = 2.99; 95% CI: 1.13-7.87), and lung squamous cell carcinoma (HR = 3.39; 95% CI: 1.15-9.95) versus those with L/S or L/L genotype. The S/S genotype combined with high arsenic exposure (>300 μg/L) had a greater risk of skin cancer compared to the genotype alone. Consistent with previous findings, participants with the S-allele had a reduced risk of lung adenocarcinoma (HR = 0.21; 95% CI: 0.03-0.68) versus those with L/L genotype. There were no significant differences in risk of urothelial carcinoma among the three genotypes. Associations of HO-1 (GT)n polymorphism with cancer risk differs by histological subtype and the polymorphism should be considered a modifier in the risk assessment of arsenic exposure.

  13. The Canoe Ridge Natural Gas Storage Project

    SciTech Connect

    Reidel, Steve P.; Spane, Frank A.; Johnson, Vernon G.

    2003-06-18

    In 1999 the Pacific Gas and Electric Gas Transmission Northwest (GTN) drilled a borehole to investigate the feasibility of developing a natural gas-storage facility in a structural dome formed in Columbia River basalts in the Columbia Basin of south-central Washington State. The proposed aquifer storage facility will be an unconventional one where natural gas will be initially injected (and later retrieved) in one or multiple previous horizons (interflow zones) that are confined between deep (>700 meters) basalt flows of the Columbia River Basalt Group. This report summarizes the results of joint investigations on that feasibility study by GTN and the US Department of Energy.

  14. Choriocarcinoma in Ongoing Pregnancy Presenting with Intracranial Metastasis

    PubMed Central

    Suri, Vanita; Sikka, Pooja; Aggarwal, Neelam; Chopra, Seema

    2016-01-01

    Choriocarcinoma presents usually as persistent trophoblastic disease, with prognosis worsening with duration from antecedent pregnancy. We present a unique case of a woman with choriocarcinoma who presented in the third trimester of pregnancy with eclampsia. She was managed with magnesium sulphate and underwent a caesarean section. However, she developed seizures in the post-partum period that were further investigated and attributed to intracranial metastatic lesions of Gestational Trophoblastic Neoplasia (GTN). We discussed the diagnostic challenge in this rare case of GTN and the grave potential it can have in such a presentation, as in our patient. PMID:28050451

  15. Modeling of void coalescence initiation and its impact on the prediction of material failure

    NASA Astrophysics Data System (ADS)

    Msolli, Sabeur; Bettaieb, Mohamed Ben; Abed-Meraim, Farid

    2016-10-01

    In the present paper, Thomason's criterion is coupled with the well-known Gurson-Tvergaard-Needleman (GTN) damage model and used for the determination of the critical void volume fraction fc, which marks the initiation of the coalescence stage. The onset of void coalescence predicted by Thomason's criterion is compared to that obtained by using a predefined fc, which is usually fitted on the basis of experimental results, as originally proposed in the GTN model. Comparisons are made in terms of both single finite element simulations and numerical results of deep drawing of a cup.

  16. Respiratory Toxicology: 1981

    DTIC Science & Technology

    1981-08-01

    therapeutic (vasodilation) effect on angina pectoris (Kalin and Kylin, 1969). It was found that PGDN, EGDN and GTN all were competitive inhibitors of MAO...when expo- sure stops, causes an angina -like effect. In severe cases, vascular spasm may then be followed by death when exposure ceases. Behavorial

  17. Shock Wave-Stimulated Periosteum for Cartilage Repair

    DTIC Science & Technology

    2013-12-01

    were added to the Gtn-HPA prior to the gelation 6 process, at a cell density of 1×105 cells/ml. In the control groups, cells received no treatment...Mesenchymal Stem Cell Viability Viability test was performed 24 hours post- gelation using the Live/Dead assay. Viability/cytotoxicity kit was used (Molecular

  18. 77 FR 48132 - Gas Transmission Northwest, LLC; Notice of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-13

    ... Energy Regulatory Commission Gas Transmission Northwest, LLC; Notice of Application Take notice that on July 31, 2012, Gas Transmission Northwest, LLC (GTN), filed in Docket No. CP12-494-000, an application... directed to Mr. Richard Parke, Manager, Certificates, Gas Transmission Northwest, LLC, 717 Texas...

  19. A comparison of patients with relapsed and chemo-refractory gestational trophoblastic neoplasia

    PubMed Central

    Powles, T; Savage, P M; Stebbing, J; Short, D; Young, A; Bower, M; Pappin, C; Schmid, P; Seckl, M J

    2007-01-01

    The majority of women requiring chemotherapy for gestational trophoblastic disease (GTN) are cured with their initial chemotherapy treatment. However, a small percentage either become refractory to treatment, or relapse after the completion of treatment. This study investigates the characteristics and outcome of these patients. Patients were identified from the Charing Cross Hospital GTD database. The outcome of these patients with relapsed disease was compared to those with refractory disease. Between 1980 and 2004, 1708 patients were treated with chemotherapy for GTN. Sixty (3.5%) patents relapsed following completion of initial therapy. The overall 5-year survival for patients with relapsed GTN was 93% (95% CI 86–100%). The overall survival for patients with low-risk and high-risk disease at presentation, who subsequently relapsed was 100% (n=35), and 84% (n=25) (95% CI: 66–96%: P<0.05), respectively. Eleven patients were identified who failed to enter remission and had refractory disease. These patients had a worse outcome compared to patients with relapsed disease (5-year survival 43% (95% CI:12–73% P<0.01)). The outcome of patients with relapsed GTN is good. However, patients with primary chemo-refractory disease do poorly and novel therapies are required for this group of patients. PMID:17299394

  20. Diagnosis, Treatment and Outcome of Gestational Trophoblastic Neoplasia in a Low Resource Income Country.

    PubMed

    Gueye, Mamour; Ndiaye-Gueye, Mame D; Kane-Gueye, Serigne M; Gassama, Omar; Diallo, Moussa; Moreau, Jean C

    2016-01-01

    Gestational trophoblastic disease (GTD) is a disease of the proliferative trophoblastic allograft. Diagnosis and treatment of GTN in low resource-income countries is challenging due to numerous factors. The objective of this study was to review outcomes of gestational trophoblastic neoplasia in women of low socioeconomic status with limited resources and social support. This study was performed at Gynecologic and Obstetric Clinic of Dakar Teaching Hospital, the reference Centre of Gestational trophoblastic diseases in Senegal from 2006 to 2015. Out of 1088 patients followed for gestational trophoblastic disease during the study period, 108 patients were diagnosed and treated for GTN: 88 low-risk and 20 high-risk. Low-risk patients received an average of 6.9 cycles of initial single-agent chemotherapy. Twelve patients had persistent disease and were switched to a second line multi-agent chemotherapy. Finally 94.3% of low-risk patients achieved remission. All high-risk patients were initially treated with multi-agent chemotherapy, averaging 7 cycles. Five of the eighty-eight low-risk patients and twelve of the 20 high-risk patients died of disease. Early adequate treatment ensures an excellent prognosis for patients with GTN. In low-income countries, difficulties encountered in diagnosis and treatments worsen the prognosis of GTN patients. Clinical trials are needed to find out affordable schedules or drugs for a better treatment.

  1. The Role of Surgery in the Management of Gestational Trophoblastic Neoplasia The Hungarian Experience.

    PubMed

    Fülöp, Vilmos; Szigetvári, Iván; Szepesi, János; Végh, György; Zsirai, László; Berkowitz, Ross S

    2016-01-01

    To review the role of surgery in the management of gestational trophoblastic neoplasia (GTN) over the past 38 years in our national trophoblastic disease center. Between January 1, 1977, and December 31, 2014, 371 patients with low-risk GTN and 190 patients with high-risk GTN were treated with chemotherapy, surgical interventions, or both. The indications for hysterectomy included excision of large uterine tumor masses, uterine hemorrhage or sepsis, or a drug-resistant uterine focus. Metastases were excised due to the presence of drug-resistant foci or complications of disease such as hemorrhage. Over the period of 1977-2014 74 hysterectomies, 15 resections of vaginal metastases, 3 omentectomies, 13 adnexectomies, 9 lung resections, I nephrectomy, 1 lung resection and nephrectomy, and 2 craniotomies were performed among our patients. While hysterectomy was performed in 51 (26.8%) of 190 high-risk patients, hysterectomy was performed in only 23 (6.2%) of 371 low-risk patients (p < 0.01). From 1977-2006 metastases were resected in 18.3% (26/142) and from 2007-2014 in 16.7% (8/48) of high-risk patients. In our center surgery, particularly in the form of hysterectomy, still plays a valuable role in the management of both low- and high-risk GTN.

  2. Triploidy—Observations in 154 Diandric Cases

    PubMed Central

    Scholz, Nanna Brink; Bolund, Lars; Nyegaard, Mette; Faaborg, Louise; Jørgensen, Mette Warming; Lund, Helle; Niemann, Isa; Sunde, Lone

    2015-01-01

    Hydatidiform moles (HMs) are abnormal human pregnancies with vesicular chorionic villi, imposing two clinical challenges; miscarriage and a risk of gestational trophoblastic neoplasia (GTN). The parental type of most HMs are either diandric diploid (PP) or diandric triploid (PPM). We consecutively collected 154 triploid or near-triploid samples from conceptuses with vesicular chorionic villi. We used analysis of DNA markers and/or methylation sensitive-MLPA and collected data from registries and patients records. We performed whole genome SNP analysis of one case of twinning (PP+PM).In all 154 triploids or near-triploids we found two different paternal contributions to the genome (P1P2M). The ratios between the sex chromosomal constitutions XXX, XXY, and XYY were 5.7: 6.9: 1.0. No cases of GTN were observed. Our results corroborate that all triploid human conceptuses with vesicular chorionic villi have the parental type P1P2M. The sex chromosomal ratios suggest approximately equal frequencies of meiosis I and meiosis II errors with selection against the XYY conceptuses or a combination of dispermy, non-disjunction in meiosis I and meiosis II and selection against XYY conceptuses. Although single cases of GTN after a triploid HM have been reported, the results of this study combined with data from previous prospective studies estimate the risk of GTN after a triploid mole to 0% (95% CI: 0–1,4%). PMID:26562155

  3. Triploidy--Observations in 154 Diandric Cases.

    PubMed

    Scholz, Nanna Brink; Bolund, Lars; Nyegaard, Mette; Faaborg, Louise; Jørgensen, Mette Warming; Lund, Helle; Niemann, Isa; Sunde, Lone

    2015-01-01

    Hydatidiform moles (HMs) are abnormal human pregnancies with vesicular chorionic villi, imposing two clinical challenges; miscarriage and a risk of gestational trophoblastic neoplasia (GTN). The parental type of most HMs are either diandric diploid (PP) or diandric triploid (PPM). We consecutively collected 154 triploid or near-triploid samples from conceptuses with vesicular chorionic villi. We used analysis of DNA markers and/or methylation sensitive-MLPA and collected data from registries and patients records. We performed whole genome SNP analysis of one case of twinning (PP+PM).In all 154 triploids or near-triploids we found two different paternal contributions to the genome (P1P2M). The ratios between the sex chromosomal constitutions XXX, XXY, and XYY were 5.7: 6.9: 1.0. No cases of GTN were observed. Our results corroborate that all triploid human conceptuses with vesicular chorionic villi have the parental type P1P2M. The sex chromosomal ratios suggest approximately equal frequencies of meiosis I and meiosis II errors with selection against the XYY conceptuses or a combination of dispermy, non-disjunction in meiosis I and meiosis II and selection against XYY conceptuses. Although single cases of GTN after a triploid HM have been reported, the results of this study combined with data from previous prospective studies estimate the risk of GTN after a triploid mole to 0% (95% CI: 0-1,4%).

  4. Department of Defense In-Transit Visibility Modifications

    DTIC Science & Technology

    2013-05-23

    14. ABSTRACT Extending operational reach within a Defense Support of Civil Authorities (DSCA) environment demands a comprehensive procurement...VISIBILITY MODIFICATIONS, by Major Charles L. Montgomery, 49 pages. Extending operational reach within a Defense Support of Civil Authorities...GAO U.S. Government Accountability Office GATES Global Air Transportation Execution System GTN Global Transportation Network HD Homeland

  5. Emerging Anticancer Potentials of Goniothalamin and Its Molecular Mechanisms

    PubMed Central

    Bukhari, Syed Nasir Abbas

    2014-01-01

    The treatment of most cancers is still inadequate, despite tremendous steady progress in drug discovery and effective prevention. Nature is an attractive source of new therapeutics. Several medicinal plants and their biomarkers have been widely used for the treatment of cancer with less known scientific basis of their functioning. Although a wide array of plant derived active metabolites play a role in the prevention and treatment of cancer, more extensive scientific evaluation of their mechanisms is still required. Styryl-lactones are a group of secondary metabolites ubiquitous in the genus Goniothalamus that have demonstrated to possess antiproliferative activity against cancer cells. A large body of evidence suggests that this activity is associated with the induction of apoptosis in target cells. In an effort to promote further research on the genus Goniothalamus, this review offers a broad analysis of the current knowledge on Goniothalamin (GTN) or 5, 6, dihydro-6-styryl-2-pyronone (C13H12O2), a natural occurring styryl-lactone. Therefore, it includes (i) the source of GTN and other metabolites; (ii) isolation, purification, and (iii) the molecular mechanisms of actions of GTN, especially the anticancer properties, and summarizes the role of GTN which is crucial for drug design, development, and application in future for well-being of humans. PMID:25247178

  6. Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates.

    PubMed

    Lisi, Monica; Oelze, Matthias; Dragoni, Saverio; Liuni, Andrew; Steven, Sebastian; Luca, Mary-Clare; Stalleicken, Dirk; Münzel, Thomas; Laghi-Pasini, Franco; Daiber, Andreas; Parker, John D; Gori, Tommaso

    2012-06-01

    Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure. In a randomized, investigator-blind parallel trial, 30 healthy (age 25-32) volunteers were randomized to receive (1) transdermal GTN (0.6 mg/h) administered for 2 h a day for 6 days; (2) oral PETN (80 mg) once a day for 6 days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8 ± 2.1%; after IR 1.0 ± 2.1%; P < 0.01). Daily, 2-h exposure to GTN partially prevented IR-induced endothelial dysfunction (FMD before IR: 7.7 ± 2.4%; after IR 4.3 ± 3.0%; P < 0.01 compared to before IR). In contrast, daily PETN administration afforded greater protection from IR-induced endothelial injury (FMD before IR: 7.9 ± 1.7%; after IR 6.4 ± 5.3%, P = ns; P < 0.05 ANOVA across groups). In vitro, incubation of human endothelial cells with GTN (but not PETN) was associated with inhibition (P < 0.01) of aldehyde dehydrogenase, an enzyme that is important for both nitrate biotransformation and ischemic preconditioning. We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in

  7. Rifabutin-loaded solid lipid nanoparticles for inhaled antitubercular therapy: Physicochemical and in vitro studies.

    PubMed

    Gaspar, Diana P; Faria, Vasco; Gonçalves, Lídia M D; Taboada, Pablo; Remuñán-López, Carmen; Almeida, António J

    2016-01-30

    Systemic administration of antitubercular drugs can be complicated by off-target toxicity to cells and tissues that are not infected by Mycobacterium tuberculosis . Delivery of antitubercular drugs via nanoparticles directly to the infected cells has the potential to maximize efficacy and minimize toxicity. The present work demonstrates the potential of solid lipid nanoparticles (SLN) as a delivery platform for rifabutin (RFB). Two different RFB-containing SLN formulations were produced using glyceryl dibehenate or glyceryl tristearate as lipid components. Full characterization was performed in terms of particle size, encapsulation and loading efficiency, morphology by transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) studies. Physical stability was evaluated when formulations were stored at 5 ± 3°C and in the freeze-dried form. Formulations were stable throughout lyophilization without significant variations on physicochemical properties and RFB losses. The SLN showed to be able to endure harsh temperature conditions as demonstrated by dynamic light scattering (DLS). Release studies revealed that RFB was almost completely released from SLN. In vitro studies with THP1 cells differentiated in macrophages showing a nanoparticle uptake of 46 ± 3% and 26 ± 9% for glyceryl dibehenate and glyceryl tristearate SLN, respectively. Cell viability studies using relevant lung cell lines (A549 and Calu-3) revealed low cytotoxicity for the SLN, suggesting these could be new potential vehicles for pulmonary delivery of antitubercular drugs.

  8. 21 CFR 172.832 - Monoglyceride citrate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION... monooleate and its citric acid monoester manufactured by the reaction of glyceryl monooleate with citric acid... percent-17 percent. (b) It is used, or intended for use, in antioxidant formulations for addition to...

