Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid.

PubMed

Flanagan, Shawn; Fang, Edward; Muñoz, Kelly A; Minassian, Sonia L; Prokocimer, Philippe G

2014-09-01

Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate. Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. Ninety healthy volunteers. Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100-400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days. A dose-dependent increase was observed in the maximum plasma concentration (1.2-5.1 μg/ml) and the area under the concentration-time curve (17.4-58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100-400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores. These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the need for dose adjustment when switching administration routes. © 2014 Cubist Pharmaceuticals. Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

Nonclinical and clinical pharmacology evidence for cardiovascular safety of saxagliptin.

PubMed

Pollack, Pia S; Chadwick, Kristina D; Smith, David M; Billger, Martin; Hirshberg, Boaz; Iqbal, Nayyar; Boulton, David W

2017-09-13

In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury. In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported. The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.

Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects.

PubMed

Togawa, Michinori; Yamaya, Hidetoshi; Rodríguez, Mónica; Nagashima, Hirotaka

2016-12-01

Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). After single oral doses, maximum plasma concentrations (C max ) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies.

A new fully human recombinant FSH (follitropin epsilon): two phase I randomized placebo and comparator-controlled pharmacokinetic and pharmacodynamic trials.

PubMed

Abd-Elaziz, Khalid; Duijkers, Ingrid; Stöckl, Lars; Dietrich, Bruno; Klipping, Christine; Eckert, Kelvin; Goletz, Steffen

2017-08-01

What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters. Recombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule. Both studies were randomized, placebo- and comparator-controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing. In the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or 150 IU once daily [QD], or 150 IU every other day [QAD], 10 subjects each) and 27 subjects received 150 IU Gonal-f, 150 IU Bravelle, or placebo for 7 days (11/10/6 subjects). Blood samples for measuring PK as well as PD parameters were collected systematically before, during and after dosing. Adverse events (AEs) and other relevant safety parameters were recorded. Data were summarized using descriptive statistics. The single- and multiple-dose PK parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) increased in a linear fashion with increasing dose levels of follitropin epsilon. Follitropin epsilon showed PK characteristics comparable to the comparators indicating that well established treatment schemes could be applied. There was a dose-response effect of single and multiple doses of follitropin epsilon on follicular growth, which was shown for the biomarker inhibin B as well as for the mean number and size of follicles. Multiple doses of 75 IU follitropin epsilon given daily, as well as 150 IU follitropin epsilon every second day, showed a follicle growth comparable with 150 IU Gonal-f given daily, while in case of daily administration of 150 IU Bravelle only weak follicle stimulation was observed. Multiple doses of 150 IU follitropin epsilon induced a much higher follicle growth compared to the same dose of Gonal-f. All single and multiple follitropin epsilon doses tested were safe and well tolerated, and overall there were no relevant differences between follitropin epsilon and the comparators in terms of safety. The average number of AEs increased with increasing dose levels. No clinically relevant abnormalities were reported for any of the other safety parameters assessed. No follitropin epsilon anti-drug antibodies were observed. The studies were conducted as a single-blind design. Hormone levels or other parameters assessed in serum are generally not considered as being subject to bias. Other assessments directly performed by the investigators, such as transvaginal ultrasound assessments, may have been subject to personal bias. No prospective calculations of statistical power had been made, as is common practice for first in human and early phase I studies in healthy volunteers. These early development studies showed that follitropin epsilon exhibits comparable PK characteristics, as well as inducing stronger PD effects in terms of follicle growth and serum inhibin B, than the comparators. Follitropin epsilon induced a dose-dependent increase in follicular growth. The results warrant further studies with this new fully human recombinant FSH. The studies were sponsored by GLYCOTOPE GmbH, Berlin, Germany. K.A-E. is an employee of QPS-Netherlands, B.V., which received funding for the studies from Glycotope GmbH; I.D. and C.K. are employees of Dinox B.V., which received funding for the studies from Glycotope GmbH; L.S. and S.G. are employees and shareholders of Glycotope GmbH; B.D. and K.E. are employees of Glycotope GmbH. www.clinicaltrials.gov: NCT01354886 (single-dose); NCT01477073 (multiple-dose). The single-dose trial was registered on 11 May 2011 while the multiple-dose trial was registered on 09 November 2011. First subject was enroled in the single-dose trial in 27 April 2011 and in the multiple-dose trial in 02 October 2011. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects

PubMed Central

German, Polina; Kearney, Brian P.; Yang, Cheng Yong; Brainard, Diana; Link, John; McNally, John; Han, LingLing; Ling, John; Mathias, Anita

2017-01-01

ABSTRACT Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable in vitro and in vivo properties, including potent antiviral activity against hepatitis C virus genotype 1 to 6 replicons, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties, to warrant clinical evaluation. The phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple (n = 7) once-daily ascending doses and of VEL in the presence and absence of food. Following administration of single and multiple doses, VEL was safe and well tolerated when administered at up to 450 mg and when administered with food. The pharmacokinetic behavior of VEL observed in humans was generally in agreement with that seen during preclinical characterization. Following administration of multiple doses, VEL trough concentrations were significantly greater than the protein-adjusted half-maximal (50%) effective concentration of VEL against HCV genotype 1 to 6 replicons at all evaluated doses greater than 5 mg. The pharmacokinetics of VEL were not significantly affected by administration with food. Collectively, the results of this study support the further clinical investigation of VEL administered once daily as part of a regimen with other pangenotypic direct-acting antivirals for the treatment of HCV infection. PMID:28193657

Effects of TD-5108 on Gastrointestinal Transit and Bowel Function in Health and Pharmacokinetics in Health and Constipation

PubMed Central

Manini, Mhd Louai; Camilleri, Michael; Goldberg, Michael; Sweetser, Seth; McKinzie, Sanna; Burton, Duane; Wong, Shekman; Kitt, Michael M.; Li, Yu-Ping; Zinsmeister, Alan R.

2010-01-01

Background TD-5108 is a potent, selective high intrinsic activity serotonin 5-HT4 receptor agonist. Aim To assess effects of TD-5108 on gastrointestinal transit and compare its pharmacokinetics (PK) in healthy volunteers (HV) and chronic constipation (CC) patients. Methods 60 HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg TD-5108 (single and 6-day dosing). Primary endpoints were colonic transit (geometric center at 24 hours, GC24) and ascending colon emptying (ACE) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Results Single dose TD-5108 significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50°mg TD-5108 accelerated all 3 endpoints. With multiple doses, TD-5108 30 mg accelerated GC24, and overall accelerated GE T1/2 at 15–50 mg. PK studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of TD-5108. Stimulation of bowel function after15 mg TD-5108 were similar in CC and controls. There were no serious adverse events; notable adverse were the predictable GI effects such as diarrhea or altered bowel movements. Conclusions TD-5108 significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted. PMID:19691492

Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti-hyperalgesic effects, in patients with sciatica.

PubMed

Okkerse, Pieter; Hay, Justin L; Versage, Eve; Tang, Yongqiang; Galluppi, Gerald; Ravina, Bernard; Verma, Ajay; Williams, Leslie; Aycardi, Ernesto; Groeneveld, Geert Jan

2016-07-01

BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica. This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ). Safety and efficacy assessments were used as endpoints. The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 μg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen. The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica. © 2016 The British Pharmacological Society.

Efficacy and Safety of Alirocumab in Japanese Subjects (Phase 1 and 2 Studies).

PubMed

Teramoto, Tamio; Kobayashi, Masahiko; Uno, Kiyoko; Takagi, Yoshiharu; Matsuoka, Osamu; Sugimoto, Masayuki; Inoue, Satoshi; Minami, Fumiko; Baccara-Dinet, Marie Thérèse

2016-07-01

We assessed the safety and tolerability of ascending single doses of alirocumab in healthy Japanese subjects and evaluated the effect of alirocumab at 3 doses (50, 75, 150 mg) on low-density lipoprotein cholesterol (LDL-C) reduction in patients with primary hypercholesterolemia on atorvastatin. A randomized, single ascending-dose study of alirocumab (100, 150, 250, or 300 mg) or placebo (3:1 ratio), administered subcutaneously, was conducted in 32 healthy Japanese men. The phase 2, randomized, double-blind, placebo-controlled, parallel-group study was performed in patients with primary hypercholesterolemia (defined as calculated LDL-C ≥100 mg/dl [2.6 mmol/l]) who were on a stable dose of atorvastatin (5 to 20 mg). Patients were randomized to alirocumab (50, 75, or 150 mg) or placebo (in single 1.0-ml injection volumes) administered every 2 weeks (Q2W) for 12 weeks; the primary outcome was the mean percent change in calculated LDL-C from baseline to week 12. Single subcutaneous administration of alirocumab in healthy subjects was well tolerated over 15 weeks and resulted in highest mean percent reductions in LDL-C from baseline of approximately 40% to 60%. In the multiple-dose study, least-square mean (SE) changes in calculated LDL-C concentrations from baseline to week 12 were -54.8% (3.1%) for alirocumab 50 mg, -62.3% (3.1%) for alirocumab 75 mg, and -71.7% (3.1%) for alirocumab 150 mg, with a least-square mean (SE) difference versus placebo of -52.2% (4.3%), -59.6% (4.3%), and -69.1% (4.3%), respectively (all p <0.0001). In conclusion, alirocumab was well tolerated and significantly reduced LDL-C concentrations in Japanese patients with primary hypercholesterolemia on atorvastatin. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Effects of morphine and naloxone on feline colonic transit

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

Krevsky, B.; Libster, B.; Maurer, A.H.

1989-01-01

The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of themore » other opioid receptors is inferred.« less

Opioid Challenge Evaluation of Blockade by Extended-Release Naltrexone in Opioid-Abusing Adults: Dose-Effects and Time-Course

PubMed Central

Bigelow, George E.; Preston, Kenzie L.; Schmittner, John; Dong, Qunming; Gastfriend, David R.

2013-01-01

Background Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans. Methods Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-hr intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) Visual Analog Scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade. Results Blockade of the VAS “any drug effect” response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150 and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing. Conclusions These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment. PMID:22079773

Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

PubMed Central

Hawke, Roy L.; Schrieber, Sarah J.; Soule, Tedi A.; Wen, Zhiming; Smith, Philip C.; Reddy, K. Rajender; Wahed, Abdus S.; Belle, Steven H.; Afdhal, Nezam H.; Navarro, Victor J.; Berman, Josh; Liu, Qi-Ying; Doo, Edward; Fried, Michael W.

2011-01-01

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg. PMID:19841158

Patient-related factors influencing detectability of coronary arteries in 320-row CT angiography in infants with complex congenital heart disease.

PubMed

Yamasaki, Yuzo; Kawanami, Satoshi; Kamitani, Takeshi; Sagiyama, Koji; Shin, Seitaro; Hino, Takuya; Nagata, Hazumu; Yabuuchi, Hidetake; Nagao, Michinobu; Honda, Hiroshi

2018-05-05

To investigate the performance of second-generation 320-row computed tomographic (CT) angiography (CTA) in detecting coronary arteries and identify factors influencing visibility of the coronary arteries in infants with complex congenital heart disease (CHD). Data of 60 infants (aged 0-2 years, median 2 months) with complex CHD who underwent examination using 320-row CTA with low-dose prospective electrocardiogram-triggered volume target scanning were reviewed. The coronary arteries of each infant were assessed using a 0-4-point scoring system based on the number of coronary segments with a visible course. Clinical parameters, the CT value in the ascending aorta, image noise, and the radiation dose were subjected to univariate and multivariate analyses. The mean coronary score for all examinations was 2.6 ± 1.5 points. The mean attenuation in the ascending aorta was 306.7 ± 66.2 HU and the mean standard deviation was 21.7 ± 4.4. The mean effective radiation dose was 1.27 ± 0.39 mSv. Multivariate regression analysis showed significant correlations between coronary score and body weight (p < 0.05) and between coronary score and the CT value in the ascending aorta (p < 0.02). Second-generation 320-row CTA with prospective electrocardiogram-triggered volume target scanning and hybrid iterative reconstruction allows good visibility of the coronary arteries in infants with complex CHD. Body weight and the CT value in the ascending aorta are important factors influencing the visibility of the coronary arteries in infants.

Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis.

PubMed

Sandborn, W J; Bhandari, B R; Fogel, R; Onken, J; Yen, E; Zhao, X; Jiang, Z; Ge, D; Xin, Y; Ye, Z; French, D; Silverman, J A; Kanwar, B; Subramanian, G M; McHutchison, J G; Lee, S D; Shackelton, L M; Pai, R K; Levesque, B G; Feagan, B G

2016-07-01

Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis. © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

PubMed Central

Fitzgerald, Kevin; White, Suellen; Borodovsky, Anna; Bettencourt, Brian R.; Strahs, Andrew; Clausen, Valerie; Wijngaard, Peter; Horton, Jay D.; Taubel, Jorg; Brooks, Ashley; Fernando, Chamikara; Kauffman, Robert S.; Kallend, David; Vaishnaw, Akshay; Simon, Amy

2018-01-01

BACKGROUND Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol. METHODS In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442.) PMID:27959715

Pitavastatin is a potent anti-inflammatory agent in the rat paw model of acute inflammation.

PubMed

Qadir, Farida; Alam, Syed Mahboob; Siddiqi, Abeer Qamar; Kamran, Afshan

2014-11-01

Statins are used extensively as anti-hyperlipidemic agents. In addition to curtailing cholesterol synthesis they have been found to have multiple actions unrelated to cholesterol lowering "the pleiotropic effects," which includes inhibition of inflammation. We aimed at investigating the effect of pitavastatin a 3rd generation statin, in suppressing acute inflammation in rat paw edema model. Male Sprague-Dawley rats were randomly assigned to one of five groups (n=8): Control, indomethacin and pitavastatin (0.2mg/kg, 0.4mg/kg, 0.8mg/kg) treated. 1hour following treatment, inflammation was induced by sub-planter injection of egg albumin into the hind paw. Anti-inflammatory effect was evaluated by measurement of edema formation every half hour for three hours, assessment of polymorphonuclear leukocyte (PMNL) infiltration and measurement of tissue damage in skin biopsies. Ascending doses of pitavastatin were found to attenuate these parameters. The lowest dose of pitavastatin (0.2mg/kg) was found to significantly reduce edema volume, PMNL infiltration and tissue damage. The efficacy of the smallest dose was found comparable to indomethacin.

Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects.

PubMed

Akahori, Mizuki; Ayalasomayajula, Surya; Langenickel, Thomas; Pal, Parasar; Zhou, Wei; Sunkara, Gangadhar

2017-06-01

LCZ696 (sacubitril/valsartan) is a novel angiotensin receptor neprilysin inhibitor (ARNI) that has been developed for treatment of heart failure patients with reduced ejection fraction and approved in the US, Europe, and many other countries. This randomized, placebo-controlled study was conducted in healthy Japanese male subjects (N = 50) to assess the pharmacokinetics and safety of single ascending oral doses (20-600 mg) of LCZ696. Food effect was also evaluated following administration of 200 mg dose. Plasma and urine samples from 40 subjects receiving LCZ696 were collected to assess pharmacokinetics of LCZ696 analytes (sacubitril, sacubitrilat, and valsartan). Following single oral dose administration of LCZ696, sacubitril and valsartan rapidly appeared in systemic circulation with a dose-linear increase in the exposure to the LCZ696 analytes. Of the administered dose, approximately 0.85 %, 54.0 %, and 8.19 % of sacubitril, sacubitrilat, and valsartan, respectively, were recovered in urine. Food reduced AUC of sacubitril, sacubitrilat, and valsartan by 21, 8, and 40 %, respectively, and C max by 72, 27, and 51 %, respectively. Single oral doses of up to 600 mg of LCZ696 were safe and generally well tolerated in healthy Japanese male subjects.

A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment.

PubMed

Morimoto, Bruce H; Schmechel, Don; Hirman, Joe; Blackwell, Andrew; Keith, Julian; Gold, Michael

2013-01-01

AL-108-211 was a placebo-controlled, ascending-dose study that explored the safety, tolerability and efficacy of 12 weeks of treatment with AL-108 in subjects with amnestic mild cognitive impairment. A total of 144 subjects were randomized in a 2:1 drug:placebo ratio. Subjects were enrolled into the low-dose group or placebo and then to the high-dose group or placebo. Pooling of the placebo groups yielded 3 groups (approx. 48/group) whose baseline demographics and disease characteristics were well matched. AL-108 was generally safe and well tolerated. Analyses of efficacy data failed to detect a statistically significant difference between the treatment groups on the composite cognitive memory score. Analyses of the individual cognitive tasks identified signals of potential efficacy in 2 tests of memory and attention. These data suggest that AL-108 was generally safe, well tolerated and merits additional investigation as a treatment for Alzheimer's disease. Copyright © 2013 S. Karger AG, Basel.

A comparison of the pharmacokinetic profile of an ascending-dose, extended-regimen combined oral contraceptive to those of other extended regimens.

PubMed

Darwish, Mona; Bond, Mary; Ricciotti, Nancy; Hsieh, Jennifer; Fiedler-Kelly, Jill; Grasela, Thaddeus

2014-11-01

Quartette (levonorgestrel [LNG]/ethinyl estradiol [EE] and EE) is an ascending-dose, extended-regimen combined oral contraceptive (COC) that consists of a constant dose of LNG 150 µg on days 1 to 84 with EE 20 µg on days 1 to 42, 25 µg on days 43 to 63, 30 µg on days 64 to 84, and 10 µg of EE monotherapy on days 85 to 91. A population pharmacokinetic (PK) model for EE was developed using nonlinear mixed-effects modeling to characterize the PK profile of EE administered in Quartette and other extended-regimen LNG/EE COCs. Model-predicted plasma concentration-time profiles demonstrated a stepwise increase in systemic exposure to EE during the first 84 days of the cycle following each EE dose change. Lower concentrations of EE were noted during the final 7-day period of EE 10 µg. Gradual increases in EE seen with Quartette may decrease the incidence of unscheduled bleeding frequently observed during early cycles of extended-regimen COCs. © The Author(s) 2014.

Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

PubMed

Glue, Paul; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, Cheung-Tak; Friedhoff, Lawrence

2015-02-01

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers. © 2014, The American College of Clinical Pharmacology.

CD206-Targeted Liposomal Myelin Basic Protein Peptides in Patients with Multiple Sclerosis Resistant to First-Line Disease-Modifying Therapies: A First-in-Human, Proof-of-Concept Dose-Escalation Study.

PubMed

Belogurov, Alexey; Zakharov, Konstantin; Lomakin, Yakov; Surkov, Kirill; Avtushenko, Sergey; Kruglyakov, Peter; Smirnov, Ivan; Makshakov, Gleb; Lockshin, Curtis; Gregoriadis, Gregory; Genkin, Dmitry; Gabibov, Alexander; Evdoshenko, Evgeniy

2016-10-01

Previously, we showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP 46-62 , MBP 124-139 and MBP 147-170 (Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including Expanded Disability Status Scale score, magnetic resonance imaging results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection. Xemys was safe and well tolerated when administered for 6 weeks to a maximum single dose of 900 μg. Expanded Disability Status Scale scores and numbers of T2-weighted and new gadolinium-enhancing lesions on magnetic resonance imaging were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and interleukin-7 decreased, whereas the level of tumor necrosis factor-α increased. These results provide evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.

Pharmacokinetics and food interaction of a novel prodrug of tenofovir, tenofovir dipivoxil fumarate, in healthy volunteers.

PubMed

Lu, C; Jia, Y; Chen, L; Ding, Y; Yang, J; Chen, M; Song, Y; Sun, X; Wen, A

2013-04-01

Tenofovir dipivoxil fumarate is a novel ester prodrug of tenofovir, a specific anti-hepatitis B virus (HBV) drug candidate. The pharmacokinetic properties and the effects of food intake on tenofovir dipivoxil have not yet been reported in healthy adults. The aim of this study was to evaluate the pharmacokinetic properties and food interaction of tenofovir dipivoxil in healthy Chinese volunteers. Pharmacokinetic studies included an ascending single dose of 150, 300, 600 mg and multiple doses of 300 mg. Food interaction was evaluated following a single oral dose of tenofovir dipivoxil fumarate 300 mg administered with a high-fat and high-energy standard breakfast or after a 12-h fast. Pharmacokinetic parameters of tenofovir given in each treatment period were calculated using non-compartmental analysis. After a single dose of 150, 300 and 600 mg, the main pharmacokinetic parameters for tenofovir were as follows: Cmax 209·6, 456·7, 989·8 ng/mL; AUClast 1744·9, 2663·5, 6010·2 ng h/mL, respectively. After multiple doses of 300 mg, the main pharmacokinetic parameters for tenofovir were Cmax 523·4 ng/mL, AUClast 4152·4 ng h/mL. After a single dose of 300 mg with a high-fat and high-energy standard breakfast, the main pharmacokinetic parameters for tenofovir were Cmax 448·5 ng/mL, AUClast 3286·8 ng h/mL. The plasma Cmax and AUC of tenofovir showed significance difference between a single dose of 300 mg and the accordingly multiple doses (P < 0·05). A standard high-fat meal enhanced mean AUClast values of tenofovir (relative AUClast  = 125·8%; 90% CI 114·5, 136·2); however, food did not show any significant on Cmax (relative Cmax  = 103·4%; 90% CI 94·6, 112·6). Oral tenofovir dipivoxil fumarate produced predictable and dose-proportional plasma tenofovir pharmacokinetics. The accumulation ratio was 1·51, suggesting tenofovir dipivoxil fumarate displayed accumulation after repeated administration. The bioavailability of tenofovir dipivoxil fumarate was increased by approximately 25% as measured by AUClast after a single dose when taken with food, compared with fasting. © 2012 Blackwell Publishing Ltd.

Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women.

PubMed

Ng, Juki; Chwalisz, Kristof; Carter, David C; Klein, Cheri E

2017-05-01

Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women. We evaluated the pharmacokinetics and pharmacodynamics of elagolix. This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days. Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events. Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women. Copyright © 2017 Endocrine Society

Catching a floating thrombus; a case report on the treatment of a large thrombus in the ascending aorta.

PubMed

de Maat, Gijs Eduard; Vigano, Giorgio; Mariani, Massimo Alessandro; Natour, Ehsan

2017-05-19

The ascending aorta is an uncommon site for non-infective thrombus. In non-aneurysmal and non-atherosclerotic vessels this condition becomes extremely rare, while it represents a source of potential cerebral and peripheral embolic events. Currently, there is no consensus in the guidelines on how to treat a free floating thrombus in ascending aorta, therefore we present our decision making process and therapeutic strategy. A healthy 48-year-old man was hospital admitted with acute abdominal pain. CT-scan showed a right renal embolism in presence of a defect in the distal ascending aorta suggestive for thrombus. After heart team discussion the patient was scheduled for surgery and successfully underwent an emergent thrombus removal. Also, owing to multiple aortic wall insertions, the ascending aorta was replaced. The patient's recovery was uneventful and histological examination showed no signs of connective tissue disorders of aortic wall while confirmed the thrombotic nature of the mass. We present a patient with a floating thrombus in the ascending aorta who underwent an ascending aorta replacement. While angio-CT scan led to a prompt diagnosis, intraoperative epi-aortic echocardiography allowed to define precise location of thrombus, minimizing operative risk. This case demonstrates that multi-disciplinary heart team discussion is essential to define a successful strategy, that surgical treatment is feasible with specific tools such as epi-aortic echocardiography.

NP001 regulation of macrophage activation markers in ALS: A phase I clinical and biomarker study

PubMed Central

MILLER, ROBERT G.; ZHANG, RONGZHEN; BLOCK, GILBERT; KATZ, JONATHAN; BAROHN, RICHARD; KASARSKIS, EDWARD; FORSHEW, DALLAS; GOPALAKRISHNAN, VIDHYA; MCGRATH, MICHAEL S.

2017-01-01

This is a phase I, placebo-controlled, single ascending dose safety and tolerability study of NP001 in patients with ALS. NP001 is a novel regulator of inflammatory macrophages and monocytes. As ALS progression is thought to be related to neuroinflammation, an additional objective of the study was to assess the effects of NP001 administration on monocyte activation markers. Thirty-two ALS patients were enrolled and received either placebo (eight) or one of four (six at each dose) ascending single i.v. doses (0.2, 0.8, 1.6 and 3.2 mg/kg NP001). Patients were monitored for safety, and blood monocyte immune activation markers CD16 and HLA-DR were assessed pre- and 24 h post-dosing. Changes from baseline were calculated. Results showed that NP001 was generally safe and well tolerated. Importantly, a single dose of NP001 caused a dose-dependent reduction in expression of monocyte CD16, a marker of monocyte activation/inflammation. Additionally, monocyte HLA-DR expression was also decreased in those patients with elevated values at baseline. In conclusion, these data indicate that NP001 has an acute effect on inflammatory monocytes in ALS patient blood. The potential for modulation of inflammation in the context of ALS disease progression will require further study with long-term follow-up. PMID:25192333

Safety, Tolerability, and Pharmacokinetic Properties of Intravenous Delafloxacin After Single and Multiple Doses in Healthy Volunteers.

PubMed

Hoover, Randall; Hunt, Thomas; Benedict, Michael; Paulson, Susan K; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

2016-01-01

The objective of this report was to determine the pharmacokinetic properties, safety, and tolerability of single and multiple doses of intravenous delafloxacin. In addition, the absolute bioavailability (BA) of the 450-mg tablet formulation of delafloxacin was determined. Three clinical trials are summarized. The first study was a randomized, double-blind, placebo-controlled, single- (300, 450, 600, 750, 900, and 1200 mg) ascending-dose study of IV delafloxacin in 62 (52 active, 10 placebo) healthy volunteers. The second study was a randomized, double-blind, placebo-controlled study of IV delafloxacin (300 mg) given as a single dose on day 1, followed by twice-daily dosing on days 2 through 14; 12 (8 active, 4 placebo) healthy volunteers were enrolled. The third study was an open-label, randomized, 2-period, 2-sequence crossover study in which 56 healthy volunteers were randomly assigned to 1 of 2 sequences of a single oral dose of delafloxacin (450-mg tablet) or IV delafloxacin (300 mg). Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were calculated. Delafloxacin Cmax values increased proportionally with increasing single IV dose for the dose range of 300 to 1200 mg, whereas the AUC values increased more than proportionally to dose for the same dose range. The mean terminal half-life of delafloxacin was approximately 12 hours (ranging from 8 to 17 hours). The volume of distribution (Vd) at steady state was approximately 35 L, which is similar to the volume of total body water. There was minimal accumulation of delafloxacin after twice-daily IV administration of 300 mg with an accumulation ratio of 1.09. The delafloxacin total exposure after a single 1-hour IV infusion of 300 mg and a single oral dose of a 450-mg tablet were equivalent with geometric least square mean ratio (90% CI) of 0.8768 (0.8356-0.9200) for AUC0-∞ and 0.8445 (0.8090-0.8815) for AUC0-t, respectively. The Cmax values of delafloxacin were not equivalent for the 2 formulations with a ratio (90% CI) of 0.5516 (0.5150-0.5908), respectively. The mean absolute bioavailability of delafloxacin was 58.8%. Delafloxacin was well tolerated in healthy volunteers after single and multiple IV doses. The total systemic exposure to IV (300 mg) and oral (450 mg) delafloxacin is comparable, supporting that a switch between the 2 formulations is appropriate. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Safety, tolerability, and pharmacokinetics of sumatriptan suppositories following single and multiple doses in healthy volunteers.

PubMed

Kunka, R L; Hussey, E K; Shaw, S; Warner, P; Aubert, B; Richard, I; Fowler, P A; Pakes, G E

1997-06-01

A suppository formulation of the 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single doses (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3-14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not dose-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to dose from 25 to 100 mg; area under the plasma concentration-time curve (AUC infinity) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5 h, and the t1/2 was approximately 2 h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t 1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite concentrations were two to three-fold higher than corresponding sumatriptan concentrations. No clinically significant accumulation of sumatriptan or its metabolite occurred. Overall, these studies show that sumatriptan administration via a suppository formulation is well tolerated, allows rapid absorption of sumatriptan, results in sumatriptan Cmax values that are proportional to dose from 25 to 100 mg, and is not associated with accumulation of sumatriptan or its metabolite.

Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose

PubMed Central

Marciani, L; Garsed, K C; Hoad, C L; Fields, A; Fordham, I; Pritchard, S E; Placidi, E; Murray, K; Chaddock, G; Costigan, C; Lam, C; Jalanka-Tuovinen, J; De Vos, W M; Gowland, P A; Spiller, R C

2014-01-01

Background Most methods of assessing colonic motility are poorly acceptable to patients. Magnetic resonance imaging (MRI) can monitor gastrointestinal motility and fluid distributions. We predicted that a dose of oral polyethylene glycol (PEG) and electrolyte solution would increase ileo-colonic inflow and stimulate colonic motility. We aimed to investigate the colonic response to distension by oral PEG electrolyte in healthy volunteers (HVs) and to evaluate the effect of single 2 L vs split (2 × 1 L) dosing. Methods Twelve HVs received a split dose (1 L the evening before and 1 L on the study day) and another 12 HVs a single dose (2 L on the main study day) of PEG electrolyte. They underwent MRI scans, completed symptom questionnaires, and provided stool samples. Outcomes included small bowel water content, ascending colon motility index, and regional colonic volumes. Key Results Small bowel water content increased fourfold from baseline after ingesting both split (p = 0.0010) and single dose (p = 0.0005). The total colonic volume increase from baseline was smaller for the split dose at 35 ± 8% than for the single dose at 102 ± 27%, p = 0.0332. The ascending colon motility index after treatment was twofold higher for the single dose group (p = 0.0103). Conclusions & Inferences Ingestion of 1 and 2 L PEG electrolyte solution caused a rapid increase in the small bowel and colonic volumes and a robust rise in colonic motility. The increase in both volumes and motility was dose dependent. Such a challenge, being well-tolerated, could be a useful way of assessing colonic motility in future studies. PMID:25060551

First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.

PubMed

Kletzl, H; Guenther, A; Höflich, A; Höflich, C; Frystyk, J; Staack, R F; Schick, E; Wandel, C; Bleich, N; Metzger, F

2017-04-01

This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50μg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated. PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV. PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease.

PubMed

Hey, John A; Yu, Jeremy Y; Versavel, Mark; Abushakra, Susan; Kocis, Petr; Power, Aidan; Kaplan, Paul L; Amedio, John; Tolar, Martin

2018-03-01

ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer's disease (AD). Tramiprosate has been found to inhibit β-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aβ42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers. Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [1] a single ascending dose (SAD) study; [2] a 14-day multiple ascending dose (MAD) study; and [3] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study. ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration (C max ) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials. ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.

Drinking sucrose enhances quinpirole-induced yawning in rats

PubMed Central

Baladi, Michelle G; Newman, Amy H; Thomas, Yvonne M; France, Charles P

2011-01-01

Food and drugs can activate brain dopamine systems and sensitivity to the effects of drugs acting on those systems is influenced by amount and content of food consumed. This study examined the effects of drinking sucrose on behavioral effects of the directly-acting dopamine receptor agonist quinpirole. Male Sprague-Dawley rats (n=6/group) had free access to water or 10% sucrose and quinpirole dose-response curves (yawning and hypothermia) were generated weekly for 8 weeks. Subsequently, all rats drank water for 8 weeks with quinpirole dose-response curves determined on weeks 9, 10, and 16. In rats drinking sucrose, the ascending (D3 receptor-mediated), but not descending (D2 receptor-mediated), limb of the yawning dose-response curve shifted leftward. The D3 receptor-selective antagonist PG01037 shifted the ascending limb of the dose-response curve to the right in all rats. When rats that previously drank sucrose drank water, their sensitivity to quinpirole did not return to normal. Quinpirole-induced hypothermia was not different between groups. These data show that drinking sucrose increases sensitivity to a dopamine D3, but not D2, receptor-mediated effect and that this change is long lasting. Dopamine receptors mediate the effects of many drugs and the actions of those drugs are likely impacted by dietary factors. PMID:21979833

Drinking sucrose enhances quinpirole-induced yawning in rats.

PubMed

Baladi, Michelle G; Newman, Amy H; Thomas, Yvonne M; France, Charles P

2011-12-01

Food and drugs can activate brain dopamine systems and sensitivity to the effects of drugs acting on those systems is influenced by amount and content of food consumed. This study examined the effects of drinking sucrose on behavioral effects of the direct-acting dopamine receptor agonist quinpirole. Male Sprague-Dawley rats (n=6/group) had free access to water or 10% sucrose and quinpirole dose-response curves (yawning and hypothermia) were generated weekly for 8 weeks. Subsequently, all rats drank water for 8 weeks with quinpirole dose-response curves determined on weeks 9, 10, and 16. In rats drinking sucrose, the ascending (D3 receptor-mediated), but not descending (D2 receptor-mediated), limb of the yawning dose-response curve shifted leftward. The D3 receptor-selective antagonist PG01037 shifted the ascending limb of the dose-response curve to the right in all rats. When rats that previously drank sucrose drank water, their sensitivity to quinpirole did not return to normal. Quinpirole-induced hypothermia was not different between groups. These data show that drinking sucrose increases sensitivity to a dopamine D3, but not D2, receptor-mediated effect and that this change is long lasting. Dopamine receptors mediate the effects of many drugs and the actions of those drugs are likely impacted by dietary factors.

EFFECT OF FOOD TRAINING AND TRAINING DOSE ON NICOTINE SELF-ADMINISTRATION IN RATS

PubMed Central

Garcia, Kristine L.P.; Lê, Anh Dzung; Tyndale, Rachel F.

2014-01-01

Few studies investigate factors that influence acquisition in nicotine self-administration (NSA), such as food training and training dose. Most have utilized peak doses along nicotine’s dose-response curve (15 and 30 μg/kg) that establish NSA in the majority of animals. To investigate the specific and combined effects of training and dose on NSA acquisition, separate and head-to head experiments using food training (FT) or spontaneous acquisition (SP) at multiple doses on the ascending limb of the dose-response curve were tested. First, rats underwent FT or SP under fixed ratio (FR1 and FR2) and progressive ratio (PR) schedules using 7.5–30 μg/kg nicotine. More rats acquired NSA with FT vs. SP at 3.75 μg/kg (56% vs. 38%) and 7.5 μg/kg (88% vs. 40%, p<0.05) and FT rats responded higher under PR. Based on these findings, rats then underwent identical NSA acquisition and PR (with and without nicotine), extinction and reinstatement induced by cue exposure and nicotine in a head-to-head comparison of FT and SP using 7.5 μg/kg. Acquisition differences were replicated: 100% FT and 60% SP rats met criteria (p<0.05). Without nicotine (cue only), no FT rats and 8% SP rats met criteria. FR and PR responding, extinction, and cue and nicotine-induced reinstatement did not differ between FT and SP. FT versus SP enhances acquisition at lower nicotine doses but does not alter subsequent behaviors. Lower doses can reinforce NSA and be used, in the absence of FT, to study influences on acquisition more closely modelling the initial phases of human smoking. PMID:25101539

Effect of food training and training dose on nicotine self-administration in rats.

PubMed

Garcia, Kristine L P; Lê, Anh Dzung; Tyndale, Rachel F

2014-11-01

Few studies investigate factors that influence acquisition in nicotine self-administration (NSA), such as food training and training dose. Most have utilized peak doses along nicotine's dose-response curve (15 and 30μg/kg) that establish NSA in the majority of animals. To investigate the specific and combined effects of training and dose on NSA acquisition, separate and head-to-head experiments using food training (FT) or spontaneous acquisition (SP) at multiple doses on the ascending limb of the dose-response curve were tested. First, rats underwent FT or SP under fixed ratio (FR1 and FR2) and progressive ratio (PR) schedules using 7.5-30μg/kg nicotine. More rats acquired NSA with FT vs. SP at 3.75μg/kg (56% vs. 38%) and 7.5μg/kg (88% vs. 40%, p<0.05) and FT rats responded higher under PR. Based on these findings, rats then underwent identical NSA acquisition and PR (with and without nicotine), extinction and reinstatement induced by cue exposure and nicotine in a head-to-head comparison of FT and SP using 7.5μg/kg. Acquisition differences were replicated: 100% FT and 60% SP rats met criteria (p<0.05). Without nicotine (cue only), no FT rats and 8% SP rats met criteria. FR and PR responding, extinction, and cue and nicotine-induced reinstatement did not differ between FT and SP. FT versus SP enhances acquisition at lower nicotine doses but does not alter subsequent behaviours. Lower doses can reinforce NSA and be used, in the absence of FT, to study influences on acquisition more closely modelling the initial phases of human smoking. Copyright © 2014 Elsevier B.V. All rights reserved.

Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects.

PubMed

Griffiths, Roland R; Johnson, Matthew W; Richards, William A; Richards, Brian D; McCann, Una; Jesse, Robert

2011-12-01

This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions. Participants were 18 adults (17 hallucinogen-naïve). Five 8-h sessions were conducted individually for each participant at 1-month intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up. Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects. Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. Implications for therapeutic trials are discussed.

Efficacy and safety of tranexamic acid as an emetic in dogs.

PubMed

Kakiuchi, Hitoshi; Kawarai-Shimamura, Asako; Fujii, Yoko; Aoki, Takuma; Yoshiike, Masaki; Arai, Hayato; Nakamura, Atsushi; Orito, Kensuke

2014-12-01

To determine dose dependency of tranexamic acid-induced emesis and the time course of the antifibrinolytic potency of tranexamic acid in dogs. 10 Beagles. In a dose-escalating experiment, ascending doses of tranexamic acid (10, 20, and 30 mg/kg, IV) were administered at 5-minute intervals until vomiting was observed. In a separate single-dose experiment, ascending doses of tranexamic acid (20, 30, 40, and 50 mg/kg, IV) were administered at 1-week intervals until vomiting was observed. Time to onset of vomiting and number of vomiting episodes were measured in both experiments. In a coagulation experiment, a single 50 mg/kg bolus of tranexamic acid was administered, and blood was obtained 1 hour before and 20 minutes, 3 hours, and 24 hours after administration. Antifibrinolytic potency of tranexamic acid was evaluated by use of a modified rotational thromboelastography method. Tranexamic acid induced vomiting in a dose-dependent manner. Vomiting frequency was ≤ 2 episodes, and vomiting concluded ≤ 250 seconds after administration. Antifibrinolytic potency of tranexamic acid was significantly higher at 20 minutes following administration, but not different by 24 hours, when compared with the potency measured before administration. No adverse effects were observed in any experiment. IV administration of tranexamic acid induced emesis in a dose-dependent manner. The antifibrinolytic potency of tranexamic acid decreased in a time-dependent manner and was resolved ≤ 24 hours after administration. Further studies are warranted to investigate the emetic and other adverse effects of tranexamic acid in dogs of various breeds and ages.

[Aortic root dilatation rate in pediatric patients with Marfan syndrome treated with losartan].

PubMed

Mariucci, Elisabetta; Guidarini, Marta; Donti, Andrea; Lovato, Luigi; Wischmeijer, Anita; Angeli, Emanuela; Gargiulo, Gaetano D; Picchio, Fernando M; Bonvicini, Marco

2015-12-01

Medical therapy with angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors and/or beta-blockers was reported to reduce aortic root dilatation rates in pediatric patients with Marfan syndrome. No data are available in the literature on losartan effects after 3 years of therapy. The aim of our study was to establish whether losartan reduces aortic root dilatation rates in pediatric patients with Marfan syndrome in the mid and long term. This is a retrospective analysis of 38 pediatric patients with Marfan syndrome followed at the Marfan Clinic of S. Orsola-Malpighi Hospital of the University of Bologna (Italy). Aortic diameters were measured at sinuses of Valsalva and proximal ascending aorta with transthoracic echocardiography. After a mean follow-up of 4.5 ± 2.5 years (range 2-9 years), aortic root z score at sinuses of Valsalva and proximal ascending aorta remained stable. The average annual rate of change in aortic root z score was -0.1 ± 0.4 and 0 ± 0.3 at sinuses of Valsalva and proximal ascending aorta, respectively. The mean dose of losartan was 0.7 ± 0.3 mg/kg/day. Three patients were non-responders, probably because of late beginning or low dose of therapy. Eight patients underwent cardiac surgery (aortic root surgery in 5 and mitral valve repair in 3), all of them started losartan later in life. Despite the retrospective design of the study and the small sample size, a beneficial effect of losartan therapy was observed in pediatric patients with Marfan syndrome in the mid and long term. Late beginning or low doses of losartan can turn off the effects of therapy.

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles.

PubMed

Jin, Yan; Smith, Claire; Hu, Leijun; Coutant, David E; Whitehurst, Kelly; Phipps, Krista; McNearney, Terry Ann; Yang, Xiao; Ackermann, Bradley; Pottanat, Thomas; Landschulz, William

2018-01-01

Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Cannabinoid Receptors Mediate Methamphetamine Induction of High Frequency Gamma Oscillations in the Nucleus Accumbens

PubMed Central

Morra, Joshua T.; Glick, Stanley D.; Cheer, Joseph F.

2012-01-01

Patients suffering from amphetamine---induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (~ 80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders. PMID:22609048

Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation.

PubMed

Richardson, A; Sakariassen, K S; Meyer, J-P; Alberts, P; Sorensen, A S

2013-03-01

This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid-induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes.. This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo. Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t½z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (>90 %). All tested doses were well tolerated. Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min.

Caffeine's Influence on Nicotine's Effects in Nonsmokers

PubMed Central

Blank, Melissa D.; Kleykamp, Bethea A.; Jennings, Janine M.; Eissenberg, Thomas

2011-01-01

Objective To determine if nicotine's effects are influenced by caffeine in nonsmoking, moderate-caffeine consuming individuals (N=20). Methods The first 3 sessions included one of 3 randomly ordered, double-blind caffeine doses (0, 75, or 150 mg, oral [po]) and 2 single-blind nicotine gum doses (2 and 4 mg) in ascending order. The fourth session (single blind) repeated the 0 mg caffeine condition. Results Nicotine increased heart rate and subjective ratings indicative of aversive effects, and decreased reaction times. These effects were independent of caffeine dose and reliable across sessions. Conclusions In nonsmokers, nicotine effects are not influenced by moderate caffeine doses. PMID:17555378

Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer

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

Morris, W. James, E-mail: jmorris@bccancer.bc.ca; BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia; Tyldesley, Scott

Purpose: To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials: ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398more » trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62). Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.« less

Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects

PubMed Central

Griffiths, R. R.; Johnson, M.W.; Richards, W. A.; Richards, B.D.; McCann, U.; Jesse, R.

2012-01-01

Rationale This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. Objectives This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions. Methods Participants were 18 adults (17 hallucinogen-naïve). Five 8-hour sessions were conducted individually for each participant at 1-month intervals. Participants were randomized to receive the four active doses in either ascending or descending order (9 participants each). Placebo was scheduled quasi-randomly. During sessions volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up. Results Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects. Conclusions Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting positive effects on attitudes, mood and behavior. Implications for therapeutic trials are discussed. PMID:21674151

Safety and pharmacokinetic profiles of phosphorodiamidate morpholino oligomers with activity against ebola virus and marburg virus: results of two single-ascending-dose studies.

PubMed

Heald, Alison E; Iversen, Patrick L; Saoud, Jay B; Sazani, Peter; Charleston, Jay S; Axtelle, Tim; Wong, Michael; Smith, William B; Vutikullird, Apinya; Kaye, Edward

2014-11-01

Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.

PubMed

Rosario, Maria; Wyant, Timothy; Leach, Timothy; Sankoh, Serap; Scholz, Catherine; Parikh, Asit; Fox, Irving; Feagan, Brian G

2016-11-01

Vedolizumab, a humanized monoclonal antibody against the α 4 β 7 integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers. Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α 4 β 7 saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored. Vedolizumab maximum observed serum concentration (C max ) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC 0-inf ) and shorter terminal elimination half-life (t 1/2 ) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α 4 β 7 was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent. Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α 4 β 7 saturation was observed at all doses. A single intravenous infusion of vedolizumab was well tolerated by healthy volunteers.

Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

PubMed Central

Frost, Charles; Wang, Jessie; Nepal, Sunil; Schuster, Alan; Barrett, Yu Chen; Mosqueda-Garcia, Rogelio; Reeves, Richard A; LaCreta, Frank

2013-01-01

Aims To evaluate apixaban single dose safety, tolerability, pharmacokinetics and pharmacodynamics and assess the effect of food on apixaban pharmacokinetics. Methods A double-blind, placebo-controlled, single ascending-dose, first-in-human study assessed apixaban safety, pharmacokinetics and pharmacodynamics in healthy subjects randomized to oral apixaban (n = 43; 0.5–2.5 mg as solution or 5–50 mg as tablets) or placebo (n = 14) under fasted conditions. An open label, randomized, two treatment crossover study investigated apixaban pharmacokinetics/pharmacodynamics in healthy subjects (n = 21) administered apixaban 10 mg in fasted and fed states. Both studies measured apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT) or a modified PT (mPT). Results In the single ascending-dose study increases in apixaban exposure appeared dose-proportional. Median tmax occurred 1.5–3.3 h following oral administration. Mean terminal half-life ranged between 3.6 and 6.8 h following administration of solution doses ≤2.5 mg and between 11.1 and 26.8 h for tablet doses ≥5 mg. Concentration-related changes in pharmacodynamic assessments were observed. After a 50 mg dose, peak aPTT, INR and mPT increased by 1.2-, 1.6- and 2.9-fold, respectively, from baseline. In the food effect study: 90% confidence intervals of geometric mean ratios of apixaban Cmax and AUC in a fed vs. fasted state were within the predefined no effect (80–125%) range. Apixaban half-life was approximately 11.5 h. The effect of apixaban on INR, PT and aPTT was comparable following fed and fasted administration. Conclusions Single doses of apixaban were well tolerated with a predictable pharmacokinetic/pharmacodynamic profile and a half-life of approximately 12 h. Apixaban can be administered with or without food. PMID:22759198

[Submucosal bacterial abscesses of the ascending colon and liver associated with portal and superior mesenteric vein thrombosis due to Enterococcus faecalis infection: a case report].