  9. 21 CFR 172.832 - Monoglyceride citrate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.832... manufactured by the reaction of glyceryl monooleate with citric acid under controlled conditions may be safely... use, in antioxidant formulations for addition to oils and fats whereby the additive does not...

  10. Assessing the Toxicity and Bioavailability of 2,4-Dinitroanisole in Acute and Sub-Chronic Exposures Using the Earthworm, Eisenia fetida

    DTIC Science & Technology

    2010-06-01

    different methods, 2nd method chosen for final study: ► Coelomocytes collected in 2 ml Guaiacol Glyceryl Ether ( GGE ) solution, centrifuged, decanted...worm to GGE t= 2mins collect coelomocyte solution 1 row per worm/treatment, obtain measurements through spectrophotometer NRRT analysis 1) 2) BUILDING

  11. 21 CFR 177.2800 - Textiles and textile fibers.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... this chapter. Di-tert-butyl hydroquinone Dimethylpolysiloxane Ethylenediaminetetraacetic acid, sodium... glycol Sodium hydroxide Sulfuric acid Formaldehyde For use as preservative only. Glyceryl mono-12... prescribed under 21 CFR 178.3740(b) of this chapter. Polyethylene, oxidized (air blown) Polyvinyl acetate...

  12. 21 CFR 184.1901 - Triacetin.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... as 1,2,3,-propanetriol triacetate or glyceryl triacetate, is the triester of glycerin and acetic acid. Triacetin can be prepared by heating glycerin with acetic anhydride alone or in the presence of finely... mixture of allyl acetate and acetic acid using a bromide salt as a catalyst. (b) The ingredient meets the...

  13. Investigations into the chemistry and insecticidal activity of euonymus europaeus seed oil and methanol extract

    USDA-ARS?s Scientific Manuscript database

    Euonymus europaeus seeds and seed oil were investigated for their volatiles using GC-MS-FID, Headspace-SPME/GC-MS-FID, and derivative GC-MS-FID for their volatiles and HPLC-DAD-CAD/MS for their non-volatile compounds. The seeds contain about 30% of fatty oil, mainly glyceryl trioleate, small amounts...

  14. Viscous lubricant composition comprising mixed esters and a silicone oil

    SciTech Connect

    Ayres, P.J.

    1981-03-03

    A viscous composition capable of substantially retaining its viscosity within a temperature range of from 5*-30* C. Comprising as its components diisopropyl adipate, a mixture of cetyl and stearyl octanoates, glyceryl tribehenate, silicone oil and a surfactant is described.

  15. 21 CFR 175.210 - Acrylate ester copolymer coating.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... emulsion defoamer. Disodium hydrogen phosphate Do. Formaldehyde Glyceryl monostearate Methyl cellulose... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Acrylate ester copolymer coating. 175.210 Section 175.210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  16. 21 CFR 175.210 - Acrylate ester copolymer coating.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... emulsion defoamer. Disodium hydrogen phosphate Do. Formaldehyde Glyceryl monostearate Methyl cellulose... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Acrylate ester copolymer coating. 175.210 Section 175.210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  17. 21 CFR 175.210 - Acrylate ester copolymer coating.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., and methacrylic acid applied in emulsion form to molded virgin fiber and heat-cured to an insoluble... application of the emulsion may include substances named in this paragraph, in an amount not to exceed that... emulsion defoamer. Disodium hydrogen phosphate Do. Formaldehyde Glyceryl monostearate Methyl cellulose...

  18. 21 CFR 175.210 - Acrylate ester copolymer coating.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., and methacrylic acid applied in emulsion form to molded virgin fiber and heat-cured to an insoluble... application of the emulsion may include substances named in this paragraph, in an amount not to exceed that... emulsion defoamer. Disodium hydrogen phosphate Do. Formaldehyde Glyceryl monostearate Methyl cellulose...

  19. Antihistamine Effect of a Pure Bioactive Compound Isolated from Slug (Diplosolenodes occidentalis) Material

    PubMed Central

    Jacob, AS; Simon, OR; Wheatle, D; Ruddock, P; McCook, K

    2014-01-01

    ABSTRACT Objective: Folklore claims of the therapeutic effect of garden slug (Diplosolenodes occidentalis) extract used to relieve bronchoconstriction in asthmatic individuals were never validated scientifically. The aim of this study was to isolate the pure bioactive compound from slug extract causing this effect. Methods: The crude ground material was prepared in ethanol and after filtration, separation by flash column chromatography method was done. The structure was elucidated by data from hydrogen and carbon nuclear magnetic resonance (NMR) profiles. The bioactive compound was assessed for dose dependent response effects on guinea pig tracheal smooth muscle pre-contracted with histamine. Receptor specificity studies were done by using HTMT dimaleate (H1 agonist). The type of antagonism was also identified. Results: The pure component isolated from garden slug material was identified by spectral studies as glyceryl trilinolenate. It caused dose-dependent relaxation in guinea pig tracheal smooth muscle strips pre-contracted with histamine, it acted via H1 type receptors and showed non-competitive antagonism. Conclusion: Glyceryl trilinolenate produced dose-dependent relaxation in tracheal smooth muscle strips in the presence of the agonist histamine. Glyceryl trilinolenate displayed non-competitive antagonism at H1 receptors in the trachea. This agent was able to alleviate bronchoconstriction in individuals presenting with atopic asthma in rural agricultural areas in Jamaica (verbal communications). It is possible that glyceryl trilinolenate can be used therapeutically to produce tracheal smooth muscle relaxation in individuals presenting with atopic asthma. PMID:25781274

  20. Presence of the methylenetetrahydrofolate reductase gene polymorphism MTHFR C677T in molar tissue but not maternal blood predicts failure of methotrexate treatment for low-risk gestational trophoblastic neoplasia.

    PubMed

    Qu, Jia; Usui, Hirokazu; Kaku, Hiroshi; Shozu, Makio

    2017-01-05

    Gestational trophoblastic neoplasia (GTN) is a rare tumor, and its genomic constitution is different from the maternal genome because of its gestational origin. Methotrexate (MTX) is a standard chemotherapeutic agent for low-risk GTN. An association between polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and MTX treatment outcome has been reported in various diseases. Thus, we examined the association between clinical outcome and MTHFR polymorphisms in both tumor and blood DNA of low-risk GTN patients. MTHFR C677T (rs1801133) and A1298C (rs1801131) were genotyped using high-resolution melting assays in 62 Japanese low-risk GTN patients and in 52 antecedent molar tissues. We compared the genotypes of MTHFR polymorphisms with the clinical outcome of 5-day MTX treatment. Twenty-five patients entered remission and 37 patients developed drug resistance or adverse effects that necessitated a drug change. The MTHFR 677T allele in molar tissue was significantly related to the need for drug change (P=0.006; odds ratio [OR], 3.13; 95% confidence interval [CI], 1.31-7.49), in contrast to MTHFR 1298C (P=0.18; OR, 0.63; 95% CI, 0.32-1.25). The MTHFR 677T and 1298C alleles obtained from patients' blood DNA were not related to MTX treatment outcome (P=0.49; OR 1.31; 95% CI, 0.61-2.91 and P=0.10; OR 0.52; 95% CI, 0.22-1.15, respectively). These data demonstrate for the first time that the genotype of MTHFR 677TT in molar tissue is associated with ineffective MTX treatment in Japanese low-risk GTN patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. LINE-1 Methylation Patterns as a Predictor of Postmolar Gestational Trophoblastic Neoplasia

    PubMed Central

    Lertkhachonsuk, Ruangsak; Paiwattananupant, Krissada; Tantbirojn, Patou; Rattanatanyong, Prakasit; Mutirangura, Apiwat

    2015-01-01

    Objective. To study the potential of long interspersed element-1 (LINE-1) methylation change in the prediction of postmolar gestational trophoblastic neoplasia (GTN). Methods. The LINE-1 methylation pattern from first trimester placenta, hydatidiform mole, and malignant trophoblast specimens were compared. Then, hydatidiform mole patients from 11999 to 2010 were classified into the following 2 groups: a remission group and a group that developed postmolar GTN. Specimens were prepared for a methylation study. The methylation levels and percentages of LINE-1 loci were evaluated for their sensitivity, specificity, and accuracy for the prediction of postmolar GTN. Results. First, 12 placentas, 38 moles, and 19 malignant trophoblast specimens were compared. The hydatidiform mole group had the highest LINE-1 methylation level (p = 0.003) and the uCuC of LINE-1 increased in the malignant trophoblast group (p ≤ 0.001). One hundred forty-five hydatidiform mole patients were classified as 103 remission and 42 postmolar GTN patients. The %mCuC and %uCmC of LINE-1 showed the lowest p value for distinguishing between the two groups (p < 0.001). The combination of the pretreatment β-hCG level (≥100,000 mIU/mL) with the %mCuC and %uCmC, sensitivity, specificity, PPV, NPV, and accuracy modified the levels to 60.0%, 92.2%, 77.4%, 83.8%, and 82.3%, respectively. Conclusions. A reduction in the partial methylation of LINE-1 occurs early before the clinical appearance of malignant transformation. The %mCuC and %uCmC of LINE-1s may be promising markers for monitoring hydatidiform moles before progression to GTN. PMID:26448937

  2. Chemotactic recruitment of adult neural progenitor cells into multifunctional hydrogels providing sustained SDF-1α release and compatible structural support.

    PubMed

    Lim, Teck Chuan; Rokkappanavar, Swetha; Toh, Wei Seong; Wang, Li-Shan; Kurisawa, Motoichi; Spector, Myron

    2013-03-01

    Without chemotactic cues and structural support, cavitary brain lesions typically fail to recruit endogenous neural progenitor cells (NPCs). Toward resolving this, we engineered multifunctional biomaterials comprising injectable gelatin-hydroxyphenylpropionic acid (Gtn-HPA) hydrogels and dextran sulfate/chitosan polyelectrolyte complex nanoparticles (PCNs) that delivered stromal cell-derived factor-1α (SDF-1α). Over 7 d of interface with in vitro tissue simulant containing adult rat hippocampal NPCs (aNPCs) and their neuronal progeny, Gtn-HPA/SDF-1α-PCN hydrogels promoted chemotactic recruitment to enhance infiltration of aNPCs by 3- to 45-fold relative to hydrogels that lacked SDF-1α or vehicles to sustain SDF-1α release. When cross-linked with 0.85-0.95 mM HO, Gtn-HPA/SDF-1α-PCN hydrogels provided optimally permissive structural support for migration of aNPCs. Specific matrix metalloproteinase (MMP) inhibitors revealed that 42, 30, and 55% of cell migration into Gtn-HPA/SDF-1α-PCN hydrogels involved MMP-2, 3, and 9, respectively, demonstrating the hydrogels to be compatible toward homing endogenous NPCs, given their expression of similar MMPs. Interestingly, PCNs utilized FGF-2 found in situ to induce chemokinesis, potentiate SDF-1α chemotactic recruitment, and increase proliferation of recruited cells, which collectively orchestrated a higher number of migrated aNPCs. Overall, Gtn-HPA/SDF-1α-PCN hydrogels prove to be promising biomaterials for injection into cavitary brain lesions to recruit endogenous NPCs and enhance neural tissue repair/regeneration.

  3. EMA-CO chemotherapy for high-risk gestational trophoblastic neoplasia: a clinical analysis of 54 patients.

    PubMed

    Lu, W-G; Ye, F; Shen, Y-M; Fu, Y-F; Chen, H-Z; Wan, X-Y; Xie, X

    2008-01-01

    This study was designed to analyze the outcomes of chemotherapy for high-risk gestational trophoblastic neoplasia (GTN) with EMA-CO regimen as primary and secondary protocol in China. Fifty-four patients with high-risk GTN received 292 EMA/CO treatment cycles between 1996 and 2005. Forty-five patients were primarily treated with EMA-CO, and nine were secondarily treated after failure to other combination chemotherapy. Adjuvant surgery and radiotherapy were used in the selected patients. Response, survival and related risk factors, as well as chemotherapy complications, were retrospectively analyzed. Thirty-five of forty-five patients (77.8%) receiving EMA-CO as first-line treatment achieved complete remission, and 77.8% (7/9) as secondary treatment. The overall survival rate was 87.0% in all high-risk GTN patients, with 93.3% (42/45) as primary therapy and 55.6% (5/9) as secondary therapy. The survival rates were significantly different between two groups (chi(2)= 6.434, P =0.011). Univariate analysis showed that the metastatic site and the number of metastatic organs were significant risk factors, but binomial distribution logistic regression analysis revealed that only the number of metastatic organs was an independent risk factor for the survival rate. No life-threatening toxicity and secondary malignancy were found. EMA-EP regimen was used for ten patients who were resistant to EMA-CO and three who relapsed after EMA-CO. Of those, 11 patients (84.6%) achieved complete remission. We conclude that EMA-CO regimen is an effective and safe primary therapy for high-risk GTN, but not an appropriate second-line protocol. The number of metastatic organs is an independent prognostic factor for the patient with high-risk GTN. EMA-EP regimen is a highly effective salvage therapy for those failing to EMA-CO.

  4. Formulation of lyotropic liquid crystal containing mulberry stem extract: influences of formulation ingredients on the formation and the nanostructure.

    PubMed

    Yhirayha, C; Soontaranon, S; Wittaya-Areekul, S; Pitaksuteepong, T

    2014-06-01

    This study focused on the formulation of lamellar lyotropic liquid crystal (LLC) loaded with mulberry stem extract (MSE). The LLC formulation tested used two oils: n-dodecane or tridecyl salicylate, a co-solvent (propylene glycol) and a single (PEG-7 glyceryl cocoate) or mixed surfactant system. The mixed surfactant was PEG-7 glyceryl cocoate/PEG-40 hydrogenated castor oil/glyceryl monooleate. The LLC formation and phase behaviour were observed by polarized optical microscopy (POM) before and after MSE loading. Nanostructure determinations on these formulations following MSE loading used small angle X-ray scattering (SAXS) at 25-40°C. Lamellar LLCs are formed more easily with n-dodecane than tridecyl salicylate. Propylene glycol, in the aqueous phase (1 : 1), failed to form LLC due to suboptimal critical packing parameter (CPP) value. A single or mixed surfactant system also influenced the formation of lamellar LLC according to the chemical structure of both oils and especially the surfactants used. The four lamellar LLC formulations selected for MSE loading were PEG-7 glyceryl cocoate/tridecyl salicylate/water; mixed surfactant/tridecyl salicylate/water; PEG-7 glyceryl cocoate/n-dodecane/water and mixed surfactant/n-dodecane/water, named F1, F2, F3 and F4, respectively. MSE in F1 and F3 did not affect the lamellar structure, while MSE in F2 and F4 enlarged the lamellar structure. The SAXS data confirmed that the LLC formulations obtained were lamellar and the structure persisted with MSE. These lamellar formulations should find widespread application for MSE and perhaps other similar herbal cosmetics. © 2014 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

  5. Changes in calcitonin gene-related peptide (CGRP) receptor component and nitric oxide receptor (sGC) immunoreactivity in rat trigeminal ganglion following glyceroltrinitrate pretreatment

    PubMed Central

    2013-01-01

    Background Nitric oxide (NO) is thought to play an important role in the pathophysiology of migraine. Infusion of the nitrovasodilator glyceroltrinitrate (nitroglycerin, GTN), which mobilizes NO in the organism, is an approved migraine model in humans. Calcitonin gene-related peptide (CGRP) is regarded as another key mediator in migraine. Increased plasma levels of CGRP have been found during spontaneous as well as nitrovasodilator-induced migraine attacks. The nociceptive processes and interactions underlying the NO and CGRP mediated headache are poorly known but can be examined in animal experiments. In the present study we examined changes in immunofluorescence of CGRP receptor components (CLR and RAMP1) and soluble guanylyl cyclase (sGC), the intracellular receptor for NO, in rat trigeminal ganglia after pretreatment with GTN. Methods Isoflurane anaesthetised rats were intravenously infused with GTN (1 mg/kg) or saline for four hours and two hours later the trigeminal ganglia were processed for immunohistochemistry. Different primary antibodies recognizing CLR, RAMP1, CGRP and sGC coupled to fluorescent secondary antibodies were used to examine immunoreactive cells in serial sections of trigeminal ganglia with epifluorescence and confocal laser scanning microscopy. Several staining protocols were examined to yield optimized immunolabeling. Results In vehicle-treated animals, 42% of the trigeminal ganglion neurons were immunopositive for RAMP1 and 41% for CLR. After GTN pretreatment CLR-immunopositivity was unchanged, while there was an increase in RAMP1-immunopositive neurons to 46%. RAMP1 and CLR immunoreactivity was also detected in satellite cells. Neurons immunoreactive for sGC were on average smaller than sGC-immunonegative neurons. The percentage of sGC-immunopositive neurons (51% after vehicle) was decreased after GTN infusion (48%). Conclusions Prolonged infusion of GTN caused increased fractions of RAMP1- and decreased fractions of s

  6. Reduction of aliphatic nitroesters and N-nitramines by Enterobacter cloacae PB2 pentaerythritol tetranitrate reductase: quantitative structure-activity relationships.

    PubMed

    Nivinskas, Henrikas; Sarlauskas, Jonas; Anusevicius, Zilvinas; Toogood, Helen S; Scrutton, Nigel S; Cenas, Narimantas

    2008-12-01

    Enterobacter cloacae PB2 NADPH:pentaerythritol tetranitrate reductase (PETNR) performs the biodegradation of explosive organic nitrate esters via their reductive denitration. In order to understand the enzyme substrate specificity, we have examined the reactions of PETNR with organic nitrates (n = 15) and their nitrogen analogues, N-nitramines (n = 4). The reactions of these compounds with PETNR were accompanied by the release of 1-2 mol of nitrite per mole of compound, but were not accompanied by their redox cycling and superoxide formation. The reduction rate constants (k(cat)/K(m)) of inositol hexanitrate, diglycerol tetranitrate, erythritol tetranitrate, mannitol hexanitrate and xylitol pentanitrate were similar to those of the established PETNR substrates, PETN and glycerol trinitrate, whereas the reactivities of hexahydro-1,3,5-trinitro-1,3,5-triazine and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine were three orders of magnitude lower. The log k(cat)/K(m) value of the compounds increased with a decrease in the enthalpy of formation of the hydride adducts [DeltaH(f)(R-O-N(OH)O(-)) or DeltaH(f)(R(1),R(2) > N-N(OH)O(-))], and with an increase in their lipophilicity (octanol/water partition coefficient, log P(ow)), and did not depend on their van der Waals' volumes. Hydrophobic organic nitroesters and hydrophilic N-nitramines compete for the same binding site in the reduced enzyme form. The role of the hydrophobic interaction of PETNR with glycerol trinitrate was supported by the positive dependence of glycerol trinitrate reactivity on the solution ionic strength. The discrimination of nitroesters and N-nitramines according to their log P(ow) values seems to be a specific feature of the Old Yellow Enzyme family of flavoenzymes.

  7. Chemoresistant Gestational Trophoblastic Neoplasia: A Case Report

    PubMed Central

    M, Sahana

    2014-01-01

    Gestational trophoblastic neoplasia (GTN) is a disease of women in reproductive age. It is one of the most chemotherapy responsive and highly curable cancer. It is diagnosed when there is clinical, radiologic, pathologic, and/or hormonal evidence of persistent or relapsed gestational trophoblastic disease. In most instances, it is cured by surgical evacuation of the uterus. If persistent, it is treated with chemotherapy which provides response in >90% of the cases. In the unresponsive persistent cases and if the women has completed her child bearing, hysterectomy is generally recommended. Here, we report a rare case of chemoresistant GTN which was confirmed to be placental-site trophoblastic tumour (PSTT) on biopsy. PMID:25177610

  8. Unusual Presentation of Hypothyroidism in a Pregnant Woman, Mimicking Gestational Trophoblastic Neoplasm

    PubMed Central

    Aminimoghaddam, Soheila; Mazloomi, Maryam; Rahimi, Maryam

    2016-01-01

    Hypothyroidism is a common health issue worldwide with varying clinical manifestations. We report a woman who experienced an incomplete abortion and undiagnosed hypothyroidism who was referred to the oncologist with the suspicion of metastatic gestational trophoblastic neoplasm (GTN). A 29-year-old woman with incomplete abortion was referred to an oncologist for possible GTN due to persistent active vaginal bleeding, an elevated beta human chorionic gonadotropin (hCG), abnormal cervical inspection exam, abnormal liver function tests, ovarian enlargement, ascites, and a pleural effusion. She was found to have hypothyroidism in further work-up. She was managed with thyroid hormone replacement therapy and her condition improved after 6 weeks. Complete resolution of the ovarian mass and pericardial and pleural effusion was achieved. This case describes an important experience; hypothyroidism should be considered in the differential diagnosis of any woman with an incomplete abortion presenting with an ovarian mass. Evaluation and correct diagnosis are important to prevent mismanagement. PMID:27034864

  9. The Global Terrestrial Network for Glaciers: an overview of recent activities

    NASA Astrophysics Data System (ADS)

    Arendt, Anthony

    2015-04-01

    The Global Terrestrial Network for Glaciers (GTN-G) is an organizational framework for three operational bodies dedicated to global mapping and monitoring of glacier changes. In this talk I will provide an overview of recent progress made by the World Glacier Monitoring Service (WGMS), the National Snow and Ice Data Center (NSIDC) and the Global Land Ice Measurements from Space (GLIMS) toward distribution and analysis of global in-situ and remotely sensed glacier observations. I will highlight new initiatives aimed at database integration, modernization of internet-based tools, and enhanced community outreach. These activities are helping to generate new discoveries in cryospheric studies, which I will illustrate through several example applications. Finally, I will outline a vision for future GTN-G efforts that will enable rapid response to anticipated glacier variations resulting from climate variability.

  10. Gestational trophoblastic tumor with liver metastasis after misoprostol abortion.

    PubMed

    Mousavi, S A; Behnamfar, F

    2009-04-01

    Early elective medical abortion is performed frequently in different countries of the world. Serious complications like gestational trophoblastic neoplasia (GTN) are uncommon and mostly nonmetastatic. High risk metastatic GTN following medical abortion is a rare event which may occur coincidentally. A 26 year-old-woman, gravida 2 para 1, 6 weeks after misoprostol abortion presented with sever nausea, vomiting, and right upper abdominal pain. Human chorionic gonadotropin (hCG) level was 2,500,000 mIU/ml and metastatic work up revealed multiple liver metastases. She totally received nine cycles of EMA-CO (ethoposide- methotrexate- actinomycin- cyclophosphamide, vincristine) regimen for treatment and consolidation. Six months after treatment she is in complete remission. Follow up of patients after medical abortion by means of single serum hCG measurement is highly recommended for early diagnosis of complications including gestational trophoblastic tumor. EMA-CO regimen seems to be an effective and safe treatment for liver metastatic gestational trophoblastic neoplasia.

  11. Clean Manufacture of 2,4,6-Trinitrotoluene (TNT) via Improved Regioselectivity in the Nitration of Toluene

    NASA Astrophysics Data System (ADS)

    Millar, Ross W.; Arber, Anthony W.; Endsor, Robert M.; Hamid, Javid; Eamon Colclough, M.

    2011-04-01

    The U.S. Department of Defense requires an environmentally benign synthesis route to manufacture military grade trinitrotoluene (TNT), which eliminates the production of red water arising from the sulfiting process for removing unsymmetrical trinitrotoluene isomers. We have found that by using a novel nitrating system, N2O5 in dichloromethane, the proportion of metasubstituted nitrotoluenes can be suppressed, and improvements have also been made to the di- and trinitration steps. As a result, TNT with a set point near that of the Mil. Spec. can be made by our process, without the need for sulfite washing; after recrystallization it exceeds the specification.

  12. Fluorinated Desensitizing Ingredients for Propellants

    DTIC Science & Technology

    1980-05-24

    Entered) 19. KEY WORDS (Continued) 20 ABSTRACT (Continued) Compound Structure 3-Fluoro-1,2- propanediol dinitrate FCH2CH(ONO2 )CH2ONO2 FDNP 3,3,3...Trifluoro-1,2- propanediol dinitrate F3 CCH(ONO2 )CH2ONO2 TFDNP 4,4,4-Trifluoro-l,2,3-butanetriol F3CCH(ONO 2 )CH(ONO2)CH2ONO 2 Trinitrate TFBTTN Preliminary...are potentially useful propellant ingredients. When compared with 1,2- propanediol dinitrate (DNP), which is currently used in Otto Fuel II, FDNP has a

  13. A study on the performance of ductile failure models under different range of stress triaxiality states with experimental validation

    NASA Astrophysics Data System (ADS)

    Amaral, Rui; Teixeira, Pedro; Azinpour, Erfan; Santos, Abel D.; César de Sá, J.

    2016-08-01

    In this work, experimental tests were carried out, under different loading conditions, in order to assess different ductile failure criteria, namely based on GTN, Johnson-Cook or Lemaitre models and to establish new proposals for improvement. Corresponding characterization for damage parameters is performed by an inverse analysis procedure, using reference experimental tests. Numerical simulations of a cross-shaped component are considered for the damage models, and results show a similar trend related with the experimental fracture evidence.

  14. Effect of nitroglycerine in popliteal preparations from patients with peripheral occlusive arteriopathy precontracted with KCl or 5-hydroxytryptamine.

    PubMed

    Ortega, Ana; Avellanal, Martin; España, Gabriel; Flores, Angel; Aleixandre, Amaya

    2003-08-01

    1. At the present time, there are no studies in isolated arteries from patients suffering from peripheral occlusive arteriopathy (POA). In the present study, we attempt to characterize the effect of nitroglycerine (GTN) in isolated popliteal preparations obtained after leg amputation in 60-90-year-old men and women suffering from POA. 2. After surgical operation, arterial samples were stored in a refrigerator at 4 degrees C and, after 12-36 h, they were cut into rings and mounted in organ baths containing Krebs'-Henseleit solution at 37 degrees C and gassed constantly with 95% CO2 and 5% O2. Because noradrenaline elicited very poor contractile responses in these preparations, in the present study we evaluated the concentration-dependent contractions induced by KCl (15-90 mmol/L) and 5-hydroxytryptamine (5-HT; 10-7 to 10-4 mol/L) in arteriopathic popliteal rings and, when the corresponding maximum contractile effect had been obtained, we also evaluated the concentration-dependent relaxing effect produced by GTN (10-10 to 10-5 mol/L) in all precontracted preparations. As a reference, similar experiments were performed in popliteal preparations obtained following surgery on non-arteriopathic vascular tissue where it was necessary to resect a certain percentage of healthy vessel. 3. The responses to KCl and 5-HT were greater in healthy vessel than in arteriopathic rings. The relaxing effect of GTN was greater in preparations precontracted with 5-HT than in those preparations precontracted with KCl. In addition, preparations precontracted with KCl relaxed even less when they were obtained from patients with POA. 4. The present data indicate that GTN is a vasodilator with little effect on depolarized arteries. The results also indicate that the effect of this drug is even less in depolarized arteries from patients with POA.

  15. Intransit Visibility: Capturing All the Source Data.

    DTIC Science & Technology

    1996-05-01

    was abandoned for apush system. Now with version 2.3, participating systems push information to an integrated database, which allows GTN to support a...Transportation (HOST) and the Global Decision Support System (GDSS). PRAMS "records non-unit passenger reservations, issues boarding passes, and generates...the terms of sale are free-on- board (FOB) destination (DoD, 1995: 3-15). Under FOB destination, the vendor delivers goods to a location specified by

  16. Uptake and Transformation of the Propellants 2,4-DNT, Perchlorate and Nitroglycerin by Grasses

    DTIC Science & Technology

    2006-07-31

    by performing hydroponic and soil experiments. The propellants 2,4-dinitrotoluene (2,4-DNT), perchlorate and nitroglycerin (GTN) often contaminate...firing ranges due to partially detonated ordnances and incomplete combustion of munitions. In hydroponic experiments, sorption of 2,4-DNT to roots was...and big bluestem (Andropogon gerardii) in the clean-up of propellant contaminated soil was assessed by performing hydroponic and soil experiments. The

  17. Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia.

    PubMed

    Lybol, C; Sweep, F C G J; Harvey, R; Mitchell, H; Short, D; Thomas, C M G; Ottevanger, P B; Savage, P M; Massuger, L F A G; Seckl, M J

    2012-06-01

    Methotrexate (MTX) alternating with folinic acid is a commonly used treatment regimen for low-risk gestational trophoblastic neoplasia (GTN). In The Netherlands, two courses of MTX are administered after normalization of serum human chorionic gonadotrophin (hCG) levels (consolidation courses), whereas in the United Kingdom, three consolidation courses are given. In a retrospective setting we compared relapse rates of women completing MTX therapy for low-risk GTN in The Netherlands and the UK. From 1980 to 2008, 351 patients were collected from the Dutch Central Registry for Hydatidiform Moles and records from the Dutch Working Party on Trophoblastic Disease. From the Charing Cross Hospital Trophoblast Disease Centre (London), 600 low-risk GTN patients were identified from 1992 to 2008. In 4.0% of patients relapse occurred after MTX treatment with three consolidation courses, whereas 8.3% of patients relapsed after MTX treatment with two consolidation courses (p=0.006). Although patients from The Netherlands had a higher level of hCG (p<0.001) and more patients had metastases before the start of treatment (p=0.012), the number of courses of MTX to achieve a normal hCG did not differ significantly between patients from The Netherlands and the UK (p=0.375). Relapse rates were higher in patients treated with two consolidation courses of MTX. Although other factors might have influenced the observed difference in relapse rates, three courses of consolidation chemotherapy may be preferable to two in the treatment of low-risk GTN in order to decrease the risk of disease relapse. A prospective randomized study would be required to confirm these findings. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Epidemiological report on the treatment of patients with gestational trophoblastic disease in 10 Brazilian referral centers: results after 12 years since International FIGO 2000 Consensus.

    PubMed

    Braga, Antonio; Uberti, Elza Maria Hartmann; Fajardo, Maria do Carmo; Viggiano, Maurício; Sun, Sue Yazaki; Grillo, Bruno Maurizio; Padilha, Sérgio Lunardon; de Andrade, Jurandyr Moreira; de Souza, Christiani Bisinoto; Madi, José Mauro; Maestá, Izildinha; Silveira, Eduardo

    2014-01-01

    To evaluate treatment of Brazilian patients with gestational trophoblastic disease (GTD). A retrospective cohort study with analysis of medical reports performed in 10 Brazilian referral centers from January 2000 to December 2011. Of 5,250 patients 3 died (0.06%) at the time of uterine evacuation. Spontaneous remission of GTD (group G1) was observed in 4,103 cases, and 1,144 (21.8%) progressed to gestational trophoblastic neoplasia (GTN) (G2). In G1 2,716 (66.2%) had complete hydatidiform mole (HM) and 1,210, partial HM (29.5%); 3,772 patients (92.7%) recovered as noted in December 2012. In G2, of 1,118 patients treated, initial histopathological results of previous gestation were complete HM (77.5% [n = 886]), partial HM (8.8% [n = 100]), and choriocarcinoma (8.0% [n = 92]); 930 (81.3%) were low-risk, 200 (17.5%) were high-risk GTN, and 14 had placental site trophoblastic tumor (PSTT) (1.2%); cure was achieved in 1,078 cases (96.4%), but 26 patients (2.3%) died (4 low-risk [0.4%], 19 high-risk [9.5%], and 3 PSTT [21.4%]). The highest death rates were due to high-risk GTN and PSTT. Patients with molar pregnancy should be referred to a referral center for an early diagnosis and prompt treatment of GTN in order to reduce the morbidity and mortality found in advanced stages.

  19. Comparison of MACT and 5Fu+ACT-D chemotherapy regimens in the treatment of low-risk gestational trophoblastic neoplasia.

    PubMed

    Wang, Yu; Miao, Jin-Wei; Wang, Tong; Wang, Yan; Wu, Yu-Mei; Kong, Wei-Min; Su, Li; Duan, Wei

    2016-04-01

    The study aimed to compare the efficacy of methotrexate (MTX) cervical injections + actinomycin-D (ACT-D)(MACT) and 5-fluorouracil (5-Fu) + actinomycin-D (5-Fu plus ACT-D) chemotherapy regimens for low-risk gestational trophoblastic neoplasia (LR-GTN). Clinical data from 66 LR-GTN patients, admitted to the Beijing Obstetrics and Gynecology Hospital from January 2010 to April 2012, were analysed retrospectively. In total, 32 patients were treated with a MACT therapeutic regimen and the remaining 34 with a 5Fu + ACT-D therapeutic regimen. Complete remission rates (CR), duration of treatment, hospital stay and toxicity effects were compared. There was no statistical difference in CR for the MACT (90.63%) or the 5-Fu plus ACT-D (100%) therapeutic regimens (p = 0.0676) or in the duration of treatment [MACT (3.50) or 5-Fu plus ACT-D (3.71; p = 0.2021)]. Moreover, the hospital stay in the 5-Fu plus ACT-D group (32.88 days) was significantly longer than for the MACT group (22.09 days; p < 0.001). Furthermore, the degree of myelosuppression, nausea and vomiting, diarrhoea, stomatitis and alopecia was more severe in the 5Fu + ACT-D group (p < 0.01). However, there was no statistical difference in the severity of liver function damage between the two groups. A shorter hospital stay, lower hospitalization cost and slightly more toxic effects were observed in LR-GTN patients treated with the MACT therapeutic regimen. We suggest that the MACT regimen should be used as first-line chemotherapy for LR-GTN.