PubMed

Norimura, Daisuke; Takeshima, Fuminao; Satou, Yoshiaki; Nakagoe, Tohru; Ohnita, Ken; Isomoto, Hajime; Nakao, Kazuhiko

2014-06-01

A 72-year-old woman with diabetes mellitus was admitted with fever and general fatigue. Blood biochemistry showed elevated hepatic and biliary enzyme levels, abdominal computed tomography showed multiple liver abscesses with portal and superior mesenteric vein thrombosis, and total colonoscopy revealed a submucosal bacterial abscess in the ascending colon. The abscesses were determined to be associated with Enterococcus faecalis infection. The patient was treated conservatively with antibiotics (meropenem) and anticoagulants (warfarin), which led to a gradual amelioration of symptoms and resolution of thrombosis.

Cannabinoid receptors mediate methamphetamine induction of high frequency gamma oscillations in the nucleus accumbens.

PubMed

Morra, Joshua T; Glick, Stanley D; Cheer, Joseph F

2012-09-01

Patients suffering from amphetamine-induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely-moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (∼80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

Randomized, Placebo-Controlled, Single-Ascending-Dose Study of BMS-791325, a Hepatitis C Virus (HCV) NS5B Polymerase Inhibitor, in HCV Genotype 1 Infection

PubMed Central

Lemm, Julie; Eley, Timothy; Liu, Menping; Berglind, Anna; Sherman, Diane; Lawitz, Eric; Vutikullird, Apinya B.; Tebas, Pablo; Gao, Min; Pasquinelli, Claudio; Grasela, Dennis M.

2014-01-01

BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC50], 3 nM) and 1b (EC50, 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.) PMID:24733462

Mental stress and psychosocial factors at work in relation to multiple-site musculoskeletal pain: a longitudinal study of kitchen workers.

PubMed

Haukka, Eija; Leino-Arjas, Päivi; Ojajärvi, Anneli; Takala, Esa-Pekka; Viikari-Juntura, Eira; Riihimäki, Hilkka

2011-04-01

Among 385 female kitchen workers, we examined (1) whether mental stress and psychosocial factors at work (job control, skill discretion, supervisor support, co-worker relationships, and hurry) predict multiple-site musculoskeletal pain (MSP; defined as pain at ≥ 3 of seven sites) and (2) reversedly, whether MSP predicts these psychosocial factors. Data were collected by questionnaire at 3-month intervals during 2 years. Trajectory analysis was applied. Four trajectories of MSP prevalence emerged: Low, Descending, Ascending, and High. For the psychosocial factors, a two-trajectory model (Ascending or High vs. Low) yielded the best fit. In logistic regression analysis, with the Low MSP trajectory as reference, poor co-worker relationships (odds ratio [OR] 3.9), mental stress (3.1) and hurry (2.1) at baseline predicted belonging to the High MSP trajectory. Also MSP at baseline predicted the trajectories (Ascending vs. Low) of low job control (2.2) and mental stress (3.2). Adverse changes in most psychosocial factors were associated with belonging to the High (ORs between 2.3 and 8.6) and Ascending (2.7-5.5) MSP trajectories. In generalized estimating equations, time-lagged by 3 months, all psychosocial factors but two predicted MSP (1.4-2.1), allowing, e.g. for MSP at baseline, and vice versa, MSP predicted low job control, low supervisor support, and mental stress (1.4-2.0), after adjustment for e.g. the relevant psychosocial factor at baseline. In conclusion, we found that several psychosocial factors predicted MSP and that MSP predicted several psychosocial factors. The results suggest a cumulative process in which adverse psychosocial factors and MSP influence each other. Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.

PubMed

Yu, Rosie Z; Gunawan, Rudy; Li, Zhaoyang; Mittleman, Robert S; Mahmood, Asif; Grundy, John S; Singleton, Walter; Geary, Richard; Wang, Yanfeng

2016-03-01

The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively. Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.

A Robust Open Ascending-price Multi-unit Auction Protocol against False-name Bids

NASA Astrophysics Data System (ADS)

Iwasaki, Atsushi; Yokoo, Makoto; Terada, Kenji

This paper develops a new ascending-price multi-unit auction protocol that has following characteristics: (i) it has an open format, (ii) sincere bidding is an equilibrium strategy even if the marginal utilities of each agent can increase and agents can submit false-name bids. False-name bids are bids submitted under fictitious names such as multiple e-mail addresses, which can be done easily in the Internet. This is the first protocol that has these two characteristics. We show that our new protocol outperforms an existing protocol, which satisfies (ii), with respect to the social surplus and the seller's revenue.

Advancements for Active Remote Sensing of Carbon Dioxide from Space using the ASCENDS CarbonHawk Experiment Simulator: First Results

NASA Astrophysics Data System (ADS)

Obland, M. D.; Nehrir, A. R.; Lin, B.; Harrison, F. W.; Kooi, S. A.; Choi, Y.; Plant, J.; Yang, M. M.; Antill, C.; Campbell, J. F.; Ismail, S.; Browell, E. V.; Meadows, B.; Dobler, J. T.; Zaccheo, T. S.; Moore, B., III; Crowell, S.

2014-12-01

The ASCENDS CarbonHawk Experiment Simulator (ACES) is an Intensity-Modulated Continuous-Wave lidar system recently developed at NASA Langley Research Center that seeks to advance technologies and techniques critical to measuring atmospheric column carbon dioxide (CO2) mixing ratios in support of the NASA Active Sensing of CO2 Emissions over Nights, Days, and Seasons (ASCENDS) mission. These advancements include: (1) increasing the power-aperture product to approach ASCENDS mission requirements by implementing multi-aperture telescopes and multiple co-aligned laser transmitters; (2) incorporating high-efficiency, high-power Erbium-Doped Fiber Amplifiers (EDFAs); (3) developing and incorporating a high-bandwidth, low-noise HgCdTe detector and transimpedence amplifier (TIA) subsystem capable of long-duration operation on Global Hawk aircraft, and (4) advancing algorithms for cloud and aerosol discrimination. The ACES instrument architecture is being developed for operation on high-altitude aircraft and will be directly scalable to meet the ASCENDS mission requirements. ACES simultaneously transmits five laser beams: three from commercial EDFAs operating near 1571 nm, and two from the Exelis oxygen (O2) Raman fiber laser amplifier system operating near 1260 nm. The Integrated-Path Differential Absorption (IPDA) lidar approach is used at both wavelengths to independently measure the CO2 and O2 column number densities and retrieve the average column CO2 mixing ratio. The outgoing laser beams are aligned to the field of view of ACES' three fiber-coupled 17.8-cm diameter athermal telescopes. The backscattered light collected by the three telescopes is sent to the detector/TIA subsystem, which has a bandwidth of 4.7 MHz and operates service-free using a tactical dewar and cryocooler. Two key laser modulation approaches are being tested to significantly mitigate the effects of thin clouds on the retrieved CO2 column amounts. Full instrument development concluded in the spring of 2014. After ground range tests of the instrument, ACES successfully completed six test flights on the Langley Hu-25 aircraft in July, 2014, and recorded data at multiple altitudes over land and ocean surfaces with and without intervening clouds. Preliminary results from these flights will be presented in this paper.

Emergence of Spatial Stream Segregation in the Ascending Auditory Pathway.

PubMed

Yao, Justin D; Bremen, Peter; Middlebrooks, John C

2015-12-09

Stream segregation enables a listener to disentangle multiple competing sequences of sounds. A recent study from our laboratory demonstrated that cortical neurons in anesthetized cats exhibit spatial stream segregation (SSS) by synchronizing preferentially to one of two sequences of noise bursts that alternate between two source locations. Here, we examine the emergence of SSS along the ascending auditory pathway. Extracellular recordings were made in anesthetized rats from the inferior colliculus (IC), the nucleus of the brachium of the IC (BIN), the medial geniculate body (MGB), and the primary auditory cortex (A1). Stimuli consisted of interleaved sequences of broadband noise bursts that alternated between two source locations. At stimulus presentation rates of 5 and 10 bursts per second, at which human listeners report robust SSS, neural SSS is weak in the central nucleus of the IC (ICC), it appears in the nucleus of the brachium of the IC (BIN) and in approximately two-thirds of neurons in the ventral MGB (MGBv), and is prominent throughout A1. The enhancement of SSS at the cortical level reflects both increased spatial sensitivity and increased forward suppression. We demonstrate that forward suppression in A1 does not result from synaptic inhibition at the cortical level. Instead, forward suppression might reflect synaptic depression in the thalamocortical projection. Together, our findings indicate that auditory streams are increasingly segregated along the ascending auditory pathway as distinct mutually synchronized neural populations. Listeners are capable of disentangling multiple competing sequences of sounds that originate from distinct sources. This stream segregation is aided by differences in spatial location between the sources. A possible substrate of spatial stream segregation (SSS) has been described in the auditory cortex, but the mechanisms leading to those cortical responses are unknown. Here, we investigated SSS in three levels of the ascending auditory pathway with extracellular unit recordings in anesthetized rats. We found that neural SSS emerges within the ascending auditory pathway as a consequence of sharpening of spatial sensitivity and increasing forward suppression. Our results highlight brainstem mechanisms that culminate in SSS at the level of the auditory cortex. Copyright © 2015 Yao et al.

Assessment of drug-drug interaction potential between ceritinib and proton pump inhibitors in healthy subjects and in patients with ALK-positive non-small cell lung cancer.

PubMed

Lau, Yvonne Y; Gu, Wen; Lin, Tiffany; Viraswami-Appanna, Kalyanee; Cai, Can; Scott, Jeffrey W; Shi, Michael

2017-06-01

The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated. A healthy subject drug-drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (C trough,ss ) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC 0-24h and C max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study. In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC 0-∞ by 76% and C max by 79%. However, based on subgroup analysis 1, patients had similar C trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC 0-24h decreased by 30% and C max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing. Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

Automatic segmentation of thoracic aorta segments in low-dose chest CT

NASA Astrophysics Data System (ADS)

Noothout, Julia M. H.; de Vos, Bob D.; Wolterink, Jelmer M.; Išgum, Ivana

2018-03-01

Morphological analysis and identification of pathologies in the aorta are important for cardiovascular diagnosis and risk assessment in patients. Manual annotation is time-consuming and cumbersome in CT scans acquired without contrast enhancement and with low radiation dose. Hence, we propose an automatic method to segment the ascending aorta, the aortic arch and the thoracic descending aorta in low-dose chest CT without contrast enhancement. Segmentation was performed using a dilated convolutional neural network (CNN), with a receptive field of 131 × 131 voxels, that classified voxels in axial, coronal and sagittal image slices. To obtain a final segmentation, the obtained probabilities of the three planes were averaged per class, and voxels were subsequently assigned to the class with the highest class probability. Two-fold cross-validation experiments were performed where ten scans were used to train the network and another ten to evaluate the performance. Dice coefficients of 0.83 +/- 0.07, 0.86 +/- 0.06 and 0.88 +/- 0.05, and Average Symmetrical Surface Distances (ASSDs) of 2.44 +/- 1.28, 1.56 +/- 0.68 and 1.87 +/- 1.30 mm were obtained for the ascending aorta, the aortic arch and the descending aorta, respectively. The results indicate that the proposed method could be used in large-scale studies analyzing the anatomical location of pathology and morphology of the thoracic aorta.

The role of the dopaminergic projections in MFB self-stimulation.

PubMed

Gallistel, C R

1986-11-01

Psychophysical experiments indicate that the first stage of the reward pathway in medial forebrain bundle self-stimulation consists of small myelinated descending axons. Pharmacological experiments show that neuroleptics attenuate or abolish the rewarding effect. This had led to the hypothesis that the descending myelinated axons synapse on an ascending dopaminergic second stage projection. 2-Deoxy-[14C]glucose autoradiography in self-stimulating animals or animals receiving automatically administered rewarding stimulation after treatment with reward-blocking doses of pimozide reveals activation of a descending myelinated system but no stimulation-produced activation of an ascending dopaminergic projection system, even though the autoradiographic method reveals the mild elevations and depressions of activity in dopaminergic terminal fields consequent upon injections of neuroleptics and amphetamine, respectively, and the strong activation of the nigrostriatal projection produced by stimulating directly in the substantia nigra. When the effects of neuroleptics and clonidine are measured by the psychophysical method (that is, by lateral shifts in the rate-frequency function), it is found that both drugs produce only gradual and rather small attenuations of rewarding efficacy up to doses at which it is no longer possible to measure their effects. It is suggested that, for neuroleptics at least, the rewarding effect abruptly fails at these doses. It is further suggested that these drugs do not act on the rewarding pathway itself, but on the process by which the rewarding signal is converted to an enduring rewarding effect.

The role of the dopaminergic projections in MFB self-stimulation.

PubMed

Gallistel, C R

1986-06-01

Psychophysical experiments indicate that the first stage of the reward pathway in medial forebrain bundle self-stimulation consists of small myelinated descending axons. Pharmacological experiments show that neuroleptics attenuate or abolish the rewarding effect. This had led to the hypothesis that the descending myelinated axons synapse on an ascending dopaminergic second stage projection. 2-Deoxy-[14C]glucose autoradiography in self-stimulating animals or animals receiving automatically administered rewarding stimulation after treatment with reward-blocking doses of pimozide reveals activation of a descending myelinated system but no stimulation-produced activation of an ascending dopaminergic projection system, even though the autoradiographic method reveals the mild elevations and depressions of activity in dopaminergic terminal fields consequent upon injections of neuroleptics and amphetamine, respectively, and the strong activation of the nigrostriatal projection produced by stimulating directly in the substantia nigra. When the effects of neuroleptics and clonidine are measured by the psychophysical method (that is, by lateral shifts in the rate-frequency function), it is found that both drugs produce only gradual and rather small attenuations of rewarding efficacy up to doses at which it is no longer possible to measure their effects. It is suggested that, for neuroleptics at least, the rewarding effect abruptly fails at these doses. It is further suggested that these drugs do not act on the rewarding pathway itself, but on the process by which the rewarding signal is converted to an enduring rewarding effect.

Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women.

PubMed

McKeand, William

2017-09-01

Bazedoxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism while having neutral or estrogen antagonist effects on the breast and endometrium. The present report describes findings from 3 Phase I clinical studies that evaluated the single-dose pharmacokinetics (study 1; n = 84), multiple-dose pharmacokinetics (study 2; n = 23), and absolute bioavailability (study 3; n = 18) of bazedoxifene. All 3 studies enrolled healthy postmenopausal women who were either naturally postmenopausal or had undergone bilateral oophorectomy at least 6 months before the start of the study. Study 1 showed that unconjugated and total (unconjugated and conjugated) bazedoxifene levels increased proportionally with ascending oral doses of bazedoxifene (through the dose range of 5-120 mg). Evaluation with or without food intake was conducted at the 10-mg dose, with no clinically relevant effect on pharmacokinetic parameters. Study 2 showed that bazedoxifene achieved steady state in 1 week and exhibited linear pharmacokinetics in doses of 5 to 40 mg with no unexpected accumulation over the dose range. In accordance with a linear pharmacokinetic profile, mean maximum plasma concentration values increased with increasing dose, with values of 1.6, 6.2, and 12.5 ng/mL for the 5-, 20-, and 40-mg doses, respectively. In study 3, tablet and capsule formulations of bazedoxifene formulations had an estimated oral bioavailability of ~6%. The clearance of bazedoxifene was 0.4 (0.1) L/h/kg based on intravenous administration. The oral formulations had comparable exposure profiles with respect to AUC and AUC0-t, and the 90% CIs for these values were within the bioequivalence limits of 80% to 125%. Bazedoxifene was safe and well tolerated in all 3 studies. These pharmacokinetic evaluations in healthy postmenopausal women found that bazedoxifene displayed linear pharmacokinetics with doses ranging from 5 to 40 mg, with no unexpected accumulation. Food did not seem to have any clinically relevant impact on pharmacokinetic parameters. Bazedoxifene had an estimated oral bioavailability of ~6% and was safe and well tolerated in the range of doses evaluated. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

A Long-Acting Human Growth Hormone With Delayed Clearance (VRS-317): Results of a Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Growth Hormone–Deficient Adults

PubMed Central

Yuen, Kevin C. J.; Conway, Gerard S.; Popovic, Vera; Merriam, George R.; Bailey, Timothy; Hamrahian, Amir H.; Biller, Beverly M. K.; Kipnes, Mark; Moore, Jerome A.; Humphriss, Eric; Cleland, Jeffrey L.

2013-01-01

Background: Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes. Objectives: This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317. Design: This was a randomized, double-blind, placebo-controlled, single ascending dose study. Patients: Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo). Setting: The study was conducted in 17 adult endocrinology centers in North America and Europe. Main Outcome Measures: Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed. Results: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3–5.0 μg/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between −1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed. Conclusions: The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing. PMID:23585663

The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men

PubMed Central

Basaria, Shehzad; Collins, Lauren; Dillon, E. Lichar; Orwoll, Katie; Storer, Thomas W.; Miciek, Renee; Ulloor, Jagadish; Zhang, Anqi; Eder, Richard; Zientek, Heather; Gordon, Gilad; Kazmi, Syed; Sheffield-Moore, Melinda

2013-01-01

Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. Methods. In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations. PMID:22459616

Hepatitis C virus RNA elimination and development of resistance in replicon cells treated with BMS-790052.

PubMed

Wang, Chunfu; Huang, Haichang; Valera, Lourdes; Sun, Jin-Hua; O'Boyle, Donald R; Nower, Peter T; Jia, Lingling; Qiu, Dike; Huang, Xin; Altaf, Aneela; Gao, Min; Fridell, Robert A

2012-03-01

BMS-790052, a first-in-class hepatitis C virus (HCV) replication complex inhibitor, targeting nonstructural protein 5A (NS5A), displays picomolar to nanomolar potency against genotypes 1 to 5. This exceptional potency translated into robust anti-HCV activity in clinical studies with HCV genotype 1-infected subjects. To date, all BMS-790052-associated resistance mutations have mapped to the N-terminal region of NS5A. To further characterize the antiviral activity of BMS-790052, HCV replicon elimination and colony formation assays were performed. Replicon was cleared from genotype 1a and 1b replicon cells in a time- and dose-dependent manner. Elimination of the genotype 1a replicon required longer treatment durations and higher concentrations of BMS-790052 than those for the genotype1b replicon. Single amino acid substitutions that conferred relatively low levels of resistance were observed at early time points and at low doses. Higher doses and longer treatment durations yielded mutations that conferred greater levels of resistance, including linked amino acid substitutions. Replicon cells that survived inhibitor treatment remained fully sensitivity to pegylated alpha interferon (pegIFN-α) and other HCV inhibitors. Moreover, genotype 1a replicon elimination was markedly enhanced when pegIFN-α and BMS-790052 were combined. Resistant variants observed in this study were very similar to those observed in a multiple ascending dose (MAD) monotherapy trial of BMS-790052, validating replicon elimination studies as a model to predict clinical resistance. Insights gained from the in vitro anti-HCV activity and resistance profiles of BMS-790052 will be used to help guide the clinical development of this novel HCV inhibitor.

Modelling atherosclerosis by proteomics: Molecular changes in the ascending aortas of cholesterol-fed rabbits.

PubMed

Xu, Jingshu; Jüllig, Mia; Middleditch, Martin J; Cooper, Garth J S

2015-09-01

The cholesterol-fed rabbit is commonly used as a model to study the vascular effects of hypercholesterolemia and resulting atherosclerotic lesions. Here we undertook a proteomic case-control investigation of ascending aortas from male New Zealand White rabbits after 10 weeks on a high-cholesterol (2% w/w) diet (HCD, n = 5) or control diet (n = 5), in order to determine the changes in response to the HCD. Histology confirmed intimal thickening in the HCD group consistent with atherosclerosis, and LC-MS/MS analysis of individually-obtained ascending aortic extracts labelled with isobaric (iTRAQ) tags enabled the identification and quantitation of 453 unique proteins above the 1% false discovery rate threshold. Of 67 proteins showing significant differences in relative abundance (p < 0.05), 62 were elevated and five decreased in ascending aortas from HCD-fed rabbits compared to controls. Six proteins were selected for validation using Multiple Reaction Monitoring, which confirmed the iTRAQ results. Many of the observed protein changes are consistent with known molecular perturbations in the ascending aorta that occur in response to hypercholesterolemia, e.g. elevation of tissue levels of apolipoproteins, extracellular matrix adhesion proteins, glycolytic enzymes, heat shock proteins and proteins involved in immune defense. We also made a number of novel observations, including a 15-fold elevation of glycoprotein (trans-membrane) nmb-like (Gpnmb) in response to HCD. Gpnmb has previously been linked to angiogenesis but not to atherosclerosis. This and additional novel observations merit further investigation as these perturbations may play important and as yet undiscovered roles in the pathogenesis of atherosclerosis in rabbits as well as humans. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

An Interactive Item Sharing Website for Creating and Conducting On-Line Testing

ERIC Educational Resources Information Center

Koong, Chorng-Shiuh; Wu, Chi-Ying

2010-01-01

Multiple intelligences, with its hypothesis and implementation, have ascended to a prominent status among the many instructional methodologies. Meanwhile, pedagogical theories and concepts are in need of more alternative and interactive assessments to prove their prevalence (Kinugasa, Yamashita, Hayashi, Tominaga, & Yamasaki, 2005). In general,…

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity

PubMed Central

Täubel, Jörg; Ferber, Georg; Lorch, Ulrike; Wang, Duolao; Sust, Mariano; Camm, A. John

2015-01-01

Background E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects. Methods Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day). Results In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis. Conclusion The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal. Trial Registration EU Clinical Trials Register EudraCT 2010 020343 13 PMID:26291080

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.

PubMed

Täubel, Jörg; Ferber, Georg; Lorch, Ulrike; Wang, Duolao; Sust, Mariano; Camm, A John

2015-01-01

E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects. Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day). In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis. The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal. EU Clinical Trials Register EudraCT 2010 020343 13.

Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

PubMed

van Gerven, J M; Roncari, G; Schoemaker, R C; Massarella, J; Keesmaat, P; Kooyman, H; Heizmann, P; Zell, M; Cohen, A F; Dingemanse, J

1997-11-01

This study aimed to investigate the pharmacodynamics and pharmacokinetics of ascending doses of Ro 48-8684, compared with midazolam, in healthy subjects during first administration to man. The study was double-blind and five-way crossover (three ascending doses, placebo, fixed midazolam dose), performed in two groups of five males. Ro 48-8684 was infused in doses of 0.1-0.3-1 mg in the first group, and 1-3-10 mg in the second, with different infusion rates (expressed as mg min(-1)) among doses. Midazolam was infused at 0.1 mg(-1) kg. Infusions were stopped after 20 min or if sedation became too strong for proper performance of saccadic eye movements. Pharmacokinetics and pharmacodynamics and their relationships were evaluated as described in the companion article. Ro 48-8684 caused dose-dependent sedation. No serious adverse events occurred. The volume of distribution and clearance of Ro 48-8684 were larger than of midazolam (337+/-114 vs 50+/-121 and 2.4+/-0.5 vs 0.47+/-0.11 l min(-1), resp). The recovery of saccadic eye movements from equal levels of sedation was on average almost half an hour faster for Ro 48-8684 than for midazolam, with considerable interindividual differences (range 2, 55 min). The doses of Ro 48-8684 leading to the same clinical endpoint as midazolam were comparable, but the corresponding predicted effect compartment concentrations of Ro 48-8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the linear concentration-effect-relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48-8684 than for midazolam (range 1.3, 3.3). The slope decreased on average 4.4-fold (range 1.6, 7.3 times), with doses of Ro 48-8684 increasing from 1 to 10 mg. The metabolite Ro 61-2466 had a longer half-life than the parent compound Ro 48-8684. The influence of this metabolite during prolonged administration should be further investigated. These results show that Ro 48-8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to Ro 48-8684 with repeated administration of rising doses due to as yet undetermined factors.

Safinamide (Newron Pharmaceuticals).

PubMed

Chazot, P L

2001-06-01

Safinamide (formerly PNU-151774E), a sodium and calcium channel modulator that also inhibits monoamine oxidase B (MAOB), is under development by Newron Pharmaceuticals for the potential treatment of epilepsy, Parkinson's disease (PD), pain and stroke [345222], [348351]. Phase I trials for epilepsy and PD have been completed, and dose-finding studies for both indications had commenced in March 2001 [401685]. The compound was previously developed by Pharmacia & Upjohn (P&U) for the potential treatment of epilepsy, an indication for which it initially reached phase I trials [294891], [345007]. Newron acquired the rights to safinamide from P&U at the end of 1998. Results from two phase I trials of the compound (single ascending dose and steady state at three doses), completed in March 2000, demonstrated that the drug is well tolerated with good bioavailability and linear pharmacokinetics [359652].

[Effect of aminazine on elaboration and extinction of an instrumental alimentary reflex in puppies].

PubMed

Lozovskaia, R G

1977-01-01

The role of the adrenoreactive structures of the stem reticular formation in the elaboration and extinction of a food-procuring reflex of lever pressing was studied in 40 to 50 days old puppies. A 0.05 mg/kg dose of chlorpromazine proved more effective than a 0.5 mg/kg dose, in reducing both the rate of formation and of extiction of the reflex. The change in the course of elaboration was connected with the appearance of the phenomenon of reinforcement anticipation, which is not inherent in normal puppies of an early age. It is assumed that a 0.05 mg/kg dose diminishes the adrenergic ascending influences which prevail in normal puppies of the given age, while a 0.5 mg/kg dose exerts not only an adreno- but a cholinolytic action as well, without changing the balance between the systems or influencing the behaviour of the puppies.

Efficacy of a novel phosphodiesterase inhibitor, E6005, in patients with atopic dermatitis: An investigator-blinded, vehicle-controlled study.

PubMed

Ohba, Fuminori; Matsuki, Shunji; Imayama, Shuhei; Matsuguma, Kyoko; Hojo, Seiichiro; Nomoto, Maiko; Akama, Hideto

2016-10-01

Phosphodiesterase type 4 (PDE4) inhibition is a well-known anti-inflammatory mechanism. However, the clinical use of PDE4 inhibitors has been compromised by the occurrence of mechanism-associated adverse reactions, which often limit the maximum tolerated dose. To minimize systemic exposure, a topically active PDE4 inhibitor with low transdermal bioavailability could be clinically useful. The purpose of this study was to evaluate the efficacy of a novel topical PDE4 inhibitor, E6005, in patients with atopic dermatitis. This randomized, investigator-blinded, vehicle-controlled, multiple ascending dose study included 40 adult male patients with atopic dermatitis, who were randomly assigned to 10 days of treatment with either E6005 ointment (0.01, 0.03, 0.1 or 0.2%) or vehicle ointment. Of 81 patients screened, 40 who had typical lesions on their posterior trunk were randomized into the study. One patient receiving 0.03% E6005 treatment discontinued because of acute gout and one receiving vehicle treatment discontinued because of progression of atopic dermatitis. The targeted lesion severity scores decreased in a concentration-dependent manner in patients treated with E6005. This drop was significant in the 0.2% E6005 ointment treatment group (mean percent change: -54.30%, p = 0.007). E6005 ointment showed anti-inflammatory efficacy in adult patients with atopic dermatitis.

Biphasic effects of alcohol as a function of circadian phase.

PubMed

Van Reen, Eliza; Rupp, Tracy L; Acebo, Christine; Seifer, Ronald; Carskadon, Mary A

2013-01-01

To assess how alcohol affects multiple sleep latency tests (MSLT) and subjective measures of stimulation/sedation when alcohol is given at different circadian phases. Twenty-seven healthy young adults (age 21-26 yr) were studied. Double-blind placebo and alcohol (vodka tonic targeting 0.05 g% concentration) beverages were each administered three times during the 20-h forced desynchrony protocol. Sleep latency tests and Biphasic Effects of Alcohol Scale (BAES) were administered on each forced desynchrony day. The outcome variables for this study include sleep onset latency (SOL) and stimulation and sedation value (from the BAES). Each outcome variable was associated with the ascending or descending limb of the breath alcohol concentration (BrAC) curve and assigned a circadian phase within a 90° bin. BrAC confirmed targeted maximal levels. Only outcome variables associated with the ascending and descending limb of the alcohol curve were analyzed for this article. Alcohol administered at a circadian time associated with greatest sleepiness showed longer SOL compared with placebo when measured on the ascending limb of the BrAC curve. We also found longer SOL with alcohol on the ascending limb of the BrAC curve in a circadian bin that favors greatest alertness. We observed shorter SOLs on the descending limb of the BrAC curve, but with no circadian phase interaction. The subjective data were partially consistent with the objective data. The physiologic findings in this study support the biphasic stimulating and sedating properties of alcohol, but limit the effect to specific circadian times.

Select spinal lesions reveal multiple ascending pathways in the rat conveying input from the male genitalia

PubMed Central

Hubscher, C H; Reed, W R; Kaddumi, E G; Armstrong, J E; Johnson, R D

2010-01-01

The specific white matter location of all the spinal pathways conveying penile input to the rostral medulla is not known. Our previous studies using rats demonstrated the loss of low but not high threshold penile inputs to medullary reticular formation (MRF) neurons after acute and chronic dorsal column (DC) lesions of the T8 spinal cord and loss of all penile inputs after lesioning the dorsal three-fifths of the cord. In the present study, select T8 lesions were made and terminal electrophysiological recordings were performed 45–60 days later in a limited portion of the nucleus reticularis gigantocellularis (Gi) and Gi pars alpha. Lesions included subtotal dorsal hemisections that spared only the lateral half of the dorsal portion of the lateral funiculus on one side, dorsal and over-dorsal hemisections, and subtotal transections that spared predominantly just the ventromedial white matter. Electrophysiological data for 448 single unit recordings obtained from 32 urethane-anaesthetized rats, when analysed in groups based upon histological lesion reconstructions, revealed (1) ascending bilateral projections in the dorsal, dorsolateral and ventrolateral white matter of the spinal cord conveying information from the male external genitalia to MRF, and (2) ascending bilateral projections in the ventrolateral white matter conveying information from the pelvic visceral organs (bladder, descending colon, urethra) to MRF. Multiple spinal pathways from the penis to the MRF may correspond to different functions, including those processing affective/pleasure/motivational, nociception, and mating-specific (such as for erection and ejaculation) inputs. PMID:20142271

Efficacy and safety of an ascending-dose, extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive.

PubMed

Portman, David J; Kaunitz, Andrew M; Howard, Brandon; Weiss, Herman; Hsieh, Jennifer; Ricciotti, Nancy

2014-04-01

To evaluate the efficacy and safety of an ascending-dose, extended-regimen (ADER) combined oral contraceptive consisting of levonorgestrel (LNG) 150 mcg/ethinyl estradiol (EE) 20 mcg for 42 days, LNG 150 mcg/EE 25 mcg for 21 days, LNG 150 mcg/EE 30 mcg for 21 days and EE 10 mcg for 7 days. This was a multicenter, open-label, phase 3, single-arm study. Sexually active women aged 18-40 years were enrolled and received ADER for up to 1 year (4 consecutive 91-day cycles). Participants kept diaries to record adherence, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index and the life-table method; safety and tolerability were assessed through reported adverse events (AEs). A total of 3701 women were enrolled and 2144 completed the study. The Pearl Index was 3.19 [95% confidence interval (CI), 2.49-4.03], based on 70 pregnancies that occurred after ADER initiation and ≤ 7 days after the last LNG/EE or EE-only pill in women aged 18-35 years, excluding cycles in which another contraceptive method was used. Life-table pregnancy rate was 2.82% (95% CI, 2.23%-3.57%) for all users aged 18-35 years. Unscheduled bleeding/spotting decreased with increasing EE doses within each cycle and decreased after cycle 1. No unexpected AEs or changes in laboratory parameters were reported. This study demonstrated that ADER effectively prevented pregnancy with a favorable safety and tolerability profile. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Bapineuzumab: A Single-Ascending-Dose Study in Patients With Mild to Moderate Alzheimer Disease.

PubMed

Lu, Ming; Brashear, H Robert

2018-06-19

This study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending subcutaneous doses of bapineuzumab in patients with mild to moderate Alzheimer disease. Forty patients were randomized across 5 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 80 mg; 8 patients each [bapineuzumab 6; placebo 2]). The incidence of treatment-emergent adverse events (TEAEs) was higher in pooled bapineuzumab cohorts (83%) than in the pooled placebo group (27.7%). Most common TEAEs in the bapineuzumab group were gastrointestinal disorders and musculoskeletal and connective tissue disorders (bapineuzumab 17% each; placebo 0%). Serious TEAEs were observed in 7% of bapineuzumab-treated patients without any deaths or adverse event-related discontinuation. The median times to reach peak measurable concentration (C max ) of bapineuzumab were 14 days for 5-, 10-, and 20-mg cohorts, 11 days for 40-mg, and 7 days for 80-mg cohorts. The apparent volume of distribution of bapineuzumab was 134.29 to 204.68 mL/kg. The total body clearance was consistent at 10 to 80 mg. The average terminal half-life ranged from 26 to 46 days (5- to 80-mg groups). Exposure to bapineuzumab increased dose-proportionally from 10 to 80 mg. There was a positive correlation between C max and area under the concentration-time curve to the last measurable concentration (AUC last ) of plasma amyloid-β, and between the C max and AUC last of serum bapineuzumab. © 2018, The American College of Clinical Pharmacology.

Technology Advancement for Active Remote Sensing of Carbon Dioxide from Space Using the ASCENDS CarbonHawk Experiment Simulator: First Results

NASA Technical Reports Server (NTRS)

Obland, Michael D.; Nehrir, Amin R.; Lin, Bing; Harrison, F. Wallace; Kooi, Susan; Choi, Yonghoon; Plant, James; Yang, Melissa; Antill, Charles; Campbell, Joel;

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.

PubMed

Ray, Kausik K; Landmesser, Ulf; Leiter, Lawrence A; Kallend, David; Dufour, Robert; Karakas, Mahir; Hall, Tim; Troquay, Roland P T; Turner, Traci; Visseren, Frank L J; Wijngaard, Peter; Wright, R Scott; Kastelein, John J P

2017-04-13

In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).

Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711.

PubMed

Lindström, Erik; Rizoska, Biljana; Henderson, Ian; Terelius, Ylva; Jerling, Markus; Edenius, Charlotte; Grabowska, Urszula

2018-05-09

Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man. The potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3-30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg. MIV-711 was a potent inhibitor of human cathepsin K (K i : 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC 50 value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data. MIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA. Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011.

Technology advancement for the ASCENDS mission using the ASCENDS CarbonHawk Experiment Simulator (ACES)

NASA Astrophysics Data System (ADS)

Obland, M. D.; Antill, C.; Browell, E. V.; Campbell, J. F.; CHEN, S.; Cleckner, C.; Dijoseph, M. S.; Harrison, F. W.; Ismail, S.; Lin, B.; Meadows, B. L.; Mills, C.; Nehrir, A. R.; Notari, A.; Prasad, N. S.; Kooi, S. A.; Vitullo, N.; Dobler, J. T.; Bender, J.; Blume, N.; Braun, M.; Horney, S.; McGregor, D.; Neal, M.; Shure, M.; Zaccheo, T.; Moore, B.; Crowell, S.; Rayner, P. J.; Welch, W.

2013-12-01

The ASCENDS CarbonHawk Experiment Simulator (ACES) is a NASA Langley Research Center project funded by NASA's Earth Science Technology Office that seeks to advance technologies critical to measuring atmospheric column carbon dioxide (CO2) mixing ratios in support of the NASA Active Sensing of CO2 Emissions over Nights, Days, and Seasons (ASCENDS) mission. The technologies being advanced are: (1) multiple transmitter and telescope-aperture operations, (2) high-efficiency CO2 laser transmitters, (3) a high bandwidth detector and transimpedance amplifier (TIA), and (4) advanced algorithms for cloud and aerosol discrimination. The instrument architecture is being developed for ACES to operate on a high-altitude aircraft, and it will be directly scalable to meet the ASCENDS mission requirements. The above technologies are critical for developing an airborne simulator and spaceborne instrument with lower platform consumption of size, mass, and power, and with improved performance. This design employs several laser transmitters and telescope-apertures to demonstrate column CO2 retrievals with alignment of multiple laser beams in the far-field. ACES will transmit five laser beams: three from commercial lasers operating near 1.57-microns, and two from the Exelis atmospheric oxygen (O2) fiber laser amplifier system operating near 1.26-microns. The Master Oscillator Power Amplifier at 1.57-microns measures CO2 column concentrations using an Integrated-Path Differential Absorption (IPDA) lidar approach. O2 column amounts needed for calculating the CO2 mixing ratio will be retrieved using the Exelis laser system with a similar IPDA approach. The three aperture telescope design was built to meet the constraints of the Global Hawk high-altitude unmanned aerial vehicle (UAV). This assembly integrates fiber-coupled transmit collimators for all of the laser transmitters and fiber-coupled optical signals from the three telescopes to the aft optics and detector package. The detector/TIA effort has improved the existing detector subsystem by: increasing its bandwidth to 5.4 MHz, exceeding the original goal of 5 MHz; reducing the overall mass from 18 lbs to <10 lbs; and increasing the duration of autonomous, service-free operation periods from 4 hrs to >24 hrs. The new detector subsystem will permit higher laser modulation rates, which provides greater flexibility for implementing thin-cloud discrimination algorithms as well as improving range resolution and error reduction, and will enable long-range flights on the Global Hawk. The cloud/aerosol discrimination work features development of new algorithms by Langley and Exelis for the avoidance of bias errors in the retrieval of column CO2 induced by the presence of thin clouds.

The effects of moderate alcohol concentrations on driving and cognitive performance during ascending and descending blood alcohol concentrations.

PubMed

Starkey, Nicola J; Charlton, Samuel G

2014-07-01

Alcohol has an adverse effect on driving performance; however, the effects of moderate doses on different aspects of the driving task are inconsistent and differ across the intoxication curve. This research aimed to investigate driving and cognitive performance asymmetries (acute tolerance and acute protracted error) accompanying the onset and recovery from moderate alcohol consumption. Sixty-one participants received a placebo, medium (target blood alcohol concentration [BAC] 0.05 mg/ml) or high (target BAC 0.08 mg/ml) dose of alcohol. Participants completed a simulated drive, cognitive tests and subjective rating scales five times over a 3.5 h period. When ascending and descending BACs (0.05 and 0.09 mg/ml) were compared participants' self-ratings of intoxication and willingness to drive showed acute tolerance. Acute protracted errors were observed for response speed, maze learning errors, time exceeding the speed limit and exaggerated steering responses to hazards. Participants' estimates of their level of intoxication were poorly related to their actual BAC levels (and hence degree of impairment), and various aspects of driving and cognitive performance worsened during descending BACs. This indicates that drivers are not good at judging their fitness to drive after drinking only moderate amounts of alcohol and suggests an important focus for public education regarding alcohol and driving. Copyright © 2014 John Wiley & Sons, Ltd.

Contamination of chlorhexidine cream used to prevent ascending urinary tract infections.

PubMed Central

Salveson, A.; Bergan, T.

1981-01-01

Chlorhexidine-containing cream is often used as an antimicrobial barrier to ascending urinary tract infection in patients with indwelling urethral catheters. The cream is dispensed in small tubes for personal use but repeated use of a tube still entails a potential infection hazard. The extent of cream contamination was analysed by emulsifying it in 1% peptone broth with 1% Tween-80 added as a wetting agent, and culturing quantitatively for bacteria and fungi by membrane filtration. Twenty-three per cent of cream samples and 35% of swabs taken from outside the tube beneath the screw cap demonstrated microbial contamination. Isolates included potential pathogens such as enterococci, staphylococci, Proteus mirabilis, Pseudomonas aeruginosa, opportunists like Moraxella spp. and diphtheroids, and contaminants such as Bacillus spp., micrococci, and a mould of the genus Cladosporium. Contamination of cream with a particular bacterial strain was found to precede urinary tract infection with the same microbe. We recommend that chlorhexidine cream for this use be dispensed in single dose units to ensure sterility. PMID:7240733

Pharmacokinetics and Tolerability of Single-Ascending Doses of Desvenlafaxine Administered to Children and Adolescents with Major Depressive Disorder.

PubMed

Findling, Robert L; Groark, James; Tourian, Karen A; Ramaker, Sara A; Chiles, Deborah; Yang, Lingfeng; Nichols, Alice I

2016-12-01

To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the effect of desvenlafaxine on depression symptoms was exploratory. The 8-week, open-label study included an initial 3.5-day inpatient period followed by a 7.5-week outpatient period. Children (7-11 years) received a single desvenlafaxine dose of 10, 25, 50, or 100 mg on day 1; adolescents (12-17 years) received desvenlafaxine 25, 50, 100, or 200 mg/day. Plasma and urine samples were collected over the initial 72-hour inpatient period. Evaluations included treatment-emergent adverse events (TEAEs), physical examinations (including Tanner Staging), vital signs, laboratory assessments, 12-lead electrocardiogram, Columbia-Suicide Severity Rating Scale, and the Children's Depression Rating Scale-Revised (CDRS-R). In all, 29 children and 30 adolescents took at least one dose of desvenlafaxine and were included in the safety population (children: 10 mg, n = 6; 25 mg, n = 7; 50 mg, n = 9; 100 mg, n = 7; adolescents: 25 mg, n = 7; 50 mg, n = 7; 100 mg, n = 8; 200 mg, n = 8). Total area under the drug concentration-time curve from 0 to infinity (AUC) appeared to increase linearly with increasing dose. Mean (standard deviation [SD]) AUC ranged from 628 (346) ng/mL (desvenlafaxine 10 mg) to 6732 (3031) ng/mL (100 mg) in children and from 1123 (361) ng/mL (25 mg) to 11,730 (3113) ng/mL (200 mg) in adolescents. During the combined inpatient and outpatient period, 16/29 (55%) children and 21/30 (70%) adolescents reported at least one TEAE. One serious adverse event (suicidal behavior) was reported. Mean (SD) change from baseline in CDRS-R total scores at week 8 was -19.00 (9.87) for children and -21.57 (11.50) for adolescents. Desvenlafaxine AUC values increased linearly with dose; body weight alone provided an adequate prediction for dose-normalized AUC. Desvenlafaxine was generally safe and well tolerated in children and adolescents for treatment up to 8 weeks.

Inhibitory effect of peptide Epitalon on colon carcinogenesis induced by 1,2-dimethylhydrazine in rats.

PubMed

Anisimov, Vladimir N; Khavinson, Vladimir Kh; Popovich, I G; Zabezhinski, Mark A

2002-09-08

The effect of synthetic pineal peptide Epitalon (Ala-Glu-Asp-Gly) on colon carcinogenesis was firstly studied in rats. Eighty 2-month-old outbred male LIO rats were subdivided into four groups and were weekly exposed to five subcutaneous injections of 1,2-dimethylhydrazine (DMH) at a single dose of 21 mg/kg body weight. Additionally, 5 days a week, some of the rats were given subcutaneous injections of saline at a dose of 0.1 ml during the whole experiment (group 1, control) or Epitalon at a single dose of 1 microg during the whole experiment (group 2), Epitalon after termination of carcinogen injections (group 3) or during the period of DMH exposure (group 4). Colon carcinomas developed in 90-100% of DMH-treated rats. The number of total colon tumors per rat was 4.1; 2.7; 3.7; 2.9 in groups 1, 2, 3, 4, respectively (the difference in groups 2 and 4 compared with group 1 is significant). In rats from group 2, colon tumors were smaller than in control animals. In group 2, the incidence, as well the multiplicity of tumors in ascending and descending colon, were significantly decreased in comparison with group 1. In group 4, the mean number of tumors per rat was significantly decreased, too. A trend to decrease the number of tumors in the rectum in rats from groups 2, 3 and 4, treated with Epitalon was found. Epitalon inhibited also the development of tumors in jejunum and ileum. Thus, our results demonstrated an inhibitory effect of Epitalon on chemically induced bowel carcinogenesis in rats.

Effect of lifelong antibiotic treatment for aortic arch prosthesis infection.

PubMed

Rupprecht, Leopold; Grosse, Jirka; Hellwig, Dirk; Schmid, Christof

2017-11-01

A patient who underwent multiple aortic operations suffered persistent infection of the ascending aorta and arch prosthesis and was finally treated with lifelong antibiotics. An 8-year follow-up with positron emission computed tomography is reported. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Development of a Physiologically Based Pharmacokinetic Model for Sinogliatin, a First-in-Class Glucokinase Activator, by Integrating Allometric Scaling, In Vitro to In Vivo Exploration and Steady-State Concentration-Mean Residence Time Methods: Mechanistic Understanding of its Pharmacokinetics.