  20. Agile Transportation for the 21st Century Objectives for the Defense Transportation System

    DTIC Science & Technology

    2002-06-01

    Defense Transportation System GRADUATE RESEARCH PROJECT Brad J. Eungard, Capt., USAF AFIT/ GMO /ENS/02E-04 ii AFIT/ GMO /ENS/02E-04...Command (USTRANSCOM) created the Global Transportation Network (GTN) as the primary command and control (C2) tool to capture and utilize in-transit...the Defense Logistics Agency (DLA) are in the process of redesigning and streamlining the Department of Defense global distribution system through the

  1. Fatal gestational trophoblastic neoplasia: An analysis of treatment failures at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978.

    PubMed

    Neubauer, Nikki L; Strohl, Anna E; Schink, Julian C; Lurain, John R

    2015-08-01

    To determine clinical factors that contributed to death from gestational trophoblastic neoplasia (GTN) at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978. Nineteen women who died of GTN from 1979-2012 were retrospectively identified and compared to 45 women previously reported on who died of GTN from 1962-1978. Clinical factors analyzed included demographics, pretreatment human chorionic gonadotropin (hCG) level, duration of disease, antecedent pregnancy, number and sites of metastases, FIGO stage and score, treatment, and cause of death. Death from GTN occurred in 19 (4%) of 483 patients treated from 1979-2012 compared to 45 (11%) of 396 patients treated from 1962-1978 (P<0.001). Pretreatment hCG level >100,000 mIU/mL, time from pregnancy event to treatment >4 months, nonmolar antecedent pregnancy and use of surgery to control metastatic disease were similar between the two treatment eras. Patients in the recent series were more likely to have presented with FIGO IV disease or brain metastasis, been initially treated with multiagent chemotherapy, and received treatment before referral to our center compared to the earlier series. The most common causes of death from 1979-2012 and 1962-1978 were hemorrhage from one or more metastatic sites (11% vs. 42%), respiratory failure (37% vs. 31%), and multiorgan failure due to widespread chemoresistant disease (42% vs. 8%), respectively. Our overall survival rate in patients with gestational trophoblastic neoplasia improved from 89% in 1962-1978 to 96% in 1979-2012. More patients treated between 1979-2012 died from widespread chemoresistant disease rather than hemorrhagic complications. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Complete molar pregnancy in adolescents from North and South America: Clinical presentation and risk of gestational trophoblastic neoplasia.

    PubMed

    Soares, Renan Rocha; Maestá, Izildinha; Colón, José; Braga, Antonio; Salazar, Aleydah; Charry, Rafael Cortés; Sun, Sue Yazaki; Goldstein, Donald P; Berkowitz, Ross S

    2016-09-01

    To compare complete hydatidiform mole (CHM) clinical presentation and risk factors associated with GTN development between North American and South American adolescents. This non-concurrent cohort study was undertaken including adolescents with CHM referred to centers in North America (New England Trophoblastic Disease Center, Harvard University, USA), and South America (Botucatu Trophoblastic Disease Center-São Paulo State University, Brazil; Trophoblastic Unit of Central University of Venezuela and Maternidad Concepcion Palacios of Caracas, Venezuela) between 1990 and 2012. Data were obtained from medical records and pathology reports. Study participants were allocated into 2 groups: North America (NA) and South America (SA). In NA and SA, 13.1% and 30.9% of patients with hydatidiform mole were adolescents, respectively. Of these, 77.6% in NA and 86.1% in SA had pathologic diagnosis of CHM (p=0.121). Vaginal bleeding (SA=69% vs NA=51%; p=0.020), anemia (SA=48% vs NA=18%; p<0.001), and elevated serum hCG (SA=232,860mIU/mL vs NA=136,412mIU/mL; p=0.039) were more frequent in SA than in NA. Median gestational age at diagnosis (SA=12weeks, NA=11weeks; p=0.030) differed whereas GTN development rate (SA=20%, NA=27%; p=0.282) showed no significant difference between groups. Compared to NA, medical complications and clinical factors associated with post-molar GTN were more frequent among SA adolescents. Medical complications and clinical factors associated with GTN development were more frequent in SA than in NA adolescents with CHM, suggesting that, in South America, awareness about the importance of diagnosing molar pregnancy early and considering CHM in the differential diagnosis in adolescents suspected to be pregnant should be raised. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Research in Natural Language Understanding

    DTIC Science & Technology

    1978-08-31

    general recognition automata. The normal decomposition of natural language description into levels of phonology , lexicon, syntax, semantics, and...GTN’S) have potential applications in scene analysis, acoustic phonetic analysis of speech, medical diagnosis, discourse analysis, and data base...use of a network ♦•.hat consumed successive phonemes from the output of an - 34 - i Report No. 3963 Bolt Beranek and Newman Inc. acoustic phonetic

  4. The Lack of a Designated National In-Transit Visibility System Affects the Synchronization of Information Sharing and the Timely Distribution of Materials during Natural Disaster Efforts

    DTIC Science & Technology

    2010-06-11

    Global Command and Communication System GTN Global Transportation Network HUD Housing and Urban Division IG Inspector General IRRIS Intelligent...outcome will most likely produce new policies and procedures. Today, the synchronization, collaboration and integration of natural disasters extend ...and performs.” 15 In order to combat some of its logistical challenges, FEMA redesigned the LMD with the intent to model “Department of Defense

  5. War in the Information Age: A Primer for Cyberspace Operations in 21st Century Warfare

    DTIC Science & Technology

    2010-01-01

    undertaking, the Soviets needed sophisticated control systems. They bought early model computers on the open market, but when Russian pipeline...whose distinctive and unique character is framed by the use of electronics and the electromagnetic spectrum to create, store, modify , exchange, and...GCCS), Global Transportation Network ( GTN ), In-Transit Visibility (ITV), Joint Tactical Radio System (JTRS), Blue Force Tracker (BFT), Theater Battle

  6. Aeromedical Evacuation: Validating Civil Reserve Air Fleet

    DTIC Science & Technology

    2009-02-25

    Requirements Center GTN Global Transportation Network xiii IAT.R 0554 GWOT Global War on Terrorism HDPLP High Deck Patient Lift Platform HLS homeland...the requirements against a PACOM plan and/or modify the program. The past several years, USTRANSCOM SG has been unsuccessful in obtaining CRAF AE...flight on September 15, 1991, and the first production model was delivered to Charleston Air Force Base, South Carolina June 14, 1993. The aircraft can

  7. The Battle Command Sustainment Support System: The Army’s Command and Control System for Logistics

    DTIC Science & Technology

    2009-05-21

    a different system to fill the void. Tapestry Industries of San Diego, CA developed the Joint Deployment Logistics Model (JDLM) for Army simulation...strategic to the tactical level and all on a graphic display the operator can modify to meet the commander’s specific requirements. The...electronically uploaded into computer databases such as the Global Transportation Network ( GTN ), the BCS3 can track those shipments projecting and

  8. Loglines. September - October 2012

    DTIC Science & Technology

    2012-10-01

    officer, said. To streamline the ordering process, the new toner contract will be available for online ordering and payment via Government Purchase...September - October 2012 Engineering Savings Story by Amanda Neumann T he federal government is one savvy shopper – minus the coupon clipping. Just like...been online that long. “That allows planners to use the data to do analytical studies that could not be done before, because GTN only retained

  9. The control of ice crystal growth and effect on porous structure of konjac glucomannan-based aerogels.

    PubMed

    Ni, Xuewen; Ke, Fan; Xiao, Man; Wu, Kao; Kuang, Ying; Corke, Harold; Jiang, Fatang

    2016-11-01

    Konjac glucomannan (KGM)-based aerogels were prepared using a combination of sol-gel and freeze-drying methods. Preparation conditions were chosen to control ice crystal growth and aerogel structure formation. The ice crystals formed during pre-freezing were observed by low temperature polarizing microscopy, and images of aerogel pores were obtained by scanning electron microscopy. The size of ice crystals were calculated and size distribution maps were drawn, and similarly for aerogel pores. Results showed that ice crystal growth and aerogel pore sizes may be controlled by varying pre-freezing temperatures, KGM concentration and glyceryl monostearate concentration. The impact of pre-freezing temperatures on ice crystal growth was explained as combining ice crystal growth rate with nucleation rate, while the impacts of KGM and glyceryl monostearate concentration on ice crystal growth were interpreted based on their influences on sol network structure.

  10. Transesterification of triglycerides using nitrogen-functionalized carbon nanotubes.

    PubMed

    Villa, Alberto; Tessonnier, Jean-Philippe; Majoulet, Olivier; Su, Dang Sheng; Schlögl, Robert

    2010-02-22

    Nitrogen-functionalized carbon nanotubes were synthesized by grafting amino groups to the surface of the nanotubes. The nanotubes exhibited promising results in the base-catalyzed liquid phase transesterification of glyceryl tributyrate with methanol, which is a model reaction for the production of biodiesel. The concentration of the active sites and the reaction parameters, such as temperature and glyceryl tributyrate to methanol ratio, were shown to significantly affect catalytic performance. The grafting technique employed allowed for design and control of the active sites. As a consequence, it was possible to design a nitrogen-functionalized carbon nanotube catalyst with a few strong, basic groups. This might be of interest for carbohydrate conversion reactions where strong basic sites are required but the pH of the solution should remain mild to avoid the degradation of the reactants and/or products.

  11. Scent gland constituents of the Middle American burrowing python, Loxocemus bicolor (Serpentes: Loxocemidae).

    PubMed

    Schulze, Thies; Weldon, Paul J; Schulz, Stefan

    2017-07-14

    Analysis by gas chromatography/mass spectrometry of the scent gland secretions of male and female Middle American burrowing pythons (Loxocemus bicolor) revealed the presence of over 300 components including cholesterol, fatty acids, glyceryl monoalkyl ethers, and alcohols. The fatty acids, over 100 of which were identified, constitute most of the compounds in the secretions and show the greatest structural diversity. They include saturated and unsaturated, unbranched and mono-, di-, and trimethyl-branched compounds ranging in carbon-chain length from 13 to 24. The glyceryl monoethers possess saturated or unsaturated, straight or methyl-branched alkyl chains ranging in carbon-chain length from 13 to 24. Alcohols, which have not previously been reported from the scent glands, possess straight, chiefly saturated carbon chains ranging in length from 13 to 24. Sex or individual differences in secretion composition were not observed. Compounds in the scent gland secretions of L. bicolor may deter offending arthropods, such as ants.

  12. Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction.

    PubMed

    Münzel, Thomas; Steven, Sebastian; Daiber, Andreas

    2014-12-01

    Given acutely, organic nitrates, such as nitroglycerin (GTN), isosorbide mono- and dinitrates (ISMN, ISDN), and pentaerythrityl tetranitrate (PETN), have potent vasodilator and anti-ischemic effects in patients with acute coronary syndromes, acute and chronic congestive heart failure and arterial hypertension. During long-term treatment, however, side effects such as nitrate tolerance and endothelial dysfunction occur, and therapeutic efficacy of these drugs rapidly vanishes. Recent experimental and clinical studies have revealed that organic nitrates per se are not just nitric oxide (NO) donors, but rather a quite heterogeneous group of drugs considerably differing for mechanisms underlying vasodilation and the development of endothelial dysfunction and tolerance. Based on this, we propose that the term nitrate tolerance should be avoided and more specifically the terms of GTN, ISMN and ISDN tolerance should be used. The present review summarizes preclinical and clinical data concerning organic nitrates. Here we also emphasize the consequences of chronic nitrate therapy on the supersensitivity of the vasculature to vasoconstriction and on the increased autocrine expression of endothelin. We believe that these so far rather neglected and underestimated side effects of chronic therapy with at least GTN and ISMN are clinically important.

  13. A fibroid or cancer? A rare case of mixed choriocarcinoma and epithelioid trophoblastic tumour.

    PubMed

    Luk, Wan Yu; Friedlander, Michael

    2013-01-01

    Background. Gestational trophoblastic disease (GTD) is a rare complication of pregnancy which is characterised by abnormal growth of the trophoblasts at the placental site. It is categorised into benign and malignant forms, which include hydatidiform moles (HMs) and gestational trophoblastic neoplasia (GTN), respectively. A mixed choriocarcinoma (CC) and epithelioid trophoblastic tumour (ETT) is an extremely rare subgroup of GTN, which is a highly curable but aggressive form of malignancy. Case. We report a case of mixed CC and ETT in a 41-year-old patient who presented with a 2-year history of menorrhagia and fibroid uterus in the absence of previous history of molar pregnancy. She had a 12-year interval between the antecedent pregnancy and presentation. She was treated with intensive regimen of adjuvant chemotherapy, etoposide, methotrexate, and actinomycin-D with etoposide and cisplatin (EMA-EP). She has remained disease free for more than 5 years. Conclusion. This case highlights the importance of considering GTN as one of the differential diagnoses value of β -HCG in patients presented with menorrhagia and growing fibroids.

  14. Residual lung lesions after completion of chemotherapy for gestational trophoblastic neoplasia: should we operate?

    PubMed Central

    Powles, T; Savage, P; Short, D; Young, A; Pappin, C; Seckl, M J

    2006-01-01

    The significance of residual lung metastasis from malignant gestational trophoblastic neoplasm (GTN) after the completion of chemotherapy is unknown. We currently do not advocate resection of these masses. Here, we investigate the outcome of these patients. Patients with residual lung abnormalities after the completion of treatment for GTN were compared to those who had a complete radiological resolution of the disease. None of the residual masses post-treatment were surgically removed. In all, 76 patients were identified. Overall 53 (70%) patients had no radiological abnormality on CXR or CT after completion of treatment. Eight (11%) patients had residual disease on CXR alone 15 patients had residual disease on CT (19%). During follow-up, two patients (2.6%) relapsed. One of these had had a complete radiological response post-treatment whereas the other had residual disease on CT. Patients with residual lung lesions after completing treatment for GTN do not appear to have an increased chance of relapse compared to those with no residual abnormality. We continue to recommend that these patients do not require pulmonary surgery for these lesions. PMID:16404359

  15. Gestational Trophoblastic Disease: Clinical and Imaging Features.

    PubMed

    Shaaban, Akram M; Rezvani, Maryam; Haroun, Reham R; Kennedy, Anne M; Elsayes, Khaled M; Olpin, Jeffrey D; Salama, Mohamed E; Foster, Bryan R; Menias, Christine O

    2017-01-01

    Gestational trophoblastic disease (GTD) is a spectrum of both benign and malignant gestational tumors, including hydatidiform mole (complete and partial), invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. The latter four entities are referred to as gestational trophoblastic neoplasia (GTN). These conditions are aggressive with a propensity to widely metastasize. GTN can result in significant morbidity and mortality if left untreated. Early diagnosis of GTD is essential for prompt and successful management while preserving fertility. Initial diagnosis of GTD is based on a multifactorial approach consisting of clinical features, serial quantitative human chorionic gonadotropin (β-hCG) titers, and imaging findings. Ultrasonography (US) is the modality of choice for initial diagnosis of complete hydatidiform mole and can provide an invaluable means of local surveillance after treatment. The performance of US in diagnosing all molar pregnancies is surprisingly poor, predominantly due to the difficulty in differentiating partial hydatidiform mole from nonmolar abortion and retained products of conception. While GTN after a molar pregnancy is usually diagnosed with serial β-hCG titers, imaging plays an important role in evaluation of local extent of disease and systemic surveillance. Imaging also plays a crucial role in detection and management of complications, such as uterine and pulmonary arteriovenous fistulas. Familiarity with the pathogenesis, classification, imaging features, and treatment of these tumors can aid in radiologic diagnosis and guide appropriate management. (©)RSNA, 2017.

  16. Uterine artery pulsatility index: a predictor of methotrexate resistance in gestational trophoblastic neoplasia

    PubMed Central

    Agarwal, R; Harding, V; Short, D; Fisher, R A; Sebire, N J; Harvey, R; Patel, D; Savage, P M; Lim, A K P; Seckl, M J

    2012-01-01

    Background: Neo-angiogenesis is a hallmark of cancer. The aim of this study was to test the hypothesis, in a prospective patient cohort, that in low-risk gestational trophoblastic neoplasia (LR-GTN) the uterine artery pulsatility index (UAPI), a measure of tumour vascularity, can predict resistance to methotrexate chemotherapy (MTX-R). Methods: 286 LR-GTN patients (Charing Cross Hospital (CXH) score 0–8, or FIGO score 0–6) were treated with methotrexate between January 2008 and June 2011 at CXH. During staging investigations, patients underwent a Doppler ultrasound to assess the UAPI. Results: 239 patients were assessable for both UAPI and MTX-R. The median UAPI was lower (higher vascularity) in MTX-R compared with MTX-sensitive patients (0.8 vs 1.4, P<0.0001). In multivariate logistic regression, UAPI⩽1 predicted MTX-R, independent of both CXH and FIGO scores. The risk of MTX-R in patients with a FIGO score of 6 and UAPI⩽1 was 100% vs 20% in patients with UAPI>1 (χ2 P<0.0001). Conclusion: UAPI represents an independently validated clinically useful predictor of MTX-R in LR-GTN. Further, consideration of whether to incorporate UAPI into the FIGO scoring system is now warranted so that patients with a score of 6 and a UAPI ⩽1 might be upstaged and offered combination chemotherapy rather than MTX. PMID:22374461

  17. Placental site trophoblastic tumors and epithelioid trophoblastic tumors: Biology, natural history, and treatment modalities.

    PubMed

    Horowitz, Neil S; Goldstein, Donald P; Berkowitz, Ross S

    2017-01-01

    Placental site (PSTT) and epithelioid trophoblastic tumor (ETT) are rare types of gestational trophoblastic neoplasia (GTN) that arise from intermediate trophoblast. Given that this cell of origin is different from other forms of GTN, it is not surprising that the clinical presentation, tumor marker profile, and treatment paradigm for PSTT and ETT are quite different as well. The mainstay for therapy for stage I PSTT and ETT is hysterectomy with adjuvant chemotherapy reserved for those presenting greater than four years from the antecedent pregnancy. Surgery is also important for metastatic disease. There is no standardized chemotherapy regimen for advanced stage disease but often consists of a platinum-containing combination therapy, usually EMA-EP or TE/TP. Despite its rarity, PSTT and ETT account for a disproportionate percentage of mortality from GTN likely resulting from their relative chemotherapy resistance. Novel therapeutic modalities therefore are needed to improve the outcomes of women with advanced stage or resistant PSTT and ETT. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Root-MUSIC analysis of nitric oxide-mediated changes in ophthalmic artery blood flow velocity waveforms.

    PubMed

    Agnew, C E; Rea, D J; McCann, A J; Lockhart, C J; Hamilton, P K; Quinn, C E; McVeigh, G E; McGivern, R C

    2009-09-01

    Clinical and experimental studies indicate that structural and functional changes in the microvasculature can predate or accompany risk factors for cardiovascular disease at the earliest stages in the disease process. In the current work, both simulated and actual Doppler ultrasound maximum blood velocity waveform envelopes recorded from the ophthalmic artery were analysed using a root-MUSIC and least squares fitting approach to determine amplitude frequency spectra. Both amplitude and frequency components of noise contaminated simulated waveforms were reliably determined indicating the robustness of the technique. The technique was then used to compare the spectral content of the ophthalmic artery blood velocity waveforms of normal controls in three test states: at baseline, following administration of GTN, a nitric oxide donor, and following administration of L-Name, a nitric oxide inhibitor. Principal components derived from root-MUSIC analysis discriminated between waveforms in baseline and non-baseline test states (p<0.00001) and between GTN and non-GTN test states (p=0.0002).

  19. GT microsatellite repeats in the heme oxygenase-1 gene promoter associated with abdominal aortic aneurysm in Croatian patients.

    PubMed

    Gregorek, Andrea Crkvenac; Gornik, Kristina Crkvenac; Polancec, Darija Stupin; Dabelic, Sanja

    2013-06-01

    Abdominal aortic aneurysm (AAA) is a complex genetic disorder caused by the interplay of genetic and environmental risk factors. The number of (GT)(n) repeats in the heme oxygenase-1 (HO-1) gene promoter modulates transcription of this enzyme, which might have anti-inflammatory, antioxidant, antiapoptotic, and antiproliferative effect. The distribution of alleles and genotypes in Croatian individuals genotyped for the (GT)(n) HO-1 polymorphism was similar to that in other European populations. Frequency of the short (S) alleles (GT < 25) was higher in AAA patients (41.9%) than in non-AAA individuals (28.2%, p = 0.0026) because there were more SL heterozygotes among the AAA patients. The SL genotype appeared to increase the risk for AAA, but the increase was not statistically significant after adjustment for age, sex, smoking, hypertension, and hyperlipidemia (OR = 1.53, 95% CI 0.90-3.09, p = 0.062). These findings contradict those of the only other study performed so far on the association of (GT)(n) HO-1 polymorphism and AAA.

  20. Ductile fracture model in the shearing process of zircaloy sheet for nuclear fuel spacer grids

    NASA Astrophysics Data System (ADS)

    Wang, Jaeyoon; Kim, Naksoo; Lee, Hyungyil

    2012-04-01

    Features of sheared edges are predicted based on material properties of Zircaloy obtained from the tensile test and ductile fracture model such as the Gurson-Tvergaard-Needleman (GTN) and Johnson-Cook models. The sheared edges formations are numerically analyzed in each ductile model. An appropriate ductile fracture model is selected to study the relative depth of sheared edges with respect to process parameters. The tendency of failure parameters that are affected by sheared edges and fracture duration is investigated. We applied changes on parameters of failure models to show that the punch force curve and the ratio of characteristic lengths could be coincided, which led us to conclude that the GTN and Johnson-Cook models are equivalent. In the Johnson-Cook model, however, the characteristic length of the sheared edges does not change as each failure parameter reaches a critical value. Hence, the FE prediction model for forming defects is developed using the GTN failure model. Finally, the characteristic length of sheared edges have been measured using the FE prediction model for shearing process parameters such as punch velocities, clearance, and tool wear. Our results showed that the punch-die clearance is the most significant factor that affects forming defects when compared to other factors.

  1. Haem arginate infusion stimulates haem oxygenase-1 expression in healthy subjects

    PubMed Central

    Doberer, D; Haschemi, A; Andreas, M; Zapf, T-C; Clive, B; Jeitler, M; Heinzl, H; Wagner, O; Wolzt, M; Bilban, M

    2010-01-01

    BACKGROUND AND PURPOSE Haem oxygenase 1 (HO-1) is an inducible protein that plays a major protective role in conditions such as ischaemia-reperfusion injury and inflammation. In this study, we have investigated the role of haem arginate (HA) in human male subjects in the modulation of HO-1 expression and its correlation with the GT length polymorphism (GTn) in the promoter of the HO-1 gene. EXPERIMENTAL APPROACH In a dose-escalation, randomized, placebo-controlled trial, seven healthy male subjects with a homozygous short (S/S) and eight with a long (L/L) GTn genotype received intravenous HA. HO-1 protein expression and mRNA levels in peripheral blood monocytes, bilirubin, haptoglobin, haemopexin and haem levels were analysed over a 48 h observation period. KEY RESULTS We found that the baseline mRNA levels of HO-1 were higher in L/L subjects, while protein levels were higher in S/S subjects. HA induced a dose-dependent increase in the baseline corrected area under the curve values of HO-1 mRNA and protein over 48 h. The response of HO-1 mRNA was more pronounced in L/L subjects but the protein level was similar across the groups. CONCLUSIONS AND IMPLICATION HA is an effective inducer of HO-1 in humans irrespective of the GTn genotype. The potential therapeutic application of HA needs to be evaluated in clinical trials. PMID:20718734

  2. Utilization of ascites plasma very low density lipoprotein triglycerides by Ehrlich cells.

    PubMed

    Brenneman, D E; Spector, A A

    1974-07-01

    Much of the lipid present in the ascites plasma in which Ehrlich cells grow is contained in very low density lipoproteins (VLDL). Chemical measurements indicated that triglycerides were taken up by the cells during in vitro incubation with ascites VLDL. When tracer amounts of radioactive triolein were incorporated into the ascites VLDL, the percentage uptakes of glyceryl tri[1-(14)C]oleate and triglycerides measured chemically were similar. The cells also took up [2-(3)H]glyceryl trioleate that was added to VLDL, but the percentage of available (3)H recovered in the cell lipids was 30-40% less than that of (1 4)C from glyceryl tri[1-(1 4)C]oleate. This difference was accounted for by water-soluble (3)H that accumulated in the incubation medium, suggesting that extensive hydrolysis accompanied the uptake of VLDL triglycerides. Radioactive fatty acids derived from the VLDL triglycerides were incorporated into cell phospholipids, glycerides, and free fatty acids, and they also were oxidized to CO(2). Triglyceride utilization increased as the VLDL concentration was raised. These results suggest that one function of the ascites plasma VLDL may be to supply fatty acid to the Ehrlich cells and that the availability of fatty acid to this tumor is determined in part by the ascites plasma VLDL concentration. Although Ehrlich cells incorporate almost no free glycerol into triglycerides, considerable amounts of [2-(3)H]glyceryl trioleate radioactivity were recovered in cell triglycerides. This indicates that at least some VLDL triglycerides were taken up intact. The net uptake of VLDL protein and cholesterol was very small relative to the triglyceride uptake, suggesting that intact triglycerides are transferred from the ascites VLDL to the Ehrlich cells and that hydrolysis occurs after the triglyceride is associated with the cells.

  3. Electrochemical characterization of bilayer lipid membrane-semiconductor junctions

    SciTech Connect

    Zhao, Xiao Kang; Baral, S.; Fendler, J.H. )

    1990-03-08

    Three different systems of glyceryl monooleate (GMO), bilayer lipid membrane (BLM) supported semiconductor particles have been prepared and characterized. A single composition of particulate semiconductor deposited only on one side of the BLM constituted system A, two different compositions of particulate semiconductors sequentially deposited on the same side of the BLM represented system B, and two different compositions of particulate semiconductors deposited on the opposite sides of the BLM made up system C.

  4. 21 CFR 184.1901 - Triacetin.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Triacetin. 184.1901 Section 184.1901 Food and....1901 Triacetin. (a) Triacetin (C8 H14O6, CAS Reg. No. 102-76-1), also known as 1,2,3,-propanetriol triacetate or glyceryl triacetate, is the triester of glycerin and acetic acid. Triacetin can be prepared by...

  5. Direct Synthesis of ESBO Derivatives-18O Labelled with Dioxirane

    PubMed Central

    Tommasi, Immacolata; Fusco, Caterina

    2013-01-01

    This work addresses a new approach developed in our laboratory, consisting in the application of isolated dimethyldioxirane (DDO, 1a) labelled with 18O for synthesis of epoxidized glyceryl linoleate (Gly-LLL, 2). We expect that this work could contribute in improving analytical methods for the determination of epoxidized soybean oil (ESBO) in complex food matrices by adopting an 18O-labelled-epoxidized triacylglycerol as an internal standard. PMID:24163617

  6. Automated Nitrocellulose Analysis

    DTIC Science & Technology

    1978-12-01

    is acceptable. (4) As would be expected from the theory of osmosis , a high saline content in the dialysis recipient stream (countersolution) is of...Block 39, II different from Report; IS. SUPPLEMENTARY NOTES IS. KEY WOROS (Continue on rereri Analysis Automated analysis Dialysis Glyceryl...Technicon AutoAnalyzer, involves aspiration of a stirred nitrocellulose suspension, dialysis against 9 percent saline, and hydrolysis with 5N sodium

  7. Comparative studies of lamivudine-zidovudine nanoparticles for the selective uptake by macrophages.

    PubMed

    Sankar, V; Nareshkumar, Parmar Nilaykumar; Ajitkumar, Gohel Nishit; Penmetsa, Shalini Devi; Hariharan, Sivaram

    2012-09-01

    The present study investigates the specific drug targeting of anti retroviral drugs, such as lamivudine and zidovudine, after intraperitoneal (i.p) injection by incorporation into polymeric nanoparticles (PNs) and solid lipid nanoparticles (SLNs). Our results showed that Glyceryl Monosterate-Poloxamer 188 SLNs (average diameter of 522.466 nm) showed slow drug release rates (63.18% of lamivudine and 62.37% of zidovudine were released in 12 hrs) among all the SLN formulations. For Poly lactic-co-glycolic acid (PLGA)-Poloxamer 188 PNs (average diameter of 70.348 nm), there were faster release rates of both lamivudine and zidovudine (97% and 94.06%, respectively, in 12 hrs). Tissue distribution studies were carried out in mice and concentrations of drugs in different organs were determined using high performance liquid chromatography (HPLC) after i.p. administration. Glyceryl Monosterate-Poloxamer 188 SLNs and PLGA-Poloxamer 188 PNs showed increase in the distribution of lamivudine and zidovudine to liver and spleen when compared to the drugs in solution. Also, Glyceryl Monosterate-P 188 SLNs showed higher concentration of drugs in RES organs than PLGA-P 188 PNs.

  8. Characterization of semi-solid Self-Emulsifying Drug Delivery Systems (SEDDS) of atorvastatin calcium by Raman image spectroscopy and chemometrics.

    PubMed

    Breitkreitz, Márcia C; Sabin, Guilherme P; Polla, Griselda; Poppi, Ronei J

    2013-01-25

    A methodology based on Raman image spectroscopy and chemometrics for homogeneity evaluation of formulations containing atorvastatin calcium in Gelucire(®) 44/14 is presented. In the first part of the work, formulations with high amounts of Gelucire(®) 44/14 (80%) and solvents of different polarities (diethylene glycol monoethyl ether, propyleneglycol, propylene glycol monocaprylate and glyceryl mono/dicaprylate/caprate) were prepared for miscibility screening evaluation by classical least squares (CLS). It was observed that Gelucire(®) 44/14 presented higher affinity for the lipophilic solvents glyceryl mono/dicaprylate/caprate and propylene glycol monocaprylate, whose samples were observed to be homogeneous, and lower affinity for the hydrophilic solvents diethylene glycol monoethyl ether and propyleneglycol, whose samples were heterogeneous. In the second part of the work, the ratio of glyceryl mono/dicaprylate/caprate and Gelucire(®) 44/14 was determined based on studies in water and allowed the selection of the proportions of these two excipients in the preconcentrate that provided supersaturation of atorvastatin upon dilution. The preconcentrate was then evaluated for homogeneity by partial least squares (PLS) and an excellent miscibility was observed in this proportion as well. Therefore, it was possible to select a formulation that presented simultaneously homogeneous preconcentrate and solubility enhancement in water by Raman image spectroscopy and chemometrics.

  9. Acute Lipotoxicity Regulates Severity of Biliary Acute Pancreatitis without Affecting Its Initiation

    PubMed Central

    Durgampudi, Chandra; Noel, Pawan; Patel, Krutika; Cline, Rachel; Trivedi, Ram N.; DeLany, James P.; Yadav, Dhiraj; Papachristou, Georgios I.; Lee, Kenneth; Acharya, Chathur; Jaligama, Deepthi; Navina, Sarah; Murad, Faris; Singh, Vijay P.

    2015-01-01

    Obese patients have worse outcomes during acute pancreatitis (AP). Previous animal models of AP have found worse outcomes in obese rodents who may have a baseline proinflammatory state. Our aim was to study the role of acute lipolytic generation of fatty acids on local severity and systemic complications of AP. Human postpancreatitis necrotic collections were analyzed for unsaturated fatty acids (UFAs) and saturated fatty acids. A model of biliary AP was designed to replicate the human variables by intraductal injection of the triglyceride glyceryl trilinoleate alone or with the chemically distinct lipase inhibitors orlistat or cetilistat. Parameters of AP etiology and outcomes of local and systemic severity were measured. Patients with postpancreatitis necrotic collections were obese, and 13 of 15 had biliary AP. Postpancreatitis necrotic collections were enriched in UFAs. Intraductal glyceryl trilinoleate with or without the lipase inhibitors resulted in oil red O–positive areas, resembling intrapancreatic fat. Both lipase inhibitors reduced the glyceryl trilinoleate–induced increase in serum lipase, UFAs, pancreatic necrosis, serum inflammatory markers, systemic injury, and mortality but not serum alanine aminotransferase, bilirubin, or amylase. We conclude that UFAs are enriched in human necrotic collections and acute UFA generation via lipolysis worsens pancreatic necrosis, systemic inflammation, and injury associated with severe AP. Inhibition of lipolysis reduces UFA generation and improves these outcomes of AP without interfering with its induction. PMID:24854864

  10. Inhibition of Listeria monocytogenes by fatty acids and monoglycerides.

    PubMed

    Wang, L L; Johnson, E A

    1992-02-01

    Fatty acids and monoglycerides were evaluated in brain heart infusion broth and in milk for antimicrobial activity against the Scott A strain of Listeria monocytogenes. C12:0, C18:3, and glyceryl monolaurate (monolaurin) had the strongest activity in brain heart infusion broth and were bactericidal at 10 to 20 micrograms/ml, whereas potassium (K)-conjugated linoleic acids and C18:2 were bactericidal at 50 to 200 micrograms/ml. C14:0, C16:0, C18:0, C18:1, glyceryl monomyristate, and glyceryl monopalmitate were not inhibitory at 200 micrograms/ml. The bactericidal activity in brain heart infusion broth was higher at pH 5 than at pH 6. In whole milk and skim milk, K-conjugated linoleic acid was bacteriostatic and prolonged the lag phase especially at 4 degrees C. Monolaurin inactivated L. monocytogenes in skim milk at 4 degrees C, but was less inhibitory at 23 degrees C. Monolaurin did not inhibit L. monocytogenes in whole milk because of the higher fat content. Other fatty acids tested were not effective in whole or skim milk. Our results suggest that K-conjugated linoleic acids or monolaurin could be used as an inhibitory agent against L. monocytogenes in dairy foods.