PubMed

Song, Ling; Zhang, Yi; Jiang, Ji; Ren, Shuang; Chen, Li; Liu, Dongyang; Chen, Xijing; Hu, Pei

2018-04-06

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (C ss -MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans. Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and C ss -MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms. On this basis, an initial mechanistic PBPK model of sinogliatin was developed. The initial PBPK model was verified using observed data from a single ascending dose (SAD) study and further optimized with various strategies. The final model was validated by simulating sinogliatin pharmacokinetics under a fed condition. The validated model was applied to support a clinical drug-drug interaction (DDI) study design and to evaluate the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure. The two-species scaling method using rat and dog data (TS- rat,dog ) was the best AS method in predicting human systemic clearance in the central compartment (CL). The IVIVE method confirmed that sinogliatin was predominantly metabolized by cytochrome P450 (CYP) 3A4. The C ss -MRT method suggested dog pharmacokinetic profiles were more similar to human pharmacokinetic profiles. The estimated CL using the AS and IVIVE approaches was within 1.5-fold of that observed. The C ss -MRT method in dogs also provided acceptable prediction of human pharmacokinetic characteristics. For the PBPK approach, the 90% confidence intervals (CIs) of the simulated maximum concentration (C max ), CL, and area under the plasma concentration-time curve (AUC) of sinogliatin were within those observed and the 90% CI of simulated time to C max (t max ) was closed to that observed for a dose range of 5-50 mg in the SAD study. The final PBPK model was validated by simulating sinogliatin pharmacokinetics with food. The 90% CIs of the simulated C max , CL, and AUC values for sinogliatin were within those observed and the 90% CI of the simulated t max was partially within that observed for the dose range of 25-200 mg in the multiple ascending dose (MAD) study. This PBPK model selected a final clinical DDI study design with itraconazole from four potential designs and also evaluated the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure. Sinogliatin pharmacokinetic properties were mechanistically understood by integrating all four methods and a mechanistic PBPK model was successfully developed and validated using clinical data. This PBPK model was applied to support the development of sinogliatin.

Phase I, randomized, double-blind, placebo-controlled, multiple intravenous, dose-ascending study of sirukumab in cutaneous or systemic lupus erythematosus.

PubMed

Szepietowski, Jacek C; Nilganuwong, Surasak; Wozniacka, Anna; Kuhn, Annegret; Nyberg, Filippa; van Vollenhoven, Ronald F; Bengtsson, Anders A; Reich, Adam; de Vries, Dick E; van Hartingsveldt, Bart; Robinson, Donald W; Gordon, Robert; Hsu, Benjamin

2013-10-01

We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). In part A, patients with histologically confirmed CLE were randomized to 4 infusions of placebo or 1, 4, or 10 mg/kg sirukumab every 2 weeks. In part B, SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5-12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were randomized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks. We treated 31 CLE patients (23 with sirukumab, 8 with placebo) and 15 SLE patients (10 with sirukumab, 5 with placebo). Adverse events (AEs) occurred more often with sirukumab than placebo in CLE patients (91% versus 63%) and in SLE patients (90% versus 80%). Sirukumab led to sustained, dose-independent decreases in white blood cell counts, absolute neutrophil counts (neutropenia), and platelet counts (thrombocytopenia) and to minor elevations in total cholesterol levels. The majority of infections were mild respiratory infections. which were reported similarly across CLE cohorts but more often in sirukumab-treated than in placebo-treated SLE patients. Two serious AEs of infection occurred (pneumonia in the 10 mg/kg-treated group and iatrogenic wound infection in the 4 mg/kg-treated group). Sirukumab showed linear pharmacokinetics in CLE patients. Systemic exposure and half-life were comparable between CLE and SLE patients. No patient developed antibodies to sirukumab through 22 weeks. C-reactive protein and serum amyloid A mean concentrations were suppressed with sirukumab from week 1 to week 14. Treatment with intravenous sirukumab infusions was generally well tolerated in both CLE and SLE patients with mild, stable, active disease. Sirukumab demonstrated linear pharmacokinetics over the dose range studied and comparable systemic exposure and half-life in CLE and SLE patients. Copyright © 2013 by the American College of Rheumatology.

Peripheral neuropathy following administration of nerve tissue antirabies vaccine.

PubMed

Arega, D; Zenebe, G

1999-10-01

In 1997, two patients were admitted to Tikur Anbessa Hospital with complaints of ascending paralysis in all extremities following administration of sheep brain tissue anti-rabies vaccine following a rabies exposure. The paralysis had started after 14 daily subcutaneous injections of the Fermi type nerve tissue vaccine. After an eight week stay in the hospital with supportive care and physiotherapy, the patients showed remarkable improvement. They received a booster dose of vaccine while in the hospital, with no deterioration in their neurological status and were discharged.

Effect of reversal of double-implantation schedule of boron in mercury cadmium telluride

NASA Astrophysics Data System (ADS)

Kumar, Rakesh; Dutt, M. B.; Nath, R.; Gopal, Vishnu; Khosla, Y. P.; Sharma, K. K.

1992-02-01

Radiation damage due to B+ ion implantation in p-type HgCdTe has been found to create Hg interstitials giving rise to n-type conversion. The implantation energies were kept at 50 and 100 keV with a dose of 1 X 1013 cm-2 each. The effect of implantation with ascending and descending orders of energies were found to be quite different from each other. Radiation enhanced diffusion is thought to be responsible for this anomaly.

Natural history of the ascending aorta after aortic valve replacement: risk factor analysis for late aortic complications after aortic valve replacement.

PubMed

Tsutsumi, Koji; Hashizume, Kenichi; Inoue, Yoshito

2016-05-01

The purpose of this study was to clarify the natural history of the ascending aorta and to identify risk factors for late ascending aortic events after first isolated aortic valve replacement (AVR). A total of 287 patients undergoing AVR were enrolled. The patients were categorized into two groups based on the diameter of the ascending aorta at the time of AVR, as determined by computed tomography: Group A (n = 233) was defined as an ascending aortic diameter <40 mm, and Group B (n = 54) was defined as an ascending aortic diameter ≥40 mm. The mean follow-up period was 7.6 years. The baseline diameter of the ascending aorta was 31.4 ± 4.8 mm in Group A and 44.7 ± 4.2 mm in Group B. These values increased to 35.9 ± 7.4 mm in Group A and 50.1 ± 7.3 mm in Group B during the follow-up period (P < 0.001). Ten patients had acute type A aortic dissection (Group A: 1 patient vs. Group B: 9 patients; P < 0.001), and three patients had enlargement of the ascending aorta to ≥55 mm in diameter (Group A: 1 patient vs. Group B: 2 patients). Multivariate analysis revealed that the baseline ascending aortic diameter was the only significant risk factor for developing late ascending aortic events (P < 0.001). AVR alone may not prevent further enlargement of the ascending aorta. An ascending aorta ≥40 mm in diameter at the time of AVR increased the risk of late ascending aortic events.

Wall stress on ascending thoracic aortic aneurysms with bicuspid compared with tricuspid aortic valve.

PubMed

Xuan, Yue; Wang, Zhongjie; Liu, Raymond; Haraldsson, Henrik; Hope, Michael D; Saloner, David A; Guccione, Julius M; Ge, Liang; Tseng, Elaine

2018-03-08

Guidelines for repair of bicuspid aortic valve-associated ascending thoracic aortic aneurysms have been changing, most recently to the same criteria as tricuspid aortic valve-ascending thoracic aortic aneurysms. Rupture/dissection occurs when wall stress exceeds wall strength. Recent studies suggest similar strength of bicuspid aortic valve versus tricuspid aortic valve-ascending thoracic aortic aneurysms; thus, comparative wall stress may better predict dissection in bicuspid aortic valve versus tricuspid aortic valve-ascending thoracic aortic aneurysms. Our aim was to determine whether bicuspid aortic valve-ascending thoracic aortic aneurysms had higher wall stresses than their tricuspid aortic valve counterparts. Patients with bicuspid aortic valve- and tricuspid aortic valve-ascending thoracic aortic aneurysms (bicuspid aortic valve = 17, tricuspid aortic valve = 19) greater than 4.5 cm underwent electrocardiogram-gated computed tomography angiography. Patient-specific 3-dimensional geometry was reconstructed and loaded to systemic pressure after accounting for prestress geometry. Finite element analyses were performed using the LS-DYNA solver (LSTC Inc, Livermore, Calif) with user-defined fiber-embedded material model to determine ascending thoracic aortic aneurysm wall stress. Bicuspid aortic valve-ascending thoracic aortic aneurysms 99th-percentile longitudinal stresses were 280 kPa versus 242 kPa (P = .028) for tricuspid aortic valve-ascending thoracic aortic aneurysms in systole. These stresses did not correlate to diameter for bicuspid aortic valve-ascending thoracic aortic aneurysms (r = -0.004) but had better correlation to tricuspid aortic valve-ascending thoracic aortic aneurysms diameter (r = 0.677). Longitudinal stresses on sinotubular junction were significantly higher in bicuspid aortic valve-ascending thoracic aortic aneurysms than in tricuspid aortic valve-ascending thoracic aortic aneurysms (405 vs 329 kPa, P = .023). Bicuspid aortic valve-ascending thoracic aortic aneurysm 99th-percentile circumferential stresses were 548 kPa versus 462 kPa (P = .033) for tricuspid aortic valve-ascending thoracic aortic aneurysms, which also did not correlate to bicuspid aortic valve-ascending thoracic aortic aneurysm diameter (r = 0.007). Circumferential and longitudinal stresses were greater in bicuspid aortic valve- than tricuspid aortic valve-ascending thoracic aortic aneurysms and were more pronounced in the sinotubular junction. Peak wall stress did not correlate with bicuspid aortic valve-ascending thoracic aortic aneurysm diameter, suggesting diameter alone in this population may be a poor predictor of dissection risk. Our results highlight the need for patient-specific aneurysm wall stress analysis for accurate dissection risk prediction. Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Listening to Another Sense: Somatosensory Integration in the Auditory System

PubMed Central

Wu, Calvin; Stefanescu, Roxana A.; Martel, David T.

2014-01-01

Conventionally, sensory systems are viewed as separate entities, each with its own physiological process serving a different purpose. However, many functions require integrative inputs from multiple sensory systems, and sensory intersection and convergence occur throughout the central nervous system. The neural processes for hearing perception undergo significant modulation by the two other major sensory systems, vision and somatosensation. This synthesis occurs at every level of the ascending auditory pathway: the cochlear nucleus, inferior colliculus, medial geniculate body, and the auditory cortex. In this review, we explore the process of multisensory integration from 1) anatomical (inputs and connections), 2) physiological (cellular responses), 3) functional, and 4) pathological aspects. We focus on the convergence between auditory and somatosensory inputs in each ascending auditory station. This review highlights the intricacy of sensory processing, and offers a multisensory perspective regarding the understanding of sensory disorders. PMID:25526698

Advanced multimodality imaging of an anomalous vessel between the ascending aorta and main pulmonary artery in a dog

PubMed Central

Markovic, Lauren E.; Kellihan, Heidi B.; Roldán-Alzate, Alejandro; Drees, Randi; Bjorling, Dale E.; Francois, Chris J.

2014-01-01

A 1-year-old male German shorthaired pointer was referred for evaluation of tachypnea and hemoptysis. A grade VI/VI left basilar continuous murmur was ausculted. Multimodality imaging consisting of thoracic radiographs, transthoracic and transesophageal echocardiography, fluoroscopy-guided selective angiography, computed tomography angiogram (CTA) and magnetic resonance angiogram (MRA), was performed on this patient. The defect included a left-to-right shunting anomalous vessel between the ascending aorta and main pulmonary artery, along with a dissecting aneurysm of the main and right pulmonary artery. An MRA postprocessing technique (PC-VIPR) was used to allow for high resolution angiographic images and further assessment of the patient’s hemodynamics prior to surgical correction. This case report describes the clinical course of a canine patient with a rare form of congenital cardiac disease, and the multiple imaging modalities that were used to aid in diagnosis and treatment. PMID:24485987

The relationship between the drug concentration profiles in plasma and the drug doses in the colon.

PubMed

Tajiri, Shinichiro; Kanamaru, Taro; Yoshida, Kazuhiro; Hosoi, Yasue; Konno, Tsutomu; Yada, Shuichi; Nakagami, Hiroaki

2010-10-01

After the dosing of an extended-release (ER) formulation, compounds may exist in solutions at various concentrations in the colon because the drugs are released at various speeds from the ER dosage form. The aim of this study was to investigate the relationship between the drug concentration profiles in plasma and the drug doses in the colon. Several drug solutions of different concentrations were directly administered into the ascending colon of dogs using a lubricated endoscope, and the effects of the drug dose on colonic absorption were estimated. As a result, dose-dependency of colonic absorption varied from compound to compound. Although the relative bioavailability of colonic administration of diclofenac, metformin and cevimeline compared to oral administration was similar regardless of the drug doses in the colon, colonic absorption of diltiazem varied according to the doses. From the results of the co-administration of verapamil and fexofenadine, it was clear that diltiazem underwent extensive hepatic and gastrointestinal first-pass metabolism, resulting in a low area under the curves (AUC) at a low drug dose. During the design of oral ER delivery systems, a colonic absorption study of candidate compounds should be carried out at several solutions of different drug concentrations and assessed carefully.

Technology Advancements for Active Remote Sensing of Carbon Dioxide from Space using the ASCENDS CarbonHawk Experiment Simulator

NASA Astrophysics Data System (ADS)

Obland, M. D.; Nehrir, A. R.; Liu, Z.; Chen, S.; Campbell, J. F.; Lin, B.; Kooi, S. A.; Fan, T. F.; Choi, Y.; Plant, J.; Yang, M. M.; Browell, E. V.; Harrison, F. W.; Meadows, B.; Dobler, J. T.; Zaccheo, T. S.

2015-12-01

This work describes advances in critical lidar technologies and techniques developed as part of the ASCENDS CarbonHawk Experiment Simulator (ACES) system for measuring atmospheric column carbon dioxide (CO2) mixing ratios in support of the NASA Active Sensing of CO2 Emissions over Nights, Days, and Seasons (ASCENDS) mission. The ACES design demonstrates advancements in: (1) enhanced power-aperture product through the use and operation of multiple co-aligned laser transmitters and a multi-aperture telescope design; (2) high-efficiency, high-power Erbium-Doped Fiber Amplifiers (EDFAs); (3) high-bandwidth, low-noise HgCdTe detector and transimpedence amplifier (TIA) subsystem capable of long-duration operation; and (4) advanced algorithms for cloud and aerosol discrimination. The ACES instrument, an Intensity-Modulated Continuous-Wave (IM-CW) lidar, was designed for high-altitude aircraft operations and can be directly applied to space instrumentation to meet the ASCENDS mission requirements. Specifically, the lidar simultaneously transmits three IM-CW laser beams from the high power EDFAs operating near 1571 nm. The outgoing laser beams are aligned to the field of view of three fiber-coupled 17.8-cm diameter telescopes, and the backscattered light collected by the same three telescopes is sent to the detector/TIA subsystem, which has a bandwidth of 4.9 MHz and operates service-free with a tactical Dewar and cryocooler. The electronic bandwidth is only slightly higher than 1 MHz, effectively limiting the noise level. Two key laser modulation approaches are being tested to significantly mitigate the effects of thin clouds on the retrieved CO2 column amounts. This work provides an over view of these technologies, the modulation approaches, and results from recent test flights.

Technology Advancements for Active Remote Sensing of Carbon Dioxide From Space using the ASCENDS CarbonHawk Experiment Simulator

NASA Astrophysics Data System (ADS)

Obland, M. D.; Liu, Z.; Campbell, J. F.; Lin, B.; Kooi, S. A.; Carrion, W.; Hicks, J.; Fan, T. F.; Nehrir, A. R.; Browell, E. V.; Meadows, B.; Davis, K. J.

2016-12-01

This work describes advances in critical lidar technologies and techniques developed as part of the ASCENDS CarbonHawk Experiment Simulator (ACES) system for measuring atmospheric column carbon dioxide (CO2) mixing ratios in support of the NASA Active Sensing of CO2 Emissions over Nights, Days, and Seasons (ASCENDS) mission. The ACES design demonstrates advancements in: (1) enhanced power-aperture product through the use and operation of multiple co-aligned laser transmitters and a multi-aperture telescope design; (2) high-efficiency, high-power Erbium-Doped Fiber Amplifiers (EDFAs); (3) high-bandwidth, low-noise HgCdTe detector and transimpedence amplifier (TIA) subsystem capable of long-duration operation; and (4) advanced algorithms for cloud and aerosol discrimination. The ACES instrument, an Intensity-Modulated Continuous-Wave (IM-CW) lidar, was designed for high-altitude aircraft operations and can be directly applied to space instrumentation to meet the ASCENDS mission requirements. Specifically, the lidar simultaneously transmits three IM-CW laser beams from the high power EDFAs operating near 1571 nm. The outgoing laser beams are aligned to the field of view of three fiber-coupled 17.8-cm diameter telescopes, and the backscattered light collected by the same three telescopes is sent to the detector/TIA subsystem, which has a bandwidth of 4.9 MHz and operates service-free with a tactical Dewar and cryocooler. The electronic bandwidth is only slightly higher than 1 MHz, effectively limiting the noise level. Two key laser modulation approaches are being tested to significantly mitigate the effects of thin clouds on the retrieved CO2 column amounts. This work provides an over view of these technologies, the modulation approaches, and results from recent test flights during the Atmospheric Carbon and Transport - America (ACT-America) Earth Venture Suborbital flight campaign.

Biphasic Effects of Alcohol as a Function of Circadian Phase

PubMed Central

Van Reen, Eliza; Rupp, Tracy L.; Acebo, Christine; Seifer, Ronald; Carskadon, Mary A.

2013-01-01

Study Objectives: To assess how alcohol affects multiple sleep latency tests (MSLT) and subjective measures of stimulation/sedation when alcohol is given at different circadian phases. Participants: Twenty-seven healthy young adults (age 21-26 yr) were studied. Design: Double-blind placebo and alcohol (vodka tonic targeting 0.05 g% concentration) beverages were each administered three times during the 20-h forced desynchrony protocol. Sleep latency tests and Biphasic Effects of Alcohol Scale (BAES) were administered on each forced desynchrony day. The outcome variables for this study include sleep onset latency (SOL) and stimulation and sedation value (from the BAES). Each outcome variable was associated with the ascending or descending limb of the breath alcohol concentration (BrAC) curve and assigned a circadian phase within a 90° bin. Measurements and Results: BrAC confirmed targeted maximal levels. Only outcome variables associated with the ascending and descending limb of the alcohol curve were analyzed for this article. Alcohol administered at a circadian time associated with greatest sleepiness showed longer SOL compared with placebo when measured on the ascending limb of the BrAC curve. We also found longer SOL with alcohol on the ascending limb of the BrAC curve in a circadian bin that favors greatest alertness. We observed shorter SOLs on the descending limb of the BrAC curve, but with no circadian phase interaction. The subjective data were partially consistent with the objective data. Conclusions: The physiologic findings in this study support the biphasic stimulating and sedating properties of alcohol, but limit the effect to specific circadian times. Citation: Van Reen E; Rupp TL; Acebo C; Seifer R; Carskadon MA. Biphasic effects of alcohol as a function of circadian phase. SLEEP 2013;36(1):137-145. PMID:23288980

ASCENDE-RT: An Analysis of Treatment-Related Morbidity for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost with a Dose-Escalated External Beam Boost for High- and Intermediate-Risk Prostate Cancer

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

Rodda, Sree; Tyldesley, Scott; Department of Surgery, University of British Columbia, Vancouver, British Columbia

Purpose: To report the genitourinary (GU) and gastrointestinal (GI) morbidity and erectile dysfunction in a randomized trial comparing 2 methods of dose escalation for high- and intermediate-risk prostate cancer. Methods and Materials: ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) enrolled 398 men, median age 68 years, who were then randomized to either a standard arm that included 12 months of androgen deprivation therapy and pelvic irradiation to 46 Gy followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. At clinic visits, investigators recorded GUmore » and GI morbidity and information on urinary continence, catheter use, and erectile function. Exclusion of 15 who received nonprotocol treatment and correction of 14 crossover events left 195 men who actually received a DE-EBRT boost and 188, an LDR-PB boost. Median follow-up was 6.5 years. Results: The LDR-PB boost increased the risk of needing temporary catheterization and/or requiring incontinence pads. At 5 years the cumulative incidence of grade 3 GU events was 18.4% for LDR-PB, versus 5.2% for DE-EBRT (P<.001). Compared with the cumulative incidence, the 5-year prevalence of grade 3 GU morbidity was substantially lower for both arms (8.6% vs 2.2%, P=.058). The 5-year cumulative incidence of grade 3 GI events was 8.1% for LDR-PB, versus 3.2% for DE-EBRT (P=.124). The 5-year prevalence of grade 3 GI toxicity was lower than the cumulative incidence for both arms (1.0% vs 2.2%, respectively). Among men reporting adequate baseline erections, 45% of LDR-PB patients reported similar erectile function at 5 years, versus 37% after DE-EBRT (P=.30). Conclusions: The incidence of acute and late GU morbidity was higher after LDR-PB boost, and there was a nonsignificant trend for worse GI morbidity. No differences in the frequency of erectile dysfunction were observed.« less

Ross procedure for ascending aortic replacement.

PubMed

Elkins, R C; Lane, M M; McCue, C

1999-06-01

Patients with aortic valve disease and aneurysm or dilatation of the ascending aorta require both aortic valve replacement and treatment of their ascending aortic disease. In children and young adults, the Ross operation is preferred when the aortic valve requires replacement, but the efficacy of extending this operation to include replacement of the ascending aorta or reduction of the dilated aorta has not been tested. We reviewed the medical records of 18 (5.9%) patients with aortic valve disease and an ascending aortic aneurysm and 26 (8.5%) patients with dilation of the ascending aorta, subgroups of 307 patients who had a Ross operation between August 1986 and February 1998. We examined operative and midterm results, including recent echocardiographic assessment of autograft valve function and ability of the autograft root and ascending aortic repair or replacement to maintain normal structural integrity. There was one operative death (2%) related to a perioperative stroke. Forty-two of 43 survivors have normal autograft valve function, with trace to mild autograft valve insufficiency, and one patient has moderate insufficiency at the most recent echocardiographic evaluation. None of the patients has dilatation of the autograft root or of the replaced or reduced ascending aorta. Early results with extension of the Ross operation to include replacement of an ascending aortic aneurysm or vertical aortoplasty for reduction of a dilated ascending aorta are excellent, with autograft valve function equal to that seen in similar patients without ascending aortic disease.

Perceived danger while intoxicated uniquely contributes to driving after drinking.

PubMed

Morris, David H; Treloar, Hayley R; Niculete, Maria E; McCarthy, Denis M

2014-02-01

Previous findings suggest that alcohol alters perceptions of risky behaviors such as drinking and driving. However, studies testing these perceptions as a predictor of drinking and driving typically measure these perceptions while participants are sober. This study tested whether the perceived danger of driving after drinking assessed while intoxicated was associated with increased willingness to drive and self-reported drinking-and-driving behavior over and above perceptions assessed while sober. Additionally, we tested the effect of acute tolerance on the perceived danger of driving after drinking assessed on the ascending and descending limbs of the breath alcohol concentration (BrAC) curve. Eighty-two young adults attended 2 counterbalanced laboratory sessions. In one session, participants consumed a moderate dose of alcohol (men: 0.72 g/kg, women: 0.65 g/kg) and reported their perceived danger of driving and willingness to drive at multiple points across the BrAC curve. On a separate occasion, participants remained sober and appraised the dangerousness of driving at a hypothetical, illegal BrAC. Perceptions of the dangerousness of driving following alcohol administration were associated with increased willingness to drive and higher rates of self-reported drinking-and-driving behavior over and above perceptions reported when sober. Furthermore, perceived danger was reduced on the descending limb of the BrAC curve, compared with the ascending limb, suggesting the occurrence of acute tolerance. Results from this study suggest that intoxicated perceptions are uniquely associated with drinking-and-driving decisions and that the perceived danger of drinking and driving is lower on the descending limb of the BrAC curve. Efforts to prevent alcohol-impaired driving have focused on increasing awareness of the danger of driving after drinking. Prevention efforts may be enhanced by educating drivers about how intoxication can alter perceived danger, and interventions may benefit from targeting perceptions of dangerousness while individuals are intoxicated in addition to when they are sober. Copyright © 2013 by the Research Society on Alcoholism.

Perceived Danger while Intoxicated Uniquely Contributes to Driving after Drinking

PubMed Central

Morris, David H.; Treloar, Hayley R.; Niculete, Maria E.; McCarthy, Denis M.

2013-01-01

Background Previous findings suggest that alcohol alters perceptions of risky behaviors such as drinking and driving. However, studies testing these perceptions as a predictor of drinking and driving typically measure these perceptions while participants are sober. The present study tested whether the perceived danger of driving after drinking assessed while intoxicated was associated with increased willingness to drive and self-reported drinking-and-driving behavior over and above perceptions assessed while sober. Additionally, we tested the effect of acute tolerance on the perceived danger of driving after drinking assessed on the ascending and descending limbs of the breath alcohol concentration (BrAC) curve. Methods Eighty-two young adults attended two counterbalanced laboratory sessions. In one session, participants consumed a moderate dose of alcohol (men: .72 g/kg, women: .65 g/kg) and reported the perceived danger of driving and their willingness to drive at multiple points across the BrAC curve. On a separate occasion, participants remained sober and appraised the dangerousness of driving at a hypothetical, illegal BrAC. Results Perceptions of the dangerousness of driving following alcohol administration were associated with increased willingness to drive and higher rates of self-reported drinking-and-driving behavior over and above perceptions reported when sober. Furthermore, perceived danger was reduced on the descending limb of the BrAC curve, compared to the ascending limb, suggesting the occurrence of acute tolerance. Conclusions Results from this study suggest that intoxicated perceptions are uniquely associated with drinking-and-driving decisions and that the perceived danger of drinking and driving is lower on the descending limb of the BrAC curve. Efforts to prevent alcohol-impaired driving have focused on increasing awareness of the danger of driving after drinking. Prevention efforts may be enhanced by educating drivers about how intoxication can alter perceived danger, and interventions may benefit from targeting perceptions of dangerousness while individuals are intoxicated in addition to when they are sober. PMID:24033630

Ascending thoracic aortic aneurysms protect against myocardial infarctions.

PubMed

Chau, Katherine; Elefteriades, John A

2014-09-01

There has been increasing evidence that ascending thoracic aortic aneurysms (TAAs) protect against atherosclerosis. However, there have been no studies examining the relationship between ascending TAAs and clinical endpoints of atherosclerosis, such as stroke or peripheral arterial disease. In this study, we aim to characterize the relationship between TAAs and a specific clinical endpoint of atherosclerosis, myocardial infarction (MI). We compared prevalence of coronary artery disease (CAD) and MIs in 487 patients who underwent surgical repair for ascending TAAs to 500 control patients who did not have an ascending TAA. Multivariate binary logistic regression was used to calculate the odds of having MI if a patient had an ascending TAA versus any of several MI risk factors. There was a significantly lower prevalence of CAD and MI in the ascending TAA group than in the control TAA group. The odds of having a MI if a patient had a MI risk factor were all > 1 (more likely to have a MI), with the lowest statistically significant odds ratio being 1.54 (age; p = 0.001) and the highest being 14.9 (family history of MI; p < 0.001). The odds ratio of having a MI if a patient had an ascending TAA, however, was near 0 at 0.05 (p < 0.001). This study provides evidence that ascending TAAs protect against MIs, adding further support to the hypothesis that ascending TAAs protect against atherosclerotic disease.

Quantitative pharmacokinetic-pharmacodynamic modelling of baclofen-mediated cardiovascular effects using BP and heart rate in rats.

PubMed

Kamendi, Harriet; Barthlow, Herbert; Lengel, David; Beaudoin, Marie-Eve; Snow, Debra; Mettetal, Jerome T; Bialecki, Russell A

2016-10-01

While the molecular pathways of baclofen toxicity are understood, the relationships between baclofen-mediated perturbation of individual target organs and systems involved in cardiovascular regulation are not clear. Our aim was to use an integrative approach to measure multiple cardiovascular-relevant parameters [CV: mean arterial pressure (MAP), systolic BP, diastolic BP, pulse pressure, heart rate (HR); CNS: EEG; renal: chemistries and biomarkers of injury] in tandem with the pharmacokinetic properties of baclofen to better elucidate the site(s) of baclofen activity. Han-Wistar rats were administered vehicle or ascending doses of baclofen (3, 10 and 30 mg·kg(-1) , p.o.) at 4 h intervals and baclofen-mediated changes in parameters recorded. A pharmacokinetic-pharmacodynamic model was then built by implementing an existing mathematical model of BP in rats. Final model fits resulted in reasonable parameter estimates and showed that the drug acts on multiple homeostatic processes. In addition, the models testing a single effect on HR, total peripheral resistance or stroke volume alone did not describe the data. A final population model was constructed describing the magnitude and direction of the changes in MAP and HR. The systems pharmacology model developed fits baclofen-mediated changes in MAP and HR well. The findings correlate with known mechanisms of baclofen pharmacology and suggest that similar models using limited parameter sets may be useful to predict the cardiovascular effects of other pharmacologically active substances. © 2016 The British Pharmacological Society.

Quantitative pharmacokinetic–pharmacodynamic modelling of baclofen‐mediated cardiovascular effects using BP and heart rate in rats

PubMed Central

Kamendi, Harriet; Barthlow, Herbert; Lengel, David; Beaudoin, Marie‐Eve; Snow, Debra

2016-01-01

Background and Purpose While the molecular pathways of baclofen toxicity are understood, the relationships between baclofen‐mediated perturbation of individual target organs and systems involved in cardiovascular regulation are not clear. Our aim was to use an integrative approach to measure multiple cardiovascular‐relevant parameters [CV: mean arterial pressure (MAP), systolic BP, diastolic BP, pulse pressure, heart rate (HR); CNS: EEG; renal: chemistries and biomarkers of injury] in tandem with the pharmacokinetic properties of baclofen to better elucidate the site(s) of baclofen activity. Experimental Approach Han‐Wistar rats were administered vehicle or ascending doses of baclofen (3, 10 and 30 mg·kg−1, p.o.) at 4 h intervals and baclofen‐mediated changes in parameters recorded. A pharmacokinetic–pharmacodynamic model was then built by implementing an existing mathematical model of BP in rats. Key Results Final model fits resulted in reasonable parameter estimates and showed that the drug acts on multiple homeostatic processes. In addition, the models testing a single effect on HR, total peripheral resistance or stroke volume alone did not describe the data. A final population model was constructed describing the magnitude and direction of the changes in MAP and HR. Conclusions and Implications The systems pharmacology model developed fits baclofen‐mediated changes in MAP and HR well. The findings correlate with known mechanisms of baclofen pharmacology and suggest that similar models using limited parameter sets may be useful to predict the cardiovascular effects of other pharmacologically active substances. PMID:27448216

An update on modeling dose-response relationships: Accounting for correlated data structure and heterogeneous error variance in linear and nonlinear mixed models.

PubMed

Gonçalves, M A D; Bello, N M; Dritz, S S; Tokach, M D; DeRouchey, J M; Woodworth, J C; Goodband, R D

2016-05-01

Advanced methods for dose-response assessments are used to estimate the minimum concentrations of a nutrient that maximizes a given outcome of interest, thereby determining nutritional requirements for optimal performance. Contrary to standard modeling assumptions, experimental data often present a design structure that includes correlations between observations (i.e., blocking, nesting, etc.) as well as heterogeneity of error variances; either can mislead inference if disregarded. Our objective is to demonstrate practical implementation of linear and nonlinear mixed models for dose-response relationships accounting for correlated data structure and heterogeneous error variances. To illustrate, we modeled data from a randomized complete block design study to evaluate the standardized ileal digestible (SID) Trp:Lys ratio dose-response on G:F of nursery pigs. A base linear mixed model was fitted to explore the functional form of G:F relative to Trp:Lys ratios and assess model assumptions. Next, we fitted 3 competing dose-response mixed models to G:F, namely a quadratic polynomial (QP) model, a broken-line linear (BLL) ascending model, and a broken-line quadratic (BLQ) ascending model, all of which included heteroskedastic specifications, as dictated by the base model. The GLIMMIX procedure of SAS (version 9.4) was used to fit the base and QP models and the NLMIXED procedure was used to fit the BLL and BLQ models. We further illustrated the use of a grid search of initial parameter values to facilitate convergence and parameter estimation in nonlinear mixed models. Fit between competing dose-response models was compared using a maximum likelihood-based Bayesian information criterion (BIC). The QP, BLL, and BLQ models fitted on G:F of nursery pigs yielded BIC values of 353.7, 343.4, and 345.2, respectively, thus indicating a better fit of the BLL model. The BLL breakpoint estimate of the SID Trp:Lys ratio was 16.5% (95% confidence interval [16.1, 17.0]). Problems with the estimation process rendered results from the BLQ model questionable. Importantly, accounting for heterogeneous variance enhanced inferential precision as the breadth of the confidence interval for the mean breakpoint decreased by approximately 44%. In summary, the article illustrates the use of linear and nonlinear mixed models for dose-response relationships accounting for heterogeneous residual variances, discusses important diagnostics and their implications for inference, and provides practical recommendations for computational troubleshooting.

Numerical Study on 4-1 Coal Seam of Xiaoming Mine in Ascending Mining

PubMed Central

Tianwei, Lan; Hongwei, Zhang; Sheng, Li; Weihua, Song; Batugin, A. C.; Guoshui, Tang

2015-01-01

Coal seams ascending mining technology is very significant, since it influences the safety production and the liberation of dull coal, speeds up the construction of energy, improves the stability of stope, and reduces or avoids deep hard rock mining induced mine disaster. Combined with the Xiaoming ascending mining mine 4-1, by numerical calculation, the paper analyses ascending mining 4-1 factors, determines the feasibility of ascending mining 4-1 coalbed, and proposes roadway layout program about working face, which has broad economic and social benefits. PMID:25866840

Effects of Acute Alcohol Tolerance on Perceptions of Danger and Willingness to Drive after Drinking

PubMed Central

Amlung, Michael T.; Morris, David H.; McCarthy, Denis M.

2014-01-01

Rationale Drinking and driving is associated with elevated rates of motor vehicle accidents and fatalities. Previous research suggests that alcohol impairs judgments about the dangers of risky behaviors; however, how alcohol affects driving-related judgments is less clear. Impairments have also been shown to differ across limbs of the blood alcohol concentration (BAC) curve, which is known as acute tolerance. Objectives Examine whether perceptions about the dangerousness of driving after drinking and willingness to drive differed across ascending and descending limbs of the BAC curve. Test whether reductions in perceived danger were associated with willingness to drive on the descending limb. Methods Fifty-six participants were randomly assigned to receive either a moderate dose of alcohol (peak BAC = 0.10 g%) or placebo. We assessed perceived dangerousness and willingness to drive at matched BACs (~0.067-0.068 g%) on the ascending and descending limbs. Results Both perceived danger and willingness to drive showed acute tolerance in the alcohol group. Participants judged driving to be significantly less dangerous and were more willing to drive on the descending limb compared to the ascending limb. The magnitude of change in perceived danger significantly predicted willingness to drive on the descending limb. Conclusions Decreased impairment associated with acute tolerance may lead individuals to underestimate the dangerousness of driving after drinking and in turn make poor decisions regarding driving. This study further emphasizes the descending limb as a period of increased risk and offers support for enhancing prevention efforts by targeting drivers at declining BAC levels. PMID:24752657

Acute tolerance to alcohol impairment of behavioral and cognitive mechanisms related to driving: drinking and driving on the descending limb.

PubMed

Weafer, Jessica; Fillmore, Mark T

2012-04-01

Alcohol effects on behavioral and cognitive mechanisms influence impaired driving performance and decisions to drive after drinking (Barry 1973; Moskowitz and Robinson 1987). To date, research has focused on the ascending limb of the blood alcohol curve, and there is little understanding of how acute tolerance to impairment of these mechanisms might influence driving behavior on the descending limb. To provide an integrated examination of the degree to which alcohol impairment of motor coordination and inhibitory control contributes to driving impairment and decisions to drive on the ascending and descending limbs of the blood alcohol curve. Social-drinking adults (N = 20) performed a testing battery that measured simulated driving performance and willingness to drive, as well as mechanisms related to driving: motor coordination (grooved pegboard), inhibitory control (cued go/no-go task), and subjective intoxication. Performance was tested in response to placebo and a moderate dose of alcohol (0.65 g/kg) twice at comparable blood alcohol concentrations: once on the ascending limb and again on the descending limb. Impaired motor coordination and subjective intoxication showed acute tolerance, whereas driving performance and inhibitory control showed no recovery from impairment. Greater motor impairment was associated with poorer driving performance under alcohol, and poorer inhibitory control was associated with more willingness to drive. Findings suggest that acute tolerance to impairment of motor coordination is insufficient to promote recovery of driving performance and that the persistence of alcohol-induced disinhibition might contribute to risky decisions to drive on the descending limb.

Effects of acute alcohol tolerance on perceptions of danger and willingness to drive after drinking.

PubMed

Amlung, Michael T; Morris, David H; McCarthy, Denis M

2014-11-01

Drinking and driving is associated with elevated rates of motor vehicle accidents and fatalities. Previous research suggests that alcohol impairs judgments about the dangers of risky behaviors; however, how alcohol affects driving-related judgments is less clear. Impairments have also been shown to differ across limbs of the blood alcohol concentration (BAC) curve, which is known as acute tolerance. The objectives of this study were to examine whether perceptions about the dangerousness of driving after drinking and willingness to drive differed across the ascending and descending limbs of the BAC curve and to test whether reductions in perceived danger were associated with willingness to drive on the descending limb. Fifty-six participants were randomly assigned to receive either a moderate dose of alcohol (peak BAC = 0.10 g%) or placebo. We assessed perceived dangerousness and willingness to drive at matched BACs (~0.067-0.068 g%) on the ascending and descending limbs. Both perceived danger and willingness to drive showed acute tolerance in the alcohol group. Participants judged driving to be significantly less dangerous and were more willing to drive on the descending limb compared to the ascending limb. The magnitude of change in perceived danger significantly predicted willingness to drive on the descending limb. Decreased impairment associated with acute tolerance may lead individuals to underestimate the dangerousness of driving after drinking and in turn make poor decisions regarding driving. This study further emphasizes the descending limb as a period of increased risk and offers support for enhancing prevention efforts by targeting drivers at declining BAC levels.

Acute tolerance to alcohol impairment of behavioral and cognitive mechanisms related to driving: drinking and driving on the descending limb

PubMed Central

Weafer, Jessica

2015-01-01

Rationale Alcohol effects on behavioral and cognitive mechanisms influence impaired driving performance and decisions to drive after drinking (Barry 1973; Moskowitz and Robinson 1987). To date, research has focused on the ascending limb of the blood alcohol curve, and there is little understanding of how acute tolerance to impairment of these mechanisms might influence driving behavior on the descending limb. Objectives To provide an integrated examination of the degree to which alcohol impairment of motor coordination and inhibitory control contributes to driving impairment and decisions to drive on the ascending and descending limbs of the blood alcohol curve. Methods Social-drinking adults (N=20) performed a testing battery that measured simulated driving performance and willingness to drive, as well as mechanisms related to driving: motor coordination (grooved pegboard), inhibitory control (cued go/no-go task), and subjective intoxication. Performance was tested in response to placebo and a moderate dose of alcohol (0.65 g/kg) twice at comparable blood alcohol concentrations: once on the ascending limb and again on the descending limb. Results Impaired motor coordination and subjective intoxication showed acute tolerance, whereas driving performance and inhibitory control showed no recovery from impairment. Greater motor impairment was associated with poorer driving performance under alcohol, and poorer inhibitory control was associated with more willingness to drive. Conclusions Findings suggest that acute tolerance to impairment of motor coordination is insufficient to promote recovery of driving performance and that the persistence of alcohol-induced disinhibition might contribute to risky decisions to drive on the descending limb. PMID:21960182

Rationale and design of A Trial of Sertraline vs. Cognitive Behavioral Therapy for End-stage Renal Disease Patients with Depression (ASCEND).

PubMed

Hedayati, S Susan; Daniel, Divya M; Cohen, Scott; Comstock, Bryan; Cukor, Daniel; Diaz-Linhart, Yaminette; Dember, Laura M; Dubovsky, Amelia; Greene, Tom; Grote, Nancy; Heagerty, Patrick; Katon, Wayne; Kimmel, Paul L; Kutner, Nancy; Linke, Lori; Quinn, Davin; Rue, Tessa; Trivedi, Madhukar H; Unruh, Mark; Weisbord, Steven; Young, Bessie A; Mehrotra, Rajnish

2016-03-01

Major Depressive Disorder (MDD) is highly prevalent in patients with End Stage Renal Disease (ESRD) treated with maintenance hemodialysis (HD). Despite the high prevalence and robust data demonstrating an independent association between depression and poor clinical and patient-reported outcomes, MDD is under-treated when identified in such patients. This may in part be due to the paucity of evidence confirming the safety and efficacy of treatments for depression in this population. It is also unclear whether HD patients are interested in receiving treatment for depression. ASCEND (Clinical Trials Identifier Number NCT02358343), A Trial of Sertraline vs. Cognitive Behavioral Therapy (CBT) for End-stage Renal Disease Patients with Depression, was designed as a multi-center, 12-week, open-label, randomized, controlled trial of prevalent HD patients with comorbid MDD or dysthymia. It will compare (1) a single Engagement Interview vs. a control visit for the probability of initiating treatment for comorbid depression in up to 400 patients; and (2) individual chair-side CBT vs. flexible-dose treatment with a selective serotonin reuptake inhibitor, sertraline, for improvement of depressive symptoms in 180 of the up to 400 patients. The evolution of depressive symptoms will also be examined in a prospective longitudinal cohort of 90 HD patients who choose not to be treated for depression. We discuss the rationale and design of ASCEND, the first large-scale randomized controlled trial evaluating efficacy of non-pharmacologic vs. pharmacologic treatment of depression in HD patients for patient-centered outcomes. Published by Elsevier Inc.

Rationale and Design of A Trial of Sertraline vs. Cognitive Behavioral Therapy for End-stage Renal Disease Patients with Depression (ASCEND)

PubMed Central

Hedayati, S. Susan; Daniel, Divya M.; Cohen, Scott; Comstock, Bryan; Cukor, Daniel; Diaz-Linhart, Yaminette; Dember, Laura M.; Dubovsky, Amelia; Greene, Tom; Grote, Nancy; Heagerty, Patrick; Katon, Wayne; Kimmel, Paul L.; Kutner, Nancy; Linke, Lori; Quinn, Davin; Rue, Tessa; Trivedi, Madhukar H.; Unruh, Mark; Weisbord, Steven; Young, Bessie A.; Mehrotra, Rajnish

2015-01-01

Major Depressive Disorder (MDD) is highly prevalent in patients with End Stage Renal Disease (ESRD) treated with maintenance hemodialysis (HD). Despite the high prevalence and robust data demonstrating an independent association between depression and poor clinical and patient-reported outcomes, MDD is under-treated when identified in such patients. This may in part be due to the paucity of evidence confirming the safety and efficacy of treatments for depression in this population. It is also unclear whether HD patients are interested in receiving treatment for depression. ASCEND (Clinical Trials Identifier Number NCT02358343), A Trial of Sertraline vs. Cognitive Behavioral Therapy (CBT) for End-stage Renal Disease Patients with Depression, was designed as a multi-center, 12-week, open-label, randomized, controlled trial of prevalent HD patients with comorbid MDD or dysthymia. It will compare (1) a single Engagement Interview vs. a control visit for the probability of initiating treatment for comorbid depression in up to 400 patients; and (2) individual chair-side CBT vs. flexible-dose treatment with a selective serotonin reuptake inhibitor, sertraline, for improvement of depressive symptoms in 180 of the up to 400 patients. The evolution of depressive symptoms will also be examined in a prospective longitudinal cohort of 90 HD patients who choose not to be treated for depression. We discuss the rationale and design of ASCEND, the first large-scale randomized controlled trial evaluating efficacy of non-pharmacologic vs. pharmacologic treatment of depression in HD patients for patient-centered outcomes. PMID:26621218

Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers.

PubMed

Grouzmann, Eric; Bigliardi, Paul; Appenzeller, Monique; Pannatier, André; Buclin, Thierry

2011-03-01

Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.

[Analysis of the importance of cosmonaut's location and orientation onboard the International space station to levels of visceral irradiation during traverse of the region of the South Atlantic Anomaly].

PubMed

Drobyshev, S G; Benghin, V V

2015-01-01

Parametric analysis of absorbed radiation dose to the cosmonaut working in the Service module (SM) of the International space station (ISS) was made with allowance for anisotropy of the radiation field of the South Atlantic Anomaly. Calculation data show that in weakly shielded SM compartments the radiation dose to poorly shielded viscera may depend essentially on cosmonaut's location and orientation relative to the ISS shell. Difference of the lens absorbed dose can be as high as 5 times depending on orientation of the cosmonaut and the ISS. The effect is less pronounced on the deep seated hematopoietic system; however, it may increase up to 2.5 times during the extravehicular activities. When the cosmonaut is outside on the ISS SM side presented eastward, the absorbed dose can be affected noticeably by remoteness from the SM. At a distance less than 1.5 meters away from the SM east side in the course of ascending circuits, the calculated lens dose is approximately half as compared with the situation when the cosmonaut is not shielded by the ISS material.

The functional organization of the left STS: a large scale meta-analysis of PET and fMRI studies of healthy adults

PubMed Central

Liebenthal, Einat; Desai, Rutvik H.; Humphries, Colin; Sabri, Merav; Desai, Anjali

2014-01-01

The superior temporal sulcus (STS) in the left hemisphere is functionally diverse, with sub-areas implicated in both linguistic and non-linguistic functions. However, the number and boundaries of distinct functional regions remain to be determined. Here, we present new evidence, from meta-analysis of a large number of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies, of different functional specificity in the left STS supporting a division of its middle to terminal extent into at least three functional areas. The middle portion of the left STS stem (fmSTS) is highly specialized for speech perception and the processing of language material. The posterior portion of the left STS stem (fpSTS) is highly versatile and involved in multiple functions supporting semantic memory and associative thinking. The fpSTS responds to both language and non-language stimuli but the sensitivity to non-language material is greater. The horizontal portion of the left STS stem and terminal ascending branches (ftSTS) display intermediate functional specificity, with the anterior-dorsal ascending branch (fatSTS) supporting executive functions and motor planning and showing greater sensitivity to language material, and the horizontal stem and posterior-ventral ascending branch (fptSTS) supporting primarily semantic processing and displaying greater sensitivity to non-language material. We suggest that the high functional specificity of the left fmSTS for speech is an important means by which the human brain achieves exquisite affinity and efficiency for native speech perception. In contrast, the extreme multi-functionality of the left fpSTS reflects the role of this area as a cortical hub for semantic processing and the extraction of meaning from multiple sources of information. Finally, in the left ftSTS, further functional differentiation between the dorsal and ventral aspect is warranted. PMID:25309312

Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Δ9-THC in cannabis users

PubMed Central

Lile, Joshua A.; Kelly, Thomas H.; Charnigo, Richard J.; Stinchcomb, Audra L.; Hays, Lon R.