  11. Development of novel sustained release matrix pellets of betahistine dihydrochloride: effect of lipophilic surfactants and co-surfactants.

    PubMed

    Shamma, Rehab Nabil; Basalious, Emad B; Shoukri, Raguia

    2012-01-01

    Sustained release matrix pellets of the freely water soluble drug, betahistine dihydrochloride (BH), were prepared using freeze pelletization technique. Different waxes and lipids (cetyl alcohol, beeswax, glyceryl tripalmitate (GTP) and glyceryl tristearate) were evaluated for the preparation of matrix pellets. A D-optimal design was employed for the optimization and to explore the effect of drug loading (X(1)), concentration of lipophilic surfactant (X(2)), concentration of co-surfactant (X(3)) and wax type (X(4)) on the release extent of the drug from matrix pellets. The entrapment efficiency (Y(1)), pellet diameter (Y(2)), and the percentage drug released at given times were selected as dependent variables. Results revealed a significant impact of all independent variables on drug release from the formulated pellets. The lipophilic surfactant significantly increased both the entrapment efficiency and the in vitro drug release and significantly decreased the pellet size. The optimized BH-loaded pellets were composed of 19.95% drug loading, 9.95% Span(®) 80 (surfactant), 0.25% Capmul(®) (co-surfactant) using glyceryl tripalmitate as a matrix former. The release profiles of the drug from hard gelatin capsule containing optimized pellets equivalent to 32 mg BH was similar to that of target release model for once-daily administration based on similarity factor. It could be concluded that a promising once-daily capsule containing sustained release pellets of BH was successfully designed.

  12. Investigation of Risk Factors, Stage and Outcome in Patients with Gestational Trophoblastic Disease since 2001 to 2011 in Iran-Yazd.

    PubMed

    Karimi-Zarchi, Mojgan; Mortazavizadeh, Mohammad Reza; Soltani-Gerdefaramrzi, Malihe; Rouhi, Mitra; Yazdian-Anari, Pouria; Ahmadiyeh, Mohammad Hosain

    2015-12-01

    Gestational trophoblastic disease (GTN) is one of the high-risk forms of pregnancy that requires a lot of attention in terms of research studies, considering its incidence and the importance of the disease in advanced form. The aim of this study was to investigate the risk factors and clinical procedure of patients with gestational trophoblastic disease from 2001 to 2002. This is a retrospective descriptive study, which was carried out on 150 patients with trophoblastic disease. These patients' files were obtained from Shohadaye Kargar and Shahid Sadoughi hospitals and women's oncology offices of Yazd city. The patients were contacted one by one and their disease situation was determined. The data obtained were recorded in a questionnaire and analyzed by SPSS software. The results indicated that the average age of the patients was 27.65 ± 8.22 with variations in age ranging from 15 to 35 year. In addition, majorities were in the age group of 20 to 40 years. 43.2 percent of the women were affected during their first gestation. 4% had molar gestation record, and 9.4% had positive family record. Mean time of survival was 93.38 ± 0.62 months (MIN ± SE), and only one died owing to chemotherapy complication. Vaginal bleeding (90%) was the most common symptom. 54.6 percent of the disease had complete mole, 30% had incomplete mole, 8.6% had invasive mole, 4.6% had choriocarcinoma and 2% had placenta site trophoblastic tumor (PSTT). Among the patients studied, 28.7% were benign in GTN group while 71.3 % were malignant in the GTN group. The malignant patients were divided into three groups per risk, and 41.2% were in the high-risk group. There was theca-lutein cyst in 54% of the patients, which had a significant relationship with the disease risk of persistent GTN. Choriocarcinoma and invasive mole is the most malignant pathology. There was significant relationship between disease interval and the beginning of chemotherapy, and theca lutein cyst and persistent GTN.

  13. The evolving role of hysterectomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center.

    PubMed

    Clark, Rachel M; Nevadunsky, Nicole S; Ghosh, Sue; Goldstein, Donald P; Berkowitz, Ross S

    2010-01-01

    To identify indications for hysterectomy in patients with gestational trophoblastic neoplasia (GTN) and to evaluate outcomes of hysterectomy in those patients. Patients who underwent hysterectomy were identified utilizing hospital medical records and the New England Trophoblastic Disease Center (NETDC) database from January 1, 1959-January 1, 2009. Demographic data as well as indication for hysterectomy, stage, World Health Organization score, chemotherapeutic regimens and outcomes were recorded. We further stratified our population into patients with hysterectomies before and after 1980 to assess how indications for and outcomes after hysterectomy may have changed at our institution over time. A total of 98 patients were identified to have undergone hysterectomy for GTN. In the entire cohort 85% (n = 83) achieved remission and 48% (n = 47) required chemotherapy after hysterectomy. Among the patients in the early cohort (n = 49), indications for hysterectomy included 15 (31%) for primary definitive management, 14 (29%) for chemotherapy resistant disease, 14 (29%) for bleeding and 6 (11%) for other reasons. Of the patients with hysterectomy for chemotherapy resistance, 9 (64%) achieved remission. In the more recent cohort (n = 49) indications for hysterectomy included 24 (49%) for primary definitive management, 19 (39%) for drug-resistant disease, 4 (8%) for bleeding and 2 (4%) for other reasons. Of the patients with hysterectomy for chemotherapy resistance, 16 (84%) achieved remission. There was a statistically significant decline in the number of hysterectomies performed for bleeding. Hysterectomy was performed for bleeding in the early cohort (1959-1980) in 14 (29%) of 49 patients but in only 4 (8%) of 49 patients in the later cohort (1981-2009) (p = 0.02). During the years 1959-2009 the number of hysterectomies performed for GTN at the NETDC has remained stable. However, at our center there has been a decline in the incidence of hysterectomy for life

  14. Study on association between genetic polymorphisms of haem oxygenase-1, tumour necrosis factor, cadmium exposure and malaria pathogenicity and severity

    PubMed Central

    2010-01-01

    Background Malaria is the most important public health problems in tropical and sub-tropical countries. Haem oxygenase (HO) enzyme and the pro-inflammatory cytokine tumour necrosis factor (TNF) have been proposed as one of the factors that may play significant role in pathogenicity/severity of malaria infection. HO is the enzyme of the microsomal haem degradation pathway that yields biliverdin, carbon monoxide, and iron. In this study, the association between malaria disease pathogenicity/severity and (GT)n repeat polymorphism in the promoter region of the inducible HO-1 including the effect of cadmium exposure (potent inducer of HO-1 transcription) as well as polymorphism of TNF were investigated. Methods Blood samples were collected from 329 cases non-severe malaria with acute uncomplicated Plasmodium falciparum malaria (UM) and 80 cases with Plasmodium vivax malaria (VM), and 77 cases with severe or cerebral malaria (SM) for analysis of genetic polymorphisms of HO-1 and TNF and cadmium levels. These patients consisted of 123 (25.3%) Thai, 243 (50.0%) Burmese and 120 (24.7%) Karen who were present at Mae Sot General Hospital, Mae Sot, Tak Province, Thailand. Results The number of (GT)n repeats of the HO-1 gene in all patients varied between 16 and 39 and categorized to short (S), medium (M) and long (L) GTn repeats. The genotype of (GT)n repeat of HO-1 was found to be significantly different among the three ethnic groups of patients. Significantly higher frequency of S/L genotype was found in Burmese compared with Thai patients, while significantly lower frequencies of S/S and M/L but higher frequency of M/M genotype was observed in Burmese compared with Karen patients. No significant association between HO-1 and TNF polymorphisms including the inducing effect of cadmium and malaria pathogenicity/severity was observed. Conclusions Difference in the expression of HO-1 genotype in different ethnic groups may contribute to different severity of malaria disease. With

  15. The Global Terrestrial Network for Permafrost Database: metadata statistics and prospective analysis on future permafrost temperature and active layer depth monitoring site distribution

    NASA Astrophysics Data System (ADS)

    Biskaborn, B. K.; Lanckman, J.-P.; Lantuit, H.; Elger, K.; Streletskiy, D. A.; Cable, W. L.; Romanovsky, V. E.

    2015-03-01

    The Global Terrestrial Network for Permafrost (GTN-P) provides the first dynamic database associated with the Thermal State of Permafrost (TSP) and the Circumpolar Active Layer Monitoring (CALM) programs, which extensively collect permafrost temperature and active layer thickness data from Arctic, Antarctic and Mountain permafrost regions. The purpose of the database is to establish an "early warning system" for the consequences of climate change in permafrost regions and to provide standardized thermal permafrost data to global models. In this paper we perform statistical analysis of the GTN-P metadata aiming to identify the spatial gaps in the GTN-P site distribution in relation to climate-effective environmental parameters. We describe the concept and structure of the Data Management System in regard to user operability, data transfer and data policy. We outline data sources and data processing including quality control strategies. Assessment of the metadata and data quality reveals 63% metadata completeness at active layer sites and 50% metadata completeness for boreholes. Voronoi Tessellation Analysis on the spatial sample distribution of boreholes and active layer measurement sites quantifies the distribution inhomogeneity and provides potential locations of additional permafrost research sites to improve the representativeness of thermal monitoring across areas underlain by permafrost. The depth distribution of the boreholes reveals that 73% are shallower than 25 m and 27% are deeper, reaching a maximum of 1 km depth. Comparison of the GTN-P site distribution with permafrost zones, soil organic carbon contents and vegetation types exhibits different local to regional monitoring situations on maps. Preferential slope orientation at the sites most likely causes a bias in the temperature monitoring and should be taken into account when using the data for global models. The distribution of GTN-P sites within zones of projected temperature change show a high

  16. Photoerasing paper and thermocoloring film

    NASA Astrophysics Data System (ADS)

    Kanakkanatt, Sebastian V.

    1997-08-01

    Thermal coloration of spiropyrans and spiroxazines at or above their melting point is well known to photochromists. The erasure of the color developed by exposure of photochromic paper by radiations of certain wavelengths in the visible region is little known. Six-nitrospirobenzopyran and 8- nitrospirobenzopyran, 8-methoxy-6-nitrospirobenzo-pyran, 6- methoxy-8-nitrospirobenzopyran, and 6,8-dinitrospirobenzopyran have been studied. The medium in which these photochromic dyes were dissolved or incorporated was limited to cellulose derivatives such as cellulose acetate, cellulose acetate- butyrate, and cellulose trinitrate. Paper coated with 6- nitrospirobenzopyran dissolved in an ethyl acetate solution of cellulose trinitrate readily colored on exposure to UV light or IR radiation and faded on exposure to light in the visible range. This unusual phenomenon, although not fully understood, is believed to be a selective light sensitizing ability of nitro groups. The applications of photoerasing paper and thermally colorable films are numerous, such as in polaroid type photography, in copy machines, and in thermally stable photochromic ophthalmic lenses.

  17. Structural determination of individual chemical species in a mixed system by iterative transformation factor analysis-based X-ray absorption spectroscopy combined with UV-visible absorption and quantum chemical calculation.

    PubMed

    Ikeda, Atsushi; Hennig, Christoph; Rossberg, André; Tsushima, Satoru; Scheinost, Andreas C; Bernhard, Gert

    2008-02-15

    A multitechnique approach using extended X-ray absorption fine structure (EXAFS) spectroscopy based on iterative transformation factor analysis (ITFA), UV-visible absorption spectroscopy, and density functional theory (DFT) calculations has been performed in order to investigate the speciation of uranium(VI) nitrate species in acetonitrile and to identify the complex structure of individual species in the system. UV-visible spectral titration suggests that there are four different species in the system, that is, pure solvated species, mono-, di-, and trinitrate species. The pure EXAFS spectra of these individual species are extracted by ITFA from the measured spectral mixtures on the basis of the speciation distribution profile calculated from the UV-visible data. Data analysis of the extracted EXAFS spectra, with the help of DFT calculations, reveals the most probable complex structures of the individual species. The pure solvated species corresponds to a uranyl hydrate complex with an equatorial coordination number (CNeq) of 5, [UO2(H2O)5]2+. Nitrate ions tend to coordinate to the uranyl(VI) ion in a bidentate fashion rather than a unidentate one in acetonitrile for all the nitrate species. The mononitrate species forms the complex of [UO2(H2O)3NO3]+ with a CNeq value of 5, while the di- and trinitrate species have a CNeq value of 6, corresponding to [UO2(H2O)2(NO3)2]0 (D2h) and [UO2(NO3)3]- (D3h), respectively.

  18. Internationally coordinated glacier monitoring - a timeline since 1894

    NASA Astrophysics Data System (ADS)

    Nussbaumer, Samuel U.; Armstrong, Richard; Fetterer, Florence; Gärtner-Roer, Isabelle; Hoelzle, Martin; Machguth, Horst; Mölg, Nico; Paul, Frank; Raup, Bruce H.; Zemp, Michael

    2016-04-01

    Changes in glaciers and ice caps provide some of the clearest evidence of climate change, with impacts on sea-level variations, regional hydrological cycles, and natural hazard situations. Therefore, glaciers have been recognized as an Essential Climate Variable (ECV). Internationally coordinated collection and distribution of standardized information about the state and change of glaciers and ice caps was initiated in 1894 and is today organized within the Global Terrestrial Network for Glaciers (GTN-G). GTN-G ensures the continuous development and adaptation of the international strategies to the long-term needs of users in science and policy. A GTN-G Steering Committee coordinates, supports and advices the operational bodies responsible for the international glacier monitoring, which are the World Glacier Monitoring Service (WGMS), the US National Snow and Ice Data Center (NSIDC), and the Global Land Ice Measurements from Space (GLIMS) initiative. In this presentation, we trace the development of the internationally coordinated glacier monitoring since its beginning in the 19th century. Today, several online databases containing a wealth of diverse data types with different levels of detail and global coverage provide fast access to continuously updated information on glacier fluctuation and inventory data. All glacier datasets are made freely available through the respective operational bodies within GTN-G, and can be accessed through the GTN-G Global Glacier Browser (http://www.gtn-g.org/data_browser.html). Glacier inventory data (e.g., digital outlines) are available for about 180,000 glaciers (GLIMS database, RGI - Randolph Glacier Inventory, WGI - World Glacier Inventory). Glacier front variations with about 45,000 entries since the 17th century and about 6,200 glaciological and geodetic mass (volume) change observations dating back to the 19th century are available in the Fluctuations of Glaciers (FoG) database. These datasets reveal clear evidence that

  19. Role of 18F-FDG PET in the management of gestational trophoblastic neoplasia.

    PubMed

    Mapelli, P; Mangili, G; Picchio, M; Gentile, C; Rabaiotti, E; Giorgione, V; Spinapolice, E G; Gianolli, L; Messa, C; Candiani, M