2013-01-01

Oral Δ9-tetrahydrocannabinol (Δ9-THC) has been evaluated as a medication for cannabis dependence, but repeated administration of acute oral doses up to 40 mg has not been effective at reducing drug-taking behavior. Larger doses might be necessary to affect cannabis use. The purpose of the present study was therefore to determine the physiological and behavioral effects of oral Δ9-THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral Δ9-THC, administered in ascending order in 15 mg increments across separate sessions, up to a maximum of 90 mg, was determined in seven cannabis users. Five subjects received all doses and two experienced untoward side effects at lower doses. Δ9-THC produced a constellation of effects consistent with previous clinical studies. Low cannabinoid concentrations were associated with significant effects on drug- sensitive measures, although progressively greater levels did not lead to proportionately larger drug effects. Considerable variability in Cmax and tmax was observed. Doses of oral Δ9-THC larger than those tested previously can be administered to individuals with a history of cannabis use, although given the pharmacokinetic variability of oral Δ9-THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response. PMID:23754596

Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans

PubMed Central

Maccecchini, Maria L; Chang, Mee Young; Pan, Catherine; John, Varghese; Zetterberg, Henrik

2012-01-01

Aim A first in human study to evaluate tolerability and pharmacokinetics followed by an early proof of mechanism (POM) study to determine whether the small orally, available molecule, Posiphen tartrate (Posiphen), lowers secreted (s) amyloid-β precursor protein (APP) α and -β, amyloid-β peptide (Aβ), tau (τ) and inflammatory markers in CSF of patients with mild cognitive impairment (MCI). Study design Posiphen single and multiple ascending dose phase 1 randomised, double blind, placebo-controlled safety, tolerance, pharmacokinetic studies were undertaken in a total of 120 healthy volunteers to define a dose that was then used in a small non-randomised study of five MCI subjects, used as their own controls, to define target engagement. Main outcome measures Pharmacodynamic: sAPPα, sAPPβ, Aβ42, τ (total (t) and phosphorylated (p)) and inflammatory marker levels were time-dependently measured over 12 h and compared prior to and following 10 days of oral Posiphen treatment in four MCI subjects who completed the study. Pharmacokinetic: plasma and CSF drug and primary metabolite concentrations with estimated brain levels extrapolated from steady-state drug administration in rats. Results Posiphen proved well tolerated and significantly lowered CSF levels of sAPPα, sAPPβ, t-τ, p-τ and specific inflammatory markers, and demonstrated a trend to lower CSF Aβ42. Conclusions These results confirm preclinical POM studies, demonstrate that pharmacologically relevant drug/metabolite levels reach brain and support the continued clinical optimisation and evaluation of Posiphen for MCI and Alzheimer's disease. PMID:22791904

Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared with 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial

PubMed Central

Hanauer, Stephen B; Sandborn, William J; Dallaire, Christian; Archambault, André; Yacyshyn, Bruce; Yeh, Chyon; Smith-Hall, Nancy

2007-01-01

BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease. PATIENTS AND METHODS: A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline. RESULTS: Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated. CONCLUSIONS: Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day. PMID:18080055

A rabbit model of cerebral microembolic signals for translational research: preclinical validation for aspirin and clopidogrel.

PubMed

Zhou, X; Kurowski, S; Wu, W; Desai, K; Chu, L; Gutstein, D E; Seiffert, D; Wang, X

2016-09-01

Essentials Microembolic signal (MES) is an independent predictor of stroke risk in patients. A rabbit model of cerebral microembolic signals was established. Therapeutic efficacy was demonstrated for aspirin and clopidogrel on microembolic signals. Potential translational value of this preclinical model of MES was demonstrated. Objectives Cerebral microembolic signals (MESs) detected by transcranial Doppler (TCD) ultrasound constitute an independent predictor of stroke risk and prognosis. The aim of this study was to develop a novel preclinical model of MESs to facilitate translational research. Methods A clinical TCD ultrasound machine was used to detect MESs in the cerebral circulation of New Zealand White rabbits. Technical feasibility was assessed for the measurement of MESs in the middle cerebral artery (MCA) by TCD. FeCl3 -induced carotid arterial thrombosis was optimized for the generation of endogenous microemboli. Ascending doses of two antithrombotic agents (aspirin and clopidogrel) were evaluated individually and in combination for their effects on both arterial thrombosis and MESs in a 30% FeCl3 -induced carotid arterial thrombosis model, along with ex vivo functional assays. Results Dose-dependent FeCl3 -induced arterial thrombosis studies showed that 30% FeCl3 resulted in the most consistent and reproducible MESs in the MCA (3.3 ± 0.7 MESs h(-1) ). Ascending-dose studies showed that the effective doses for 50% inhibition (ED50 ) of thrombus formation, based on integrated blood flow and thrombus weight, respectively, were 3.1 mg kg(-1) and 4.2 mg kg(-1) orally for aspirin, and 0.3 mg kg(-1) and 0.28 mg kg(-1) orally for clopidogrel. The ED50 values for MES incidence were 12.7 mg kg(-1) orally for aspirin, and 0.25 mg kg(-1) orally for clopidogrel. Dual treatment with aspirin (5 mg kg(-1) ) and clopidogel (0.3 mg kg(-1) ) resulted in significant reductions in cerebral MESs (P < 0.05) as compared with monotherapy with either agent. Conclusions Our study demonstrated the successful establishment of the MES model in rabbits, and it may provide translational value for MESs and ischemic stroke research. © 2016 International Society on Thrombosis and Haemostasis.

Vertically operating flight vehicle for drilling and agricultural use

NASA Technical Reports Server (NTRS)

Pabst, W.

1986-01-01

The invention deals with an aircraft which ascends and descends vertically and which is used for recreational aircraft, as well as for drilling and in agriculture. The invention combines the floating effect of a parachute with the helicopter to develop a flight vehicle with multiple uses which go beyond those of contemporary flight vehicles. Both hub mechanisms and thrust power are implemented to achieve this goal. Four designs are described in detail.

Comparison of metabolic cost and cardiovascular response to stair ascending and descending with walkers and canes in older adults.

PubMed

Foley, Michael; Bowen, Brett

2014-09-01

To compare oxygen cost (mL·kg(-1)·m(-1)) and cardiovascular response (beats/m) and oxygen consumption (mL·kg(-1)·min(-1)) and heart rate (beats/min) to stair ascending and descending with walkers, with canes, and without assistive devices (ADs) in older adults. Descriptive, repeated measures. Indoor stairway. Convenience sample of able-bodied volunteers, non-AD users (N=14; mean age, 63.71 ± 11.7 y; mean body mass, 72.7 ± 14.1 kg; mean height, 165.7 ± 9.2 cm). Participants performed 4 randomized trials of stair ascending and descending at their own self-selected speed with 3 ADs: single-point cane, standard walker (SW), and wheeled walker (WW). They also performed unassisted stair ascending and descending. Each trial consisted of a 5-minute steady-state session followed by a 2-minute data collection period. Steady-state expired ventilations were collected in Douglas bags for metabolic analysis. Oxygen cost (mL·kg(-1)·m(-1)), heart rate (HR) response (beats/m), oxygen consumption (mL·kg(-1)·min(-1)), and HR (beats/min) were compared for each trial of stair ascending and descending using analysis of variance repeated measures (P<.05). Greater oxygen cost (per meter) was found for stair ascending and descending using the single-point cane (121%), SW (217%), and WW (232%) compared with unassisted stair ascending and descending (P<.05). Increased HR response (per meter) was found for stair ascending and descending using the single-point cane (116%), SW (126%), and WW (147%) compared with unassisted stair ascending and descending (P<.05). However, oxygen consumption (per minute) and HR (per minute) were not significantly increased during stair ascending and descending with the ADs compared with unassisted stair ascending and descending. Participants stair ascended and descended at significantly (P<.05) reduced speeds during trials with the ADs. This research should aid clinicians by providing evidence to base recommendations on regarding AD usage when encountering stairs during home and community ambulation. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

[Clinical trial on treatment of Parkinson's disease of Gan-Shen yin deficiency type by recipe for nourishing Gan-Shen].

PubMed

Zhao, Hong; Li, Wen-Wei; Gao, Jun-Peng

2007-09-01

To observe the curative effect of the recipe for nourishing Gan-Shen on Parkinson's disease (PD) of Gan-Shen yin deficiency type. One hundred and twenty-one PD patients were ran-domly assigned by blocking design to the control group and the treated group in the ratio of 1:1. All were treated according to the international medication guiding principle for PD treatment, but the treated group was ad-ministered with the recipe for nourishing Gan-Shen additionally. The treatment course lasted for 12 consecutive months, and the end point was the end of the 12th month. The unified Parkinson's disease rating scale (UP-DRS) score, TCM primary and secondary symptom scores were evaluated before treatment, every 3 months of treatment and at the end point. The average daily levodopa dose and the Hoehn & Yahr grading were assessed before treatment and at the end point. After treatment, UPDRS score in both groups showed an ascending trend at a slower rate in the treated groups than in the control group. At the 9th and 12th month of medication, a significant difference was found in UPDRS score between the two groups (P < 0.05), and the TCM symptom score was obviously lower in the treated group than in the control group (P < 0.05). At the end point of the trial, the average daily levodopa dose used was lower in the treated group than in the control group (P < 0.05) and there was no significant difference in the Hoehn & Yahr score between the two groups (P > 0.05). The recipe for norishing Gan-Shen can slow the ascending trend of UPDRS score in the PD patients, improve the symptoms of Gan-Shen yin deficiency, and decrease the daily levodopa dose used, showing a curative effect on PD of Gan-Shen yin deficiency type.

On the pharmacology of ascending, descending and recurrent postsynatic inhibition of the cuneothalamic relay cells in the cat

PubMed Central

Kelly, J. S.; Renaud, L. P.

1973-01-01

1. In cats decerebrated or anaesthetized with pentobarbitone, cells of the middle third of the cuneate nucleus that were excited by tactile stimulation of the ipsilateral forelimb (responding to displacement of hairs, skin or joints) and inhibited by electrical stimulation of the contralateral pyramid, were invariably inhibited by electrical stimulation of the ipsilateral forepaw and the contralateral forelimb nerves. 2. In 50% of the cats, the cells were more fully identified by placing electrodes stereotaxically in the contralateral medial lemniscus. Recurrent inhibition was always a concomitant of the antidromic action potential. 3. The intensity and the duration of inhibition evoked by all of these pathways was totally resistant to iontophoretic and intravenous strychnine in doses at least 5 times that required to block completely the response of the same cells to iontophoretic glycine and was extremely sensitive to either iontophoretic bicuculline or picrotoxin. 4. Although the inhibition was invariably sensitive to intravenous picrotoxin, no significant change occurred in the duration or intensity of the inhibition when bicuculline was administered intravenously (5 or 6 times) as repeated doses of 0·2 mg/kg. 5. Postsynaptic inhibition in the cuneate may be mediated by γ-aminobutyric acid released from the nerve terminals of a common pool of interneurones shared by ascending, descending and recurrent pathways. Since the receptors involved in this pathway are resistant to intravenous bicuculline, they may well be distinct from those responsible for changes in the primary afferent terminal excitability, usually believed to be associated with presynaptic inhibition. PMID:4357959

In vitro dose measurements in a human cadaver with abdomen/pelvis CT scans.

PubMed

Zhang, Da; Padole, Atul; Li, Xinhua; Singh, Sarabjeet; Khawaja, Ranish Deedar Ali; Lira, Diego; Liu, Tianyu; Shi, Jim Q; Otrakji, Alexi; Kalra, Mannudeep K; Xu, X George; Liu, Bob

2014-09-01

To present a study of radiation dose measurements with a human cadaver scanned on a clinical CT scanner. Multiple point dose measurements were obtained with high-accuracy Thimble ionization chambers placed inside the stomach, liver, paravertebral gutter, ascending colon, left kidney, and urinary bladder of a human cadaver (183 cm in height and 67.5 kg in weight) whose abdomen/pelvis region was scanned repeatedly with a multidetector row CT. The flat energy response and precision of the dosimeters were verified, and the slight differences in each dosimeter's response were evaluated and corrected to attain high accuracy. In addition, skin doses were measured for radiosensitive organs outside the scanned region with OSL dosimeters: the right eye, thyroid, both nipples, and the right testicle. Three scan protocols were used, which shared most scan parameters but had different kVp and mA settings: 120-kVp automA, 120-kVp 300 mA, and 100-kVp 300 mA. For each protocol three repeated scans were performed. The tube starting angle (TSA) was found to randomly vary around two major conditions, which caused large fluctuations in the repeated point dose measurements: for the 120-kVp 300 mA protocol this angle changed from approximately 110° to 290°, and caused 8%-25% difference in the point dose measured at the stomach, liver, colon, and urinary bladder. When the fluctuations of the TSA were small (within 5°), the maximum coefficient of variance was approximately 3.3%. The soft tissue absorbed doses averaged from four locations near the center of the scanned region were 27.2±3.3 and 16.5±2.7 mGy for the 120 and 100-kVp fixed-mA scans, respectively. These values were consistent with the corresponding size specific dose estimates within 4%. The comparison of the per-100-mAs tissue doses from the three protocols revealed that: (1) dose levels at nonsuperficial locations in the TCM scans could not be accurately deduced by simply scaling the fix-mA doses with local mA values; (2) the general power law relationship between dose and kVp varied from location to location, with the power index ranged between 2.7 and 3.5. The averaged dose measurements at both nipples, which were about 0.6 cm outside the prescribed scan region, ranged from 23 to 27 mGy at the left nipple, and varied from 3 to 20 mGy at the right nipple over the three scan protocols. Large fluctuations over repeated scans were also observed, as a combined result of helical scans of large pitch (1.375) and small active areas of the skin dosimeters. In addition, the averaged skin dose fell off drastically with the distance to the nearest boundary of the scanned region. This study revealed the complexity of CT dose fluctuation and variation with a human cadaver.

Aortic Cross-Sectional Area/Height Ratio and Outcomes in Patients With Bicuspid Aortic Valve and a Dilated Ascending Aorta.

PubMed

Masri, Ahmad; Kalahasti, Vidyasagar; Svensson, Lars G; Alashi, Alaa; Schoenhagen, Paul; Roselli, Eric E; Johnston, Douglas R; Rodriguez, L Leonardo; Griffin, Brian P; Desai, Milind Y

2017-06-01

In patients with bicuspid aortic valve and dilated proximal ascending aorta, we sought to assess (1) factors associated with increased longer-term cardiovascular mortality and (2) incremental prognostic use of indexing aortic root to patient height. We studied 969 consecutive bicuspid aortic valve patients (50±13 years; 87% men) with proximal aorta ≥4 cm, who also had a gated contrast-enhanced thoracic computed tomography or magnetic resonance angiography. A ratio of ascending aortic area/height was calculated on tomography, and ≥10 cm 2 /m was considered abnormal, as previously reported. Society of Thoracic Surgeons score and cardiovascular death were recorded. Greater than or equal to III+ aortic regurgitation and severe aortic stenosis were seen in 37% and 10%, respectively. Society of Thoracic Surgeons score and right ventricular systolic pressure were 2±3 and 15±16 mm Hg, respectively. Abnormal ascending aortic area/height ratio was noted in 33%; 44% underwent ascending aortic surgery at 34 days. At 10.8 years (interquartile range, 9.6-12.3), 82 (9%) died (0.4% in-hospital postoperative mortality). On multivariable Cox survival analysis, ascending aortic area/height ratio (hazard ratio, 2; 95% confidence interval, 1.20-3.35) was associated with cardiovascular death, whereas aortic surgery (hazard ratio, 0.46; confidence interval, 0.26-0.80) was associated with improved survival (both P <0.01). Of the 405 patients with ascending aortic diameter of 4.5 to 5.5 cm, 64% had an abnormal ascending aortic area/height ratio, and 70% deaths occurred in patients with an abnormal ratio. In bicuspid aortic valve patients with dilated proximal ascending aorta, ascending aortic area/height ratio was independently associated with cardiovascular death. © 2017 American Heart Association, Inc.

Perinatal Group B Streptococcal Infections: Virulence Factors, Immunity, and Prevention Strategies.

PubMed

Vornhagen, Jay; Adams Waldorf, Kristina M; Rajagopal, Lakshmi

2017-11-01

Group B streptococcus (GBS) or Streptococcus agalactiae is a β-hemolytic, Gram-positive bacterium that is a leading cause of neonatal infections. GBS commonly colonizes the lower gastrointestinal and genital tracts and, during pregnancy, neonates are at risk of infection. Although intrapartum antibiotic prophylaxis during labor and delivery has decreased the incidence of early-onset neonatal infection, these measures do not prevent ascending infection that can occur earlier in pregnancy leading to preterm births, stillbirths, or late-onset neonatal infections. Prevention of GBS infection in pregnancy is complex and is likely influenced by multiple factors, including pathogenicity, host factors, vaginal microbiome, false-negative screening, and/or changes in antibiotic resistance. A deeper understanding of the mechanisms of GBS infections during pregnancy will facilitate the development of novel therapeutics and vaccines. Here, we summarize and discuss important advancements in our understanding of GBS vaginal colonization, ascending infection, and preterm birth. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans

PubMed Central

Carter, Lawrence P.; Reissig, Chad J.; Johnson, Matthew W.; Klinedinst, Margaret A.; Griffiths, Roland R.

2012-01-01

BACKGROUND Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. METHODS Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg /70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 hours. RESULTS Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM. CONCLUSION The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse. PMID:22989498

[Application of a tape-like bandage for the ascending aorta in its poststenotic dilation and correction of the aortal valve stenosis].

PubMed

Popov, V V; Bol'shak, A A

2014-06-01

The aortal valve prosthesis in combination with a tape-like bandage of ascending aorta application was performed in 106 patients, suffering a failure with predominance of the aortal valve stenosis in conjunction with the ascending aorta poststenotic dilation, in a 2005 - 2014 yrs period in the clinic. The hospital lethality have constituted 0.9%. In accordance to echocardiography, the ascending aorta diameter preoperatively have constituted (48.7 +/- 1.4) mm at average, before discharge from the hospital--(40.1 +/- 1.2) mm, in late follow-up period--(41.3 +/- 1.2) mm. It is expedient to recommend the original method of a tape-like bandage of ascending aorta from the base of noncoronary sinus in the aortal sinuses dilation (45 mm and more) in combination with the aortal valve prosthesis in poststenotic dilation of ascending aorta.

Nephrectomy in patients with Caroli’s and ADPKD may be associated with increased morbidity

PubMed Central

Aguilar, Martin; Meterissian, Sarkis; Levesque, Sebastien; Andonian, Sero

2011-01-01

Autosomal dominant polycystic kidney disease (ADPKD), characterized by multiple bilateral renal cysts, is the most common inherited disorder of the kidney and an important cause of end-stage renal disease (ESRD). Caroli’s disease is a much less frequent condition with ectasia of the intrahepatic biliary system. A clear association between autosomal recessive and Caroli’s disease has been described, but only 4 cases of ADPKD and Caroli’s disease have been reported with 2 postoperative mortalities. The aim of this case is to increase the awareness of intra-operative and postoperative complications. A 66 year-old male was diagnosed with ADPKD and Caroli’s disease with hepatosplenomegaly and 4 episodes of ascending cholangitis. After 3 years of hemodialysis for ESRD, he received a cadaveric renal allograft. Subsequently, he developed paroxysmal atrial fibrillation. Upon anticoagulation, he developed multiple episodes of gross hematuria from the left native kidney. After the anticoagulation therapy was discontinued, he underwent bilateral nephrectomies of his native kidneys. Intra-operatively, a splenic laceration could not be managed conservatively. Therefore, splenectomy was performed. In addition, he developed ascending cholangitis post-operatively that was treated with antibiotics. He was discharged on postoperative day 18. Genetic testing revealed that the patient is heterozygote for a large deletion in PKD1 gene, which encompasses all tested exons (exons 1–44). PMID:21470545

A Case of Taenia asiatica Infection Diagnosed by Colonoscopy.

PubMed

Kim, Heung Up; Chung, Young-Bae

2017-02-01

A case of Taenia asiatica infection detected by small bowel series and colonoscopy is described. The patient was a 42-year-old Korean man accompanied by discharge of movable proglottids via anus. He used to eat raw pig liver but seldom ate beef. Small bowel series radiologic examinations showed flat tape-like filling defects on the ileum. By colonoscopy, a moving flat tapeworm was observed from the terminal ileum to the ascending colon. The tapeworm was identified as T. asiatica by mitochondrial DNA sequencing. The patient was prescribed with a single oral dose (16 mg/kg) of praziquantel.

A Case of Taenia asiatica Infection Diagnosed by Colonoscopy

PubMed Central

Kim, Heung Up; Chung, Young-Bae

2017-01-01

A case of Taenia asiatica infection detected by small bowel series and colonoscopy is described. The patient was a 42-year-old Korean man accompanied by discharge of movable proglottids via anus. He used to eat raw pig liver but seldom ate beef. Small bowel series radiologic examinations showed flat tape-like filling defects on the ileum. By colonoscopy, a moving flat tapeworm was observed from the terminal ileum to the ascending colon. The tapeworm was identified as T. asiatica by mitochondrial DNA sequencing. The patient was prescribed with a single oral dose (16 mg/kg) of praziquantel. PMID:28285508

Evaluation and Influence of Brachiocephalic Branch Re-entry in Patients With Type A Acute Aortic Dissection.

PubMed

Yasuda, Shota; Imoto, Kiyotaka; Uchida, Keiji; Karube, Norihisa; Minami, Tomoyuki; Goda, Motohiko; Suzuki, Shinichi; Masuda, Munetaka

2016-12-22

Stanford type A acute aortic dissection (A-AAD) extends to the brachiocephalic branches in some patients. After ascending aortic replacement, a remaining re-entry tear in the distal brachiocephalic branches may act as an entry and result in a patent false lumen in the aortic arch. However, the effect of brachiocephalic branch re-entry concomitant with A-AAD remains unknown.Methods and Results:Eighty-five patients with A-AAD who underwent ascending aortic replacement in which both preoperative and postoperative multiple-detector computed tomography (MDCT) scans could be evaluated were retrospectively studied. The presence of a patent false lumen in at least one of the brachiocephalic branches on preoperative MDCT was defined as brachiocephalic branch re-entry, and 41 patients (48%) had this. Postoperatively, 47 of 85 (55%) patients had a patent false lumen in the aortic arch. False lumen remained patent after operation in 34 out of the 41 (83%) patients with brachiocephalic branch re-entry, as compared to that in 13 of the 44 (30%) patients without such re-entry (P<0.001). Brachiocephalic branch re-entry was a significant risk factor for a late increase in the aortic arch diameter greater than 10 mm (P=0.047). Brachiocephalic branch re-entry in patients with A-AAD is related to a patent false lumen in the aortic arch early after ascending aortic replacement and is a risk factor for late aortic arch enlargement.

Carbachol-induced volume adaptation in mouse bladder and length adaptation via rhythmic contraction in rabbit detrusor.

PubMed

Speich, John E; Wilson, Cameron W; Almasri, Atheer M; Southern, Jordan B; Klausner, Adam P; Ratz, Paul H

2012-10-01

The length-tension (L-T) relationships in rabbit detrusor smooth muscle (DSM) are similar to those in vascular and airway smooth muscles and exhibit short-term length adaptation characterized by L-T curves that shift along the length axis as a function of activation and strain history. In contrast to skeletal muscle, the length-active tension (L-T(a)) curve for rabbit DSM strips does not have a unique peak tension value with a single ascending and descending limb. Instead, DSM can exhibit multiple ascending and descending limbs, and repeated KCl-induced contractions at a particular muscle length on an ascending or descending limb display increasingly greater tension. In the present study, mouse bladder strips with and without urothelium exhibited KCl-induced and carbachol-induced length adaptation, and the pressure-volume relationship in mouse whole bladder displayed short-term volume adaptation. Finally, prostaglandin-E(2)-induced low-level rhythmic contraction produced length adaptation in rabbit DSM strips. A likely role of length adaptation during bladder filling is to prepare DSM cells to contract efficiently over a broad range of volumes. Mammalian bladders exhibit spontaneous rhythmic contraction (SRC) during the filling phase and SRC is elevated in humans with overactive bladder (OAB). The present data identify a potential physiological role for SRC in bladder adaptation and motivate the investigation of a potential link between short-term volume adaptation and OAB with impaired contractility.

COMBINED REPLACEMENT OF THE AORTIC VALVE AND ASCENDING AORTA IN JEHOVAH'S WITNESSES: REPORT OF TWO CASES

PubMed Central

Beddermann, Christoph; Norman, John C.; Cooley, Denton A.

1979-01-01

Two Jehovah's Witnesses with large ascending thoracic aortic aneurysms and aortic insufficiency secondary to annuloaortic ectasia underwent successful combined replacement of the aortic valve and the ascending aorta. One patient received a composite graft containing an aortic valve prosthesis, which necessitated supravalvular coronary ostia reimplantation; the other patient underwent separate aortic valve and left supracoronary ascending aneurysm replacement, with reimplantation of the right coronary ostium into the graft. No blood or blood derivatives were administered. Both patients had uneventful recoveries and continue to do well. To our knowledge, they represent the first reported cases of successful combined replacement of the aortic valve and ascending aorta in Jehovah's Witnesses. Images PMID:15216324

Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation.

PubMed

Yates, Justin R; Breitenstein, Kerry A; Gunkel, Benjamin T; Hughes, Mallory N; Johnson, Anthony B; Rogers, Katherine K; Shape, Sara M

Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making. Copyright © 2016 Elsevier Inc. All rights reserved.

Expression of three isoforms of Na-K-2Cl cotransporter (NKCC2) in the kidney and regulation by dehydration.

PubMed

Itoh, Kazuko; Izumi, Yuichiro; Inoue, Takeaki; Inoue, Hideki; Nakayama, Yushi; Uematsu, Takayuki; Fukuyama, Takashi; Yamazaki, Taiga; Yasuoka, Yukiko; Makino, Takeshi; Nagaba, Yasushi; Tomita, Kimio; Kobayashi, Noritada; Kawahara, Katsumasa; Mukoyama, Masashi; Nonoguchi, Hiroshi

2014-10-24

Sodium reabsorption via Na-K-2Cl cotransporter 2 (NKCC2) in the thick ascending limbs has a major role for medullary osmotic gradient and subsequent water reabsorption in the collecting ducts. We investigated intrarenal localization of three isoforms of NKCC2 mRNA expressions and the effects of dehydration on them in rats. To further examine the mechanisms of dehydration, the effects of hyperosmolality on NKCC2 mRNA expression in microdissected renal tubules was studied. RT-PCR and RT-competitive PCR were employed. The expressions of NKCC2a and b mRNA were observed in the cortical thick ascending limbs (CAL) and the distal convoluted tubules (DCT) but not in the medullary thick ascending limbs (MAL), whereas NKCC2f mRNA expression was seen in MAL and CAL. Two-day dehydration did not affect these mRNA expressions. In contrast, hyperosmolality increased NKCC2 mRNA expression in MAL in vitro. Bradykinin dose-dependently decreased NKCC2 mRNA expression in MAL. However, dehydration did not change NKCC2 protein expression in membrane fraction from cortex and outer medulla and in microdissected MAL. These data show that NKCC2a/b and f types are mainly present in CAL and MAL, respectively. Although NKCC2 mRNA expression was stimulated by hyperosmolality in vitro, NKCC2 mRNA and protein expressions were not stimulated by dehydration in vivo. These data suggest the presence of the inhibitory factors for NKCC2 expression in dehydration. Considering the role of NKCC2 for the countercurrent multiplier system, NKCC2f expressed in MAL might be more important than NKCC2a/b. Copyright © 2014 Elsevier Inc. All rights reserved.

Cisapride stimulates contraction of idiopathic megacolonic smooth muscle in cats.

PubMed

Hasler, A H; Washabau, R J

1997-01-01

We have previously shown that cisapride, a substituted piperidinyl benzamide, stimulates contraction of healthy feline colonic smooth muscle. The purpose of the present investigation was to determine the effect of cisapride on feline idiopathic megacolonic smooth muscle function. Longitudinal smooth muscle strips from ascending and descending colon were obtained from cats with idiopathic megacolon, suspended in a 1.5 mM Ca(2+)-HEPES buffer solution (37 degrees C, 100% O2, pH 7.4), attached to isometric force transducers, and stretched to optimal muscle length (Lo). Control responses were obtained at each muscle site with acetylcholine (10(-8) to 10(-4) M), substance P (10(-11) to 10(-7) M), or potassium chloride (10 to 80 mM). Muscles were then stimulated with cumulative (10(-9) to 10(-6) M) doses of cisapride in the absence or presence of tetrodotoxin (10(-6) M) and atropine (10(-6) M), or in a 0 calcium HEPES buffer solution. In cats with idiopathic megacolon, cisapride stimulated contractions of longitudinal smooth muscle from both the ascending and the descending colon. Cisapride-induced contractions were similar in magnitude to those induced by substance P and acetylcholine in the ascending colon, but were less than those observed in the descending colon. Cisapride-induced contractions in megacolonic smooth muscle were only partially inhibited by tetrodotoxin and atropine, but were virtually abolished by removal of extracellular calcium. We concluded that cisapride-induced contractions of feline megacolonic smooth muscle are largely smooth muscle mediated and dependent on influx of extracellular calcium. Cisapride-induced contractions in megacolonic smooth muscle are only partially dependent on enteric cholinergic nerves. Thus, cisapride may be useful in the treatment of cats with idiopathic megacolon.

Spinal cord neuron classes in embryos of the smooth newt Triturus vulgaris: a horseradish peroxidase and immunocytochemical study.

PubMed

Harper, C E; Roberts, A

1993-04-29

Spinal cord neurons were investigated in embryos of Triturus vulgaris, the smooth newt, just prior to hatching. These embryos can swim if freed from their egg membranes. Horseradish peroxidase (HRP) labelling, together with GABA and glycine immunocytochemistry (ICC), revealed nine distinct anatomical classes of neuron. 1. Ventrolateral motoneurons with mainly dorsal dendrites, sometimes a descending central axon and peripheral axon innervating the trunk muscles. 2. Dorsal primary sensory Rohon-Beard neurons innervating skin and with dorsal ascending and descending axons in spinal cord. 3. Commissural interneurons with mid-cord unipolar soma, glycine-like immunoreactivity, dendrites on initial segment of ventral axon which crosses cord to ascend or branch. 4. Dorsolateral commissural interneurons with multipolar soma in dorsolateral position with dorsal dendrites and ventral axon which crosses and ascends or branches. 5. Giant dorsolateral commissural interneurons with large dorsolateral somata widely spaced (130-250 microns spacing) with process projecting dorsally to other side, dorsolateral dendrites and ventral axon which crosses to ascend and branch. 6. Dorsolateral ascending interneurons in dorsolateral position with multipolar soma and ascending axon on same side. 7. Ascending interneurons with unipolar soma, GABA-like immunoreactivity and ascending axon on same side. 8. Descending interneurons with bi- or multi-polar soma, extensive dorsal and ventral dendrites, and descending axon on same side. They may also have ascending axons. 9. Kolmer-Agduhr cerebrospinal fluid contacting neurons with cilia and microvilli in lateral corners of neural canal. GABA-like immunoreactivity, no dendrites and ascending axon. Eight of the nine cells classes were found to bear a marked resemblance to neurons previously described in zebrafish and Xenopus embryos in terms of their anatomy, distribution and immunoreactivity to GABA and glycine. Homologies and possible functions are discussed. Giant dorsolateral commissural neurons, were not found in Xenopus or teleosts but were present in Ambystoma mexicanum and Neoceratodus. The regular, possibly segmental longitudinal distribution pattern of these cells within the cord is unusual among amphibian spinal neurons.

Dilatation of the initially non-aneurysmal ascending aorta after replacement of a bicuspid versus tricuspid aortic valve.

PubMed

Zhang, Jing; Fan, Guangpu; Zhao, Hui; Wang, Xu; Wang, Zhiwei; Zhang, Peide; Wang, Wei

2016-12-01

Objective To compare the aortic diameter after isolated aortic valve replacement (AVR) in patients with a bicuspid (BAV) or tricuspid aortic valve (TAV) and an initially normal ascending aorta. Methods Patients with an ascending aortic diameter of < 45 mm who had undergone isolated AVR were studied. Ultrasonic cardiographic measurements of the ascending aortic diameter made pre- and postoperatively and follow-up data concerning adverse aortic events and death were analyzed. Results A total of 613 patients were included in this retrospective study; of these, 211 had a BAV and 402 had a TAV. In both groups, the ascending aorta significantly expanded but was non-aneurysmal during follow-up; however, the difference between the two groups was not significant. Cox regression analysis showed no significant effect associated with the presence of a BAV on adverse aortic events or death. Conclusion Dilatation of the ascending aorta was observed after AVR in both groups, but was not more pronounced in patients with a BAV. Long-term follow-up for ascending aortic aneurysm is necessary after AVR in both patients with a BAV and those with a TAV.

Dilatation of the initially non-aneurysmal ascending aorta after replacement of a bicuspid versus tricuspid aortic valve

PubMed Central

Zhang, Jing; Fan, Guangpu; Zhao, Hui; Wang, Xu; Wang, Zhiwei; Zhang, Peide

2016-01-01

Objective To compare the aortic diameter after isolated aortic valve replacement (AVR) in patients with a bicuspid (BAV) or tricuspid aortic valve (TAV) and an initially normal ascending aorta. Methods Patients with an ascending aortic diameter of < 45 mm who had undergone isolated AVR were studied. Ultrasonic cardiographic measurements of the ascending aortic diameter made pre- and postoperatively and follow-up data concerning adverse aortic events and death were analyzed. Results A total of 613 patients were included in this retrospective study; of these, 211 had a BAV and 402 had a TAV. In both groups, the ascending aorta significantly expanded but was non-aneurysmal during follow-up; however, the difference between the two groups was not significant. Cox regression analysis showed no significant effect associated with the presence of a BAV on adverse aortic events or death. Conclusion Dilatation of the ascending aorta was observed after AVR in both groups, but was not more pronounced in patients with a BAV. Long-term follow-up for ascending aortic aneurysm is necessary after AVR in both patients with a BAV and those with a TAV. PMID:27484890

Defining unnecessary disinfection procedures for single-dose and multiple-dose vials.

PubMed

Buckley, T; Dudley, S M; Donowitz, L G

1994-11-01

Recommendations in the literature conflict on the necessity of disinfecting single-use vials prior to aspiration of fluid. Interventions to disinfect the stopper surface on multiple-dose vials vary considerably. To determine the necessity of alcohol disinfection of the stopper on single-dose vials and to compare povidone-iodine and alcohol versus alcohol-only disinfection of the stopper prior to each needle penetration on multiple-dose vials. The rubber stopper surfaces of 100 single-dose vials were cultured for the presence of bacteria. To determine the efficacy of two procedures for disinfection of multiple-dose vials, 87 stopper surfaces routinely disinfected with both povidone-iodine and alcohol were cultured for bacteria. After a change in practice, 100 multiple-dose vials routinely disinfected with alcohol only were cultured for the presence of bacteria. Of the cultures done on single-dose vial stoppers, 99% were sterile. A comparison of the two disinfection techniques for multiple-dose vials revealed that 83 (95%) of the 87 vials prepped with both povidone-iodine and alcohol were sterile, compared with all stoppers disinfected with alcohol only. This study shows the lack of necessity of any disinfection procedure on the rubber stopper of single-dose vials and the efficacy of alcohol only for disinfecting the stopper of multiple-dose vials.

Study of the Blood Supply Fraction of the Ascending Aorta and Its Effect in Diagnosing Early Ascending Aortic Atherosclerosis.

PubMed

Wang, Kun; Cao, Tiesheng; Zhao, Lianbi; Yang, Yong; Feng, Yang; Duan, Yunyou; Yuan, Lijun; Xing, Changyang; Ren, Huari

2016-03-01

To investigate the capacity of blood storage of certain large arteries during diastole, we first studied the ascending aorta by echocardiography. The concept of the blood supply fraction of the ascending aorta was then introduced to evaluate elastic retraction of the ascending aortic wall and determine its role in diagnosing early atherosclerosis of the ascending aorta. First, we enrolled 120 healthy volunteers and divided them into 3 groups according to age: 20 to 35 years (B1 group), 36 to 50 years (B2 group), and 51 to 65 years (B3 group); there were 40 volunteers in each group. We used echocardiography to measure the blood supply fraction in each volunteer and compared the results for each group. Then we enrolled 40 patients (51-65 years) with early atherosclerosis of the ascending aorta, measured the blood supply fraction of each, and compared the results with the B3 group. The mean blood supply fractions ± SD in the B1, B2, and B3 groups were 21.75% ± 1.53%, 20.76% ± 1.62%, and 18.44% ± 1.19%, respectively. The fraction in the B3 group was significantly lower than those in the B1 and B2 groups (P < .01). The fraction in the patients with early atherosclerosis was 14.92% ± 1.01%, which was obviously lower than that in the B3 group (P < .01). The blood supply fraction of the ascending aorta decreases with age, and it could be used as a parameter for diagnosis of early atherosclerosis of the ascending aorta. © 2016 by the American Institute of Ultrasound in Medicine.

Resveratrol increases nitric oxide production in the rat thick ascending limb via Ca2+/calmodulin.

PubMed

Gonzalez-Vicente, Agustin; Cabral, Pablo D; Garvin, Jeffrey L

2014-01-01

The thick ascending limb of the loop of Henle reabsorbs 30% of the NaCl filtered through the glomerulus. Nitric oxide (NO) produced by NO synthase 3 (NOS3) inhibits NaCl absorption by this segment. Resveratrol, a polyphenol, has beneficial cardiovascular and renal effects, many of which are mediated by NO. Resveratrol increases intracellular Ca2+ (Cai) and AMP kinase (AMPK) and NAD-dependent deacetylase sirtuin1 (SIRT1) activities, all of which could activate NO production. We hypothesized that resveratrol stimulates NO production by thick ascending limbs via a Ca2+/calmodulin-dependent mechanism. To test this, the effect of resveratrol on NO bioavailability was measured in thick ascending limb suspensions. Cai was measured in single perfused thick ascending limbs. SIRT1 activity and expression were measured in thick ascending limb lysates. Resveratrol (100 µM) increased NO bioavailability in thick ascending limb suspensions by 1.3±0.2 AFU/mg/min (p<0.03). The NOS inhibitor L-NAME blunted resveratrol-stimulated NO bioavailability by 96±11% (p<0.03). The superoxide scavenger tempol had no effect. Resveratrol elevated Cai from 48±7 to 135±24 nM (p<0.01) in single tubules. In Ca2+-free media, the resveratrol-induced increase in NO was blunted by 60±20% (p<0.05) and the rise in Cai reduced by 80%. Calmodulin inhibition prevented the resveratrol-induced increase in NO (p<0.002). AMPK inhibition had no effect. Resveratrol did not increase SIRT1 activity. We conclude that resveratrol increases NO production in thick ascending limbs via a Ca2+/calmodulin dependent mechanism, and SIRT1 and AMPK do not participate. Resveratrol-stimulated NO production in thick ascending limbs may account for part of its beneficial effects.

Case report and review of the literature total endovascular repair of acute ascending aortic rupture: a case report and review of the literature.

PubMed

McCallum, John C; Limmer, Karl K; Perricone, Anthony; Bandyk, Dennis; Kansal, Nikhil

2013-07-01

Thoracic aortic endografting has been successfully implemented to treat aneurysmal disease of the distal aortic arch and descending thoracic aorta. Although there are reports of ascending aortic endovascular interventions, the total endovascular repair of a ruptured ascending aorta secondary to a Type A dissection has not been described. We report the case of a 77-year-old patient who presented with a ruptured ascending aortic aneurysm secondary to degeneration of a Stanford type A aortic dissection. His surgical history was significant for orthotropic heart transplant 19 years prior. The dissection, aneurysm, and rupture occurred in the native aorta distal to the ascending aortic suture line. At presentation, he was hemodynamically unstable with a right hemothorax. We placed 3 Medtronic Talent Thoracic Stent Graft devices (Medtronic Inc, Minneapolis, MN) across the suture line in the ascending aorta, excluding the rupture. The patient survived and has been followed to 25 months.

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

Pacaci, P; Cebe, M; Mabhouti, H

Purpose: In this study, dosimetric comparison of field in field (FIF) and intensity modulated radiation therapy (IMRT) techniques used for treatment of whole breast radiotherapy (WBRT) were made. The dosimetric accuracy of treatment planning system (TPS) for Anisotropic Analytical Algorithm (AAA) and Acuros XB (AXB) algorithms in predicting PTV and OAR doses was also investigated. Methods: Two different treatment planning techniques of left-sided breast cancer were generated for rando phantom. FIF and IMRT plans were compared for doses in PTV and OAR volumes including ipsilateral lung, heart, left ascending coronary artery, contralateral lung and the contralateral breast. PTV and OARsmore » doses and homogeneity and conformality indexes were compared between two techniques. The accuracy of TPS dose calculation algorithms was tested by comparing PTV and OAR doses measured by thermoluminescent dosimetry with the dose calculated by the TPS using AAA and AXB for both techniques. Results: IMRT plans had better conformality and homogeneity indexes than FIF technique and it spared OARs better than FIF. While both algorithms overestimated PTV doses they underestimated all OAR doses. For IMRT plan, PTV doses, overestimation up to 2.5 % was seen with AAA algorithm but it decreased to 1.8 % when AXB algorithm was used. Based on the results of the anthropomorphic measurements for OAR doses, underestimation greater than 7 % is possible by the AAA. The results from the AXB are much better than the AAA algorithm. However, underestimations of 4.8 % were found in some of the points even for AXB. For FIF plan, similar trend was seen for PTV and OARs doses in both algorithm. Conclusion: When using the Eclipse TPS for breast cancer, AXB the should be used instead of the AAA algorithm, bearing in mind that the AXB may still underestimate all OAR doses.« less

Treatment with high-dose antidepressants severely exacerbates the pathological outcome of experimental Escherichia coli infections in poultry.

PubMed

Kromann, Sofie; Kudirkiene, Egle; Li, Lili; Thoefner, Ida; Daldorph, Elisabeth; Christensen, Jens Peter; Meng, Hecheng; Olsen, Rikke Heidemann

2017-01-01

There is an urgent need for novel antibiotics as the current antibiotics are losing their value due to increased resistance among clinically important bacteria. Sertraline, an on-marked anti-depressive drug, has been shown to modify bacterial activity in vitro, including increasing the susceptibility of Escherichia coli to antibiotics. The aim of the present study was to investigate if the antimicrobial activity of sertraline could be documented under clinical settings, hereunder if sertraline could potentiate the effect of tetracycline in treatment of an experimentally induced ascending infection in poultry. A total of 40 chickens were divided in four groups of 10 chickens each. All chickens were challenged with 4x103 colony forming units (CFU) of a tetracycline resistant E. coli strain using a surgical infection model, and subsequently treated with either high-dose sertraline, tetracycline, a combination hereof or received no treatment. Seven days post challenge all birds were submitted to necropsy and scored pathologically for lesions. The average lesion scores were significantly higher (P<0.05) in the groups that were treated with high-dose sertraline or high-dose sertraline combined with tetracycline. In conclusion high-dose treatments (four times the maximum therapeutic dose for treating human depression) with sertraline as an adjuvant for treatment of antibiotic resistant E. coli infections exacerbate the pathological outcome of infection in chickens.

Treatment with high-dose antidepressants severely exacerbates the pathological outcome of experimental Escherichia coli infections in poultry

PubMed Central

Kromann, Sofie; Kudirkiene, Egle; Li, Lili; Thoefner, Ida; Daldorph, Elisabeth; Christensen, Jens Peter; Meng, Hecheng

2017-01-01

There is an urgent need for novel antibiotics as the current antibiotics are losing their value due to increased resistance among clinically important bacteria. Sertraline, an on-marked anti-depressive drug, has been shown to modify bacterial activity in vitro, including increasing the susceptibility of Escherichia coli to antibiotics. The aim of the present study was to investigate if the antimicrobial activity of sertraline could be documented under clinical settings, hereunder if sertraline could potentiate the effect of tetracycline in treatment of an experimentally induced ascending infection in poultry. A total of 40 chickens were divided in four groups of 10 chickens each. All chickens were challenged with 4x103 colony forming units (CFU) of a tetracycline resistant E. coli strain using a surgical infection model, and subsequently treated with either high-dose sertraline, tetracycline, a combination hereof or received no treatment. Seven days post challenge all birds were submitted to necropsy and scored pathologically for lesions. The average lesion scores were significantly higher (P<0.05) in the groups that were treated with high-dose sertraline or high-dose sertraline combined with tetracycline. In conclusion high-dose treatments (four times the maximum therapeutic dose for treating human depression) with sertraline as an adjuvant for treatment of antibiotic resistant E. coli infections exacerbate the pathological outcome of infection in chickens. PMID:29020098

Surgical exclusion of postsurgical pseudoaneurysm of the ascending aorta

PubMed Central

Barik, Ramachandra; Patnaik, Amar Narayana; Kumar, Ravintula Venkata; Mohapatra, Rudra Prasad; Medep, Vikas; Nemani, Lalita

2014-01-01

Pseudoaneurysm of ascending aorta after cardiac surgery is rare in children. We report a case of successful surgical exclusion of ascending aortic pseudoaneurysm in a 15-year-old boy. The neck of the aneurysm was in close proximity to the right coronary artery (RCA). PMID:24987261

Concentration-Response Modeling of ECG Data From Early-Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk - Experience From the Development Program of Lemborexant.

PubMed

Murphy, Patricia J; Yasuda, Sanae; Nakai, Kenya; Yoshinaga, Takashi; Hall, Nancy; Zhou, Meijian; Aluri, Jagadeesh; Rege, Bhaskar; Moline, Margaret; Ferry, Jim; Darpo, Borje

2017-01-01

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration-response (CR) modeling applied to data from 2 multiple ascending-dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to "bridge" pharmacokinetic and safety data between Japanese and non-Japanese subjects (J-MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high-precision measurement technique and evaluated using a linear mixed-effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was -0.00002 milliseconds per ng/mL (90%CI, -0.01019 to 0.01014 milliseconds). The highest observed C max was 400 ng/mL, representing a margin 8-fold above exposures expected for the highest planned clinical dose. The model-predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, -3.49 to 5.78 milliseconds). In neither the J-MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early-phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies. © 2016, The American College of Clinical Pharmacology.

Ascending aortic aneurysm causing hoarse voice: a variant of Ortner's syndrome

PubMed Central

Eccles, Sinan Robert; Banks, John; Kumar, Pankaj

2012-01-01

A 68-year-old man with a persistent hoarse voice was found to have a left vocal cord paralysis. Clinical examination revealed signs consistent with aortic regurgitation. Subsequent investigation revealed an ascending aortic aneurysm. He underwent aortic root and ascending aorta replacement and his hoarseness improved. Ortner's syndrome refers to hoarseness due to recurrent laryngeal nerve palsy secondary to a cardiovascular abnormality. Recurrent laryngeal nerve palsy due to aneurysmal dilation of the ascending aorta is extremely rare, with aneurysms of the aortic arch being a more common cause. PMID:23060380

Biaxial tensile tests of the porcine ascending aorta.

PubMed

Deplano, Valérie; Boufi, Mourad; Boiron, Olivier; Guivier-Curien, Carine; Alimi, Yves; Bertrand, Eric

2016-07-05

One of the aims of this work is to develop an original custom built biaxial set-up to assess mechanical behavior of soft tissues. Stretch controlled biaxial tensile tests are performed and stereoscopic digital image correlation (SDIC) is implemented to measure the 3D components of the generated displacements. Using this experimental device, the main goal is to investigate the mechanical behavior of porcine ascending aorta in the more general context of human ascending aorta pathologies. The results highlight that (i) SDIC arrangement allows accurate assessment of displacements and so stress strain curves, (ii) porcine ascending aorta has a nearly linear and anisotropic mechanical behavior until 30% of strain, (iii) porcine ascending aorta is stiffer in the circumferential direction than in the longitudinal one, (iv) the material coefficient representing the interaction between the two loading directions is thickness dependent, (v) taking into account the variability of the samples the stress values are independent of the stretch rate in the range of values from 10(-3) to 10(-1)s(-1) and finally, (vi) unlike other segments of the aorta, 4-month-old pigs ascending aorta is definitely not a relevant model to investigate the mechanical behavior of the human ascending aorta. Copyright © 2016 Elsevier Ltd. All rights reserved.

In vitro dose measurements in a human cadaver with abdomen/pelvis CT scans

PubMed Central

Zhang, Da; Padole, Atul; Li, Xinhua; Singh, Sarabjeet; Khawaja, Ranish Deedar Ali; Lira, Diego; Liu, Tianyu; Shi, Jim Q.; Otrakji, Alexi; Kalra, Mannudeep K.; Xu, X. George; Liu, Bob

2014-01-01

Purpose: To present a study of radiation dose measurements with a human cadaver scanned on a clinical CT scanner. Methods: Multiple point dose measurements were obtained with high-accuracy Thimble ionization chambers placed inside the stomach, liver, paravertebral gutter, ascending colon, left kidney, and urinary bladder of a human cadaver (183 cm in height and 67.5 kg in weight) whose abdomen/pelvis region was scanned repeatedly with a multidetector row CT. The flat energy response and precision of the dosimeters were verified, and the slight differences in each dosimeter's response were evaluated and corrected to attain high accuracy. In addition, skin doses were measured for radiosensitive organs outside the scanned region with OSL dosimeters: the right eye, thyroid, both nipples, and the right testicle. Three scan protocols were used, which shared most scan parameters but had different kVp and mA settings: 120-kVp automA, 120-kVp 300 mA, and 100-kVp 300 mA. For each protocol three repeated scans were performed. Results: The tube starting angle (TSA) was found to randomly vary around two major conditions, which caused large fluctuations in the repeated point dose measurements: for the 120-kVp 300 mA protocol this angle changed from approximately 110° to 290°, and caused 8% − 25% difference in the point dose measured at the stomach, liver, colon, and urinary bladder. When the fluctuations of the TSA were small (within 5°), the maximum coefficient of variance was approximately 3.3%. The soft tissue absorbed doses averaged from four locations near the center of the scanned region were 27.2 ± 3.3 and 16.5 ± 2.7 mGy for the 120 and 100-kVp fixed-mA scans, respectively. These values were consistent with the corresponding size specific dose estimates within 4%. The comparison of the per-100-mAs tissue doses from the three protocols revealed that: (1) dose levels at nonsuperficial locations in the TCM scans could not be accurately deduced by simply scaling the fix-mA doses with local mA values; (2) the general power law relationship between dose and kVp varied from location to location, with the power index ranged between 2.7 and 3.5. The averaged dose measurements at both nipples, which were about 0.6 cm outside the prescribed scan region, ranged from 23 to 27 mGy at the left nipple, and varied from 3 to 20 mGy at the right nipple over the three scan protocols. Large fluctuations over repeated scans were also observed, as a combined result of helical scans of large pitch (1.375) and small active areas of the skin dosimeters. In addition, the averaged skin dose fell off drastically with the distance to the nearest boundary of the scanned region. Conclusions: This study revealed the complexity of CT dose fluctuation and variation with a human cadaver. PMID:25186398

Integrated Path Differential Absorption Lidar Optimizations Based on Pre-Analyzed Atmospheric Data for ASCENDS Mission Applications

NASA Technical Reports Server (NTRS)

Pliutau, Denis; Prasad, Narasimha S.

2012-01-01

In this paper a modeling method based on data reductions is investigated which includes pre analyzed MERRA atmospheric fields for quantitative estimates of uncertainties introduced in the integrated path differential absorption methods for the sensing of various molecules including CO2. This approach represents the extension of our existing lidar modeling framework previously developed and allows effective on- and offline wavelength optimizations and weighting function analysis to minimize the interference effects such as those due to temperature sensitivity and water vapor absorption. The new simulation methodology is different from the previous implementation in that it allows analysis of atmospheric effects over annual spans and the entire Earth coverage which was achieved due to the data reduction methods employed. The effectiveness of the proposed simulation approach is demonstrated with application to the mixing ratio retrievals for the future ASCENDS mission. Independent analysis of multiple accuracy limiting factors including the temperature, water vapor interferences, and selected system parameters is further used to identify favorable spectral regions as well as wavelength combinations facilitating the reduction in total errors in the retrieved XCO2 values.

Knowledge-based iterative model reconstruction: comparative image quality and radiation dose with a pediatric computed tomography phantom.

PubMed

Ryu, Young Jin; Choi, Young Hun; Cheon, Jung-Eun; Ha, Seongmin; Kim, Woo Sun; Kim, In-One

2016-03-01

CT of pediatric phantoms can provide useful guidance to the optimization of knowledge-based iterative reconstruction CT. To compare radiation dose and image quality of CT images obtained at different radiation doses reconstructed with knowledge-based iterative reconstruction, hybrid iterative reconstruction and filtered back-projection. We scanned a 5-year anthropomorphic phantom at seven levels of radiation. We then reconstructed CT data with knowledge-based iterative reconstruction (iterative model reconstruction [IMR] levels 1, 2 and 3; Philips Healthcare, Andover, MA), hybrid iterative reconstruction (iDose(4), levels 3 and 7; Philips Healthcare, Andover, MA) and filtered back-projection. The noise, signal-to-noise ratio and contrast-to-noise ratio were calculated. We evaluated low-contrast resolutions and detectability by low-contrast targets and subjective and objective spatial resolutions by the line pairs and wire. With radiation at 100 peak kVp and 100 mAs (3.64 mSv), the relative doses ranged from 5% (0.19 mSv) to 150% (5.46 mSv). Lower noise and higher signal-to-noise, contrast-to-noise and objective spatial resolution were generally achieved in ascending order of filtered back-projection, iDose(4) levels 3 and 7, and IMR levels 1, 2 and 3, at all radiation dose levels. Compared with filtered back-projection at 100% dose, similar noise levels were obtained on IMR level 2 images at 24% dose and iDose(4) level 3 images at 50% dose, respectively. Regarding low-contrast resolution, low-contrast detectability and objective spatial resolution, IMR level 2 images at 24% dose showed comparable image quality with filtered back-projection at 100% dose. Subjective spatial resolution was not greatly affected by reconstruction algorithm. Reduced-dose IMR obtained at 0.92 mSv (24%) showed similar image quality to routine-dose filtered back-projection obtained at 3.64 mSv (100%), and half-dose iDose(4) obtained at 1.81 mSv.

Spontaneous rupture of the ascending aorta.

PubMed

Bin Mahmood, Syed Usman; Ulrich, Andrew; Safdar, Basmah; Geirsson, Arnar; Mangi, Abeel A

2018-02-01

Nontraumatic, spontaneous rupture of the ascending aorta is rare and the etiology is largely unknown. We reviewed seven patients from our institution, with no known aortic disease or hereditary connective tissue disorder that presented with spontaneous ascending aortic rupture from 2012 to 2017. Most patients presented with non-radiating chest pain along with hypertension (71.4%). The mean ascending aortic diameter at rupture was 4.60 ± 0.62 cm. The median door-to-operating room time was 2.58 h, resulting from effective implementation of an aortic emergency protocol. There were no operative mortalities. In patients with ascending aortic rupture, aortic diameter may not always correlate with the risk of rupture. Rapid diagnosis combined with a multidisciplinary approach is vital for the successful management of these high-risk patients. © 2018 Wiley Periodicals, Inc.

Resveratrol Increases Nitric Oxide Production in the Rat Thick Ascending Limb via Ca2+/Calmodulin

PubMed Central

Gonzalez-Vicente, Agustin; Cabral, Pablo D.; Garvin, Jeffrey L.

2014-01-01

The thick ascending limb of the loop of Henle reabsorbs 30% of the NaCl filtered through the glomerulus. Nitric oxide (NO) produced by NO synthase 3 (NOS3) inhibits NaCl absorption by this segment. Resveratrol, a polyphenol, has beneficial cardiovascular and renal effects, many of which are mediated by NO. Resveratrol increases intracellular Ca2+ (Cai) and AMP kinase (AMPK) and NAD-dependent deacetylase sirtuin1 (SIRT1) activities, all of which could activate NO production. We hypothesized that resveratrol stimulates NO production by thick ascending limbs via a Ca2+/calmodulin-dependent mechanism. To test this, the effect of resveratrol on NO bioavailability was measured in thick ascending limb suspensions. Cai was measured in single perfused thick ascending limbs. SIRT1 activity and expression were measured in thick ascending limb lysates. Resveratrol (100 µM) increased NO bioavailability in thick ascending limb suspensions by 1.3±0.2 AFU/mg/min (p<0.03). The NOS inhibitor L-NAME blunted resveratrol-stimulated NO bioavailability by 96±11% (p<0.03). The superoxide scavenger tempol had no effect. Resveratrol elevated Cai from 48±7 to 135±24 nM (p<0.01) in single tubules. In Ca2+-free media, the resveratrol-induced increase in NO was blunted by 60±20% (p<0.05) and the rise in Cai reduced by 80%. Calmodulin inhibition prevented the resveratrol-induced increase in NO (p<0.002). AMPK inhibition had no effect. Resveratrol did not increase SIRT1 activity. We conclude that resveratrol increases NO production in thick ascending limbs via a Ca2+/calmodulin dependent mechanism, and SIRT1 and AMPK do not participate. Resveratrol-stimulated NO production in thick ascending limbs may account for part of its beneficial effects. PMID:25314136

The influence of seasons and lunar cycle on hospital outcomes following ascending aortic dissection repair.

PubMed

Shuhaiber, Jeffrey H; Fava, Joseph L; Shin, Tai; Dobrilovic, Nikola; Ehsan, Afshin; Bert, Arthur; Sellke, Frank

2013-11-01

The effect of the lunar cycle and seasonal variation on ascending aortic dissection surgery outcomes is unknown. We investigated these temporal effects on risk-adjusted hospital mortality and then on the length of stay (LOS) following surgery for survivors. We examined prospectively collected data from cardiac operations at two major centres within a single state between January 1996 and December 2011. We first examined the relationship between the lunar cycle and seasonal variation, along with demographic and risk profile covariates, with mortality using univariate analyses, followed by multiple logistic regression modelling that controlled for demographic and patient risk variables including age, gender, risk profile (diabetes, hypertension, dyslipidaemia and renal failure), and two surgical groups: Group A, consisting of patients having repair of ascending aorta dissection repair only, and Group B, with those having ascending aorta repair plus aortic valve surgery or coronary bypass surgery or both. We further examined the relationship with LOS using both univariate and multiple regression analyses. There were 210 patients who had repair of dissection in the study period, with 109 patients in Group A and 101 in Group B. The average age of this sample was 59.5 (standard deviation = 16.0), 65.7% were male and 18.1% died prior to discharge following repair. The greatest percentage of deaths occurred in winter (31.6%, n = 12), while the least were in summer (21.1%, n = 8) and fall (21.1%, n = 8). An overall χ(2) test found there was no difference in mortality for season (P = 0.55). Univariate analyses also found the age of patients who died vs lived was significantly higher (65.9 vs 58.1 years; P = 0.001), and a significantly greater (P = 0.029) percentage of patients with diabetes vs without diabetes died (41.7 vs 16.7%). Univariate analyses found all other covariates were not significantly related to mortality. In the multiple logistic regression model, there was no significant effect for season, while the odds of dying increased with age (odds ratio [OR] = 1.04, 95% confidence interval [95% CI] = 1.01-1.07, P = 0.012), and the odds of dying in the full-moon cycle vs the new moon cycle was significantly reduced (OR = 0.21, 95% CI = 0.05-0.81, P = 0.024). No other covariate significantly increased or decreased the odds of death, including diabetes risk, which had been significantly related to death in the univariate analysis. Within a linear regression model that examined the relationship with LOS, Group B (P = 0.020), male sex (P = 0.036) and the full-moon lunar phase (P = 0.001) were significantly related to shorter LOS. Season had no effect on mortality or LOS following aortic dissection repair, while patient age significantly increased the odds of death. The full-moon cycle appeared to reduce the odds of death, and the full-moon cycle, along with being male and requiring a concomitant cardiac procedure, was associated with shorter LOS.

In vitro dose measurements in a human cadaver with abdomen/pelvis CT scans

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

Zhang, Da; Padole, Atul; Li, Xinhua

2014-09-15

Purpose: To present a study of radiation dose measurements with a human cadaver scanned on a clinical CT scanner. Methods: Multiple point dose measurements were obtained with high-accuracy Thimble ionization chambers placed inside the stomach, liver, paravertebral gutter, ascending colon, left kidney, and urinary bladder of a human cadaver (183 cm in height and 67.5 kg in weight) whose abdomen/pelvis region was scanned repeatedly with a multidetector row CT. The flat energy response and precision of the dosimeters were verified, and the slight differences in each dosimeter's response were evaluated and corrected to attain high accuracy. In addition, skin dosesmore » were measured for radiosensitive organs outside the scanned region with OSL dosimeters: the right eye, thyroid, both nipples, and the right testicle. Three scan protocols were used, which shared most scan parameters but had different kVp and mA settings: 120-kVp automA, 120-kVp 300 mA, and 100-kVp 300 mA. For each protocol three repeated scans were performed. Results: The tube starting angle (TSA) was found to randomly vary around two major conditions, which caused large fluctuations in the repeated point dose measurements: for the 120-kVp 300 mA protocol this angle changed from approximately 110° to 290°, and caused 8% − 25% difference in the point dose measured at the stomach, liver, colon, and urinary bladder. When the fluctuations of the TSA were small (within 5°), the maximum coefficient of variance was approximately 3.3%. The soft tissue absorbed doses averaged from four locations near the center of the scanned region were 27.2 ± 3.3 and 16.5 ± 2.7 mGy for the 120 and 100-kVp fixed-mA scans, respectively. These values were consistent with the corresponding size specific dose estimates within 4%. The comparison of the per-100-mAs tissue doses from the three protocols revealed that: (1) dose levels at nonsuperficial locations in the TCM scans could not be accurately deduced by simply scaling the fix-mA doses with local mA values; (2) the general power law relationship between dose and kVp varied from location to location, with the power index ranged between 2.7 and 3.5. The averaged dose measurements at both nipples, which were about 0.6 cm outside the prescribed scan region, ranged from 23 to 27 mGy at the left nipple, and varied from 3 to 20 mGy at the right nipple over the three scan protocols. Large fluctuations over repeated scans were also observed, as a combined result of helical scans of large pitch (1.375) and small active areas of the skin dosimeters. In addition, the averaged skin dose fell off drastically with the distance to the nearest boundary of the scanned region. Conclusions: This study revealed the complexity of CT dose fluctuation and variation with a human cadaver.« less

Depth dose measurements with the Liulin-5 experiment inside the spherical phantom of the MATROSHKA-R project onboard the International Space Station

NASA Astrophysics Data System (ADS)

Semkova, J.; Koleva, R.; Maltchev, St.; Bankov, N.; Benghin, V.; Chernykh, I.; Shurshakov, V.; Petrov, V.; Drobyshev, S.; Nikolaev, I.

2012-02-01

The Liulin-5 experiment is a part of the international project MATROSHKA-R on the Russian segment of the ISS, which uses a tissue-equivalent spherical phantom equipped with a set of radiation detectors. The objective of the MATROSHKA-R project is to provide depth dose distribution of the radiation field inside the sphere in order to get more information on the distribution of dose in a human body. Liulin-5 is a charged particle telescope using three silicon detectors. It measures time resolved energy deposition spectra, linear energy transfer (LET) spectra, particle flux, and absorbed doses of electrons, protons and heavy ions, simultaneously at three depths along the radius of the phantom. Measurements during the minimum of the solar activity in cycle 23 show that the average absorbed daily doses at 40 mm depth in the phantom are between 180 μGy/day and 220 μGy/day. The absorbed doses at 165 mm depth in the phantom decrease by a factor of 1.6-1.8 compared to the doses at 40 mm depth due to the self-shielding of the phantom from trapped protons. The average dose equivalent at 40 mm depth is 590 ± 32 μSV/day and the galactic cosmic rays (GCR) contribute at least 70% of the total dose equivalent at that depth. Shown is that due to the South Atlantic Anomaly (SAA) trapped protons asymmetry and the direction of Liulin-5 lowest shielding zone the dose rates on ascending and descending nodes in SAA are different. The data obtained are compared to data from other radiation detectors on ISS.

Ascending Aortic Aneurysm Is an Inherited Disease: A Contemporary Literature Review Based on Hill's Criteria of Specificity, Strength of Association, and Biological Coherence.

PubMed

Ahmad, Mirza Mujadil; Kiani, Immad Arif; Ammar, Khawaja Afzal; Ahmad, Mirza Nubair; Khandheria, Bijoy K; Paterick, Timothy E; Jain, Renuka; Tajik, A Jamil

There is growing evidence of a differential etiological basis for thoracic aortic aneurysms (TAA), with ascending (As) TAAs being genetically mediated and descending (Des) TAAs more strongly related to acquired pathologies. A comprehensive literature review of this hypothesis has not been carried out. We carried out a systematic literature review based on the latest guidelines on TAA endorsed by the American Heart Association. The etiologies were classified as genetic and inherited, the studies were tabulated accordingly, and Hill's epidemiological criteria of causality were applied. We found 38 studies addressing the etiology of TAAs. Out of these, 17 were about genetic causes, 9 about acquired causes, and 4 had information regarding both etiologies. Multiple genetic studies showed a strong association of As TAA with different genetic mutations. Contrary to commonly held beliefs, acquired causes, that is, dyslipidemia, diabetes, and atherosclerosis, were negatively associated with As TAA and positively associated with Des TAA. Hypertension was only associated with Des TAA and dissections (TAAD), not with As TAA. Multiple studies fulfilled the criteria of strength of association (n = 4), consistency (n = 9), specificity (n = 5), temporality (24), biological gradient (n = 3), plausibility (n = 38), biological coherence (n = 25), experiment (n = 4), and analogy (n = 6). Our literature review supports the hypothesis that As TAA is genetically mediated and Des TAA is predominantly an acquired pathology, and supports the argument for genetic testing in all cases of As TAA.

Decreased expression of fibulin-4 in aortic wall of aortic dissection.

PubMed

Huawei, P; Qian, C; Chuan, T; Lei, L; Laing, W; Wenlong, X; Wenzhi, L

2014-02-01

In this research, we will examine the expression of Fibulin-4 in aortic wall to find out its role in aortic dissection development. The samples of aortic wall were obtained from 10 patients operated for acute ascending aortic dissection and five patients for chronic ascending aortic dissection. Another 15 pieces of samples from patients who had coronary artery bypass were as controls. The aortic samples were stained with aldehyde magenta dyeing to evaluate the arrangement of elastic fibers. The Fibulin-4 protein and mRNA expression were both determined by Western blot and realtime quantitative polymerase chain reaction. Compared with the control group, both in acute and chronic ascending aortic dissection, elastic fiber fragments increased and the expression of fibulin-4 protein significantly decreased (P= 0.045 < 0.05). The level of fibulin-4 mRNA decreased in acute ascending aortic dissection (P= 0.034 < 0.05), while it increased in chronic ascending aortic dissection (P=0.004 < 0.05). The increased amounts of elastic fiber fragments were negatively correlated with the expression of fibulin-4 mRNA in acute ascending aortic dissection. In conclusion, in aortic wall of ascending aortic dissection, the expression of fibulin-4 protein decreased and the expression of fibulin-4 mRNA was abnormal. Fibulin-4 may play an important role in the pathogenesis of aortic dissection.

Repair of Multiple Subclavian and Axillary Artery Aneurysms in a 58-Year-Old Man with Marfan Syndrome.

PubMed

Dolapoglu, Ahmet; de la Cruz, Kim I; Preventza, Ourania; Coselli, Joseph S

2016-10-01

Dilation of the ascending aorta and aortic dissections are often seen in Marfan syndrome; however, true aneurysms of the subclavian and axillary arteries rarely seem to develop in patients who have this disease. We present the case of a 58-year-old man with Marfan syndrome who had undergone a Bentall procedure and thoracoabdominal aortic repair for an aortic dissection and who later developed multiple aneurysmal dilations of his right subclavian and axillary arteries. The aneurysms were successfully repaired by means of a surgical bypass technique in which a Dacron graft was placed between the carotid and brachial arteries. We also discuss our strategy for determining the optimal surgical approach in these patients.

Stenting of the ascending aorta revisited.

PubMed

Moiduddin, Nasser J; Rios, Rodrigo; El-Said, Howaida; Moore, John W

2017-10-01

Despite few institutions stenting the ascending aorta, it has been discouraged because of the proximity of the aortic valve, the coronary artery orifices, and the aortic arch branches. We describe a small case series of patients having acquired stenosis of the ascending that was relieved successfully by stenting. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation

PubMed Central

Grover, Anita; Benet, Leslie Z.

2013-01-01

Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives. PMID:21499748

A penetrating atherosclerotic ulcer rupture in the ascending aorta with hemopericardium: a case report.

PubMed

Liu, Yuan-Hao; Ke, Hung-Yen; Lin, Yi-Chang; Tsai, Chien-Sung

2016-07-11

Acute aortic syndrome, including classic aortic dissection, intramural aortic hematoma, and penetrating atherosclerotic ulcer (PAU), is a term used to describe a group of conditions with similar clinical symptoms, but with different pathophysiological mechanisms. PAU is a lesion that penetrates the internal elastic lamina through the media. It is usually located in the descending aorta and rarely observed in the ascending aorta. A 76-year-old man with a history of essential hypertension was brought to the emergency department (ED) because of a sudden-onset chest pain at rest. He had not been taking his medication as ordered. His vital signs in the ED were a blood pressure of 82/60 mmHg, heart rate of 158 beats per min, respiratory rate of 22 breaths per min, and a body temperature of 37.2 °C. An electrocardiogram did not show an ST segment elevation, and cardiac enzymes were within normal limits. No widening mediastinum was found on chest radiography, but a large pericardial effusion with an impending cardiac tamponade was revealed on echocardiography. The diagnosis of PAU rupture in the ascending aorta with hemopericardium was made with chest computed tomography. An emergent sternotomy and ascending aorta reconstruction were performed. A ruptured ulcerative plaque through the intima to the adventitia without flap dissection in the ascending aorta was confirmed. The patient was discharged 18 days after the operation. Although PAU in the ascending aorta is uncommon, it is commonly lethal when it ruptures. With the current advances in endovascular techniques and devices, endovascular repair of PAU in the ascending aorta is currently recommended only for high-risk patients unsuitable for open repair. However, we anticipate that endovascular repair may become feasible in patients with PAU in the ascending aorta in the future.

Pulmonary arterial hypertension in children: diagnosis using ratio of main pulmonary artery to ascending aorta diameter as determined by multi-detector computed tomography.

PubMed

Caro-Domínguez, Pablo; Compton, Gregory; Humpl, Tilman; Manson, David E

2016-09-01

The ratio of the transverse diameter of the main pulmonary artery (MPA) to ascending aorta as determined at multi-detector CT is a tool that can be used to assess the pulmonary arterial size in cases of pulmonary arterial hypertension in children. To establish a ratio of MPA to ascending aorta diameter using multi-detector CT imaging suggestive of pulmonary arterial hypertension in children. We hypothesize that a defined ratio of MPA to ascending aorta is identifiable on multi-detector CT and that higher ratios can be used to reliably diagnose the presence of pulmonary arterial hypertension in children. We calculated the multi-detector CT ratio of MPA to ascending aorta diameter in 44 children with documented pulmonary arterial hypertension by right heart catheterization and in 44 age- and gender-matched control children with no predisposing factors for pulmonary arterial hypertension. We compared this multi-detector-CT-determined ratio with the MPA pressure in the study group, as well as with the ratio of MPA to ascending aorta in the control group. A threshold ratio value was calculated to accurately identify children with pulmonary arterial hypertension. Children with documented primary pulmonary arterial hypertension have a significantly higher ratio of MPA to ascending aorta (1.46) than children without pulmonary arterial hypertension (1.11). A ratio of 1.3 carries a positive likelihood of 34 and a positive predictive value of 97% for the diagnosis of pulmonary arterial hypertension. The pulmonary arteries were larger in children with pulmonary arterial hypertension than in a control group of normal children. A CT-measured ratio of MPA to ascending aorta of 1.3 should raise the suspicion of pulmonary arterial hypertension in children.

Complications at the Proximal Landing Zone of Endovascular Stent Grafts Deployed in Surgically Replaced Ascending Aorta.

PubMed

Kotha, Vamshi K; Herget, Eric J; Appoo, Jehangir J

2016-11-01

The ascending aorta, with its hostile angulations and forces, is the next frontier in the evolution of endovascular surgery. Type II hybrid arch repair, involving surgical replacement of the ascending aorta, arch debranching, and stent graft deployment in the ascending aortic graft, offers an opportunity to study the behavior of an endovascular prosthesis in the ascending aorta. We report complications seen at the proximal landing zone after type II hybrid arch repair. A dedicated imaging protocol was used to monitor 20 consecutive patients who underwent type II hybrid arch repair at a single center from June 2009 to July 2014. Mean age was 66 years (range, 47 to 82 years). Mean imaging follow-up was 34 months (range, 12 to 64 months). There was 1 operative death (5%). Bird beaking (>5 mm of nonapposition) of the stent graft at the proximal landing zone occurred in 12 patients, and >20 mm of bird beaking occurred in 7 patients. Proximal landing zone complications occurred in 4 patients (20%), comprising 2 type Ia endoleaks, 1 graft migration, and 1 graft infolding detected on postoperative days 4, 11, 5, and 755, respectively. Three patients underwent endovascular reintervention for proximal landing zone complications. There were no late deaths. Thoracic aortic stent grafts may be prone to proximal landing zone complications when deployed in the ascending aorta. Bird beaking is common when endografts are deployed in the Dacron (DuPont, Wilmington, DE) ascending aorta. Angulation issues will likely need to be overcome by stent graft refinement to enable future closed chest approaches to the ascending aorta. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Effect of short-term vs. long-term elevation of dietary protein intake on responsiveness of rat thick ascending limbs to peptide hormones.

PubMed

Goldstein, David L; Plaga, Kimberly

2002-10-01

We compared the renal responses of rats on three diet regimens. Rats received either 8% protein food (low-protein, LP) for 10 weeks following weaning, 8% protein for 9 weeks followed by 1 week on 30% protein (short-term high-protein, SHP), or 30% protein for 10 weeks (high-protein, HP). Kidneys from HP rats were enlarged by approximately 50%, or 20% when corrected for body mass. Most of this hypertrophy resulted from enlargement of the inner stripe of the outer medulla, site of the thick ascending limbs (TAL), and TAL from HP rats were larger in diameter. SHP rats had TAL diameters similar to HP rats, but changes in renal mass or height of renal zones did not reach statistical significance. The activity of adenylyl cyclase (AC) in TAL, measured from the accumulation of cAMP in isolated tubules, increased with dose of both arginine vasopressin (AVP) and glucagon in all rats. However, HP rats had significantly higher hormone-induced AC activity than LP or SHP rats, which were not different from each other. Our results suggest that tubule hypertrophy may precede up-regulation of hormone-sensitive AC activity during the progression of renal response to elevated dietary protein.

[Continuous insulin therapy versus multiple insulin injections in the management of type 1 diabetes: a longitutinal study].

PubMed

Ribeiro, Maria Estela Bellini; Del Roio Liberatore Junior, Raphael; Custodio, Rodrigo; Martinelli Junior, Carlos Eduardo

2016-01-01

To compare multiple doses of insulin and continuous insulin infusion therapy as treatment for type 1 diabetes melito. 40 patients with type 1 diabetes melito (21 female) with ages between 10 and 20 years (mean=14.2) and mean duration of diabetes of 7 years used multiple doses of insulin for at least 6 months and after that, continuous insulin infusion therapy for at least 6 months. Each one of the patients has used multiple doses of insulin and continuous insulin infusion therapy. For analysis of HbA1c, mean glycated hemoglobin levels (mHbA1c) were obtained during each treatment period (multiple doses of insulin and continuous insulin infusion therapy period). Although mHbA1c levels were lower during continuous insulin infusion therapy the difference was not statistically significant. During multiple doses of insulin, 14.2% had mHbA1c values below 7.5% vs. 35.71% while on continuous insulin infusion therapy; demonstrating better glycemic control with the use of continuous insulin infusion therapy. During multiple doses of insulin, 15-40 patients have severe hypoglycemic events versus 5-40 continuous insulin infusion therapy. No episodes of ketoacidosis events were recorded. This is the first study with this design comparing multiple doses of insulin and continuous insulin infusion therapy in Brazil showing no significant difference in HbA1c; hypoglycemic events were less frequent during continuous insulin infusion therapy than during multiple doses of insulin and the percentage of patients who achieved a HbA1c less than 7.5% was greater during continuous insulin infusion therapy than multiple doses of insulin therapy. Copyright © 2015 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.

Aortic valve stenosis and aortic diameters determine the extent of increased wall shear stress in bicuspid aortic valve disease.

PubMed

Farag, Emile S; van Ooij, Pim; Planken, R Nils; Dukker, Kayleigh C P; de Heer, Frederiek; Bouma, Berto J; Robbers-Visser, Danielle; Groenink, Maarten; Nederveen, Aart J; de Mol, Bas A J M; Kluin, Jolanda; Boekholdt, S Matthijs

2018-02-16

Use of 4-dimensional flow magnetic resonance imaging (4D-flow MRI) derived wall shear stress (WSS) heat maps enables identification of regions in the ascending aorta with increased WSS. These regions are subject to dysregulation of the extracellular matrix and elastic fiber degeneration, which is associated with aortic dilatation and dissection. To evaluate the effect of the presence of aortic valve stenosis and the aortic diameter on the peak WSS and surface area of increased WSS in the ascending aorta. Prospective. In all, 48 bicuspid aortic valve (BAV) patients (38.1 ± 12.4 years) and 25 age- and gender-matched healthy individuals. Time-resolved 3D phase contrast MRI with three-directional velocity encoding at 3.0T. Peak systolic velocity, WSS, and aortic diameters were assessed in the ascending aorta and 3D heat maps were used to identify regions with elevated WSS. Comparisons between groups were performed by t-tests. Correlations were investigated by univariate and multivariate regression analysis. Elevated WSS was present in 15 ± 11% (range; 1-35%) of the surface area of the ascending aorta of BAV patients with aortic valve stenosis (AS) (n = 10) and in 6 ± 8% (range; 0-31%) of the ascending aorta of BAV patients without AS (P = 0.005). The mid-ascending aortic diameter negatively correlated with the peak ascending aortic WSS (R = -0.413, P = 0.004) and the surface area of elevated WSS (R = -0.419, P = 0.003). Multivariate linear regression analysis yielded that the height of peak WSS and the amount of elevated WSS depended individually on the presence of aortic valve stenosis and the diameter of the ascending aorta. The extent of increased WSS in the ascending aorta of BAV patients depends on the presence of aortic valve stenosis and aortic dilatation and is most pronounced in the presence of AS and a nondilated ascending aorta. 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. © 2018 The Authors Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.

Influence of Al³⁺ addition on the flocculation and sedimentation of activated sludge: comparison of single and multiple dosing patterns.

PubMed

Wen, Yue; Zheng, Wanlin; Yang, Yundi; Cao, Asheng; Zhou, Qi

2015-05-15

In this study, the flocculation and sedimentation performance of activated sludge (AS) with single and multiple dosing of trivalent aluminum (Al(3+)) were studied. The AS samples were cultivated in sequencing batch reactors at 22 °C. The dosages of Al(3+) were 0.00, 0.125, 0.5, 1.0, and 1.5 meq/L for single dosing, and 0.1 meq/L for multiple dosing. Under single dosing conditions, as Al(3+) dosage increased, the zeta potential, total interaction energy, and effluent turbidity decreased, whereas the sludge volume index (SVI) increased, indicating that single Al(3+) dosing could enhance sludge flocculation, but deteriorate sedimentation. By comparison, adding an equal amount of Al(3+) through multiple dosing achieved a similar reduction in turbidity, but the zeta potential was higher, while the loosely bound extracellular polymeric substances (LB-EPS) content and SVI remarkably declined. Although the difference in the flocculation performances between the two dosing patterns was not significant, the underlying mechanisms were quite distinct: the interaction energy played a more important role under single dosing conditions, whereas multiple dosing was more effective in reducing the EPS content. Multiple dosing, which allows sufficient time for sludge restructuring and floc aggregation, could simultaneously optimize sludge flocculation and sedimentation. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Phase I clinical trial of lodenafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, in healthy male volunteers.

PubMed

Mendes, Gustavo D; dos Santos Filho, Hilton Oliveira; dos Santos Pereira, Alberto; Mendes, Fabiana D; Ilha, Jaime O; Alkharfy, Khalid M; De Nucci, Gilberto

2012-12-01

Lodenafil carbonate is a new phosphodiesterase Type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 - 100 mg) single oral doses to healthy male volunteers (n = 33). The study was an open label, dose-escalation, Phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg - 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16, 20 and 24 h post-dosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements, clinical and laboratory exams and ECG revealed no significant changes even at higher doses. Lodenafil carbonate was not detected in any samples, indicating that it acts as a prodrug. The mean lodenafil pharmacokinetic parameters for tmax and t1/2 were 1.6 ( ± 0.4) h and 3.3 ( ± 1.1) h, respectively. This study demonstrated that lodenafil carbonate was well tolerated and showed a good safety profile in healthy male volunteers.

Quantitative evaluation of local pulmonary distribution of TiO2 in rats following single or multiple intratracheal administrations of TiO2 nanoparticles using X-ray fluorescence microscopy.

PubMed

Zhang, Guihua; Shinohara, Naohide; Kano, Hirokazu; Senoh, Hideki; Suzuki, Masaaki; Sasaki, Takeshi; Fukushima, Shoji; Gamo, Masashi

2016-10-01

Uneven pulmonary nanoparticle (NP) distribution has been described when using single-dose intratracheal administration tests. Multiple-dose intratracheal administrations with small quantities of NPs are expected to improve the unevenness of each dose. The differences in local pulmonary NP distribution (called microdistribution) between single- and multiple-dose administrations may cause differential pulmonary responses; however, this has not been evaluated. Here, we quantitatively evaluated the pulmonary microdistribution (per mesh: 100 μm × 100 μm) of TiO2 in lung sections from rats following one, two, three, or four doses of TiO2 NPs at a same total dosage of 10 mg kg(-1) using X-ray fluorescence microscopy. The results indicate that: (i) multiple-dose administrations show lower variations in TiO2 content (ng mesh(-1) ) for sections of each lobe; (ii) TiO2 appears to be deposited more in the right caudal and accessory lobes located downstream of the administration direction of NP suspensions, and less so in the right middle lobes, irrespective of the number of doses; (iii) there are not prominent differences in the pattern of pulmonary TiO2 microdistribution between rats following single and multiple doses of TiO2 NPs. Additionally, the estimation of pulmonary TiO2 deposition for multiple-dose administrations imply that every dose of TiO2 would be randomly deposited only in part of the fixed 30-50% of lung areas. The evidence suggests that multiple-dose administrations do not offer remarkable advantages over single-dose administration on the pulmonary NP microdistribution, although multiple-dose administrations may reduce variations in the TiO2 content for each lung lobe. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

The effect of proximal anastomosis on the expansion rate of a dilated ascending aorta in coronary artery bypass surgery: a prospective study

PubMed Central

Balcı, Ahmet Yavuz; Vural, Unsal; Özdemir, MD Fatih; Kızılay, Mehmet; Şenocak, Mutlu; Kayacıoğlu, Ilyas; Yekeler, Ibrahim; Aksoy, Rezan; Satılmış,, Seçkin; Şaşkın, Huseyin

2017-01-01

Summary Background: This study was designed to determine the short- and long-term effects of proximal aortic anastomosis, performed during isolated coronary artery bypass grafting (CABG) in patients with dilatation of the ascending aorta who did not require surgical intervention. Methods: The study was performed on 192 (38 female and 160 male patients; mean age, 62.1 ± 9.2 years; range, 42–80 years) patients with dilatation of the ascending aorta who underwent CABG surgery between 1 June 2006 and 31 May 2014. In group 1 (n = 114), the saphenous vein and left internal mammarian artery grafts were used, and proximal anastomosis was performed on the ascending aorta. In group 2 (n = 78), left and right internal mammarian artery grafts were used, and proximal aortic anastomosis was not performed. Pre-operatively and in the first and third years postoperatively, the ascending aortic diameter was measured and recorded using transthoracic echocardiography at four different regions (annulus, sinus of Valsalva, sinotubular junction and tubular aorta). Results: A statistically significant difference was found between the groups for the number of grafts used and the duration of aortic cross-clamping and cardiopulmonary bypass. No significant intergroup difference was seen for the mean diameter of the ascending aorta (p > 0.05). Annual changes in the aortic diameter were found to be extremely significantly different in both groups (p = 0.0001). Mean values of the aortic diameter at the level of the sinotubular junction and tubular ascending aorta, mean aortic diameters (p = 0.002 and p = 0.0001, respectively), annual increase in diameter (p = 0.0001 and p = 0.0001, respectively), and mean annual difference in diameter (p = 0.0001 and p = 0.0001, respectively) at one and three years postoperatively were statistically significantly different between the groups. Conclusion: In patients with ascending aortic dilatation who did not require surgical intervention and who had proximal anastomosis of the ascending aorta and underwent only CABG, we detected statistically significant increases in the diameter of the sinotubular junction and tubular aorta up to three years postoperatively. PMID:27701487

International experience with endovascular therapy of the ascending aorta with a dedicated endograft.

PubMed

Tsilimparis, Nikolaos; Debus, E Sebastian; Oderich, Gustavo S; Haulon, Stephan; Terp, Kim Allan; Roeder, Blayne; Detter, Christian; Kölbel, Tilo

2016-06-01

The objective of this study was to evaluate the safety and feasibility of a novel stent graft specifically designed for treatment of the ascending aorta. This was a multicenter, retrospective analysis of all consecutive patients treated with the dedicated Zenith Ascend TAA Endovascular Graft (William Cook Europe, Bjaeverskov, Denmark) for pathologic processes requiring stent grafting of the ascending aorta. The graft is short (6.5 cm), with a delivery system designed for transfemoral placement in the ascending aorta. In 10 patients (five men; age, 67 years; range, 26-90 years), the Zenith Ascend graft was implanted for the following indications: dissection (n = 5) and aneurysm (n = 4) of the ascending aorta and fixation of an intraprocedural dislocated aortic valve (n = 1). All patients were judged to be at high risk for open surgery (nine patients were classified as American Society of Anesthesiologists class 3 or class 4). A transfemoral approach was selected in eight cases and a transapical approach in two. All endografts were successfully deployed without intraoperative adverse events at the targeted landing zone. Clinical success in coverage of the lesions was achieved in all cases with the exception of an attempted treatment of an intraprocedural aortic valve implantation dissection that resulted in early mortality. The 30-day survival was 90%. Early neurologic events included one patient with stroke and paraplegia and one patient with a transient ischemic attack. One patient underwent early evacuation of a hemopericardium. There were two late reinterventions for persisting endoleaks. At a mean follow-up of 10 months (range, 1-36 months), three late deaths occurred, with one treatment related, as a result of graft infection. Despite the fact that in this first published series the graft was frequently used as a "rescue tool" outside its intended indication, treatment with the Zenith Ascend graft in this early experience appears to be safe and feasible for repair of ascending aorta pathologic processes in high-risk patients unsuitable for open repair. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

The effect of proximal anastomosis on the expansion rate of a dilated ascending aorta in coronary artery bypass surgery: a prospective study.

PubMed

Yavuz Balci, Ahmet; Vural, Unsal; Aksoy, Rezan; Özdemir, M Fatih; Satilmiş, Seçkin; Kizilay, Mehmet; Şenocak, Mutlu; Şaşkin, Huseyin; Kayacioğlu, Ilyas; Yekeler, Ibrahim

This study was designed to determine the short- and long-term effects of proximal aortic anastomosis, performed during isolated coronary artery bypass grafting (CABG) in patients with dilatation of the ascending aorta who did not require surgical intervention. The study was performed on 192 (38 female and 160 male patients; mean age, 62.1 ± 9.2 years; range, 42-80 years) patients with dilatation of the ascending aorta who underwent CABG surgery between 1 June 2006 and 31 May 2014. In group 1 (n = 114), the saphenous vein and left internal mammarian artery grafts were used, and proximal anastomosis was performed on the ascending aorta. In group 2 (n = 78), left and right internal mammarian artery grafts were used, and proximal aortic anastomosis was not performed. Pre-operatively and in the first and third years postoperatively, the ascending aortic diameter was measured and recorded using transthoracic echocardiography at four different regions (annulus, sinus of Valsalva, sinotubular junction and tubular aorta). A statistically significant difference was found between the groups for the number of grafts used and the duration of aortic cross-clamping and cardiopulmonary bypass. No significant intergroup difference was seen for the mean diameter of the ascending aorta (p > 0.05). Annual changes in the aortic diameter were found to be extremely significantly different in both groups (p = 0.0001). Mean values of the aortic diameter at the level of the sinotubular junction and tubular ascending aorta, mean aortic diameters (p = 0.002 and p = 0.0001, respectively), annual increase in diameter (p = 0.0001 and p = 0.0001, respectively), and mean annual difference in diameter (p = 0.0001 and p = 0.0001, respectively) at one and three years postoperatively were statistically significantly different between the groups. In patients with ascending aortic dilatation who did not require surgical intervention and who had proximal anastomosis of the ascending aorta and underwent only CABG, we detected statistically significant increases in the diameter of the sinotubular junction and tubular aorta up to three years postoperatively.

Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model.

PubMed

Yamazaki, Shinji; Johnson, Theodore R; Smith, Bill J

2015-10-01

An orally available multiple tyrosine kinase inhibitor, crizotinib (Xalkori), is a CYP3A substrate, moderate time-dependent inhibitor, and weak inducer. The main objectives of the present study were to: 1) develop and refine a physiologically based pharmacokinetic (PBPK) model of crizotinib on the basis of clinical single- and multiple-dose results, 2) verify the crizotinib PBPK model from crizotinib single-dose drug-drug interaction (DDI) results with multiple-dose coadministration of ketoconazole or rifampin, and 3) apply the crizotinib PBPK model to predict crizotinib multiple-dose DDI outcomes. We also focused on gaining insights into the underlying mechanisms mediating crizotinib DDIs using a dynamic PBPK model, the Simcyp population-based simulator. First, PBPK model-predicted crizotinib exposures adequately matched clinically observed results in the single- and multiple-dose studies. Second, the model-predicted crizotinib exposures sufficiently matched clinically observed results in the crizotinib single-dose DDI studies with ketoconazole or rifampin, resulting in the reasonably predicted fold-increases in crizotinib exposures. Finally, the predicted fold-increases in crizotinib exposures in the multiple-dose DDI studies were roughly comparable to those in the single-dose DDI studies, suggesting that the effects of crizotinib CYP3A time-dependent inhibition (net inhibition) on the multiple-dose DDI outcomes would be negligible. Therefore, crizotinib dose-adjustment in the multiple-dose DDI studies could be made on the basis of currently available single-dose results. Overall, we believe that the crizotinib PBPK model developed, refined, and verified in the present study would adequately predict crizotinib oral exposures in other clinical studies, such as DDIs with weak/moderate CYP3A inhibitors/inducers and drug-disease interactions in patients with hepatic or renal impairment. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Modeling Rabbit Responses to Single and Multiple Aerosol ...