    2013-04-01

    Gestational trophoblastic neoplasia (GTN) is a rare and aggressive tumour that is usually sensitive to chemotherapy. The usefulness of conventional imaging modalities in evaluating treatment response is limited, mainly due to the difficulty in differentiating between residual tumour tissue and necrosis. The aim of the present study was to evaluate the role of FDG PET or PET/CT in primary staging and in monitoring treatment efficacy. The effect of FDG PET and combined PET/CT on the management of patients with GTN was also evaluated comparing the differences between standard treatments based on conventional imaging and alternative treatments based on PET. This retrospective study included 41 patients with GTN referred to San Raffaele Hospital between 2002 and 2010. All patients were studied by either PET or PET/CT in addition to conventional imaging. Of the 41 patients, 38 were evaluated for primary staging of GTN and 3 patients for chemotherapy resistance after first-line chemotherapy performed in other Institutions. To validate the PET data, PET and PET/CT findings were compared with those from conventional imaging, including transvaginal ultrasonography (TV-US) in those with uterine disease, CT and chest plain radiography in those with lung disease and whole-body CT in those with systemic metastases. Conventional imaging was considered positive for the presence of uterine disease and/or metastases when abnormal findings relating to GTN were reported. PET and PET/CT were considered concordant with conventional imaging when metabolic active disease was detected at the sites corresponding to the pathological findings on conventional imaging. In addition, in 12 of the 41 patients showing extrauterine disease, FDG PET/CT was repeated to monitor treatment efficacy, in 8 after normalization of beta human chorionic gonadotropin (βHCG) and in 4 with βHCG resistance. In some patients, PET or PET/CT findings led to an alternative nonconventional treatment, and this was

  20. Association of HMOX1 and NQO1 Polymorphisms with Metabolic Syndrome Components

    PubMed Central

    Martínez-Hernández, Angélica; Córdova, Emilio J.; Rosillo-Salazar, Oscar; García-Ortíz, Humberto; Contreras-Cubas, Cecilia; Islas-Andrade, Sergio; Revilla-Monsalve, Cristina; Salas-Labadía, Consuelo; Orozco, Lorena

    2015-01-01

    Metabolic syndrome (MetS) is among the most important public health problems worldwide, and is recognized as a major risk factor for various illnesses, including type 2 diabetes mellitus, obesity, and cardiovascular diseases. Recently, oxidative stress has been suggested as part of MetS aetiology. The heme oxygenase 1 (HMOX1) and NADH:quinone oxidoreductase 1 (NQO1) genes are crucial mediators of cellular defence against oxidative stress. In the present study, we analysed the associations of HMOX1 (GT)n and NQO1 C609T polymorphisms with MetS and its components. Our study population comprised 735 Mexican Mestizos unrelated volunteers recruited from different tertiary health institutions from Mexico City. In order to know the HMOX1 (GT)n and NQO1 C609T allele frequencies in Amerindians, we included a population of 241 Amerindian native speakers. Their clinical and demographic data were recorded. The HMOX1 (GT)n polymorphism was genotyped using PCR and fluorescence technology. NQO1 C609T polymorphism genotyping was performed using TaqMan probes. Short allele (<25 GT repeats) of the HMOX1 polymorphism was associated with high systolic and diastolic blood pressure, and the T allele of the NQO1 C609T polymorphism was associated with increased triglyceride levels and decreased HDL-c levels, but only in individuals with MetS. This is the first study to analyse the association between MetS and genes involved in oxidative stress among Mexican Mestizos. Our data suggest that polymorphisms of HMOX1 and NQO1 genes are associated with a high risk of metabolic disorders, including high systolic and diastolic blood pressure, hypertriglyceridemia, and low HDL-c levels in Mexican Mestizo individuals. PMID:25933176

  1. Androgenic anabolic steroids and arterial structure and function in male bodybuilders.

    PubMed

    Sader, M A; Griffiths, K A; McCredie, R J; Handelsman, D J; Celermajer, D S

    2001-01-01

    The study examined arterial and cardiac structure and function in bodybuilders using androgenic anabolic steroids (AAS), compared to non-steroid-using bodybuilder controls. Adverse cardiovascular events have been reported in bodybuilders taking anabolic steroids. The cardiovascular effects of AAS, however, have not been investigated in detail. We recruited 20 male bodybuilders (aged 35 +/- 3 years), 10 actively using AAS and 10 who denied ever using steroids. Serum lipid and hormone levels, carotid intima-media thickness (IMT), arterial reactivity, and left ventricular (LV) dimensions were measured. Vessel diameter was measured by ultrasound at rest, during reactive hyperemia (an endothelium-dependent response, leading to flow-mediated dilation, FMD), and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Arterial reactivity was also measured in 10 age-matched non-bodybuilding sedentary controls. Use of AAS was associated with significant decreases in high density lipoprotein cholesterol, sex hormone binding globulin, testosterone and gonadotrophin levels, and significant increases in LV mass and self-reported physical strength (p < 0.05). Carotid IMT (0.60 +/- 0.04 mm vs. 0.63 +/- 0.07 mm), arterial FMD (4.7 +/- 1.4% vs. 4.1 +/- 0.7%) and GTN responses (11.0 +/- 1.9% vs. 14.4 +/- 1.7%) were similar in both bodybuilding groups (p > 0.2). The GTN responses were significantly lower and carotid IMT significantly higher in both bodybuilding groups, however, compared with the non-bodybuilding sedentary controls (p = 0.01). Although high-level bodybuilding is associated with impaired vascular reactivity and increased arterial thickening, the use of AAS per se is not associated with significant abnormalities of arterial structure or function.

  2. Advancing global hydro-climatological data archives to support climate change impact assessments on water resources

    NASA Astrophysics Data System (ADS)

    Saile, P.

    2012-12-01

    Climate variations and changing climate will very likely alter the rate and nature of hydrological processes and consequently affect water resources in many regions. Current General Circulation Models and downscaling methods that are increasingly used to assess changes in the water cycle and water resource vulnerabilities introduce a cascade of uncertainties that cannot realistically be dealt with at the moment and are too inaccurate to support improved decision-making for water management and for future water systems design. Therefore, water managers need not only improved hydrological and climate modelling and downscaling methods but also access to adequate hydro-meteorological monitoring networks. The Global Terrestrial Network for Hydrology (GTN-H), a joint effort by the World Meteorological Organization (WMO) and several global observing systems, aims at integrating in-situ and remote sensing hydrological observations with hydrological model results held by its partner institutions to support a wide range of hydrological applications including research of global and regional climate change. Adhering to the different needs of all data users (scientists, policy makes and other stakeholders) and bridging the gap between the distributed datasets, currently a new information system is being developed to enable web-based discovery, access and analysis of observation data and derived products served through GTN-H. This system is built on international standards published by the Open Geospatial Consortium (OGC) using open standardized web services, namely (1) Catalogue Services for data discovery, (2) Web Map Services for data visualization and (3) Web Feature Services, Web Coverage Services and Sensor Observation Services for data access. This presentation will give an overview about the GTN-H data archive and the design of the new information system including an outlook of its potential use for water related climate change impact assessments.

  3. Alcohol acutely increases vascular reactivity together with insulin sensitivity in type 2 diabetic men.

    PubMed

    Schaller, G; Kretschmer, S; Gouya, G; Haider, D G; Mittermayer, F; Riedl, M; Wagner, O; Pacini, G; Wolzt, M; Ludvik, B

    2010-01-01

    Moderate alcohol consumption is associated with increased insulin sensitivity and reduced cardiovascular risk. We hypothesized that this relates to a direct effect of alcohol and therefore investigated whether acute alcohol intake altered insulin sensitivity or endothelial function in patients with type 2 diabetes. In an open-label two period design, the effect of a single oral dose of 40 g of alcohol (168 ml 40% vodka) on an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and on endothelium-dependent (flow mediated, FMD) or endothelium-independent (glyceroltrinitrate (GTN)-induced) vasodilation of the brachial artery measured by ultrasound was studied. Experiments were carried out in twelve male patients with type 2 diabetes mellitus (64+/-6 years, body mass index 28.4+/-5.7 kg/m (2)). Baseline insulin sensitivity index (S (I)) was 1.10+/-0.34 min (-1).microU (-1).ml, baseline FMD was +4.1+/-3.0%, and GTN-induced vasodilation +7.4+/-2.3% from resting brachial artery diameter. Acute alcohol intake increased alcohol plasma levels to 0.33+/-0.04 per thousand, S (I) to 1.86+/-0.45 min (-1).microU (-1).ml (p<0.05), and FMD to +8.2+/-2.8% (p<0.05), while GTN-induced dilation remained unchanged. No relationship was detectable between the observed changes. We conclude that alcohol intake acutely increases endothelium-dependent brachial artery vasodilation in patients with type 2 diabetes together with insulin sensitivity. This acute effect might explain some beneficial effects of low alcohol consumption in epidemiological observations.

  4. Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction.

    PubMed

    Mittermayer, Friedrich; Pleiner, Johannes; Schaller, Georg; Zorn, Stefan; Namiranian, Khodadad; Kapiotis, Stylianos; Bartel, Gregor; Wolfrum, Mathias; Brügel, Mathias; Thiery, Joachim; Macallister, Raymond J; Wolzt, Michael

    2005-10-01

    Acute inflammation causes endothelial dysfunction, which is partly mediated by oxidant stress and inactivation of nitric oxide. The contribution of depletion of tetrahydrobiopterin (BH(4)), the cofactor required for nitric oxide generation, is unclear. In this randomized, double-blind, three-way crossover study, forearm blood flow (FBF) responses to ACh and glyceryltrinitrate (GTN) were measured before and 3.5 h after infusion of Escherichia coli endotoxin (LPS, 20 IU/kg iv) in eight healthy men. The effect of intra-arterial BH(4) (500 microg/min), placebo, or vitamin C (24 mg/min) was studied on separate days 3.5 h after LPS infusion. In addition, human umbilical vein endothelial cells were incubated for 24 h with vitamin C and LPS. ACh and GTN caused dose-dependent forearm vasodilation. The FBF response to ACh, which was decreased by 23 +/- 17% (P < 0.05) by LPS infusion, was restored to baseline reactivity by BH(4) and vitamin C. FBF responses to GTN were not affected by BH(4) or vitamin C. LPS increased leukocyte count, high-sensitivity C-reactive protein, IL-6, IL-1beta, IFN-gamma, monocyte chemoattractant protein-1, pulse rate, and body temperature and decreased platelet count and vitamin C concentration. Vitamin C increased forearm plasma concentration of BH(4) by 32% (P < 0.02). Incubation with LPS and vitamin C, but not LPS alone, increased intracellular BH(4) concentration in human umbilical vein endothelial cells. Impaired endothelial function during acute inflammation can be restored by BH(4) or vitamin C. Vitamin C may exert some of its salutary effects by increasing BH(4) concentration.

  5. Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter.

    PubMed

    Repessé, Yohann; Peyron, Ivan; Dimitrov, Jordan D; Dasgupta, Suryasarathi; Moshai, Elika Farrokhi; Costa, Catherine; Borel-Derlon, Annie; Guillet, Benoit; D'Oiron, Roseline; Aouba, Achille; Rothschild, Chantal; Oldenburg, Johannes; Pavlova, Anna; Kaveri, Srinivas V; Lacroix-Desmazes, Sébastien

    2013-10-01

    Induction of heme oxygenase-1, a stress-inducible enzyme with anti-inflammatory activity, reduces the immunogenicity of therapeutic factor VIII in experimental hemophilia A. In humans, heme oxygenase-1 expression is modulated by polymorphisms in the promoter of the heme oxygenase-1-encoding gene (HMOX1). We investigated the relationship between polymorphisms in the HMOX1 promoter and factor VIII inhibitor development in severe hemophilia A. We performed a case-control study on 99 inhibitor-positive patients and 263 patients who did not develop inhibitors within the first 150 cumulative days of exposure to therapeutic factor VIII. Direct sequencing and DNA fragment analysis were used to study (GT)n polymorphism and single nucleotide polymorphisms located at -1135 and -413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies or genotypes, and inhibitor development. Our results demonstrate that inhibitor-positive patients had a higher frequency of alleles with large (GT)n repeats (L: n≥30), which are associated with lesser heme oxygenase-1 expression (odds ratio 2.31; 95% confidence interval 1.46-3.66; P<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT)n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% versus 17.1%) (odds ratio 2.21, 95% confidence interval 1.30-3.76; P<0.01). To our knowledge, this is the first association identified between HMOX1 promoter polymorphism and development of anti-drug antibodies. Our study paves the way towards modulation of the endogenous anti-inflammatory machinery of hemophilia patients to reduce the risk of inhibitor development.

  6. Second Curettage for Low-Risk Nonmetastatic Gestational Trophoblastic Neoplasia.

    PubMed

    Osborne, Raymond J; Filiaci, Virginia L; Schink, Julian C; Mannel, Robert S; Behbakht, Kian; Hoffman, James S; Spirtos, Nick M; Chan, John K; Tidy, John A; Miller, David S

    2016-09-01

    To evaluate the efficacy and safety of second uterine curettage in lieu of chemotherapy for patients with low-risk, nonmetastatic gestational trophoblastic neoplasia (GTN) and to evaluate whether response to second curettage is independent of patient age, World Health Organization (WHO) risk score, registration human chorionic gonadotropin (hCG) level, lesion size, and depth of myometrial invasion measured on ultrasound examination. This was a cooperative group multicenter prospective phase II study. Prestudy testing included quantitative hCG level, pelvic ultrasonography, and chest radiography. Patients were categorized according to WHO risk scoring criteria (low risk with a score of 0-6). Sixty-four women with newly diagnosed low-risk, nonmetastatic GTN were enrolled. Four patients were excluded. Twenty-four patients (40%) (lower 95% confidence limit 27.6%) were cured after second curettage. An additional two patients (3%) achieved a complete response but did not complete follow-up. Overall, 26 of 60 patients were able to avoid chemotherapy. Surgical failure was observed in 34 women (59%) and was more common in women 19 years old or younger or 40 years old or older. One case of grade 1 uterine perforation was successfully managed by observation. Four grade 1 and one grade 3 uterine hemorrhages were reported. New metastatic disease (lung) was identified in one of these women after second curettage. In three patients (surgical failures), the second curettage pathology was placental site trophoblastic tumor, and it was placental nodule in one additional patient. Second uterine curettage as initial treatment for low-risk, nonmetastatic GTN cures 40% of patients without significant morbidity. ClinicalTrials.gov, https://clinicaltrials.gov/, NCT00521118.

  7. Immunohistochemistry Study of P53 and C-erbB-2 Expression in Trophoblastic Tissue and Their Predictive Values in Diagnosing Malignant Progression of Simple Molar Pregnancy

    PubMed Central

    Hasanzadeh, Malihe; Sharifi, Norrie; Farazestanian, Marjaneh; Nazemian, Seyed Saman; Madani Sani, Faezeh

    2016-01-01

    Background Finding a tumor marker to predict the aggressive behavior of molar pregnancy in early stages has yet been a topic for studies. Objectives In this survey we planned to study patients with molar pregnancy to 1) assess the p53 and c-erbB-2 expression in trophoblastic tissue, 2) to study the relationship between their expression intensity and progression of a molar pregnancy to gestational trophoblastic neoplasia, and 3) to determine a cut off value for the amount of p53 and c-erbB-2 expression which might correlate with aggressive behavior of molar pregnancy. Patients and Methods In a prospective cross sectional study by using a high accuracy technique EnVision Tm system for immunohistochemistry staining of molar pregnancy samples, we evaluated p53 and c-erbB-2 expression in cytotrophoblast and syncytiotrophoblast and the correlation of their expression with progression of molar pregnancy to gestational trophoblastic neoplasia (GTN). Normal prostatic tissue and Breast cancer tissue were used as positive controls. Results We studied 28 patients with simple molar pregnancy (SMP) and 30 with GTN. Cytotrophobalst had significantly higher expression of p53 and c-erbB-2 and syncytiotrophoblast had greater expression of p53 in GTN group as compared to SMP group. The cut off values for percentage of p53 positive immunostained cytotrophoblast and syncytiotrophoblast were 5.5% and 2.5%. In c-erbB-2 positive membranous stained cytotrophoblast the cut off was 12.5%. Conclusions Our data suggests that over expression of p53 and c-erbB-2 is associated with malignant progression of molar pregnancy. We encountered that high expression of p53 and c-erbB-2 in trophoblastic cells could predict gestational trophoblastic neoplasia during the early stages. PMID:27703642

  8. Gestational trophoblastic disease: a 21-year review of the clinical experience at an Argentinean public hospital.

    PubMed

    Bianconi, Maria Inés; Otero, Silvina; Moscheni, Oriana; Alvarez, Lucia; Storino, Claudio; Jankilevich, Gustavo

    2012-01-01

    To analyze the clinical trends of gestational trophoblastic disease (GTD) in a public hospital of Buenos Aires, Argentina. A review of the clinical records of 358 patients with a diagnosis of GTD admitted to Durand Trophoblastic Disease Center between 1990 and February 2011 was performed. Features of diagnosis, treatment and follow-up were analyzed. A total of 358 cases of GTD were reviewed. Hydatidiform mole was diagnosed in 340 patients; of those 223 (66%) experienced spontaneous remission after evacuation. Of the 135 patients with persistent gestational trophoblastic neoplasia (GTN), 99 (73%) had low-risk GTN, 32 (26%) had high-risk GTN and 4 had either placental site trophoblastic disease or epithelioid trophoblastic tumor. In the low-risk group the first-line treatment was methotrexate and the second-line treatment was actinomycin D, etoposide, cytoxan, and oncovin (EMA/CO), with a complete response rate of 100%. High-risk patients whose WHO prognostic scores were 7-13 were treated initially with EMA/CO. Patients whose scores were >13 were treated with EMA/PE, where platinum and etoposide replaced oncovin and cytoxan. Salvage therapy in patients with relapse or resistant disease were treated with a wide variety of chemotherapy regimens. The complete response rate was 98.2%. Compliance was 100%. Three patients died. In all cases the outcome was related with inadequate initial treatment. This protocol is in agreement with international consensus. It was useful, safe and feasible in our population. The compliance with international guidelines allows reach a successful treatment and follow-up in one Latin-American population.