EPA Pesticide Factsheets

Journal Article Survival models are developed here to predict response and time-to-response for mortality in rabbits following exposures to single or multiple aerosol doses of Bacillus anthracis spores. Hazard function models were developed for a multiple dose dataset to predict the probability of death through specifying dose-response functions and the time between exposure and the time-to-death (TTD). Among the models developed, the best-fitting survival model (baseline model) has an exponential dose-response model with a Weibull TTD distribution. Alternative models assessed employ different underlying dose-response functions and use the assumption that, in a multiple dose scenario, earlier doses affect the hazard functions of each subsequent dose. In addition, published mechanistic models are analyzed and compared with models developed in this paper. None of the alternative models that were assessed provided a statistically significant improvement in fit over the baseline model. The general approach utilizes simple empirical data analysis to develop parsimonious models with limited reliance on mechanistic assumptions. The baseline model predicts TTDs consistent with reported results from three independent high-dose rabbit datasets. More accurate survival models depend upon future development of dose-response datasets specifically designed to assess potential multiple dose effects on response and time-to-response. The process used in this paper to dev

Pharmacokinetics of sulfamethoxazole and trimethoprim in Pacific white shrimp, Litopenaeus vannamei, after oral administration of single-dose and multiple-dose.

PubMed

Ma, Rongrong; Wang, Yuan; Zou, Xiong; Hu, Kun; Sun, Beibei; Fang, Wenhong; Fu, Guihong; Yang, Xianle

2017-06-01

The tissue distribution and depletion of sulfamethoxazole (SMZ) and trimethoprim (TMP) were studied in Pacific white shrimp, Litopenaeus vannamei, after single-dose and multiple-dose oral administration of SMZ-TMP (5:1) via medicated feed. In single-dose oral administration, shrimps were fed once at a dose of 100 mg/kg (drug weight/body weight). In multiple-dose oral administration, shrimps were fed three times a day for three consecutive days at a dose of 100mg/kg. The results showed the kinetic characteristic of SMZ was different from TMP in Pacific white shrimp. In the single-dose administration, the SMZ was widely distributed in the tissues, while TMP was highly concentrated in the hepatopancreas. The t 1/2z values of SMZ were larger and persist longer than TMP in Pacific white shrimp. In the multiple-dose administration, SMZ accumulated well in the tissues, and reached steady state level after successive administrations, while TMP did not. TMP concentration even appeared the downward trend with the increase of drug times. Compared with the single dose, the t 1/2z values of SMZ in hepatopancreas (8.22-11.33h) and muscle (6.53-10.92h) of Pacific white shrimps rose, but the haemolymph dropped (13.76-11.03) in the multiple-dose oral administration. Meanwhile, the corresponding values of TMP also rose in hepatopancreas (4.53-9.65h) and muscle (2.12-2.71h), and declined in haemolymph (7.38-5.25h) following single-dose and multiple-dose oral administration in Pacific white shrimps. In addition, it is worth mentioning that the ratios of SMZ and TMP were unusually larger than the general aim ratio. Copyright © 2017 Elsevier B.V. All rights reserved.

[Hypobaric chamber as a test of the aircrew of Russain Air Forces].

PubMed

Shishov, A A; Olenev, N I; Shishkin, A N; Filatov, V N

2014-04-01

Authors research clinical medical importance of hypobaric ascends to an attitude of 5000 meters for 20 minutes for detection of latent forms of diseases and assessment of professional health and ascends to an attitude of 5000 and 6000 meters for 5 minutes when performing psychophysiological training for high altitude flying. According to test of 1326 pilots of Russian Air Forces, including pilots with different diseases, hypobaric ascends showed high diagnostic effectiveness for the professional health assessment. By using of both methods it was revealed that frequency of detection of decreased tolerance to hypoxia is the same (in average in 2,7 and 3,1% of total number of patients). By ascends in 38 patients (2,9%) was revealed decreased tolerance to hypoxia of medium level. It indicated about low functional state and space capacity of pilots. It was proved that hypobaric ascends of 5000 and 6000 meters for 5 minutes could be considered as an effective method of checkup of aircrew for the aviation physical examination.

Ascending aortic injuries following blunt trauma.

PubMed

Sun, Xiumei; Hong, Jenny; Lowery, Robert; Goldstein, Steven; Wang, Zuyue; Lindsay, Joseph; Hill, Peter C; Corso, Paul J

2013-11-01

The diagnosis and the management of traumatic thoracic aortic injuries have undergone significant changes due to new technology and improved prehospital care. Most of the discussions have focused on descending aortic injuries. In this review, we discuss the recent management of ascending aortic injuries. We found 5 cohort studies on traumatic aortic injuries and 11 case reports describing ascending aortic injuries between 1998 to the present through Medline research. Among case reports, 78.9% of cases were caused by motor vehicle accidents (MVA). 42.1% of patients underwent emergent open repair and the operative mortality was 12.5%. 36.8% underwent delayed repair. Associated injuries occurred in 84.2% of patients. Aortic valve injury was concurrent in 26.3% of patients. The incidence of ascending aortic injury ranged 1.9-20% in cohort studies. Traumatic injuries to the ascending aorta are relatively uncommon among survivors following blunt trauma. Aortography has been replaced by computed tomography and echocardiography as a diagnostic tool. Open repair, either emergent or delayed, remains the treatment of choice. © 2013 Wiley Periodicals, Inc.

Dynamic magmatic processes at a continental rift caldera, observed using satellite geodesy

NASA Astrophysics Data System (ADS)

Lloyd, Ryan; Biggs, Juliet; Birhanu, Yelebe; Wilks, Matt; Gottsmann, Jo; Kendall, Mike; Lewi, Elias

2016-04-01

Large silicic calderas are a key feature of developing continental rifts, such as the Main Ethiopian Rift (MER), and are often observed to be deforming. Corbetti is one such example of a Holocene caldera in the MER that is undergoing deformation. However, the cause of the unrest, and the relationship to rift processes such as magma storage, transport and extension remain poorly understood. To investigate, we use InSAR (ascending and descending Cosmo-SkyMed data) and continuous GPS to observe the temporal and spatial evolution of sustained uplift at the Corbetti Caldera. Within the caldera, which was thought to have formed ~200 ka, there is evidence for numerous periods of resurgent volcanism in the form of plinian eruptions as well as effusive obsidian flows. How the sources of these varying styles of volcanism are reconciled at depth and in time is currently poorly constrained. Previous research has shown that pre-rift structures have a significant influence on the strain field, and hence on the magmatic and hydrothermal processes which drive it. The Cosmo-SkyMed data used in this study was specifically chosen such that each ascending image has a corresponding descending image acquired as contemporaneously as possible. This is necessary, given the rate of uplift, so as to reduce the number of assumptions when constructing time-series from multiple look directions, and when incorporating GPS data. We decompose the ascending and descending line-of-site deformation signals into vertical and east-west components and use finite source modeling to constrain the depth and geometry of the source of deformation. These results are then compared to available seismic, dynamic microgravity and magnetotelluric data to better understand this system, and how it is related to the volcanic hazard and local geothermal resources.

Elevated plasma B-type natriuretic peptide concentration and resistive index, but not decreased aortic distensibility, associate with impaired blood flow at popliteal artery in type 2 diabetic patients.

PubMed

Tajima, Yoshitaka; Suzuki, Eiji; Saito, Jun; Murase, Hiroshi; Horikawa, Yukio; Takeda, Jun

2015-01-01

Blood flow in lower extremity arteries is frequently impaired in diabetic patients even though they have a normal ankle-brachial index (ABI 1.0-1.4). Risk factors contributing to this lower extremity arterial disease have not been fully elucidated. We enrolled 52 type 2 diabetic patients with normal ABI and 30 age-matched nondiabetic subjects consecutively admitted to our hospital. Plasma B-type natriuretic peptide (BNP) concentrations were measured. Distensibility in ascending thoracic and abdominal aortas as well as total flow volume and resistive index at popliteal artery were evaluated by gated magnetic resonance imaging. An automatic device was used to measure ABI and brachial-ankle pulse-wave velocity (baPWV). Diabetic patients showed lower distensibility in ascending thoracic aorta (p<0.001) and total flow volume (p<0.001) and higher baPWV (p<0.001) and resistive index (p=0.005) and similar BNP and distensibility in abdominal aorta compared to nondiabetic subjects. Simple linear regression analyses revealed that distensibility in ascending thoracic (p=0.019) and abdominal (p=0.030) aortas positively as well as baPWV (p=0.020), resistive index (p<0.001) and BNP (p<0.001) negatively correlated with total flow volume. Stepwise multiple regression analysis demonstrated that increased BNP and resistive index were independent risk factors for total flow volume in diabetic patients (r(2)=0.639, p<0.001). These results indicate that increased plasma BNP levels and peripheral vascular resistance, but not decreased aortic distensibility, associate with impaired blood flow in lower extremity arteries in diabetic patients.

A Comparison of Potential IM-CW Lidar Modulation Techniques for ASCENDS CO2 Column Measurements From Space

NASA Technical Reports Server (NTRS)

Campbell, Joel F.; Lin, Bing; Nehrir, Amin R.; Harrison, F. Wallace; Obland, Michael D.; Ismail, Syed

2014-01-01

Global atmospheric carbon dioxide (CO2) measurements through the Active Sensing of CO2 Emissions over Nights, Days, and Seasons (ASCENDS) Decadal Survey recommended space mission are critical for improving our understanding of CO2 sources and sinks. IM-CW (Intensity Modulated Continuous Wave) lidar techniques are investigated as a means of facilitating CO2 measurements from space to meet the ASCENDS science requirements. In previous laboratory and flight experiments we have successfully used linear swept frequency modulation to discriminate surface lidar returns from intermediate aerosol and cloud contamination. Furthermore, high accuracy and precision ranging to the surface as well as to the top of intermediate clouds, which is a requirement for the inversion of the CO2 column-mixing ratio from the instrument optical depth measurements, has been demonstrated with the linear swept frequency modulation technique. We are concurrently investigating advanced techniques to help improve the auto-correlation properties of the transmitted waveform implemented through physical hardware to make cloud rejection more robust in special restricted scenarios. Several different carrier based modulation techniques are compared including orthogonal linear swept, orthogonal non-linear swept, and Binary Phase Shift Keying (BPSK). Techniques are investigated that reduce or eliminate sidelobes. These techniques have excellent auto-correlation properties while possessing a finite bandwidth (by way of a new cyclic digital filter), which will reduce bias error in the presence of multiple scatterers. Our analyses show that the studied modulation techniques can increase the accuracy of CO2 column measurements from space. A comparison of various properties such as signal to noise ratio (SNR) and time-bandwidth product are discussed.

Urinary symptoms following external beam radiotherapy of the prostate: Dose-symptom correlates with multiple-event and event-count models.

PubMed

Yahya, Noorazrul; Ebert, Martin A; Bulsara, Max; House, Michael J; Kennedy, Angel; Joseph, David J; Denham, James W

2015-11-01

This study aimed to compare urinary dose-symptom correlates after external beam radiotherapy of the prostate using commonly utilised peak-symptom models to multiple-event and event-count models which account for repeated events. Urinary symptoms (dysuria, haematuria, incontinence and frequency) from 754 participants from TROG 03.04-RADAR trial were analysed. Relative (R1-R75 Gy) and absolute (A60-A75Gy) bladder dose-surface area receiving more than a threshold dose and equivalent uniform dose using exponent a (range: a ∈[1 … 100]) were derived. The dose-symptom correlates were analysed using; peak-symptom (logistic), multiple-event (generalised estimating equation) and event-count (negative binomial regression) models. Stronger dose-symptom correlates were found for incontinence and frequency using multiple-event and/or event-count models. For dysuria and haematuria, similar or better relationships were found using peak-symptom models. Dysuria, haematuria and high grade (⩾ 2) incontinence were associated to high dose (R61-R71 Gy). Frequency and low grade (⩾ 1) incontinence were associated to low and intermediate dose-surface parameters (R13-R41Gy). Frequency showed a parallel behaviour (a=1) while dysuria, haematuria and incontinence showed a more serial behaviour (a=4 to a ⩾ 100). Relative dose-surface showed stronger dose-symptom associations. For certain endpoints, the multiple-event and event-count models provide stronger correlates over peak-symptom models. Accounting for multiple events may be advantageous for a more complete understanding of urinary dose-symptom relationships. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Left Ventricular Assist Device Implantation with Concomitant Aortic Valve and Ascending Aortic Replacement

PubMed Central

Panholzer, Bernd; Cremer, Jochen; Haneya, Assad

2018-01-01

Left ventricular assist device (LVAD) is nowadays a routine therapy for patients with advanced heart failure. We present the case of a 74-year-old male patient who was admitted to our center with terminal heart failure in dilated cardiomyopathy and ascending aortic aneurysm with aortic valve regurgitation. The LVAD implantation with simultaneous aortic valve and supracoronary ascending aortic replacement was successfully performed. PMID:29552039

Left Ventricular Assist Device Implantation with Concomitant Aortic Valve and Ascending Aortic Replacement.

PubMed

Huenges, Katharina; Panholzer, Bernd; Cremer, Jochen; Haneya, Assad

2018-01-01

Left ventricular assist device (LVAD) is nowadays a routine therapy for patients with advanced heart failure. We present the case of a 74-year-old male patient who was admitted to our center with terminal heart failure in dilated cardiomyopathy and ascending aortic aneurysm with aortic valve regurgitation. The LVAD implantation with simultaneous aortic valve and supracoronary ascending aortic replacement was successfully performed.

Carbon dioxide and ethanol release from champagne glasses, under standard tasting conditions.

PubMed

Liger-Belair, Gérard; Beaumont, Fabien; Bourget, Marielle; Pron, Hervé; Parvitte, Bertrand; Zéninari, Virginie; Polidori, Guillaume; Cilindre, Clara

2012-01-01

A simple glass of champagne or sparkling wine may seem like the acme of frivolity to most people, but in fact, it may rather be considered as a fantastic playground for any fluid physicist or physicochemist. In this chapter, results obtained concerning various steps where the CO₂ molecule plays a role (from its ingestion in the liquid phase during the fermentation process to its progressive release in the headspace above the tasting glass) are gathered and synthesized to propose a self-consistent and global overview of how gaseous and dissolved CO₂ impact champagne and sparkling wine science. Some recent investigations, conducted through laser tomography techniques, on ascending bubbles and ascending-bubble-driven flow patterns found in champagne glasses are reported, which illustrate the fine interplay between ascending bubbles and the fluid around under standard tasting conditions. The simultaneous monitoring of gaseous CO₂ and ethanol in the headspace of both a flute and a coupe filled with champagne was reported, depending on whether or not the glass shows effervescence. Both gaseous CO₂ and ethanol were found to be enhanced by the presence of ascending bubbles, thus confirming the close link between ascending bubbles, ascending-bubble-driven flow patterns, and the release of gaseous CO₂ and volatile organic compounds. Copyright © 2012 Elsevier Inc. All rights reserved.

Aortic valve dysfunction and aortic dilation in adults with coarctation of the aorta.

PubMed

Clair, Mathieu; Fernandes, Susan M; Khairy, Paul; Graham, Dionne A; Krieger, Eric V; Opotowsky, Alexander R; Singh, Michael N; Colan, Steven D; Meijboom, Erik J; Landzberg, Michael J

2014-01-01

To determine the prevalence of aortic valve dysfunction, aortic dilation, and aortic valve and ascending aortic intervention in adults with coarctation of the aorta (CoA). Aortic valve dysfunction and aortic dilation are rare among children and adolescents with CoA. With longer follow-up, adults may be more likely to have progressive disease. We retrospectively reviewed all adults with CoA, repaired or unrepaired, seen at our center between 2004 and 2010. Two hundred sixteen adults (56.0% male) with CoA were identified. Median age at last evaluation was 28.3 (range 18.0 to 75.3) years. Bicuspid aortic valve (BAV) was present in 65.7%. At last follow-up, 3.2% had moderate or severe aortic stenosis, and 3.7% had moderate or severe aortic regurgitation. Dilation of the aortic root or ascending aorta was present in 28.0% and 41.6% of patients, respectively. Moderate or severe aortic root or ascending aortic dilation (z-score > 4) was present in 8.2% and 13.7%, respectively. Patients with BAV were more likely to have moderate or severe ascending aortic dilation compared with those without BAV (19.5% vs. 0%; P < 0.001). Age was associated with ascending aortic dilation (P = 0.04). At most recent follow-up, 5.6% had undergone aortic valve intervention, and 3.2% had aortic root or ascending aortic replacement. In adults with CoA, significant aortic valve dysfunction and interventions during early adulthood were uncommon. However, aortic dilation was prevalent, especially of the ascending aorta, in patients with BAV. © 2013 Wiley Periodicals, Inc.

Augmentation of the Ascending Component of the Peristaltic Reflex and Substance P Release by Glial Cell Line-Derived Neurotrophic Factor (GDNF)

PubMed Central

Grider, JR; Heuckeroth, RO; Kuemmerle, JF; Murthy, KS

2010-01-01

Glial cell line derived neurotrophic factor (GDNF) is present in adult gut although its role in the mature enteric nervous system is not well defined. The aim of the present study was to examine the role of GDNF as neuromodulator of the ascending phase of the peristaltic reflex. Colonic segments were prepared as flat sheets and placed in compartmented chambers so as to separate the sensory and motor limbs of the reflex. Ascending contraction was measured in the orad compartment and mucosal stroking stimuli (2-8 strokes) were applied in the caudad compartment. GDNF and substance P release were measured and the effects of GDNF and GDNF antibody on contraction and release were determined. Mice with reduced levels of GDNF (Gdnf+/-) and wild type littermates were also examined. GDNF was released in a stimulus-dependent manner into the orad motor but not caudad sensory compartment. Addition of GDNF to the orad motor but not caudad sensory compartment augmented ascending contraction and substance P release. Conversely, addition of GDNF antibody to the orad motor but not caudad sensory compartment reduced ascending contraction and substance P release. Similarly, the ascending contraction and substance P release into the orad motor compartment was reduced in Gdnf+/- mice as compared to wild type littermates. The results suggest that endogenous GDNF is released during the ascending contraction component of the peristaltic reflex where it acts as a neuromodulator to augment substance P release from motor neurons thereby augmenting contraction of circular muscle orad to the site of stimulation. PMID:20331804

Augmentation of the ascending component of the peristaltic reflex and substance P release by glial cell line-derived neurotrophic factor.

PubMed

Grider, J R; Heuckeroth, R O; Kuemmerle, J F; Murthy, K S

2010-07-01

Glial cell line-derived neurotrophic factor (GDNF) is present in adult gut although its role in the mature enteric nervous system is not well defined. The aim of the present study was to examine the role of GDNF as neuromodulator of the ascending phase of the peristaltic reflex. Colonic segments were prepared as flat sheets and placed in compartmented chambers so as to separate the sensory and motor limbs of the reflex. Ascending contraction was measured in the orad compartment and mucosal stroking stimuli (two to eight strokes) were applied in the caudad compartment. GDNF and substance P (SP) release were measured and the effects of GDNF and GDNF antibody on contraction and release were determined. Mice with reduced levels of GDNF (Gdnf(+/-)) and wild type littermates were also examined. GDNF was released in a stimulus-dependent manner into the orad motor but not caudad sensory compartment. Addition of GDNF to the orad motor but not caudad sensory compartment augmented ascending contraction and SP release. Conversely, addition of GDNF antibody to the orad motor but not caudad sensory compartment reduced ascending contraction and SP release. Similarly, the ascending contraction and SP release into the orad motor compartment was reduced in Gdnf(+/-) mice as compared to wild type littermates. The results suggest that endogenous GDNF is released during the ascending contraction component of the peristaltic reflex where it acts as a neuromodulator to augment SP release from motor neurons thereby augmenting contraction of circular muscle orad to the site of stimulation.

A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition.

PubMed

Cuvier, V; Lorch, U; Witte, S; Olivier, A; Gibot, S; Delor, I; Garaud, J J; Derive, M; Magguilli-Salcedo, M

2018-06-08

The peptide nangibotide is the first clinical-stage agent targeting the immunoreceptor TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) and is being investigated as a novel therapy for acute inflammatory disorders such as septic shock. This first-in-man, randomised, double-blind, ascending dose, placebo-controlled Phase I study evaluated the safety, tolerability, and pharmacokinetics of nangibotide. 27 healthy subjects (aged 18-45 years) were randomised into eight groups. Nangibotide was administered as a single continuous intravenous infusion. The first two groups received a single I.V. dose of 1 and 10 mg, respectively, over 15 min. Subsequent groups were randomised in a product: placebo 3:1 ratio at doses ranging from 0.03 to 6 mg/kg/h over 7 h 45 min, preceded by a 15-minute loading dose of up to 5 mg/kg. Nangibotide was safe and well tolerated up to the highest dose tested. There were only few adverse events and they were mild in severity and considered unrelated to treatment. Nangibotide displayed dose-proportional PK properties, with a clearance of 6.6 L/kg/h for a subject of 70 kg and a 3 min effective half-life, which are compatible with extensive enzymatic metabolism in blood. Central and peripheral volumes of distribution were 16.7 L and 15.9 L respectively, indicating limited distribution of the drug mainly in blood and interstitial fluid. No circulating anti-drug antibodies were detectable up to 28 days after administration. The novel immunomodulator nangibotide displayed favourable safety and PK profiles at all doses, including expected pharmacologically active doses, and warrants further clinical development. This article is protected by copyright. All rights reserved.

LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2-overexpressing breast or gastric cancer.

PubMed

Takahashi, Shunji; Kobayashi, Takayuki; Tomomatsu, Junichi; Ito, Yoshinori; Oda, Hisanobu; Kajitani, Tatsuhiro; Kakizume, Tomoyuki; Tajima, Takeshi; Takeuchi, Hiromi; Maacke, Heiko; Esaki, Taito

2017-01-01

Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients. LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status. The maximum tolerated dose was not reached, and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer, and 50% of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11-14 days. No anti-LJM716 antibodies were detected. LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed. ClinicalTrials.gov NCT01911936.

High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens

PubMed Central

Carter, Lawrence P.; Johnson, Matthew W.; Mintzer, Miriam Z.; Klinedinst, Margaret A.; Griffiths, Roland R.

2013-01-01

Rationale Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM. Objective This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam. Methods Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg/70kg), and placebo were administered to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Subjective, behavioral, and physiological effects were assessed repeatedly after drug administration for 6 hours. Results Triazolam produced dose-related increases in subject-rated sedation, observer-rated sedation, and behavioral impairment. DXM produced a profile of dose-related physiological and subjective effects differing from triazolam. DXM effects included increases in blood pressure, heart rate, and emesis, increases in observer-rated effects typical of classic hallucinogens (e.g. distance from reality, visual effects with eyes open and closed, joy, anxiety), and participant ratings of stimulation (e.g. jittery, nervous), somatic effects (e.g. tingling, headache), perceptual changes, end-of-session drug liking, and mystical-type experience. After 400 mg/70kg DXM, 11 of 12 participants indicated on a pharmacological class questionnaire that they thought they had received a classic hallucinogen (e.g. psilocybin). Drug effects resolved without significant adverse effects by the end of the session. In a 1-month follow up volunteers attributed increased spirituality and positive changes in attitudes, moods, and behavior to the session experiences. Conclusions High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin. PMID:22526529

Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients.

PubMed

Cadranel, Jacques; Cortot, Alexis B; Lena, Hervé; Mennecier, Bertrand; Do, Pascal; Dansin, Eric; Mazieres, Julien; Chouaid, Christos; Perol, Maurice; Barlesi, Fabrice; Robinet, Gilles; Friard, Sylvie; Thiberville, Luc; Audigier-Valette, Clarisse; Vergnenegre, Alain; Westeel, Virginie; Slimane, Khemaies; Buturuga, Alexandru; Moro-Sibilot, Denis; Besse, Benjamin

2018-01-01

Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase ( ALK ) positive ( ALK + ) non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced ALK + or ROS proto-oncogene 1 positive ( ROS1 + ) tumours. Patients received oral ceritinib (750 mg·day -1 as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had ALK + NSCLC and 13 had ROS1 + NSCLC. The median age of ALK + patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and 50.0% had brain metastases. Of the 149 efficacy evaluable ALK + NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0% versus 42.4%) and those receiving prior crizotinib for >5 months (51.6% versus 36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day -1 ) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with ALK + NSCLC.

Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial.

PubMed

Forteza, Alberto; Evangelista, Arturo; Sánchez, Violeta; Teixidó-Turà, Gisela; Sanz, Paz; Gutiérrez, Laura; Gracia, Teresa; Centeno, Jorge; Rodríguez-Palomares, José; Rufilanchas, Juan Jose; Cortina, José; Ferreira-González, Ignacio; García-Dorado, David

2016-03-21

To determine the efficacy of losartan vs. atenolol in aortic dilation progression in Marfan syndrome (MFS) patients. A phase IIIb, randomized, parallel, double-blind study was conducted in 140 MFS patients, age range: 5-60 years, with maximum aortic diameter <45 mm who received losartan (n = 70) or atenolol (n = 70). Doses were raised to a maximum of 1.4 mg/kg/day or 100 mg/day. The primary end-point was the change in aortic root and ascending aorta maximum diameter indexed by body surface area on magnetic resonance imaging after 36 months of treatment. No serious drug-related adverse effects were observed. Five patients presented aortic events during a follow-up (one in the losartan and four in the atenolol groups, P = 0.366). After 3 years of follow-up, aortic root diameter increased significantly in both groups: 1.1 mm (95% CI 0.6-1.6) in the losartan and 1.4 mm (95% CI 0.9-1.9) in the atenolol group, with aortic dilatation progression being similar in both groups: absolute difference between losartan and atenolol -0.3 mm (95% CI -1.1 to 0.4, P = 0.382) and indexed by BSA -0.5 mm/m2 (95% CI -1.2 to 0.1, P = 0.092). Similarly, no significant differences were found in indexed ascending aorta diameter changes between the losartan and atenolol groups: -0.3 mm/m2 (95% CI -0.8 to 0.3, P = 0.326). Among patients with MFS, the use of losartan compared with atenolol did not result in significant differences in the progression of aortic root and ascending aorta diameters over 3 years of follow-up. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Longitudinal and Circumferential Strain of the Proximal Aorta

PubMed Central

Bell, Vanessa; Mitchell, William A.; Sigurðsson, Sigurður; Westenberg, Jos J. M.; Gotal, John D.; Torjesen, Alyssa A.; Aspelund, Thor; Launer, Lenore J.; de Roos, Albert; Gudnason, Vilmundur; Harris, Tamara B.; Mitchell, Gary F.

2014-01-01

Background Accurate assessment of mechanical properties of the proximal aorta is a requisite first step for elucidating the pathophysiology of isolated systolic hypertension. During systole, substantial proximal aortic axial displacement produces longitudinal strain, which we hypothesize causes variable underestimation of ascending aortic circumferential strain compared to values in the longitudinally constrained descending aorta. Methods and Results To assess effects of longitudinal strain, we performed magnetic resonance imaging in 375 participants (72 to 94 years old, 204 women) in the Age, Gene/Environment Susceptibility‐Reykjavik Study and measured aortic circumferential and longitudinal strain. Circumferential ascending aortic area strain uncorrected for longitudinal strain was comparable in women and men (mean [95% CI], 8.3 [7.8, 8.9] versus 7.9 [7.4, 8.5]%, respectively, P=0.3). However, longitudinal strain was greater in women (8.5±2.5 versus 7.0±2.5%, P<0.001), resulting in greater longitudinally corrected circumferential ascending aortic strain (14.4 [13.6, 15.2] versus 13.0 [12.4, 13.7]%, P=0.010). Observed circumferential descending aortic strain, which did not require correction (women: 14.0 [13.2, 14.8], men: 12.4 [11.6, 13.2]%, P=0.005), was larger than uncorrected (P<0.001), but comparable to longitudinally corrected (P=0.12) circumferential ascending aortic strain. Carotid‐femoral pulse wave velocity did not correlate with uncorrected ascending aortic strain (R=−0.04, P=0.5), but was inversely related to longitudinally corrected ascending and observed descending aortic strain (R=−0.15, P=0.004; R=−0.36, P<0.001, respectively). Longitudinal strain was also inversely related to carotid‐femoral pulse wave velocity and other risk factors for higher aortic stiffness including treated hypertension. Conclusions Longitudinal strain creates substantial and variable errors in circumferential ascending aortic area strain measurements, particularly in women, and should be considered to avoid misclassification of ascending aortic stiffness. PMID:25523153

Loss of pulse pressure amplification between the ascending and descending aorta in patients after an aortic arch repair.

PubMed

Murakami, Tomoaki; Shiraishi, Masahiro; Nawa, Tomohiro; Takeda, Atsuhito

2017-03-01

One of the most important problems in patients with an aortic coarctation after an aortic arch repair is future cardiovascular disease. We previously reported the enhancement of the aortic pressure wave reflection in patients and hypothesized that the enhancement was caused by a new pressure wave reflection generated from the repaired site. To prove the hypothesis, we analyzed the pressure waveform in the ascending and descending aorta and examined their pulse pressure (PP) amplification. Fifteen patients after an aortic arch repair without a recoarctation were enrolled. The ascending and descending aorta pressure waveforms were recorded by a pressure sensor mounted catheter. The pressures were compared with those of age-matched controls. The patient's age was 7.3 ± 2.7 years, and they underwent the aortic arch repair at 30.1 ± 29.0 days. The ascending aorta SBP (106.1 ± 12.7 mmHg) was higher than in the control patients (97.9 ± 14.3) (P = 0.015). The PP at the ascending aorta in the patients (41.3 ± 7.8) was wider than that in the controls (36.4 ± 5.0) (P = 0.010). There was no difference concerning the PP at the descending aorta between the patients (41.0 ± 7.7) and controls (40.5 ± 6.5). The difference in the PP between the descending and ascending aorta (PP at the descending aorta - PP at the ascending aorta) in the patients was -0.3 ± 1.7 and 5.1 ± 2.9 in the controls (P < 0.0001). The ascending aortic PP was augmented in the patients after the aortic arch repair. It could be one of the causes of future cardiovascular disease.

Diagnostic performance of focused cardiac ultrasound performed by emergency physicians for the assessment of ascending aorta dilation and aneurysm.

PubMed

Nazerian, Peiman; Vanni, Simone; Morello, Fulvio; Castelli, Matteo; Ottaviani, Maddalena; Casula, Claudia; Petrioli, Alessandra; Bartolucci, Maurizio; Grifoni, Stefano

2015-05-01

The diagnostic performance of transthoracic focused cardiac ultrasound (FoCUS) performed by emergency physicians (EP) to estimate ascending aorta dimensions in the acute setting has not been prospectively studied. The diagnostic accuracy and the interobserver variability of EP-performed FoCUS were investigated to estimate thoracic aortic dilation and aneurysm compared with the results of computed tomography angiography (CTA). This was a prospective single-center cohort study of a convenience sample of patients who underwent CTA in the emergency department for suspected aortic pathology. FoCUS was performed before CTA, and the maximum ascending aorta diameter evaluated in parasternal long-axis view. Aorta diameter < 40 mm by visual estimation or by diameter measurement was considered normal. Measurements were recorded in all patients with aorta diameter ≥ 40 mm. Diagnostic accuracy of FoCUS for detection of aortic dilation (diameter ≥ 40 mm) and aneurysm (diameter ≥ 45 mm) were calculated considering the CTA result as reference standard. In a subgroup of patients, a second EP-sonographer performed FoCUS to evaluate interobserver agreement for the diagnosis of ascending aorta dilation. A total of 140 patients were enrolled in the study. Ascending aorta dilation and aneurysm were detected with FoCUS in 50 (35.7%) and in 27 (17.8%) patients, respectively. Sensitivity and specificity of FoCUS were 78.6% (95% confidence interval [CI] = 65.6% to 88.4%) and 92.9% (95% CI = 85.1% to 97.3%), respectively, for ascending aorta dilation and 64.7% (95% CI = 46.5% to 80.2%) and 95.3% (95% CI = 89.3% to 98.4%), respectively, for ascending aorta aneurysm. Interobserver agreement of FoCUS was k = 0.82. FoCUS performed by EP is specific for ascending aorta dilation and aneurysm when compared to CTA and appears a reproducible technique. © 2015 by the Society for Academic Emergency Medicine.

Bacterial Hyaluronidase Promotes Ascending GBS Infection and Preterm Birth.

PubMed

Vornhagen, Jay; Quach, Phoenicia; Boldenow, Erica; Merillat, Sean; Whidbey, Christopher; Ngo, Lisa Y; Adams Waldorf, K M; Rajagopal, Lakshmi

2016-06-28

Preterm birth increases the risk of adverse birth outcomes and is the leading cause of neonatal mortality. A significant cause of preterm birth is in utero infection with vaginal microorganisms. These vaginal microorganisms are often recovered from the amniotic fluid of preterm birth cases. A vaginal microorganism frequently associated with preterm birth is group B streptococcus (GBS), or Streptococcus agalactiae However, the molecular mechanisms underlying GBS ascension are poorly understood. Here, we describe the role of the GBS hyaluronidase in ascending infection and preterm birth. We show that clinical GBS strains associated with preterm labor or neonatal infections have increased hyaluronidase activity compared to commensal strains obtained from rectovaginal swabs of healthy women. Using a murine model of ascending infection, we show that hyaluronidase activity was associated with increased ascending GBS infection, preterm birth, and fetal demise. Interestingly, hyaluronidase activity reduced uterine inflammation but did not impact placental or fetal inflammation. Our study shows that hyaluronidase activity enables GBS to subvert uterine immune responses, leading to increased rates of ascending infection and preterm birth. These findings have important implications for the development of therapies to prevent in utero infection and preterm birth. GBS are a family of bacteria that frequently colonize the vagina of pregnant women. In some cases, GBS ascend from the vagina into the uterine space, leading to fetal injury and preterm birth. Unfortunately, little is known about the mechanisms underlying ascending GBS infection. In this study, we show that a GBS virulence factor, HylB, shows higher activity in strains isolated from cases of preterm birth than those isolates from rectovaginal swabs of healthy women. We discovered that GBS rely on HylB to avoid immune detection in uterine tissue, but not placental tissue, which leads to increased rates of fetal injury and preterm birth. These studies provide novel insight into the underlying mechanisms of ascending infection. Copyright © 2016 Vornhagen et al.

Impact of multiple-dose versus single-dose inhaler devices on COPD patients’ persistence with long-acting β2-agonists: a dispensing database analysis

PubMed Central

van Boven, Job FM; van Raaij, Joost J; van der Galiën, Ruben; Postma, Maarten J; van der Molen, Thys; Dekhuijzen, PN Richard; Vegter, Stefan

2014-01-01

Background: With a growing availability of different devices and types of medication, additional evidence is required to assist clinicians in prescribing the optimal medication in relation to chronic obstructive pulmonary disease (COPD) patients’ persistence with long-acting β2-agonists (LABAs). Aims: To assess the impact of the type of inhaler device (multiple-dose versus single-dose inhalers) on 1-year persistence and switching patterns with LABAs. Methods: A retrospective observational cohort study was performed comparing a cohort of patients initiating multiple-dose inhalers and a cohort initiating single-dose inhalers. The study population consisted of long-acting bronchodilator naive COPD patients, initiating inhalation therapy with mono-LABAs (formoterol, indacaterol or salmeterol). Analyses were performed using pharmacy dispensing data from 1994 to 2012, obtained from the IADB.nl database. Study outcomes were 1-year persistence and switching patterns. Results were adjusted for initial prescriber, initial medication, dosing regimen and relevant comorbidities. Results: In all, 575 patients initiating LABAs were included in the final study cohort. Among them, 475 (83%) initiated a multiple-dose inhaler and 100 (17%) a single-dose inhaler. Further, 269 (47%) initiated formoterol, 9 (2%) indacaterol and 297 (52%) salmeterol. There was no significant difference in persistence between users of multiple-dose or single-dose inhalers (hazard ratio: 0.98, 95% confidence interval: 0.76–1.26, P=0.99). Over 80% re-started or switched medication. Conclusions: There seems no impact of inhaler device (multiple-dose versus single-dose inhalers) on COPD patients’ persistence with LABAs. Over 80% of patients who initially seemed to discontinue LABAs, re-started their initial medication or switched inhalers or medication within 1 year. PMID:25274453

Salicylate-induced changes in auditory thresholds of adolescent and adult rats.

PubMed

Brennan, J F; Brown, C A; Jastreboff, P J

1996-01-01

Shifts in auditory intensity thresholds after salicylate administration were examined in postweanling and adult pigmented rats at frequencies ranging from 1 to 35 kHz. A total of 132 subjects from both age levels were tested under two-way active avoidance or one-way active avoidance paradigms. Estimated thresholds were inferred from behavioral responses to presentations of descending and ascending series of intensities for each test frequency value. Reliable threshold estimates were found under both avoidance conditioning methods, and compared to controls, subjects at both age levels showed threshold shifts at selective higher frequency values after salicylate injection, and the extent of shifts was related to salicylate dose level.

76 FR 20513 - Revision of the Requirements for Constituent Materials

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-13

... in multiple-dose containers must contain a preservative, except that a preservative need not be added... contamination of multiple-dose containers of vaccines that did not contain a preservative.\\2\\ As discussed... Workshop on Thimerosal Vaccines,'' p. 24, August 11, 1999. Preservatives in multiple-dose containers have a...

Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes.

PubMed

Hatorp, V; Huang, W C; Strange, P

1999-04-01

Pharmacokinetic profiles of single- and multiple-dose regimens of repaglinide were evaluated in 12 elderly subjects with type 2 diabetes. On day 1, following a 10-hour fast, subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, each subject received a 2-mg dose of repaglinide 15 minutes before each of the three main meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve (AUC), log(AUC), maximal concentration (Cmax), log(Cmax), time to maximal concentration (Tmax), and half-life (T(1/2)), were determined at completion of the single- and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7. The mean log(AUC) values after multiple dosing were significantly higher than the values obtained after a single dose. The mean values for log(Cmax), and Tmax were comparable after each dosing regimen. The T(1/2) of repaglinide after multiple dosing was 1.7 hours. The trough values for repaglinide were low. No hypoglycemic events were reported. The pharmacokinetic profiles of repaglinide after single- and multiple-dose regimens were similar, and repaglinide was well tolerated by elderly subjects with type 2 diabetes.

Reproducibility of the kinematics and kinetics of the lower extremity during normal stair-climbing.

PubMed

Yu, B; Kienbacher, T; Growney, E S; Johnson, M E; An, K N

1997-05-01

The purpose of this study was to examine the intrasubject reproducibility of the kinematic and kinetic measures of the lower extremity during normal stair-climbing. Three-dimensional video and force-plate data were collected for three trials per subject during each of three conditions: ascending, descending, and level walking. Three-dimensional angles and moments of the ankle, knee, and hip joints were calculated. The coefficient of multiple correlation was used to determine the intrasubject reproducibility of joint angles and resultant moments. Analysis of variance with repeated measures was conducted to compare the magnitudes of the coefficients between different steps, different joints, and different joint functions. The results showed that (a) generally, the kinematic and kinetic measures of normal subjects climbing stairs were reproducible; (b) the kinetic measures during the transition steps from level walking to ascending and from descending to level walking were significantly less reproducible than those during the other steps; (c) the data from the sagittal plane were more reproducible than those from the other two planes; and (d) the kinetic measures were more reproducible than the kinematic measures, especially for abduction-adduction and internal-external rotation.

Concentrations and loads of cadmium, lead, and zinc measured on the ascending and descending limbs of the 1999 snowmelt-runoff hydrographs for nine water-quality stations, Coeur d'Alene River basin, Idaho

USGS Publications Warehouse

Woods, Paul F.

2001-01-01

Hysteresis effects on concentrations and loads over the ascending and descending limbs of the snowmelt-runoff hydrograph were quite apparent, especially for whole-water recoverable constituents. Hysteresis is present when a property, such as constituent concentration or load, has different values for a given discharge over the ascending and descending limbs of a hydrograph. During this study, loads of whole-water recoverable constituents on the ascending limb were between 1.5 and 3.6 times larger than those mea- sured on the descending limb at nearly equal discharge. In contrast, dissolved constituents showed minimal hysteresis effects.

Natural history of moderately dilated tubular ascending aorta: implications for determining the optimal imaging interval.

PubMed

Park, Kay-Hyun; Chung, Suryeun; Kim, Dong Jung; Kim, Jun Sung; Lim, Cheong

2017-05-01

For a moderately dilated ascending aorta (diameter 35-54 mm), current guidelines recommend continuous annual or semi-annual examinations with computed tomography or magnetic resonance imaging. However, few data have shown the yield and benefit of such a protocol. This study aimed to investigate the fate of a moderately dilated ascending aorta and thereby determine the adequate imaging interval. In our institutional database, we identified adult patients having an ascending aortic diameter ≥40 mm in contrast-enhanced computed tomography and follow-up imaging(s) after ≥1 year. Of the 509 patients (mean age 67.2 ± 10.4 years) enrolled in the study, the maximal diameter of the ascending aorta was compared between the first and last images. Also, their medical records were reviewed to investigate the associated illness and clinical events. The mean growth rate of the patients with a 40-44 mm ( n  = 321), 45-49 mm ( n  = 142) and ≥50 mm ( n  = 46) ascending aorta was 0.3 ± 0.5, 0.3 ± 0.5 and 0.7 ± 0.9 mm/year, respectively. During the mean interval of 4.3 ± 2.4 years, significant progression (diameter increase by ≥5 mm) occurred in 3.4, 5.6 and 21.7%, respectively. The 3- to 5-year rates of freedom from significant progression were 99.1%-96.5% (40-44 mm) and 97.8%-96.4% (45-49 mm). In multivariate analysis, initial ascending aortic diameter ≥45 mm and aortic valve regurgitation were significantly associated with significant progression. Acute type A aortic dissection occurred in 5 patients (1%), before the maximal diameter of the ascending aorta reached 55 mm or significant progression was observed. For a moderately dilated ascending aorta not exceeding 45 mm in maximal diameter and stable in the first annual follow-up image, a 3- to 4-year interval would be reasonable before subsequent imaging. More frequent imaging may be warranted in patients with aortic valve insufficiency or with an aortic diameter ≥45 mm. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Single- and multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel agent for the treatment of premature ejaculation.

PubMed

Modi, Nishit B; Dresser, Mark J; Simon, Mary; Lin, Denise; Desai, Dhaval; Gupta, Suneel

2006-03-01

Dapoxetine is a serotonin transporter inhibitor currently in development for the treatment of premature ejaculation. This randomized, 2-sequence, 2-treatment crossover study assessed the single- and multiple-dose pharmacokinetics of dapoxetine following once-daily administration of dapoxetine 30 mg and 60 mg to healthy male volunteers. Dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations reached approximately 1 hour after dosing; plasma concentrations after single doses of dapoxetine decreased rapidly to approximately 5% of peak concentrations by 24 hours. Elimination was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours. Dapoxetine showed time-invariant pharmacokinetics and dose proportionality between doses, and its pharmacokinetics was unaffected by multiple dosing. The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing. There were no serious adverse events; the most commonly reported adverse events were diarrhea, dizziness, and nausea.

Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade.

PubMed

Kuang, Shao-Qing; Geng, Liang; Prakash, Siddharth K; Cao, Jiu-Mei; Guo, Steven; Villamizar, Carlos; Kwartler, Callie S; Peters, Andrew M; Brasier, Allan R; Milewicz, Dianna M

2013-09-01

Although hypertension is the most common risk factor for thoracic aortic diseases, it is not understood how increased pressures on the ascending aorta lead to aortic aneurysms. We investigated the role of angiotensin II type 1 receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model. Two weeks after TAC, the increased biomechanical pressures led to ascending aortic dilatation and thickening of the medial and adventitial layers of the aorta. There was significant adventitial hyperplasia and inflammatory responses in TAC ascending aortas were accompanied by increased adventitial collagen, elevated inflammatory and proliferative markers, and increased cell density attributable to accumulation of myofibroblasts and macrophages. Treatment with losartan significantly blocked TAC-induced vascular inflammation and macrophage accumulation. However, losartan only partially prevented TAC-induced adventitial hyperplasia, collagen accumulation, and ascending aortic dilatation. Increased Tgfb2 expression and phosphorylated-Smad2 staining in the medial layer of TAC ascending aortas were effectively blocked with losartan. In contrast, the increased Tgfb1 expression and adventitial phospho-Smad2 staining were only partially attenuated by losartan. In addition, losartan significantly blocked extracellular signal-regulated kinase activation and reactive oxygen species production in the TAC ascending aorta. Inhibition of the angiotensin II type 1 receptor using losartan significantly attenuated the vascular remodeling associated with TAC but did not completely block the increased transforming growth factor-β1 expression, adventitial Smad2 signaling, and collagen accumulation. These results help to delineate the aortic transforming growth factor-β signaling that is dependent and independent of the angiotensin II type 1 receptor after TAC.

Machine-learning phenotypic classification of bicuspid aortopathy.

PubMed

Wojnarski, Charles M; Roselli, Eric E; Idrees, Jay J; Zhu, Yuanjia; Carnes, Theresa A; Lowry, Ashley M; Collier, Patrick H; Griffin, Brian; Ehrlinger, John; Blackstone, Eugene H; Svensson, Lars G; Lytle, Bruce W

2018-02-01

Bicuspid aortic valves (BAV) are associated with incompletely characterized aortopathy. Our objectives were to identify distinct patterns of aortopathy using machine-learning methods and characterize their association with valve morphology and patient characteristics. We analyzed preoperative 3-dimensional computed tomography reconstructions for 656 patients with BAV undergoing ascending aorta surgery between January 2002 and January 2014. Unsupervised partitioning around medoids was used to cluster aortic dimensions. Group differences were identified using polytomous random forest analysis. Three distinct aneurysm phenotypes were identified: root (n = 83; 13%), with predominant dilatation at sinuses of Valsalva; ascending (n = 364; 55%), with supracoronary enlargement rarely extending past the brachiocephalic artery; and arch (n = 209; 32%), with aortic arch dilatation. The arch phenotype had the greatest association with right-noncoronary cusp fusion: 29%, versus 13% for ascending and 15% for root phenotypes (P < .0001). Severe valve regurgitation was most prevalent in root phenotype (57%), followed by ascending (34%) and arch phenotypes (25%; P < .0001). Aortic stenosis was most prevalent in arch phenotype (62%), followed by ascending (50%) and root phenotypes (28%; P < .0001). Patient age increased as the extent of aneurysm became more distal (root, 49 years; ascending, 53 years; arch, 57 years; P < .0001), and root phenotype was associated with greater male predominance compared with ascending and arch phenotypes (94%, 76%, and 70%, respectively; P < .0001). Phenotypes were visually recognizable with 94% accuracy. Three distinct phenotypes of bicuspid valve-associated aortopathy were identified using machine-learning methodology. Patient characteristics and valvular dysfunction vary by phenotype, suggesting that the location of aortic pathology may be related to the underlying pathophysiology of this disease. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Ascending-ramp biphasic waveform has a lower defibrillation threshold and releases less troponin I than a truncated exponential biphasic waveform.

PubMed

Huang, Jian; Walcott, Gregory P; Ruse, Richard B; Bohanan, Scott J; Killingsworth, Cheryl R; Ideker, Raymond E

2012-09-11

We tested the hypothesis that the shape of the shock waveform affects not only the defibrillation threshold but also the amount of cardiac damage. Defibrillation thresholds were determined for 11 waveforms-3 ascending-ramp waveforms, 3 descending-ramp waveforms, 3 rectilinear first-phase biphasic waveforms, a Gurvich waveform, and a truncated exponential biphasic waveform-in 6 pigs with electrodes in the right ventricular apex and superior vena cava. The ascending, descending, and rectilinear waveforms had 4-, 8-, and 16-millisecond first phases and a 3.5-millisecond rectilinear second phase that was half the voltage of the first phase. The exponential biphasic waveform had a 60% first-phase and a 50% second-phase tilt. In a second study, we attempted to defibrillate after 10 seconds of ventricular fibrillation with a single ≈30-J shock (6 pigs successfully defibrillated with 8-millisecond ascending, 8-millisecond rectilinear, and truncated exponential biphasic waveforms). Troponin I blood levels were determined before and 2 to 10 hours after the shock. The lowest-energy defibrillation threshold was for the 8-milliseconds ascending ramp (14.6±7.3 J [mean±SD]), which was significantly less than for the truncated exponential (19.6±6.3 J). Six hours after shock, troponin I was significantly less for the ascending-ramp waveform (0.80±0.54 ng/mL) than for the truncated exponential (1.92±0.47 ng/mL) or the rectilinear waveform (1.17±0.45 ng/mL). The ascending ramp has a significantly lower defibrillation threshold and at ≈30 J causes 58% less troponin I release than the truncated exponential biphasic shock. Therefore, the shock waveform affects both the defibrillation threshold and the amount of cardiac damage.

Cerebral and Renal Oxygen Saturation Are Not Compromised in the Presence of Retrograde Blood Flow in either the Ascending or Descending Aorta in Term or Near-Term Infants with Left-Sided Obstructive Lesions.

PubMed

van der Laan, Michelle E; Mebius, Mirthe J; Roofthooft, Marcus T R; Bos, Arend F; Berger, Rolf M F; Kooi, Elisabeth M W

2017-01-01

In infants with left-sided obstructive lesions (LSOL), the presence of retrograde blood flow in either the ascending or descending aorta may lead to diminished cerebral and renal blood flow, respectively. Our aim was to compare cerebral and renal tissue oxygen saturation (rSO2) between infants with LSOL with antegrade and retrograde blood flow in the ascending aorta and with and without diastolic backflow in the descending aorta. Based on 2 echocardiograms, the study group was categorized according to the direction of blood flow in the ascending and descending aorta. We measured cerebral and renal rSO2 using near-infrared spectroscopy and calculated fractional tissue oxygen extraction (FTOE). Nineteen infants with LSOL, admitted to the NICU between 0 and 28 days after birth, were included. Infants with antegrade blood flow (n = 12) and infants with retrograde blood flow in the ascending aorta (n = 7) had similar cerebral rSO2 and FTOE during both echocardiograms. Only during the first echocardiogram, infants with retrograde blood flow in the ascending aorta had lower renal FTOE (0.14 vs. 0.32, p = 0.04) and tended to have higher renal rSO2 (80 vs. 65%, p = 0.09). The presence of diastolic backflow in the descending aorta was not associated with cerebral or renal rSO2 and FTOE during the first (n = 8) as well as the second echocardiogram (n = 10). Retrograde blood flow in the ascending aorta was not associated with cerebral oxygenation, while diastolic backflow in the descending aorta was not associated with renal oxygenation in infants with LSOL. © 2017 S. Karger AG, Basel.

Hemiarch Reconstruction Vs Clamped Aortic Anastomosis for Concomitant Ascending Aortic Aneurysm.

PubMed

Sultan, Ibrahim; Bianco, Valentino; Yajzi, Ibrahim; Kilic, Arman; Dufendach, Keith; Cardounel, Arturo; Althouse, Andrew D; Masri, Ahmad; Navid, Forozan; Gleason, Thomas G

2018-05-03

Deep hypothermic circulatory arrest (DHCA) is often avoided in patients with concomitant ascending aortic pathology when treating other cardiac disease to avoid increased risk of morbidity and mortality. We hypothesized that the use of DHCA with retrograde cerebral perfusion (RCP) does not add incremental risk to ascending aortic replacement alone in the setting of concomitant cardiac surgery. 408 ascending aortic ± hemiarch replacements and aortic (root)/mitral/tricuspid valve(s), CABG, or MAZE procedures were performed for concomitant cardiac disease. DHCA with RCP was used for all hemiarch replacements or the ascending aorta was replaced with an aortic cross-clamp proximal to the innominate artery. Propensity-score matching was used to match similar ascending patients vs. hemiarch patients; the final propensity score matched patients on age, gender, BMI, previous heart surgery, pre-op aortic insufficiency, pre-op aortic stenosis, pre-op EF, and operative variables. Propensity-score matching yielded 116 pairs of Non-hemiarch patients vs. 116 hemiarch patients. Within the propensity-score matched cohort, there were no differences in postoperative stroke (1.7% vs. 3.4%, p = 0.41), new postoperative dialysis (6.0% vs. 5.2%, p = 0.78), postoperative renal insufficiency (27.6% vs. 19.8%, p = 0.16), 30-day mortality (2.6% vs. 3.4%, p = 0.701), or 1-year mortality (4.3% vs. 4.3%, p = 1.00) CONCLUSIONS: Hemiarch replacement using DHCA with RCP does not increase the risk of operative complications compared to a normothermic, clamped-distal aortic anastomosis, and therefore its use should not be limited when planning complex multi-procedural reconstructions during elective ascending thoracic aortic replacement with concomitant cardiac surgery. Copyright © 2018. Published by Elsevier Inc.

SPARKy - Spring Ankle with Regenerative Kinetics to Build a New Generation of Transtibial Prostheses

DTIC Science & Technology

2010-07-01

walking on inclines/declines, and ascending/descending stairs We are able to walk continuously over ground and can walk up and down slopes and... stairs . Walking up a slope and ascending stairs needs to be improved, adding extra propulsion. The propulsion walking down stairs needs to be...bodied subjects walking on flat even surfaces, inclines/declines, and ascending/descending stairs – In Process 4. Using able bodied test data, a

Ascending aorta dilatation in patients with bicuspid aortic valve stenosis: a prospective CMR study.

PubMed

Rossi, Alexia; van der Linde, Denise; Yap, Sing Chien; Lapinskas, Thomas; Kirschbaum, Sharon; Springeling, Tirza; Witsenburg, Maarten; Cuypers, Judith; Moelker, Adriaan; Krestin, Gabriel P; van Dijk, Arie; Johnson, Mark; van Geuns, Robert-Jan; Roos-Hesselink, Jolien W

2013-03-01

The aim of this study was to evaluate the natural progression of aortic dilatation and its association with aortic valve stenosis (AoS) in patients with bicuspid aortic valve (BAV). Prospective study of aorta dilatation in patients with BAV and AoS using cardiac magnetic resonance (CMR). Aortic root, ascending aorta, aortic peak velocity, left ventricular systolic and diastolic function and mass were assessed at baseline and at 3-year follow-up. Of the 33 enrolled patients, 5 needed surgery, while 28 patients (17 male; mean age: 31 ± 8 years) completed the study. Aortic diameters significantly increased at the aortic annulus, sinus of Valsalva and tubular ascending aorta levels (P < 0.050). The number of patients with dilated tubular ascending aortas increased from 32 % to 43 %. No significant increase in sino-tubular junction diameter was observed. Aortic peak velocity, ejection fraction and myocardial mass significantly increased while the early/late filling ratio significantly decreased at follow-up (P < 0.050). The progression rate of the ascending aorta diameter correlated weakly with the aortic peak velocity at baseline (R (2) = 0.16, P = 0.040). BAV patients with AoS showed a progressive increase of aortic diameters with maximal expression at the level of the tubular ascending aorta. The progression of aortic dilatation correlated weakly with the severity of AoS.

Correlation of ascending aorta elasticity and the severity of coronary artery stenosis in hypertensive patients with coronary heart disease assessed by M-mode and tissue Doppler echocardiography.

PubMed

Lu, Qixiu; Liu, Houlin

2015-03-01

The main objective of this study is to investigate the relationship between ascending aorta elasticity and the severity of coronary artery stenosis in essential hypertensive patients with coronary heart disease (CHD) using M-mode and tissue Doppler echocardiography. A total of 184 hypertensive patients with CHD were enrolled. Patients were divided into three groups based on the severity of coronary stenosis measured by coronary arteriography (CAG): slight stenosis (group 1), moderate stenosis (group 2) and serious stenosis (group 3). M-mode and tissue Doppler echocardiography were performed, and elasticity indexes of ascending aorta including stiffness index, distensibility index, and S wave speed of anterior wall were calculated and correlated with the severity of coronary stenosis. Ascending aorta stiffness index was increased, whereas distensibility index and S wave speed of anterior wall were decreased in moderate and severe stenosis groups compared with slight stenosis group (P < 0.01). Elasticity indexes change in a stepwise pattern with the narrowness of coronary artery, and there was a significant correlation between aortic elasticity and severity of coronary artery by Pearson correlation analysis (P < 0.01). Elasticity indexes of ascending aorta correlate well with severity of coronary stenosis. Elasticity indexes of ascending aorta can serve as predictors for coronary arterial lesion in hypertensive patients.

The 2014 ASCENDS Field Campaign - a Carbon Dioxide Laser Absorption Spectrometer Perspective

NASA Astrophysics Data System (ADS)

Spiers, G. D.; Menzies, R. T.; Jacob, J. C.; Geier, S.; Fregoso, S. F.

2014-12-01

NASA's ASCENDS mission has been flying several candidate lidar instruments on board the NASA DC-8 aircraft to obtain column integrated measurements of Carbon Dioxide. Each instrument uses a different approach to making the measurement and combined they have allowed for the informed development of the ASCENDS mission measurement requirements(1). The JPL developed Carbon Dioxide Laser Absorption Spectrometer, CO2LAS is one of these instruments. The CO2LAS measures the weighted, column averaged carbon dioxide between the aircraft and the ground using a continuous-wave heterodyne technique. The instrument operates at a 2.05 micron wavelength optimized for enhancing sensitivity to boundary layer carbon dioxide. Since the 2013 field campaign the instrument has undergone significant upgrades that improve the data collection efficiency and instrument stability and has recently been re-integrated onto the NASA DC-8 for the August 2014 ASCENDS field campaign. This presentation will summarize the instrument and algorithm improvements and review the 2014 field campaign flights and preliminary results. (1) Abshire, J.B. et al., "An overview of NASA's ASCENDS Mission lidar measurement requirements", submitted to 2014 Fall AGU Conference.

Hemolytic anemia caused by aortic flap and inversion of felt strip after ascending aorta replacement.

PubMed

Sakaguchi, Masayuki; Takano, Tamaki

2016-08-02

Hemolysis related to a kinked prosthetic graft or inner felt strip is a very rare complication after aortic surgery. We describe herein a case of hemolytic anemia that developed due to aortic flap of the dissection and inversion of an inner felt strip that was applied at the proximal anastomosis of a replaced ascending aorta 10 years previously. A 74-year-old woman presented with consistent hemolytic anemia 10 years after replacement of the ascending aorta to treat Stanford type A acute aortic dissection. The cause of hemolysis was attributed to mechanical injury of red blood cells at a site of stenosis caused by aortic flap of the dissection and inversion of the felt strip used for the proximal anastomosis. Repeated resection of the strip and graft replacement of the ascending aorta resolved this problem. We considered that blood flow disrupted by a jet of blood at the site of the proximal inner felt strip was the cause of severe hemolysis, we describe rare hemolytic anemia at the site of aortic flap and inverted felt strip after replacement of the ascending aorta.

EphrinB3/EphA4-mediated guidance of ascending and descending spinal tracts.

PubMed

Paixão, Sónia; Balijepalli, Aarathi; Serradj, Najet; Niu, Jingwen; Luo, Wenqin; Martin, John H; Klein, Rüdiger

2013-12-18

The spinal cord contains many descending and ascending longitudinal tracts whose development appears to be controlled by distinct guidance systems. We identified a population of dorsal spinal neurons marked by coexpression of the transcription factor Zic2 and the guidance receptor EphA4. Zic2+;EphA4+ neurons are surrounded by mechanosensory terminals, suggesting innervation by mechanoreceptor afferents. Their axons form an ipsilateral ascending pathway that develops during embryogenesis and projects within the ventral aspect of the dorsal funiculus, the same location as the descending corticospinal tract (CST), which develops postnatally. Interestingly, the same guidance mechanism, namely, ephrinB3-induced EphA4 forward signaling, is required for the guidance of both ascending and descending axon tracts. Our analysis of conditional EphA4 mutant mice also revealed that the development of the dorsal funiculus occurs independently of EphA4 expression in descending CST axons and is linked to the distribution of Zic2+;EphA4+ spinal neurons and the formation of the ascending pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of Acute Oral Naltrexone on the Subjective and Physiological Effects of Oral D-Amphetamine and Smoked Cocaine in Cocaine Abusers

PubMed Central

Comer, Sandra D; Mogali, Shanthi; Saccone, Phillip A; Askalsky, Paula; Martinez, Diana; Walker, Ellen A; Jones, Jermaine D; Vosburg, Suzanne K; Cooper, Ziva D; Roux, Perrine; Sullivan, Maria A; Manubay, Jeanne M; Rubin, Eric; Pines, Abigail; Berkower, Emily L; Haney, Margaret; Foltin, Richard W

2013-01-01

Despite the prevalent worldwide abuse of stimulants, such as amphetamines and cocaine, no medications are currently approved for treating this serious public health problem. Both preclinical and clinical studies suggest that the opioid antagonist naltrexone (NTX) is effective in reducing the abuse liability of amphetamine, raising the question of whether similar positive findings would be obtained for cocaine. The purpose of this study was to evaluate the ability of oral NTX to alter the cardiovascular and subjective effects of D-amphetamine (D-AMPH) and cocaine (COC). Non-treatment-seeking COC users (N=12) completed this 3-week inpatient, randomized, crossover study. Participants received 0, 12.5, or 50 mg oral NTX 60 min before active or placebo stimulant administration during 10 separate laboratory sessions. Oral AMPH (0, 10, and 20 mg; or all placebo) was administered in ascending order within a laboratory session using a 60-min interdose interval. Smoked COC (0, 12.5, 25, and 50 mg; or all placebo) was administered in ascending order within a laboratory session using a 14-min interdose interval. Active COC and AMPH produced dose-related increases in cardiovascular function that were of comparable magnitude. In contrast, COC, but not AMPH, produced dose-related increases in several subjective measures of positive drug effect (eg, high, liking, and willingness to pay for the drug). NTX did not alter the cardiovascular effects of AMPH or COC. NTX also did not alter positive subjective ratings after COC administration, but it did significantly reduce ratings of craving for COC and tobacco during COC sessions. These results show that (1) oral AMPH produces minimal abuse-related subjective responses in COC smokers, and (2) NTX reduces craving for COC and tobacco during COC sessions. Future studies should continue to evaluate NTX as a potential anti-craving medication for COC dependence. PMID:23736314

Reduced benzodiazepine sensitivity in patients with panic disorder: comparison with patients with obsessive-compulsive disorder and normal subjects.

PubMed

Roy-Byrne, P; Wingerson, D K; Radant, A; Greenblatt, D J; Cowley, D S

1996-11-01

The authors sought to replicate their previous finding of reduced response to diazepam in patients with panic disorder, to test whether this effect was specific for panic disorder, and to determine whether this reduced response was merely an artifact of resistance to sedation from anxiety-related overarousal. The effects of four increasing intravenous doses of diazepam on saccadic eye movement velocity and accuracy (the latter being a saccadic variable that is unaffected by sedation), short-term memory, and self- and observer-rated sedation were assessed in 18 patients with panic disorder, 15 patients with obsessive-compulsive disorder, and 14 normal comparison subjects. The ratios of effect to blood level areas under the curve for both ascending and descending limbs of the effect/blood level curves were compared for each variable. Patients with panic disorder showed significantly less diazepam effect on saccadic velocity and accuracy for the ascending limb of the blood level curve than comparison subjects. Patients with obsessive-compulsive disorder showed similar differences from comparison subjects but only for saccadic velocity. There were no group differences in diazepam effects on memory and sedation. Patients with panic disorder are less sensitive than comparison subjects to diazepam. Although this difference is not an artifact of resistance to sedation, it may not be specific for panic disorder but rather may reflect a more nonspecific aspect of anxiety disorders.

A Phase 1, Single-center, Double-blind, Placebo-controlled Study in Healthy Subjects to Assess the Safety, Tolerability, Clinical Effects, and Pharmacokinetics-Pharmacodynamics of Intravenous Cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a Single Ascending Bolus Dose.

PubMed

Struys, Michel M R F; Valk, Beatrijs I; Eleveld, Douglas J; Absalom, Anthony R; Meyer, Peter; Meier, Sascha; den Daas, Izaak; Chou, Thomas; van Amsterdam, Kai; Campagna, Jason A; Sweeney, Steven P

2017-07-01

Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new "soft" etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose-response and pharmacokinetic/pharmacodynamic relationships. Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer's assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated. Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration-effect relationship was described for the modified observer's assessment of alertness/sedation and Bispectral Index. This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.

21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

Code of Federal Regulations, 2011 CFR

2011-04-01

... vivo bioavailability study. 320.27 Section 320.27 Food and Drugs FOOD AND DRUG ADMINISTRATION... Guidelines on the design of a multiple-dose in vivo bioavailability study. (a) Basic principles. (1) In... labeling of the test product. (3) A multiple-dose study may be required to determine the bioavailability of...

A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-05-01

A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects. Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a minimum of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatography-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated. Δ(9)-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concentration (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concentration (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported. The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.

A systematic review of primary endovascular repair of the ascending aorta.

PubMed

Muetterties, Corbin E; Menon, Rohan; Wheatley, Grayson H

2018-01-01

Endovascular repair of the ascending aorta is currently limited to patients at high surgical risk with aortic diseases originating above the sinotubular junction. A number of different endovascular technologies and approaches have been used, although no consensus exists regarding a standardized technique. To better understand real-world endovascular approaches to the ascending aorta, we performed a comprehensive review of the types of endovascular aortic stents and associated vascular access used in repair of the ascending aorta. A search of the MEDLINE database was conducted from January 1, 1995, through January 31, 2017, with the search term "ascending aortic stent." Studies involving endovascular stenting in which the primary therapy was confined exclusively to the ascending aorta were included. Studies involving hybrid arch procedures and surgical replacement of the ascending aorta associated with aortic stenting were excluded. The type of aortic stent, underlying aortic disease, and surgical approach were recorded along with outcomes, need for reinterventions, and follow-up. A total of 46 publications that focused on primary endovascular repair of the ascending aorta were identified. Thirteen different aortic stent grafts of various designs were used in 118 total patients. The most commonly used device types were thoracic stents (n = 84 [71.2%]) along with abdominal cuffs (n = 13 [11%]) and custom-made grafts (n = 12 [10.2%]). The most commonly treated aortic disease was type A aortic dissection (n = 59 [50%]), followed by aortic pseudoaneurysm (n = 35 [29.7%]), aortic aneurysm (n = 6 [5.1%]), penetrating atherosclerotic ulcer (n = 5 [4.2%]), and acute aortic rupture (n = 3 [2.5%]). Femoral arterial access was used in 62.7% of patients (n = 74); transapical (n = 17 [14.4%]), carotid (n = 15 [12.7%]), and axillary (n = 8 [6.8%]) approaches were also used. The overall type I endoleak rate was 18.6% (n = 22), with 11 patients (9.3%) requiring reintervention. Other complications included all-cause mortality (n = 18 [15.2%]), conversions to open surgery (n = 4 [3.4%]), and cerebrovascular complications (n = 4 [3.4%]). Aorta-related mortality was 5% (n = 6), and average follow-up was 17.2 months. Despite the absence of a dedicated aortic stent graft for the ascending aorta, patients with a range of ascending aortic diseases are being successfully treated by endovascular technologies. For optimal outcomes, patient selection is critical to align aortic anatomy with the limited device sizing options, and it should be reserved for patients at high surgical risk. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Cumulative effective dose associated with radiography and CT of adolescents with spinal injuries.

PubMed

Lemburg, Stefan P; Peters, Soeren A; Roggenland, Daniela; Nicolas, Volkmar; Heyer, Christoph M

2010-12-01

The purpose of this study was to analyze the quantity and distribution of cumulative effective doses in diagnostic imaging of adolescents with spinal injuries. At a level 1 trauma center from July 2003 through June 2009, imaging procedures during initial evaluation and hospitalization and after discharge of all patients 10-20 years old with spinal fractures were retrospectively analyzed. The cumulative effective doses for all imaging studies were calculated, and the doses to patients with spinal injuries who had multiple traumatic injuries were compared with the doses to patients with spinal injuries but without multiple injuries. The significance level was set at 5%. Imaging studies of 72 patients (32 with multiple injuries; average age, 17.5 years) entailed a median cumulative effective dose of 18.89 mSv. Patients with multiple injuries had a significantly higher total cumulative effective dose (29.70 versus 10.86 mSv, p < 0.001) mainly owing to the significantly higher CT-related cumulative effective dose to multiple injury patients during the initial evaluation (18.39 versus 2.83 mSv, p < 0.001). Overall, CT accounted for 86% of the total cumulative effective dose. Adolescents with spinal injuries receive a cumulative effective dose equal to that of adult trauma patients and nearly three times that of pediatric trauma patients. Areas of focus in lowering cumulative effective dose should be appropriate initial estimation of trauma severity and careful selection of CT scan parameters.

MPI_XSTAR: MPI-based parallelization of XSTAR program

NASA Astrophysics Data System (ADS)

Danehkar, A.

2017-12-01

MPI_XSTAR parallelizes execution of multiple XSTAR runs using Message Passing Interface (MPI). XSTAR (ascl:9910.008), part of the HEASARC's HEAsoft (ascl:1408.004) package, calculates the physical conditions and emission spectra of ionized gases. MPI_XSTAR invokes XSTINITABLE from HEASoft to generate a job list of XSTAR commands for given physical parameters. The job list is used to make directories in ascending order, where each individual XSTAR is spawned on each processor and outputs are saved. HEASoft's XSTAR2TABLE program is invoked upon the contents of each directory in order to produce table model FITS files for spectroscopy analysis tools.

Intracardiac echocardiographic guidance for hemodynamic assessment in a patient with congenital abnormalities and a prosthetic aortic valve.

PubMed

Papafaklis, M I; Ligthart, J M R; Vaina, S; Witsenburg, M; Bogers, A J J C; Serruys, P W

2005-01-01

In this case report, we present the use of intracardiac echocardiography (ICE) for guiding the cardiac catheterization and subsequent hemodynamic investigation in an unusual patient case with multiple congenital abnormalities (bicuspid aortic valve, left cervical aortic arch, two aortic coarctations) and two aortic valve replacement operations in the past. The ICE catheter (AcuNav) permitted us to accurately and safely puncture the interatrial septum and place the Swan-Ganz catheter in the left ventricle; additionally, visualization of the aortic coarctation in the ascending aorta was also achieved.

Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects.

PubMed

Shin, Dongseong; Lee, SeungHwan; Yi, Sojeong; Yoon, Seo Hyun; Cho, Joo-Youn; Bahng, Mi Young; Jang, In-Jin; Yu, Kyung-Sang

2017-01-01

DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects. A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated. After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2-3 h and was eliminated with terminal elimination half-life of 17.9-28.7 h. The mean renal clearance was 3.7-5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20-80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized C max and AUC 0- t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported. In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20-80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less.

Does three-dimensional transesophageal echocardiography provide incremental value in percutaneous closure of ascending aortic pseudoaneurysm?

PubMed

Elkaryoni, Ahmed; Hsiung, Ming C; Arisha, Mohammed J; Ahmad, Amier; Nanda, Navin C; Mohamed, Ahmed H; Attia, Doaa; Sachdeva, Ankush; Singh, Lovepreet; Yin, Wei-Hsian

2017-07-01

Ascending aortic pseudoaneurysms (AO PSAs), if left untreated, are complicated by a high rate of rupture resulting in significant morbidity and mortality. New transcatheter modalities have emerged as acceptable surgical alternatives for their management. We present a case of an ascending aortic PSA in which intraoperative two- and three-dimensional transesophageal echocardiography (2DTEE and 3DTEE) provided a comprehensive assessment of the PSA in pre- and postclosure settings. © 2017, Wiley Periodicals, Inc.

Case report: Open replacement of incomplete semi-circular traumatic ruptures of the ascending and descending aorta.

PubMed

Mytsyk, Miroslawa; Grapow, Martin T R; Shahinian, Jasmin; Maurer, Markus; Gurke, Lorenz; Eckstein, Friedrich S

2016-07-16

An incomplete traumatic rupture of the ascending aorta is a rare but life-threatening condition. Hence, the assessment of the extent of the injury prior to therapy is crucial. We report a case of a 50-year-old male with traumatic aortic rupture who underwent emergency surgery after the evaluation of computed tomography scan (CT-scan). The surgical treatment involved replacement of the ascending aorta and stent implantation in descending aorta due to its covered rupture.

A Theory of Fundamentalism: An Inquiry Into the Origin and Development of the Movement.

DTIC Science & Technology

1995-09-28

Also see Mitchell, The Society of Muslim Brothers. 55. See Ehud Sprinzak, The Ascendance of Israel’s Radical Right , Oxford: Oxford University Press...accepted the proposal. 57. Sprinzak, The Ascendancy of Israel’s Radical Right , writes (p. 65): A most significant response to the crisis of the Yom...to achieve interim agreements with Egypt and Syria. 58. Lustick, For the Land and the Lord, p. 42. 59. Sprinzak, The Ascendancy of Israel’s Radical

Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

NASA Astrophysics Data System (ADS)

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

2014-02-01

Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study.

PubMed

Lublin, Fred D; Bowen, James D; Huddlestone, John; Kremenchutzky, Marcelo; Carpenter, Adam; Corboy, John R; Freedman, Mark S; Krupp, Lauren; Paulo, Corri; Hariri, Robert J; Fischkoff, Steven A

2014-11-01

Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection. PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Intrusion of granitic magma into the continental crust facilitated by magma pulsing and dike-diapir interactions: Numerical simulations

NASA Astrophysics Data System (ADS)

Cao, Wenrong; Kaus, Boris J. P.; Paterson, Scott

2016-06-01

We conducted a 2-D thermomechanical modeling study of intrusion of granitic magma into the continental crust to explore the roles of multiple pulsing and dike-diapir interactions in the presence of visco-elasto-plastic rheology. Multiple pulsing is simulated by replenishing source regions with new pulses of magma at a certain temporal frequency. Parameterized "pseudo-dike zones" above magma pulses are included. Simulation results show that both diking and pulsing are crucial factors facilitating the magma ascent and emplacement. Multiple pulses keep the magmatic system from freezing and facilitate the initiation of pseudo-dike zones, which in turn heat the host rock roof, lower its viscosity, and create pathways for later ascending pulses of magma. Without diking, magma cannot penetrate the highly viscous upper crust. Without multiple pulsing, a single magma body solidifies quickly and it cannot ascent over a long distance. Our results shed light on the incremental growth of magma chambers, recycling of continental crust, and evolution of a continental arc such as the Sierra Nevada arc in California.

Seawifs Technical Report Series. Volume 2: Analysis of Orbit Selection for Seawifs: Ascending Versus Descending Node

NASA Technical Reports Server (NTRS)

Hooker, Stanford B. (Editor); Firestone, Elaine R. (Editor); Gregg, Watson W.

1992-01-01

Due to range safety considerations, the Sea-viewing Wide Field-of-view Sensor (SeaWiFS) ocean color instrument may be required to be launched into a near-noon descending node, as opposed to the ascending node used by the predecessor sensor, the Coastal Zone Color Scanner (CZCS). The relative importance of ascending versus descending near-noon orbits was assessed here to determine if descending node will meet the scientific requirements of SeaWiFS. Analyses focused on ground coverage, local times of coverage, solar and viewing geometries (zenith and azimuth angles), and sun glint. Differences were found in the areas covered by individual orbits, but were not important when taken over a 16 day repeat time. Local time of coverage was also different: for ascending node orbits the Northern Hemisphere was observed in the morning and the Southern Hemisphere in the afternoon, while for descending node orbits the Northern Hemisphere was observed in the afternoon and the Southern in the morning. There were substantial differences in solar azimuth and spacecraft azimuth angles both at equinox and at the Northern Hemisphere summer solstice. Negligible differences in solar and spacecraft zenith angles, relative azimuth angles, and sun glint were obtained at the equinox. However, large differences were found in solar zenith angles, relative azimuths, and sun glint for the solstice. These differences appeared to compensate across the scan, however, an increase in sun glint in descending node over that in ascending node on the western part of the scan was compensated by a decrease on the eastern part of the scan. Thus, no advantage or disadvantage could be conferred upon either ascending node or descending node for noon orbits. Analyses were also performed for ascending and descending node orbits that deviated from a noon equator crossing time. For ascending node, afternoon orbits produced the lowest mean solar zenith angles in the Northern Hemisphere, and morning orbits produced the lowest angles for the Southern Hemisphere. For descending node, morning orbits produced the lowest mean solar zenith angles for the Northern Hemisphere; afternoon orbits produced the lowest angles for the Southern Hemisphere.

Multiple sound source localization using gammatone auditory filtering and direct sound componence detection

NASA Astrophysics Data System (ADS)

Chen, Huaiyu; Cao, Li

2017-06-01

In order to research multiple sound source localization with room reverberation and background noise, we analyze the shortcomings of traditional broadband MUSIC and ordinary auditory filtering based broadband MUSIC method, then a new broadband MUSIC algorithm with gammatone auditory filtering of frequency component selection control and detection of ascending segment of direct sound componence is proposed. The proposed algorithm controls frequency component within the interested frequency band in multichannel bandpass filter stage. Detecting the direct sound componence of the sound source for suppressing room reverberation interference is also proposed, whose merits are fast calculation and avoiding using more complex de-reverberation processing algorithm. Besides, the pseudo-spectrum of different frequency channels is weighted by their maximum amplitude for every speech frame. Through the simulation and real room reverberation environment experiments, the proposed method has good performance. Dynamic multiple sound source localization experimental results indicate that the average absolute error of azimuth estimated by the proposed algorithm is less and the histogram result has higher angle resolution.

Quantum trajectories for high-order-harmonic generation from multiple rescattering events in the long-wavelength regime

NASA Astrophysics Data System (ADS)

He, Lixin; Li, Yang; Wang, Zhe; Zhang, Qingbin; Lan, Pengfei; Lu, Peixiang

2014-05-01

We have performed the quantum trajectory analysis for high-order-harmonic generation (HHG) with different driving laser wavelengths. By defining the ratio of HHG yields of the Nth and first rescattering events (YN/Y1), we quantitatively evaluate the HHG contributions from multiple rescatterings. The results show that the HHG yield ratio increases gradually with the increase of the laser wavelength, which demonstrates that high-order rescatterings provide ascendent contributions to HHG at longer wavelength. By calculating the classical electron trajectories, we find significant differences exist in the electron behaviors between the first and high-order rescatterings. Further investigations have demonstrated that the increasing HHG yield ratio is mainly attributed to the relatively smaller contributions from the short path of the first electron rescattering at longer laser wavelength.

Dependence of energy characteristics of ascending swirling air flow on velocity of vertical blowing

NASA Astrophysics Data System (ADS)

Volkov, R. E.; Obukhov, A. G.; Kutrunov, V. N.

2018-05-01

In the model of a compressible continuous medium, for the complete Navier-Stokes system of equations, an initial boundary problem is proposed that corresponds to the conducted and planned experiments and describes complex three-dimensional flows of a viscous compressible heat-conducting gas in ascending swirling flows that are initiated by a vertical cold blowing. Using parallelization methods, three-dimensional nonstationary flows of a polytropic viscous compressible heat-conducting gas are constructed numerically in different scaled ascending swirling flows under the condition when gravity and Coriolis forces act. With the help of explicit difference schemes and the proposed initial boundary conditions, approximate solutions of the complete system of Navier-Stokes equations are constructed as well as the velocity and energy characteristics of three-dimensional nonstationary gas flows in ascending swirling flows are determined.

Comparison of the structure of the aortic valve and ascending aorta in adults having aortic valve replacement for aortic stenosis versus for pure aortic regurgitation and resection of the ascending aorta for aneurysm.

PubMed

Roberts, William Clifford; Vowels, Travis James; Ko, Jong Mi; Filardo, Giovanni; Hebeler, Robert Frederick; Henry, Albert Carl; Matter, Gregory John; Hamman, Baron Lloyd

2011-03-01

There is debate concerning whether an aneurysmal ascending aorta should be replaced when associated with a dysfunctioning aortic valve that is to be replaced. To examine this issue, we divided the patients by type of aortic valve dysfunction-either aortic stenosis (AS) or pure aortic regurgitation (AR)-something not previously undertaken. Of 122 patients with ascending aortic aneurysm (unassociated with aortitis or acute dissection), the aortic valve was congenitally malformed (unicuspid or bicuspid) in 58 (98%) of the 59 AS patients, and in 38 (60%) of the 63 pure AR patients. Ascending aortic medial elastic fiber loss (EFL) (graded 0 to 4+) was zero or 1+ in 53 (90%) of the AS patients, in 20 (53%) of the 38 AR patients with bicuspid valves, and in all 12 AR patients with tricuspid valves unassociated with the Marfan syndrome. An unadjusted analysis showed that, among the 96 patients with congenitally malformed valves, the 38 AR patients had a significantly higher likelihood of 2+ to 4+ EFL than the 58 AS patients (crude odds ratio: 8.78; 95% confidence interval: 2.95, 28.13). These data strongly suggest that the type of aortic valve dysfunction-AS versus pure AR-is very helpful in predicting loss of aortic medial elastic fibers in patients with ascending aortic aneurysms and aortic valve disease.

A fully automated multi-modal computer aided diagnosis approach to coronary calcium scoring of MSCT images

NASA Astrophysics Data System (ADS)

Wu, Jing; Ferns, Gordon; Giles, John; Lewis, Emma

2012-03-01

Inter- and intra- observer variability is a problem often faced when an expert or observer is tasked with assessing the severity of a disease. This issue is keenly felt in coronary calcium scoring of patients suffering from atherosclerosis where in clinical practice, the observer must identify firstly the presence, followed by the location of candidate calcified plaques found within the coronary arteries that may prevent oxygenated blood flow to the heart muscle. However, it can be difficult for a human observer to differentiate calcified plaques that are located in the coronary arteries from those found in surrounding anatomy such as the mitral valve or pericardium. In addition to the benefits to scoring accuracy, the use of fast, low dose multi-slice CT imaging to perform the cardiac scan is capable of acquiring the entire heart within a single breath hold. Thus exposing the patient to lower radiation dose, which for a progressive disease such as atherosclerosis where multiple scans may be required, is beneficial to their health. Presented here is a fully automated method for calcium scoring using both the traditional Agatston method, as well as the volume scoring method. Elimination of the unwanted regions of the cardiac image slices such as lungs, ribs, and vertebrae is carried out using adaptive heart isolation. Such regions cannot contain calcified plaques but can be of a similar intensity and their removal will aid detection. Removal of both the ascending and descending aortas, as they contain clinical insignificant plaques, is necessary before the final calcium scores are calculated and examined against ground truth scores of three averaged expert observer results. The results presented here are intended to show the feasibility and requirement for an automated scoring method to reduce the subjectivity and reproducibility error inherent with manual clinical calcium scoring.

Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis.

PubMed

Sandborn, William J; Regula, Jaroslaw; Feagan, Brian G; Belousova, Elena; Jojic, Njegica; Lukas, Milan; Yacyshyn, Bruce; Krzeski, Piotr; Yeh, Chyon-Hwa; Messer, Christi A; Hanauer, Stephen B

2009-12-01

It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC. A multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physician's Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment. The primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, -11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events. Delayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC.

Dose rate effect on micronuclei induction in human blood lymphocytes exposed to single pulse and multiple pulses of electrons.

PubMed

Acharya, Santhosh; Bhat, N N; Joseph, Praveen; Sanjeev, Ganesh; Sreedevi, B; Narayana, Y

2011-05-01

The effects of single pulses and multiple pulses of 7 MV electrons on micronuclei (MN) induction in cytokinesis-blocked human peripheral blood lymphocytes (PBLs) were investigated over a wide range of dose rates per pulse (instantaneous dose rate). PBLs were exposed to graded doses of 2, 3, 4, 6, and 8 Gy of single electron pulses of varying pulse widths at different dose rates per pulse, ranging from 1 × 10(6) Gy s(-1) to 3.2 × 10(8) Gy s(-1). Different dose rates per pulse were achieved by changing the dose per electron pulse by adjusting the beam current and pulse width. MN yields per unit absorbed dose after irradiation with single electron pulses were compared with those of multiple pulses of electrons. A significant decrease in the MN yield with increasing dose rates per pulse was observed, when dose was delivered by a single electron pulse. However, no reduction in the MN yield was observed when dose was delivered by multiple pulses of electrons. The decrease in the yield at high dose rates per pulse suggests possible radical recombination, which leads to decreased biological damage. Cellular response to the presence of very large numbers of chromosomal breaks may also alter the damage.

Fight for your breeding right: hierarchy re-establishment predicts aggression in a social queue

PubMed Central

Wong, Marian; Balshine, Sigal

2011-01-01

Social aggression is one of the most conspicuous features of animal societies, yet little is known about the causes of individual variation in aggression within social hierarchies. Recent theory suggests that when individuals form queues for breeding, variation in social aggression by non-breeding group members is related to their probability of inheriting breeding status. However, levels of aggression could also vary as a temporary response to changes in the hierarchy, with individuals becoming more aggressive as they ascend in rank, in order to re-establish dominance relationships. Using the group-living fish, Neolamprologus pulcher, we show that subordinates became more aggressive after they ascended in rank. Female ascenders exhibited more rapid increases in aggression than males, and the increased aggression was primarily directed towards group members of adjacent rather than non-adjacent rank, suggesting that social aggression was related to conflict over rank. Elevated aggression by ascenders was not sustained over time, there was no relationship between rank and aggression in stable groups, and aggression given by ascenders was not sex-biased. Together, these results suggest that the need to re-establish dominance relationships following rank ascension is an important determinant of variation in aggression in animal societies. PMID:20880857

Fight for your breeding right: hierarchy re-establishment predicts aggression in a social queue.

PubMed

Wong, Marian; Balshine, Sigal

2011-04-23

Social aggression is one of the most conspicuous features of animal societies, yet little is known about the causes of individual variation in aggression within social hierarchies. Recent theory suggests that when individuals form queues for breeding, variation in social aggression by non-breeding group members is related to their probability of inheriting breeding status. However, levels of aggression could also vary as a temporary response to changes in the hierarchy, with individuals becoming more aggressive as they ascend in rank, in order to re-establish dominance relationships. Using the group-living fish, Neolamprologus pulcher, we show that subordinates became more aggressive after they ascended in rank. Female ascenders exhibited more rapid increases in aggression than males, and the increased aggression was primarily directed towards group members of adjacent rather than non-adjacent rank, suggesting that social aggression was related to conflict over rank. Elevated aggression by ascenders was not sustained over time, there was no relationship between rank and aggression in stable groups, and aggression given by ascenders was not sex-biased. Together, these results suggest that the need to re-establish dominance relationships following rank ascension is an important determinant of variation in aggression in animal societies.

Endovascular approach to treat ascending aortic pseudoaneurysm in a patient with previous CABG and very high surgical risk.

PubMed

Zago, Alexandre C; Saadi, Eduardo K; Zago, Alcides J

2011-10-01

Pseudoaneurysm of the ascending aorta is an uncommon pathology and a challenge in high-risk patients who undergo conventional surgery because of high operative morbidity and mortality. Endovascular exclusion of an aortic pseudoaneurysm using an endoprosthesis is a less invasive approach, but few such cases have been reported. Moreover, the use of this approach poses unique therapeutic challenges because there is no specific endoprosthesis for ascending aortic repair, particularly to treat patients with previous coronary artery bypass graft (CABG). We describe the case of a 74-year-old patient who had undergone CABG and later presented with an iatrogenic ascending aortic pseudoaneurysm that occurred during an angiography. This patient was at very high risk for surgical treatment and, therefore, an endovascular approach was adopted: percutaneous coronary intervention for the left main coronary artery, left anterior descending and left circumflex native coronary arteries followed by endovascular endoprosthesis deployment in the ascending aorta to exclude the pseudoaneurysm. Both procedures were successfully performed, and the patient was discharged without complications 4 days later. At 5 months' clinical follow-up, his clinical condition was good and he had no complications. Copyright © 2011 Wiley-Liss, Inc.

Bacterial Hyaluronidase Promotes Ascending GBS Infection and Preterm Birth

PubMed Central

Vornhagen, Jay; Quach, Phoenicia; Boldenow, Erica; Merillat, Sean; Whidbey, Christopher; Ngo, Lisa Y.; Adams Waldorf, K. M.

2016-01-01

ABSTRACT Preterm birth increases the risk of adverse birth outcomes and is the leading cause of neonatal mortality. A significant cause of preterm birth is in utero infection with vaginal microorganisms. These vaginal microorganisms are often recovered from the amniotic fluid of preterm birth cases. A vaginal microorganism frequently associated with preterm birth is group B streptococcus (GBS), or Streptococcus agalactiae. However, the molecular mechanisms underlying GBS ascension are poorly understood. Here, we describe the role of the GBS hyaluronidase in ascending infection and preterm birth. We show that clinical GBS strains associated with preterm labor or neonatal infections have increased hyaluronidase activity compared to commensal strains obtained from rectovaginal swabs of healthy women. Using a murine model of ascending infection, we show that hyaluronidase activity was associated with increased ascending GBS infection, preterm birth, and fetal demise. Interestingly, hyaluronidase activity reduced uterine inflammation but did not impact placental or fetal inflammation. Our study shows that hyaluronidase activity enables GBS to subvert uterine immune responses, leading to increased rates of ascending infection and preterm birth. These findings have important implications for the development of therapies to prevent in utero infection and preterm birth. PMID:27353757

Single coronary artery with bicuspid aortic valve stenosis and aneurysm of the ascending aorta: report of a case.

PubMed

Ishida, Narihiro; Shimabukuro, Katsuya; Matsuno, Yukihiro; Ogura, Hiroki; Takemura, Hirofumi

2014-03-01

A 73-year-old man with a severely stenosed bicuspid valve and an aneurysm of the ascending aorta underwent valve and aortic surgery. Preoperative imaging revealed a single coronary artery arising from the right side of the sinus of Valsalva and a branch that perfused into the left side of the heart to pass through the front of the pulmonary artery. We replaced the aortic valve and ascending aorta, painstakingly avoiding damage to the coronary artery and obstruction of the sole coronary ostium.

Percutaneous closure of a large ascending aortic pseudoaneurysm.