  9. Relationship between race and clinical characteristics, extent of disease, and response to chemotherapy in patients with low-risk gestational trophoblastic neoplasia.

    PubMed

    Maestá, Izildinha; Berkowitz, Ross S; Goldstein, Donald P; Bernstein, Marilyn R; Ramírez, Luz Angela C; Horowitz, Neil S

    2015-07-01

    To evaluate the potential effects of race on clinical characteristics, extent of disease, and response to chemotherapy in women with postmolar low-risk gestational trophoblastic neoplasia (GTN). This non-concurrent cohort study was undertaken including patients with FIGO-defined postmolar low-risk GTN treated with comparable doses and schedules of chemotherapy at the New England Trophoblastic Disease Center (NETDC) between 1973 and 2012. Racial groups investigated included whites, African American and Asians. Information on patient characteristics and response to chemotherapy (need for second line chemotherapy, reason for changing to an alternative chemotherapy, number of cycles/regimens, need for combination chemotherapy, and time to hCG remission) was obtained. Of 316 women, 274 (86.7%) were white, 19 (6%) African American, and 23 (7.3%) Asian. African Americans were significantly younger than white and Asian women (p=0.008). Disease presentation, and extent of disease, including antecedent molar histology, median time to persistence, median hCG level at persistence, rate of D&C at persistence, presence of metastatic disease, and FIGO stage and risk score were similar among races. Need for second line chemotherapy (p=0.023), and median number of regimens (p=0.035) were greater in Asian women than in other races. Low-risk GTN was more aggressive in Asian women, who were significantly more likely to need second line chemotherapy and a higher number of chemotherapy regimens to achieve complete remission than women of African American and Asian descent. Further studies involving racial differences related to clinical, biological and environmental characteristics are needed. Copyright © 2015. Published by Elsevier Inc.

  10. Clinical Presentation of Complete Hydatidiform Mole and Partial Hydatidiform Mole at a Regional Trophoblastic Disease Center in the United States Over the Past 2 Decades.

    PubMed

    Sun, Sue Yazaki; Melamed, Alexander; Joseph, Naima T; Gockley, Allison Ann; Goldstein, Donald Peter; Bernstein, Marilyn R; Horowitz, Neil S; Berkowitz, Ross Stuart

    2016-02-01

    The aim of this study was to compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among cases of complete mole (CM) and partial mole (PM) from 1994 to 2013. This study included all cases of patients with CM and PM from our trophoblastic disease center between 1994 and 2013. Their clinical and pathologic reports were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin levels, and the rate of progression to GTN were compared. The median gestational age at evacuation was 9 weeks for CM and 12 weeks for PM (P < 0.001). Patients with PM had lower pre-evacuation serum human chorionic gonadotropin levels (P < 0.001), and they were also less likely to present with vaginal bleeding (P < 0.001), biochemical hyperthyroidism (P < 0.001), anemia (P < 0.001), uterine size greater than dates (P < 0.001), and hyperemesis (P = 0.002). Consequently, patients with PM were less likely to have been clinically diagnosed as moles compared with CM prior to uterine evacuation (P < 0.001). The development of GTN occurred in 17.7% (33/186) and 4.1% (7/169) of patients with CM and PM, respectively (P < 0.001). This study indicates that, at our center over the past 20 years, both CM and PM were usually evacuated in the first trimester of pregnancy. Because CM more commonly presents with the signs and symptoms of molar disease than PM, CM is more commonly diagnosed prior to evacuation.

  11. Long-term active-layer dynamics: results of 22 years of field observations in Northern Hemisphere permafrost regions.

    NASA Astrophysics Data System (ADS)

    Shiklomanov, N. I.; Nelson, F. E.; Streletskiy, D. A.; Klene, A. E.; Biskaborn, B. K.

    2016-12-01

    The uppermost layer of seasonal thawing above permafrost (the active layer) is an important regulator of energy and mass fluxes between the surface and the atmosphere in the polar regions. Active layer monitoring is an important component of efforts to assess the effects of global change in permafrost environments. The Circumpolar Active Layer Monitoring (CALM) program, established in the early 1990s, is designed to observe temporal and spatial variability of the active layer and its response to changes and variations in climatic conditions. The CALM network is an integral part of the Global Terrestrial Network for Permafrost (GTN-P), operating under the auspices of the Global Terrestrial Observing System (GTOS) /Global Climate Observing System (GCOS). Standardized thaw depth observations in the Northern Hemisphere are available for more than 200 GTN-P/CALM sites in the Northern Hemisphere. At each of the sites spatially distributed ALT measurements have been conducted annually by mechanical probing. The locations of sites represent generalized surface and subsurface conditions characteristic of broader regions. The data are assimilated and distributed though the CALM (www.gwu.edu/ calm) and GTN-P (gtnpdatabase.org) online databases. In this presentation we use data from approximately 20 years of continuous observations to examine temporal trends in active-layer thickness for several representative Arctic regions. Results indicate substantial interannual fluctuations in active-layer thickness, primarily in response to variations in air temperature. Decadal trends in ALT vary by region. A progressive increase in ALT has been observed in the Nordic countries, the Russian European North, West Siberia, East Siberia, the Russian Far East, and the Interior of Alaska. North American Arctic sites show no apparent thaw depth trend over 22-years of record. However, combined active layer, ground temperature and heave/subsidence observations conducted in northern Alaska

  12. Elastic clearance change in axisymmetric shearing process

    NASA Astrophysics Data System (ADS)

    Yoshida, Yoshinori

    2016-10-01

    An axisymmetric shearing experiment is conducted for a sheet of low carbon steel and stainless steel. Elastic change in the clearance between punch and die is measured. The increase of the clearance in shearing is confirmed and the influence of sheared material's flow stress on the clearance change is shown. Finite element analysis (FEA) of shearing with Gurson-Tvergaard-Needlman model (GTN model) is conducted for shearing of the carbon steels with rigid tools as a numerical experiment. Burr height is predicted in the FEA and the result is compared with the experimental result. In addition, the influence of the clearance on stress state in the material is investigated.

  13. Microsatellite polymorphism in the heme oxygenase-1 promoter is associated with nonsevere and late-onset preeclampsia.

    PubMed

    Kaartokallio, Tea; Klemetti, Miira M; Timonen, Anni; Uotila, Jukka; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Lakkisto, Päivi; Laivuori, Hannele

    2014-07-01

    Preeclampsia is a serious and phenotypically heterogeneous vascular pregnancy disorder. Heme oxygenase-1 (HO-1) is a stress response enzyme that may protect the maternal endothelium and facilitate adequate metabolic adaptation to pregnancy by its antioxidant and anti-inflammatory functions. HO-1 stress response is modulated by HO-1 gene (HMOX1) polymorphisms. Individuals with the long allele of a guanine-thymine (GTn) microsatellite repeat located in the promoter region of HMOX1 have a higher risk of cardiometabolic diseases compared with those with the short allele. We investigated whether the long GTn allele of HMOX1 is associated with subtypes of preeclampsia. The GTn repeat was genotyped in 759 patients and in 779 controls from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort using DNA fragment analysis. In subtype analyses, the long-long (LL) genotype was associated with nonsevere (additive model: odds ratio [OR], 1.94; 95% confidence interval [CI], 1.13-3.31; recessive model: OR, 1.39; 95% CI, 1.02-1.89) and late-onset (additive model: OR, 1.44; 95% CI, 1.02-2.05; recessive model: OR, 1.28; 95% CI, 1.02-1.59) preeclampsia and with preeclampsia without a small-for-gestational-age infant (recessive model: OR, 1.27; 95% CI, 1.02-1.58). The long allele was associated with nonsevere (OR, 1.35; 95% CI, 1.07-1.70) and late-onset (OR, 1.21; 95% CI, 1.03-1.42) preeclampsia and with preeclampsia without a small-for-gestational-age infant (OR, 1.19; 95% CI, 1.02-1.40). Moreover, both the LL genotype and the long allele were associated with preeclampsia in women who had smoked during pregnancy. In conclusion, the GTn long allele seems to predispose to late-onset, less severe form of preeclampsia. This finding supports the role of HO-1 in the pathogenesis of preeclampsia and suggests that the HO-1 pathway may provide a potential target for the treatment of preeclampsia.

  14. Transgenic Phytoremediation Blasts onto the Scene

    SciTech Connect

    Hooker, Brian S.; Skeen, R S.

    1999-05-01

    The EPA National Priority List contains 22 ammunition production and processing sites that are laden with explosive and propellant wastes. With levels of 2,4,6-trinitrotoluene (TNT) contamination as high as 200 g/kg of solids, some of these sites are literally on the verge of exploding. They also present serious exposure risks to humans and wildlife, as many of these contaminants are also strong toxins and mutagens. In this issue, French et al. describe a new option for cleaning up this dangerous mixture: the use of transgenic plants. They engineered plants to express a bacterial enzyme that can completely denitrify TNT and trinitroglycerin (GTN) into harmless compounds.

  15. Modeling the ductile fracture and the plastic anisotropy of DC01 steel at room temperature and low strain rates

    NASA Astrophysics Data System (ADS)

    Tuninetti, V.; Yuan, S.; Gilles, G.; Guzmán, C. F.; Habraken, A. M.; Duchêne, L.

    2016-08-01

    This paper presents different extensions of the classical GTN damage model implemented in a finite element code. The goal of this study is to assess these extensions for the numerical prediction of failure of a DC01 steel sheet during a single point incremental forming process, after a proper identification of the material parameters. It is shown that the prediction of failure appears too early compared to experimental results. Though, the use of the Thomason criterion permitted to delay the onset of coalescence and consequently the final failure.

  16. Data Integration Tool: From Permafrost Data Translation Research Tool to A Robust Research Application

    NASA Astrophysics Data System (ADS)

    Wilcox, H.; Schaefer, K. M.; Jafarov, E. E.; Strawhacker, C.; Pulsifer, P. L.; Thurmes, N.

    2016-12-01

    The United States National Science Foundation funded PermaData project led by the National Snow and Ice Data Center (NSIDC) with a team from the Global Terrestrial Network for Permafrost (GTN-P) aimed to improve permafrost data access and discovery. We developed a Data Integration Tool (DIT) to significantly speed up the time of manual processing needed to translate inconsistent, scattered historical permafrost data into files ready to ingest directly into the GTN-P. We leverage this data to support science research and policy decisions. DIT is a workflow manager that divides data preparation and analysis into a series of steps or operations called widgets. Each widget does a specific operation, such as read, multiply by a constant, sort, plot, and write data. DIT allows the user to select and order the widgets as desired to meet their specific needs. Originally it was written to capture a scientist's personal, iterative, data manipulation and quality control process of visually and programmatically iterating through inconsistent input data, examining it to find problems, adding operations to address the problems, and rerunning until the data could be translated into the GTN-P standard format. Iterative development of this tool led to a Fortran/Python hybrid then, with consideration of users, licensing, version control, packaging, and workflow, to a publically available, robust, usable application. Transitioning to Python allowed the use of open source frameworks for the workflow core and integration with a javascript graphical workflow interface. DIT is targeted to automatically handle 90% of the data processing for field scientists, modelers, and non-discipline scientists. It is available as an open source tool in GitHub packaged for a subset of Mac, Windows, and UNIX systems as a desktop application with a graphical workflow manager. DIT was used to completely translate one dataset (133 sites) that was successfully added to GTN-P, nearly translate three datasets

  17. Short-chain flavor ester synthesis in organic media by an E. coli whole-cell biocatalyst expressing a newly characterized heterologous lipase.

    PubMed

    Brault, Guillaume; Shareck, François; Hurtubise, Yves; Lépine, François; Doucet, Nicolas

    2014-01-01

    Short-chain aliphatic esters are small volatile molecules that produce fruity and pleasant aromas and flavors. Most of these esters are artificially produced or extracted from natural sources at high cost. It is, however, possible to 'naturally' produce these molecules using biocatalysts such as lipases and esterases. A gene coding for a newly uncovered lipase was isolated from a previous metagenomic study and cloned into E. coli BL21 (DE3) for overexpression using the pET16b plasmid. Using this recombinant strain as a whole-cell biocatalyst, short chain esters were efficiently synthesized by transesterification and esterification reactions in organic media. The recombinant lipase (LipIAF5-2) showed good affinity toward glyceryl trioctanoate and the highest conversion yields were obtained for the transesterification of glyceryl triacetate with methanol. Using a simple cetyl-trimethylammonium bromide pretreatment increased the synthetic activity by a six-fold factor and the whole-cell biocatalyst showed the highest activity at 40°C with a relatively high water content of 10% (w/w). The whole-cell biocatalyst showed excellent tolerance to alcohol and short-chain fatty acid denaturation. Substrate affinity was equally effective with all primary alcohols tested as acyl acceptors, with a slight preference for methanol. The best transesterification conversion of 50 mmol glyceryl triacetate into isoamyl acetate (banana fragrance) provided near 100% yield after 24 hours using 10% biocatalyst loading (w/w) in a fluidized bed reactor, allowing recycling of the biocatalyst up to five times. These results show promising potential for an industrial approach aimed at the biosynthesis of short-chain esters, namely for natural flavor and fragrance production in micro-aqueous media.

  18. Short-Chain Flavor Ester Synthesis in Organic Media by an E. coli Whole-Cell Biocatalyst Expressing a Newly Characterized Heterologous Lipase

    PubMed Central

    Brault, Guillaume; Shareck, François; Hurtubise, Yves; Lépine, François; Doucet, Nicolas

    2014-01-01

    Short-chain aliphatic esters are small volatile molecules that produce fruity and pleasant aromas and flavors. Most of these esters are artificially produced or extracted from natural sources at high cost. It is, however, possible to ‘naturally’ produce these molecules using biocatalysts such as lipases and esterases. A gene coding for a newly uncovered lipase was isolated from a previous metagenomic study and cloned into E. coli BL21 (DE3) for overexpression using the pET16b plasmid. Using this recombinant strain as a whole-cell biocatalyst, short chain esters were efficiently synthesized by transesterification and esterification reactions in organic media. The recombinant lipase (LipIAF5-2) showed good affinity toward glyceryl trioctanoate and the highest conversion yields were obtained for the transesterification of glyceryl triacetate with methanol. Using a simple cetyl-trimethylammonium bromide pretreatment increased the synthetic activity by a six-fold factor and the whole-cell biocatalyst showed the highest activity at 40°C with a relatively high water content of 10% (w/w). The whole-cell biocatalyst showed excellent tolerance to alcohol and short-chain fatty acid denaturation. Substrate affinity was equally effective with all primary alcohols tested as acyl acceptors, with a slight preference for methanol. The best transesterification conversion of 50 mmol glyceryl triacetate into isoamyl acetate (banana fragrance) provided near 100% yield after 24 hours using 10% biocatalyst loading (w/w) in a fluidized bed reactor, allowing recycling of the biocatalyst up to five times. These results show promising potential for an industrial approach aimed at the biosynthesis of short-chain esters, namely for natural flavor and fragrance production in micro-aqueous media. PMID:24670408

  19. Aquivion Perfluorosulfonic Superacid as an Efficient Pickering Interfacial Catalyst for the Hydrolysis of Triglycerides.

    PubMed

    Shi, Hui; Fan, Zhaoyu; Hong, Bing; Pera-Titus, Marc

    2017-09-11

    Rational design of the surface properties of heterogeneous catalysts can boost the interfacial activity in biphasic reactions through the generation of Pickering emulsions. This concept, termed Pickering interfacial catalysis (PIC), has shown promising credentials in acid-catalyzed transesterification, ester hydrolysis, acetalization, etherification, and alkylation reactions. PIC has now been applied to the efficient, solvent-free hydrolysis of the triglyceride glyceryl trilaurate to lauric acid, catalyzed by Aquivion perfluorosulfonic superacid at mild conditions (100 °C and ambient pressure). © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.