PubMed

Nogueira, Marta Afonso; Fiarresga, António; de Sousa, Lídia; Galrinho, Ana; Santos, Ninel; Nobre, Isabel; Laranjeira, Álvaro; Cruz Ferreira, Rui

2016-02-01

Pseudoaneurysm of the ascending aorta is a rare complication, usually after thoracic surgery or trauma. Since surgical repair is associated with very high morbidity and mortality, percutaneous closure has been described as an alternative. In this regard, we present a case in which a symptomatic large pseudoaneurysm of the ascending aorta was treated percutaneously due to the high surgical risk. Despite the technical difficulties, this procedure had a good final result followed by clinical success. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Pathologic aneurysmal dilation of the ascending aorta and dilation of the main pulmonary artery in patients with Kabuki syndrome: valve-sparing aortic root replacement.

PubMed

Dyamenahalli, Umesh; Abraham, Boban; Fontenot, Eudice; Prasad, Vinay; Imamura, Michiaki

2007-01-01

We report the aneurysmal dilation of the ascending aorta and the main pulmonary artery in 2 children with Kabuki syndrome. In 1 patient, there was progressive aneurysmal dilation of the ascending aorta necessitating aortoplasty. Histologic examination of the resected aorta revealed disrupted and fragmented elastic fibers in the medial layer, along with mucinous degeneration of the aortic wall. This is the first recognition and report of these findings as part of the Kabuki syndrome.

Chronic antihypertensive treatment improves pulse pressure but not large artery mechanics in a mouse model of congenital vascular stiffness

PubMed Central

Halabi, Carmen M.; Broekelmann, Thomas J.; Knutsen, Russell H.; Ye, Li; Mecham, Robert P.

2015-01-01

Increased arterial stiffness is a common characteristic of humans with Williams-Beuren syndrome and mouse models of elastin insufficiency. Arterial stiffness is associated with multiple negative cardiovascular outcomes, including myocardial infarction, stroke, and sudden death. Therefore, identifying therapeutic interventions that improve arterial stiffness in response to changes in elastin levels is of vital importance. The goal of this study was to determine the effect of chronic pharmacologic therapy with different classes of antihypertensive medications on arterial stiffness in elastin insufficiency. Elastin-insufficient mice 4–6 wk of age and wild-type littermates were subcutaneously implanted with osmotic micropumps delivering a continuous dose of one of the following: vehicle, losartan, nicardipine, or propranolol for 8 wk. At the end of treatment period, arterial blood pressure and large artery compliance and remodeling were assessed. Our results show that losartan and nicardipine treatment lowered blood pressure and pulse pressure in elastin-insufficient mice. Elastin and collagen content of abdominal aortas as well as ascending aorta and carotid artery biomechanics were not affected by any of the drug treatments in either genotype. By reducing pulse pressure and shifting the working pressure range of an artery to a more compliant region of the pressure-diameter curve, antihypertensive medications may mitigate the consequences of arterial stiffness, an effect that is drug class independent. These data emphasize the importance of early recognition and long-term management of hypertension in Williams-Beuren syndrome and elastin insufficiency. PMID:26232234

Patella height is not altered by descending medial open-wedge high tibial osteotomy (HTO) compared to ascending HTO.

PubMed

Krause, Matthias; Drenck, Tobias Claus; Korthaus, Alexander; Preiss, Achim; Frosch, Karl-Heinz; Akoto, Ralph

2018-06-01

The primary purpose of the study was to gain insight into geometric changes of the patellar height (PH) and posterior tibial slope (PTS) after a biplanar ascending medial open-wedge high tibial osteotomy (HTO) compared to biplanar descending medial open-wedge HTO in patients with genu varum. Sixty-four patients (mean age 45.2 ± 8.7 years, females n = 24, males n = 40) with varus malalignment and medial gonarthrosis were retrospectively studied. Patients received either a biplanar ascending or descending medial open-wedge HTO. Radiographic analysis included the assessment of standing total leg axis, PH, and PTS prior to and after surgery. In the ascending HTO group, PH decreased significantly by 4.0% (p = 0.037, Caton-Deschamps index) after an average leg axis valgus-producing correction of 7.1° ± 2.8°. In the descending HTO group, with an average leg axis correction of 7.0° ± 3.7°, there were no significant PH changes. There were no significant differences between the ascending and descending HTO groups regarding PTS or leg axis. The mean post-operative leg axis between ascending (1.6° ± 1.9°) and descending HTO (1.9° ± 2.4°) was not significantly different. Compared to the biplanar ascending medial open-wedge HTO, the descending HTO did not influence patella height or increase the posterior tibial slope. In order to respect patellofemoral and slope-related knee kinematics, a biplanar descending medial open-wedge HTO has proven useful to control patella height and posterior tibial slope. These findings underscore the importance of the preoperative patella height assessment in the osteotomy planning and subsequent choice of the biplanar osteotomy direction. IV.

Three-dimensional, high-resolution skeletal kinematics of the avian wing and shoulder during ascending flapping flight and uphill flap-running.

PubMed

Baier, David B; Gatesy, Stephen M; Dial, Kenneth P

2013-01-01

Past studies have shown that birds use their wings not only for flight, but also when ascending steep inclines. Uphill flap-running or wing-assisted incline running (WAIR) is used by both flight-incapable fledglings and flight-capable adults to retreat to an elevated refuge. Despite the broadly varying direction of travel during WAIR, level, and descending flight, recent studies have found that the basic wing path remains relatively invariant with reference to gravity. If so, joints undergo disparate motions to maintain a consistent wing path during those specific flapping modes. The underlying skeletal motions, however, are masked by feathers and skin. To improve our understanding of the form-functional relationship of the skeletal apparatus and joint morphology with a corresponding locomotor behavior, we used XROMM (X-ray Reconstruction of Moving Morphology) to quantify 3-D skeletal kinematics in chukars (Alectoris chukar) during WAIR (ascending with legs and wings) and ascending flight (AF, ascending with wings only) along comparable trajectories. Evidence here from the wing joints demonstrates that the glenohumeral joint controls the vast majority of wing movements. More distal joints are primarily involved in modifying wing shape. All bones are in relatively similar orientations at the top of upstroke during both behaviors, but then diverge through downstroke. Total excursion of the wing is much smaller during WAIR and the tip of the manus follows a more vertical path. The WAIR stroke appears "truncated" relative to ascending flight, primarily stemming from ca. 50% reduction in humeral depression. Additionally, the elbow and wrist exhibit reduced ranges of angular excursions during WAIR. The glenohumeral joint moves in a pattern congruent with being constrained by the acrocoracohumeral ligament. Finally, we found pronounced lateral bending of the furcula during the wingbeat cycle during ascending flight only, though the phasic pattern in chukars is opposite of that observed in starlings (Sturnus vulgaris).

Analysis for orbital rendezvous of Chang'E-5 using SBI technique

NASA Astrophysics Data System (ADS)

Huang, Y.; Shan, Q.; Li, P.

2016-12-01

Chang'E-5 will be launched in later 2017/early 2018 using a new generation rocket from Wenchang satellite launch center, Hainan, China. It is a lunar sampling return mission, and it is the first time for China to carry out orbital rendezvous and docking in the Moon. How to achieve orbital rendezvous successfully in the Moon is very important in Chang'E-5 mission. Orbital rendezvous will be implemented between an orbiter and an ascender 200 km above the Moon. The ground tracking techniques include range, Doppler and VLBI, and they will be used to track the orbiter and the ascender when the ascender is about 70 km farther away from the orbiter. Later the ascender will approach the orbiter automatically. As a successful example, in Chang'E-3, the differential phase delay (delta delay) data between the rover and the lander are obtained with a random error of about 1 ps, and the relative position of the rover is determined with an accuracy of several meters by using same beam VLBI (SBI) technique. Here the application of the SBI technique for Chang'E-5 orbital rendezvous is discussed. SBI technique can be used to track the orbiter and the ascender simultaneously when they are in the same beam. Delta delay of the two probes can be derived, and the measurement accuracy is much higher than that of the traditional VLBI data because of the cancelation of common errors. Theoretically it can result in a more accurate relative orbit between the two probes. In the simulation, different strategies are discussed to analyze the contribution of SBI data to the orbit accuracy improvement especially relative orbit between the orbiter and ascender. The simulation results show that the relative position accuracy of the orbiter and ascender can reach about 1 m with delta delay data of 10 ps.

[Ascending one-dimensional thin layer chromatography in specific blood diagnosis (author's transl)].

PubMed

Bernardelli, B; Masotti, G

1976-01-01

A brief review of the literature on chromatography in forensic haematology is followed by a report of the results obtained by using ascending one-dimensional thin layer chromatography in specific blood diagnosis.

A case of granuloma of the ascending colon due to penetration of Trichuris trichiura.

PubMed

Kojima, Y; Sakuma, H; Izumi, R; Nakagawara, G; Miyazaki, I; Yoshimura, H

1981-01-01

A 33 year-old woman was admitted with chief complaint of abdominal pain and high fever. A barium-enema showed serration and a tumor was seen in the proximal ascending colon. At laparotomy, a localized tumor about 5 cm in diameter was located in the proximal portion of the ascending colon. The operation was made according to the ileoceal resection. On the macroscopic examination of the resected specimen, a small hole penetrating into the subserosa of the ascending colon was noticed and a tumor measuring approximately 3 x 1.2 x 1 cm was located under the hole. A female worm, Trichuris trichiura, was found to be harbored in the adjacent site of the lesion. Histopathologic examination revealed granulomatous tissue reaction due to penetrating of Trichuris trichiura. The patient is in good health now 20 months after operation.

PEGylated carboxyhemoglobin bovine (SANGUINATE): results of a phase I clinical trial.

PubMed

Misra, Hemant; Lickliter, Jason; Kazo, Friedericke; Abuchowski, Abraham

2014-08-01

PEGylated carboxyhemoglobin bovine (SANGUINATE) is a dual action carbon monoxide releasing (CO)/oxygen (O2 ) transfer agent for the treatment of hypoxia. Its components inhibit vasoconstriction, decrease extravasation, limit reactive oxygen species production, enhance blood rheology, and deliver oxygen to the tissues. Animal models of cerebral ischemia, peripheral ischemia, and myocardial ischemia demonstrated SANGUINATE's efficacy in reducing myocardial infarct size, limiting necrosis from cerebral ischemia, and promoting more rapid recovery from hind limb ischemia. In a Phase I trial, three cohorts of eight healthy volunteers received single ascending doses of 80, 120, or 160 mg/kg of SANGUINATE. Two volunteers within each cohort served as a saline control. There were no serious adverse events. Serum haptoglobin decreased, but did not appear to be dose related. The T1/2 was dose dependent and ranged from 7.9 to 13.8 h. In addition to the Phase I trial, SANGUINATE was used under an expanded access emergency Investigational New Drug. SANGUINATE was found to be safe and well tolerated in a Phase I clinical trial, and therefore it will advance into further clinical trials in patients. © 2014 The Authors. Artificial Organs published by Wiley Periodicals, Inc. on behalf of International Center for Artificial Organs and Transplantation (ICAOT).

Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum.

PubMed

Johnson, Matthew W; MacLean, Katherine A; Reissig, Chad J; Prisinzano, Thomas E; Griffiths, Roland R

2011-05-01

Salvinorin A is a potent, selective nonnitrogenous kappa opioid agonist and the known psychoactive constituent of Salvia divinorum, a member of the mint family that has been used for centuries by Mazatec shamans of Mexico for divination and spiritual healing. S. divinorum has over the last several years gained increased popularity as a recreational drug. This is a double-blind, placebo controlled study of salvinorin A in 4 psychologically and physically healthy hallucinogen-using adults. Across sessions, participants inhaled 16 ascending doses of salvinorin A and 4 intermixed placebo doses under comfortable and supportive conditions. Doses ranged from 0.375 μg/kg to 21 μg/kg. Subject-rated drug strength was assessed every 2 min for 60 min after inhalation. Orderly time- and dose-related effects were observed. Drug strength ratings peaked at 2 min (first time point) and definite subjective effects were no longer present at approximately 20 min after inhalation. Dose-related increases were observed on questionnaire measures of mystical-type experience (Mysticism Scale) and subjective effects associated with classic serotonergic (5-HT2(A)) hallucinogens (Hallucinogen Rating Scale). Salvinorin A did not significantly increase heart rate or blood pressure. Participant narratives indicated intense experiences characterized by disruptions in vestibular and interoceptive signals (e.g., change in spatial orientation, pressure on the body) and unusual and sometimes recurring themes across sessions such as revisiting childhood memories, cartoon-like imagery, and contact with entities. Under these prepared and supportive conditions, salvinorin A occasioned a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type effects. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats.

PubMed

Klein, Charlotte; Karanges, Emily; Spiro, Adena; Wong, Alexander; Spencer, Jarrah; Huynh, Thanh; Gunasekaran, Nathan; Karl, Tim; Long, Leonora E; Huang, Xu-Feng; Liu, Kelly; Arnold, Jonathon C; McGregor, Iain S

2011-11-01

The interactions between Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models. The aim of this study is to examine whether the behavioural effects of THC, and blood and brain THC levels are affected by pre-treatment with equivalent CBD doses. Adolescent rats were treated with ascending daily THC doses over 21 days (1 then 3 then 10 mg/kg). Some rats were given equivalent CBD doses 20 min prior to each THC injection to allow examination of possible antagonistic effects of CBD. During dosing, rats were assessed for THC and CBD/THC effects on anxiety-like behaviour, social interaction and place conditioning. At the end of dosing, blood and brain levels of THC, and CB(1) and 5-HT(1A) receptor binding were assessed. CBD potentiated an inhibition of body weight gain caused by chronic THC, and mildly augmented the anxiogenic effects, locomotor suppressant effects and decreased social interaction seen with THC. A trend towards place preference was observed in adolescent rats given CBD/THC but not those given THC alone. With both acute and chronic administration, CBD pre-treatment potentiated blood and brain THC levels, and lowered levels of THC metabolites (THC-COOH and 11-OH-THC). CBD co-administration did not alter the THC-induced decreases in CB(1) receptor binding and no drug effects on 5-HT(1A) receptor binding were observed. CBD can potentiate the psychoactive and physiological effects of THC in rats, most likely by delaying the metabolism and elimination of THC through an action on the CYP450 enzymes that metabolise both drugs.

In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy.

PubMed

Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W

2012-01-01

Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle's geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.

Colonic metastasis from breast carcinoma: a case report.

PubMed

Tsujimura, Kazuma; Teruya, Tsuyoshi; Kiyuna, Masaya; Higa, Kuniki; Higa, Junko; Iha, Kouji; Chinen, Kiyoshi; Asato, Masaya; Takushi, Yasukatsu; Ota, Morihito; Dakeshita, Eijirou; Nakachi, Atsushi; Gakiya, Akira; Shiroma, Hiroshi

2017-07-05

Colonic metastasis from breast carcinoma is very rare. Here, we report a case of colonic metastasis from breast carcinoma. The patient was a 51-year-old woman. She had upper abdominal pain, vomiting, and diarrhea, repeatedly. We performed abdominal contrast-enhanced computed tomography (CT) to investigate these symptoms. The CT scan revealed a tumor in the ascending colon with contrast enhancement and showed an expanded small intestine. For further investigation of this tumor, we performed whole positron emission tomography-computed tomography (PET-CT). The PET-CT scan revealed fluorodeoxyglucose uptake in the ascending colon, mesentery, left breast, and left axillary region. Analysis of biopsy samples obtained during colonoscopy revealed signet ring cell-like carcinoma. Moreover, biopsy of the breast tumor revealed invasive lobular carcinoma. Therefore, the preoperative diagnosis was colonic metastasis from breast carcinoma. Open ileocecal resection was performed. The final diagnosis was multiple metastatic breast carcinomas, and the TNM classification was T2N1M1 Stage IV. We presented a rare case of colonic metastasis from breast carcinoma. PET-CT may be useful in the diagnosis of metastatic breast cancer. When analysis of biopsy samples obtained during colonoscopy reveals signet ring cell-like carcinoma, the possibility of breast cancer as the primary tumor should be considered.

Failing left ventricle to ascending aorta conduit-Hybrid implantation of a melody valve and NuMed covered stent.

PubMed

Gössl, Mario; Johnson, Jonathan N; Hagler, Donald J

2014-04-01

We present the case of a 36-year-old woman with increasing shortness of breath, a new 3/4 diastolic murmur, and a complex history of LV outflow tract obstruction. She has undergone multiple surgeries including the replacement of her old LV apex to ascending aorta conduit with a 20-mm Gore-Tex tube graft, addition of a 24-mm homograft sutured between the conduit and the LV apex, and insertion of a 21-mm Freestyle porcine valve conduit between the Gore-Tex tube graft and allograft at age 23. The current assessment showed a failing Freestyle conduit prosthesis leading to left heart decompensation. Due to substantial surgical risk, the patient underwent successful implantation of a Melody valve into the Gore-Tex tube and exclusion of the failing Freestyle bioprosthesis with a NuMed CP stent in a hybrid procedure. The case nicely illustrates the collaborative potential of cardiovascular surgeons and interventional cardiologists in the new arena of a hybrid operating room. Complex hybrid procedures like the current one, especially those including percutaneous placements of valves, offer therapeutic options for patients that are otherwise too high risk for conventional open heart surgery. Copyright © 2013 Wiley Periodicals, Inc.

Synchronous quintuple primary gastrointestinal tract malignancies: Case report

PubMed Central

Kim, Soo-Hong; Park, Byung-Soo; Kim, Hyun Sung; Kim, Jae Hun

2017-01-01

Multiple primary malignancy is defined as two or more malignancies detected in an individual person. In particular, synchronous quintuple primary malignancy is extremely rare. A 52-year-old male with anal pain and intermittent blood-tinged stool was diagnosed with malignancies in the stomach, jejunum, ascending colon, transverse colon and rectum. He underwent a subtotal gastrectomy, segmental resection of the jejunum and total protocolectomy with end ileostomy. The postoperative pathologic findings were moderate differentiated gastric adenocarcinoma (pT1bN0M0, pStageIA), combined adenocarcinoma and neuroendocrine carcinoma of the jejunum (pT3N0M0, pStageIIA), three mucinous adenocarcinoma of the ascending colon (pT3N0M0, pStageIIA), transverse colon (pT1N0M0, pStageI) and rectum (pT3N1aM0, pStageIIIB). The tumors did not lack MLH-1 and MSH-2 expression, as the markers (bat26, D5S346, bat25, D2S123) suggest MSI-H presence. Adjuvant chemoradiotherapy was started according to regimen, FOLFOX 4 for advanced rectal cancer. Six years post-operation, the patient is currently attending regular follow-ups without recurrence or metastasis. PMID:28104993

Nitric oxide-mediated intersegmental modulation of cycle frequency in the crayfish swimmeret system.

PubMed

Yoshida, Misaki; Nagayama, Toshiki; Newland, Philip

2018-05-21

Crayfish swimmerets are paired appendages located on the ventral side of each abdominal segment that show rhythmic beating during forward swimming produced by central pattern generators in most abdominal segments. For animals with multiple body segments and limbs, intersegmental coordination of central pattern generators in each segment is crucial for the production of effective movements. Here we develop a novel pharmacological approach to analyse intersegmental modulation of swimmeret rhythm by selectively elevating nitric oxide levels and reducing them with pharmacological agents, in specific ganglia. Bath application of L-arginine, the substrate NO synthesis, increased the cyclical spike responses of the power-stroke motor neurons. By contrast the NOS inhibitor, L-NAME decreased them. To determine the role of the different local centres in producing and controlling the swimmeret rhythm, these two drugs were applied locally to two separate ganglia following bath application of carbachol. Results revealed that there was both ascending and descending intersegmental modulation of cycle frequency of the swimmeret rhythm in the abdominal ganglia and that synchrony of cyclical activity between segments of segments was maintained. We also found that there were gradients in the strength effectiveness in modulation, that ascending modulation of the swimmeret rhythm was stronger than descending modulation. © 2018. Published by The Company of Biologists Ltd.

Aortic wrapping for a dilated ascending aorta in bicuspid aortic stenosis.

PubMed

Choi, Min Suk; Jeong, Dong Seop; Lee, Hae Young; Sung, Kiick; Kim, Wook Sung; Lee, Young Tak; Park, Pyo Won

2015-01-01

Ascending aorta wrapping is rarely recommended for the management of dilated aorta, because of late complications. The aim of the present study was to analyze the early and late outcomes of the aortic wrapping technique at the time of aortic valve replacement (AVR) for bicuspid aortic stenosis (BAS). Among patients who underwent primary AVR for BAS between 2002 and 2011, 79 who underwent ascending aortic wrapping (wrapping group) were compared with 144 patients who underwent AVR alone. The preoperative ascending aortic diameters were larger in the wrapping group (40.9±4.2 mm vs. 48.6±4.0 mm, P<0.001). Operative technique was to wrap the ascending aorta transversely with a semi-elliptically resected Dacron graft. The follow-up for the wrapping group was 76.5±35.5 (median 71.1) months. There were no early deaths. Early and late morbidity did not differ between groups. The 24 late deaths, including 10 cardiac-related deaths, occurred in the entire group; 3 sudden deaths occurred only in the AVR group. The 10-year overall survival in the wrapping group was higher than the AVR group (88.1±6.8% vs. 80.0±4.6%, P=0.048). No late aortic complications were detected. The aortic diameter was reduced from 49.5±4.1 mm to 45.3±5.0 mm after wrapping (P<0.001). The aortic wrapping technique may be an option for treating a moderately dilated ascending aorta in selected patients undergoing AVR for BAS. Longer follow-up, however, is necessary to verify later complications.

Aortic expansion rate in patients with dilated post-stenotic ascending aorta submitted only to aortic valve replacement long-term follow-up.

PubMed

Gaudino, Mario; Anselmi, Amedeo; Morelli, Mauro; Pragliola, Claudio; Tsiopoulos, Vasileios; Glieca, Franco; Possati, Gianfederico

2011-08-02

This study was conceived to describe the evolution of aortic dimensions in patients with moderate post-stenotic ascending aorta dilation (50 to 59 mm) submitted to aortic valve replacement (AVR) alone. The appropriate treatment of post-stenotic ascending aorta dilation has been poorly investigated. Ninety-three patients affected by severe isolated calcific aortic valve stenosis in the tricuspid aortic valve accompanied by moderate dilation of the ascending aorta (50 to 59 mm) were submitted to AVR only. All patients were followed for a mean of 14.7 ± 4.8 years by means of periodic clinical evaluations and echocardiography and tomography scans of the thorax. Operative mortality was 1.0% (1 patient). During the follow-up, 16 patients died and 2 had to be reoperated for valve dysfunction. No patients experienced acute aortic events (rupture, dissection, pseudoaneurysm), and no patient had to be reoperated on the aorta. There was not a substantial increase in aortic dimensions: mean aortic diameter was 57 ± 11 mm at the end of the follow-up versus 56 ± 02 mm pre-operatively (p = NS). The mean ascending aorta expansion rate was 0.3 ± 0.2 mm/year. In the absence of connective tissue disorders, AVR alone is sufficient to prevent further aortic expansion in patients with moderate post-stenotic dilation of the ascending aorta. Aortic replacement can probably be reserved for patients with a long life expectancy. Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Stress axis regulation during social ascension in a group-living cichlid fish.

PubMed

Culbert, Brett M; Gilmour, Kathleen M; Balshine, Sigal

2018-06-19

Animals living in groups often form social hierarchies, with characteristic behaviours and physiologies associated with rank. However, when social opportunities arise and a subordinate ascends into a dominant position, quick adjustments are necessary to secure this position. Such periods of social transition are typically associated with elevated glucocorticoid production, but the precise regulation of the stress axis during these occasions is not well understood. Using the group-living cichlid, Neolamprologus pulcher, the effects of social ascension on the stress axis were assessed. Ascenders rapidly filled experimentally created vacancies, adopting a dominant behavioural phenotype within 72 h-elevating aggression, activity, and workload, while receiving high rates of affiliative behaviours from their group members. Despite assuming behavioural dominance within their groups, ascenders displayed higher cortisol levels than dominants three days post-ascension. Additionally, compared to subordinates, ascenders had increased transcript abundance of steroidogenic acute regulatory protein (star) and cytochrome p450 side-chain cleavage enzyme (p450scc) in the head kidney, indicating activation of the stress axis. Cortisol levels were lowest in ascenders that displayed low rates of aggression, potentially reflecting the reestablishment of social stability in these groups. Increased transcript abundance of both glucocorticoid receptors (gr1 and gr2) in the brain's preoptic area (POA) of ascenders compared to dominants suggested an enhanced capacity for cortisol regulation via negative feedback. Our results reveal a regulatory cascade of behavioural and physiological interactions and highlight the importance of investigating the underlying mechanisms regulating the stress axis. Copyright © 2018. Published by Elsevier Inc.

Elastic properties of the young aorta: ex vivo perfusion experiments in a porcine model.

PubMed

Krüger, Tobias; Grigoraviciute, Akvile; Veseli, Kujtim; Schibilsky, David; Wendel, Hans P; Schneider, Wilke; Schlensak, Christian

2015-08-01

To investigate the regional and directional compliance/distensibility of the healthy aorta. Complete fresh porcine aortas (n = 11) were perfused ex vivo under defined haemodynamic parameters using a custom-made pulse duplicator. Both circumferential and longitudinal compliance were measured optically. The pulse duplicator was able to perfuse the entire aorta with arbitrary haemodynamic parameters, generating a physiological pulse curve. Aortic compliance is pressure dependent, as we observed a linear relationship between pressure and distension in the range of 5-200 mmHg; however, above 200 mmHg, the porcine aorta behaved in an inelastic manner. Circumferential compliance was highest in the ascending aorta (24%/100 mmHg) but significantly (P < 0.05) decreased in both the arch (18%/100 mmHg) and the descending aorta (15%/100 mmHg). Longitudinal compliance was highest in the ascending aorta and clearly exceeded circumferential compliance. Compliance was significantly (P < 0.05) higher in the outer curvatures of the ascending aorta and the aortic arch compared with the compliance of the inner curvature at these locations (30%/100 vs 23%/100 mmHg in the ascending aorta and 20%/100 vs 9%/100 mmHg in the arch, respectively). Longitudinal compliance of the ascending aorta, particularly the outer curvature, is predominantly responsible for the 'Windkessel effect'. Pathological changes such as elongation and pronounced angulation of the ascending aorta increase stress on the outer curvature and may be important factors in the development of aortic dissection. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Blood flow characteristics in the ascending aorta after TAVI compared to surgical aortic valve replacement.

PubMed

Trauzeddel, Ralf Felix; Löbe, Ulrike; Barker, Alex J; Gelsinger, Carmen; Butter, Christian; Markl, Michael; Schulz-Menger, Jeanette; von Knobelsdorff-Brenkenhoff, Florian

2016-03-01

Ascending aortic blood flow characteristics are altered after aortic valve surgery, but the effect of transcatheter aortic valve implantation (TAVI) is unknown. Abnormal flow may be associated with aortic and cardiac remodeling. We analyzed blood flow characteristics in the ascending aorta after TAVI in comparison to conventional stented aortic bioprostheses (AVR) and healthy subjects using time-resolved three-dimensional flow-sensitive cardiovascular magnetic resonance imaging (4D-flow MRI). Seventeen patients with TAVI (Edwards Sapien XT), 12 with AVR and 9 healthy controls underwent 4D-flow MRI of the ascending aorta. Target parameters were: severity of vortical and helical flow pattern (semiquantitative grading from 0 = none to 3 = severe) and the local distribution of systolic wall shear stress (WSSsystole). AVR revealed significantly more extensive vortical and helical flow pattern than TAVI (p = 0.042 and p = 0.002) and controls (p < 0.001 and p = 0.001). TAVI showed significantly more extensive vortical flow than controls (p < 0.001). Both TAVI and AVR revealed marked blood flow eccentricity (64.7 and 66.7%, respectively), whereas controls showed central blood flow (88.9%). TAVI and AVR exhibited an asymmetric distribution of WSSsystole in the mid-ascending aorta with local maxima at the right anterior aortic wall and local minima at the left posterior wall. In contrast, controls showed a symmetric distribution of WSSsystole along the aortic circumference. Blood flow was significantly altered in the ascending aorta after TAVI and AVR. Changes were similar regarding WSSsystole distribution, while TAVI resulted in less helical and vortical blood flow.

Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections.

PubMed

Ankomah, Peter; Levin, Bruce R

2014-06-10

The successful treatment of bacterial infections is the product of a collaboration between antibiotics and the host's immune defenses. Nevertheless, in the design of antibiotic treatment regimens, few studies have explored the combined action of antibiotics and the immune response to clearing infections. Here, we use mathematical models to examine the collective contribution of antibiotics and the immune response to the treatment of acute, self-limiting bacterial infections. Our models incorporate the pharmacokinetics and pharmacodynamics of the antibiotics, the innate and adaptive immune responses, and the population and evolutionary dynamics of the target bacteria. We consider two extremes for the antibiotic-immune relationship: one in which the efficacy of the immune response in clearing infections is directly proportional to the density of the pathogen; the other in which its action is largely independent of this density. We explore the effect of antibiotic dose, dosing frequency, and term of treatment on the time before clearance of the infection and the likelihood of antibiotic-resistant bacteria emerging and ascending. Our results suggest that, under most conditions, high dose, full-term therapy is more effective than more moderate dosing in promoting the clearance of the infection and decreasing the likelihood of emergence of antibiotic resistance. Our results also indicate that the clinical and evolutionary benefits of increasing antibiotic dose are not indefinite. We discuss the current status of data in support of and in opposition to the predictions of this study, consider those elements that require additional testing, and suggest how they can be tested.

Hemodynamic responses to dexmedetomidine in critically injured intubated pediatric burned patients: a preliminary study.

PubMed

Shank, Erik S; Sheridan, Robert L; Ryan, Colleen M; Keaney, Timothy J; Martyn, J A Jeevendra

2013-01-01

Because of ineffectiveness and tolerance to benzodiazepines and opioids developing with time, drugs acting via other receptor systems (eg, α-2 agonists) have been advocated in burn patients to improve sedation and analgesia. This study in severely burned pediatric subjects examined the hemodynamic consequences of dexmedetomidine (Dex) administration. Eight intubated patients with ≥20 to 79% TBSA burns were studied between 7 and 35 days after injury. After baseline measurements of mean arterial blood pressure and heart rhythm were taken, each patient received a 1.0 µg/kg bolus of Dex followed by an ascending dose infusion protocol (0.7-2.5 µg/kg/hr), with each dose administered for 15 minutes. There was significant hypotension (27±7.5%, average drop in mean arterial pressure [MAP] ± SD), and a decrease in heart rate (HR; 19% ± 7, average drop in HR ± SD). The average HR decreased from 146 beats per minute to 120. No bradycardia (HR < 60) or heart blocks were observed. In three patients, the MAP decreased to <50mm Hg with the bolus dose of Dex. Of the remaining five patients, three patients completed the study receiving the highest infusion dose of Dex (2.5 µg/kg/hr), whereas in 2 patients the infusion part of the study was begun, but the study was stopped due to persistent hypotension (MAP < 50mm Hg). These observations indicate that a bolus dose of Dex (1.0 µg/kg for 10 minutes) and high infusion rates may require fluid resuscitation or vasopressor support to maintain normotension in critically injured pediatric burn patients.

Safety, pharmacokinetic and pharmacodynamic properties of TV-1106, a long-acting GH treatment for GH deficiency.

PubMed

Cohen-Barak, Orit; Sakov, Anat; Rasamoelisolo, Michele; Bassan, Merav; Brown, Kurt; Mendzelevski, Boaz; Spiegelstein, Ofer

2015-11-01

TV-1106 (Teva Pharmaceuticals) is a genetically fused recombinant protein of human GH (hGH) and human serum albumin, in development for treatment of GH deficiency (GHD). TV-1106 is expected to have an extended duration of action compared to daily GH treatment and may enable a reduction in the frequency of injections and improve compliance and quality of life for adults and children requiring GHD therapy. To assess the safety, local tolerability, pharmacokinetics and pharmacodynamics of TV-1106 following single s.c. injections in healthy male volunteers. Subjects (n=56) were assigned to one of seven ascending dose groups (3-100 mg) and received either a single dose of TV-1106 (n=6) or placebo (n=2) by s.c. injection. Eighteen subjects reported 43 adverse effects (AEs), which were mild to moderate; no serious AEs (SAEs) occurred. In 50, 70 and 100 mg groups there were mild to moderate increases in heart rate and systolic blood pressure that significantly correlated with higher levels of IGF1. TV-1106 showed pharmacokinetic characteristics of a long-acting hGH as demonstrated by a terminal elimination half-life of 23-35 h, delayed time of peak concentration, and systemic levels seen up to 7 days after dosing. IGF1 levels increased in a dose-dependent manner, before reaching a plateau, with levels above baseline extending beyond 7 days post dose. Single administration of TV-1106 up to 100 mg was safe in healthy volunteers. Pharmacokinetics and pharmacodynamics support once-weekly administration in patients with GHD. © 2015 The authors.

Current practice of antibiotic prophylaxis for surgical fixation of closed long bone fractures: a survey of 297 members of the Orthopaedic Trauma Association.

PubMed

Gans, Itai; Jain, Amit; Sirisreetreerux, Norachart; Haut, Elliott R; Hasenboehler, Erik A

2017-01-01

The risk of postoperative surgical site infection after long bone fracture fixation can be decreased with appropriate antibiotic use. However, there is no agreement on the superiority of a single- or multiple-dose perioperative regimen of antibiotic prophylaxis. The purpose of this study is to determine the following: 1) What are the current practice patterns of orthopaedic trauma surgeons in using perioperative antibiotics for closed long bone fractures? 2) What is the current knowledge of published antibiotic prophylaxis guidelines among orthopaedic trauma surgeons? 3) Are orthopaedic surgeons willing to change their current practices? A questionnaire was distributed via email between September and December 2015 to 955 Orthopaedic Trauma Association members, of whom 297 (31%) responded. Most surgeons (96%) use cefazolin as first-line infection prophylaxis. Fifty-nine percent used a multiple-dose antibiotic regimen, 39% used a single-dose regimen, and 2% varied this decision according to patient factors. Thirty-six percent said they were unfamiliar with Centers for Disease Control and Prevention (CDC) antibiotic prophylaxis guidelines; only 30% were able to select the correct CDC recommendation from a multiple-choice list. However, 44% of surgeons said they followed CDC recommendations. Fifty-six percent answered that a single-dose antibiotic prophylaxis regimen was not inferior to a multiple-dose regimen. If a level-I study comparing a single preoperative dose versus multiple perioperative antibiotic dosing regimen for treatment of closed long bone fractures were published, most respondents (64%) said they would fully follow these guidelines, and 22% said they would partially change their practice to follow these guidelines. There is heterogeneity in the use of single- versus multiple-dose antibiotic prophylaxis for surgical repair of closed long bone fractures. Many surgeons were unsure of current evidence-based recommendations regarding perioperative antibiotic use. Most respondents indicated they would be receptive to high-level evidence regarding the single- versus multiple-dose perioperative prophylactic antibiotics for the treatment of closed long bone fractures.

ASSESSING POPULATION EXPOSURES TO MULTIPLE AIR POLLUTANTS USING A MECHANISTIC SOURCE-TO-DOSE MODELING FRAMEWORK

EPA Science Inventory

The Modeling Environment for Total Risks studies (MENTOR) system, combined with an extension of the SHEDS (Stochastic Human Exposure and Dose Simulation) methodology, provide a mechanistically consistent framework for conducting source-to-dose exposure assessments of multiple pol...

Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome.

PubMed

Jiménez-Altayó, Francesc; Siegert, Anna-Maria; Bonorino, Fabio; Meirelles, Thayna; Barberà, Laura; Dantas, Ana P; Vila, Elisabet; Egea, Gustavo

2017-01-01

Marfan syndrome (MFS) is a hereditary disorder of the connective tissue that causes life-threatening aortic aneurysm, which initiates at the aortic root and can progress into the ascending portion. However, analysis of ascending aorta reactivity in animal models of MFS has remained elusive. Epidemiologic evidence suggests that although MFS is equally prevalent in men and women, men are at a higher risk of aortic complications than non-pregnant women. Nevertheless, there is no experimental evidence to support this hypothesis. The aim of this study was to explore whether there are regional and sex differences in the thoracic aorta function of mice heterozygous for the fibrillin 1 ( Fbn1 ) allele encoding a missense mutation ( Fbn1 C1039G/+ ), the most common class of mutation in MFS. Ascending and descending thoracic aorta reactivity was evaluated by wire myography. Ascending aorta mRNA and protein levels, and elastic fiber integrity were assessed by qRT-PCR, Western blotting, and Verhoeff-Van Gieson histological staining, respectively. MFS differently altered reactivity in the ascending and descending thoracic aorta by either increasing or decreasing phenylephrine contractions, respectively. When mice were separated by sex, contractions to phenylephrine increased progressively from 3 to 6 months of age in MFS ascending aortas of males, whereas contractions in females were unchanged. Endothelium-dependent relaxation was unaltered in the MFS ascending aorta of either sex; an effect related to augmented endothelium-dependent hyperpolarization-type dilations. In MFS males, the non-selective cyclooxygenase (COX) inhibitor indomethacin prevented the MFS-induced enhancement of phenylephrine contractions linked to increased COX-2 expression. In MFS mice of both sexes, the non-selective nitric oxide synthase inhibitor L-NAME revealed negative feedback of nitric oxide on phenylephrine contractions, which was associated with upregulation of eNOS in females. Finally, MFS ascending aortas showed a greater number of elastic fiber breaks than the wild-types, and males exhibited more breaks than females. These results show regional and sex differences in Fbn1 C1039G/+ mice thoracic aorta contractility and aortic media injuries. The presence of more pronounced aortic alterations in male mice provides experimental evidence to support that male MFS patients are at increased risk of suffering aortic complications.

Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome

PubMed Central

Jiménez-Altayó, Francesc; Siegert, Anna-Maria; Bonorino, Fabio; Meirelles, Thayna; Barberà, Laura; Dantas, Ana P.; Vila, Elisabet; Egea, Gustavo

2017-01-01

Marfan syndrome (MFS) is a hereditary disorder of the connective tissue that causes life-threatening aortic aneurysm, which initiates at the aortic root and can progress into the ascending portion. However, analysis of ascending aorta reactivity in animal models of MFS has remained elusive. Epidemiologic evidence suggests that although MFS is equally prevalent in men and women, men are at a higher risk of aortic complications than non-pregnant women. Nevertheless, there is no experimental evidence to support this hypothesis. The aim of this study was to explore whether there are regional and sex differences in the thoracic aorta function of mice heterozygous for the fibrillin 1 (Fbn1) allele encoding a missense mutation (Fbn1C1039G/+), the most common class of mutation in MFS. Ascending and descending thoracic aorta reactivity was evaluated by wire myography. Ascending aorta mRNA and protein levels, and elastic fiber integrity were assessed by qRT-PCR, Western blotting, and Verhoeff-Van Gieson histological staining, respectively. MFS differently altered reactivity in the ascending and descending thoracic aorta by either increasing or decreasing phenylephrine contractions, respectively. When mice were separated by sex, contractions to phenylephrine increased progressively from 3 to 6 months of age in MFS ascending aortas of males, whereas contractions in females were unchanged. Endothelium-dependent relaxation was unaltered in the MFS ascending aorta of either sex; an effect related to augmented endothelium-dependent hyperpolarization-type dilations. In MFS males, the non-selective cyclooxygenase (COX) inhibitor indomethacin prevented the MFS-induced enhancement of phenylephrine contractions linked to increased COX-2 expression. In MFS mice of both sexes, the non-selective nitric oxide synthase inhibitor L-NAME revealed negative feedback of nitric oxide on phenylephrine contractions, which was associated with upregulation of eNOS in females. Finally, MFS ascending aortas showed a greater number of elastic fiber breaks than the wild-types, and males exhibited more breaks than females. These results show regional and sex differences in Fbn1C1039G/+ mice thoracic aorta contractility and aortic media injuries. The presence of more pronounced aortic alterations in male mice provides experimental evidence to support that male MFS patients are at increased risk of suffering aortic complications. PMID:29187826

Interaction of immobilized avidin with an aequorin-biotin conjugate: an aequorin-linked assay for biotin.

PubMed

Feltus, A; Ramanathan, S; Daunert, S

1997-12-01

Biotinylated recombinant aequorin was used in the development of a heterogeneous bioluminescence binding assay for biotin. This assay is based on a competition between a biotinylated aequorin conjugate and biotin for the binding sites of avidin immobilized on solid particles. Dose-response curves were obtained that relate solid-phase aequorin activity to the concentration of biotin. Under certain experimental conditions these curves were biphasic; i.e., as the biotin concentration increased, the solid-phase aequorin activity first increased reaching a maximum and then decreased at higher biotin concentrations. This "hook" effect was observed with four different types of immobilization supports. The effect was more pronounced when low concentrations of aequorin-biotin conjugate were used, and diminished at a high conjugate concentration. This behavior indicates a possible positive cooperativity in the interaction between the immobilized avidin and biotin. Scatchard plot analysis was also consistent with a positive cooperativity mechanism. By using the ascending portion of the dose-response curve, the detection limit of the assay for biotin was 1 x 10(-15) M (100 zmol of biotin in the sample). Copyright 1997 Academic Press.

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles

PubMed Central

Smith, Claire; Hu, Leijun; Coutant, David E.; Whitehurst, Kelly; Phipps, Krista; McNearney, Terry Ann; Yang, Xiao; Ackermann, Bradley; Pottanat, Thomas; Landschulz, William

2017-01-01

Abstract Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator‐blind, parallel‐group, multiple‐ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose‐dependent blockade of the EP4 receptor. Compared with placebo, 24‐h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070. PMID:28857461

Estrogenic modulation of auditory processing: a vertebrate comparison

PubMed Central

Caras, Melissa L.

2013-01-01

Sex-steroid hormones are well-known regulators of vocal motor behavior in several organisms. A large body of evidence now indicates that these same hormones modulate processing at multiple levels of the ascending auditory pathway. The goal of this review is to provide a comparative analysis of the role of estrogens in vertebrate auditory function. Four major conclusions can be drawn from the literature: First, estrogens may influence the development of the mammalian auditory system. Second, estrogenic signaling protects the mammalian auditory system from noise- and age-related damage. Third, estrogens optimize auditory processing during periods of reproductive readiness in multiple vertebrate lineages. Finally, brain-derived estrogens can act locally to enhance auditory response properties in at least one avian species. This comparative examination may lead to a better appreciation of the role of estrogens in the processing of natural vocalizations and may provide useful insights toward alleviating auditory dysfunctions emanating from hormonal imbalances. PMID:23911849

A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

PubMed

Sayed, Sehrish; Van Dam, Nicholas T; Horn, Sarah R; Kautz, Marin M; Parides, Michael; Costi, Sara; Collins, Katherine A; Iacoviello, Brian; Iosifescu, Dan V; Mathé, Aleksander A; Southwick, Steven M; Feder, Adriana; Charney, Dennis S; Murrough, James W

2018-01-01

Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519). © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

Diverticular colitis of the ascending colon preceding the onset of ulcerative colitis.

PubMed

Maeshiro, Tatsuji; Hokama, Akira; Kinjo, Tetsu; Fujita, Jiro

2014-06-30

We present a case of diverticular colitis of the ascending colon preceding the onset of ulcerative colitis. A 58-year-old man presented with positive faecal occult blood test. Colonoscopy disclosed diverticular colitis of the ascending colon. After a year's follow-up, typical ulcerative colitis developed and diverticular colitis improved. Diverticular colitis is a newly established disorder of chronic segmental mucosal inflammation affected by diverticular disease. There is increasing recognition of such cases with diverticular colitis preceding ulcerative colitis. There may be a possible pathogenic relationship between the two diseases. 2014 BMJ Publishing Group Ltd.

The effects of changes in response-independent pay upon human masseter EMG. M.A. Thesis

NASA Technical Reports Server (NTRS)

Proni, T. J.

1973-01-01

Electromyographic activity of the masseter muscle was recorded in five human subjects who were presented with systematically varied rates of non-contingent pay. Rates of pay were varied between sessions in either a descending or an ascending series. The number of masseter contractions was found to be greater during the descending series than during the ascending series, especially when a descending series of pay changes followed an ascending series. Verbal physical displays of anger and aggression were noted during descending series. These data indicated a possible relation between masseter contractions and aggression.

The use of a stentless porcine bioprosthesis to repair an ascending aortic aneurysm in combination with aortic valve regurgitation.

PubMed Central

Akpinar, B; Sanisoğlu, I; Konuralp, C; Akay, H; Güden, M; Sönmez, B

1999-01-01

Over the years, many surgical methods have evolved for the treatment of ascending aortic aneurysm in combination with aortic valve regurgitation; however, precise guidelines for optimal surgical techniques for varying presentations have not been defined. We describe the use of a stentless porcine bioprosthesis (Medtronic Freestyle) in a patient with an ascending aortic aneurysm and aortic regurgitation. We used the complete root replacement method, and anastomosed a Dacron graft (Hemashield) between the bioprosthetic valve and the native aorta to replace the distal part of the aneurysm. Images PMID:10524742

ERB master archival tape specification no. T 134081 ERB MAT, revision 1

NASA Technical Reports Server (NTRS)

1984-01-01

The Earth radiation budget (ERB)MAT tapes are generated by the ERB MATGEN software using the IBM 3081 computer system operated by the Science and Applications Computer Center at Goddard Space Flight Center. All MAT's are 9-track and MAT data are in ascending time order. The gross tape format for NIMBUS year-1 and year-2 MAT's is different from the format of MAT's starting with year-3. The MATs from the first two years are to contain one day's worth of data while all other MATs are to contain multiple day's worth of data stacked onto the tapes.

Generating level-dependent models of cervical and thoracic spinal cord injury: Exploring the interplay of neuroanatomy, physiology, and function.

PubMed

Wilcox, Jared T; Satkunendrarajah, Kajana; Nasirzadeh, Yasmin; Laliberte, Alex M; Lip, Alyssa; Cadotte, David W; Foltz, Warren D; Fehlings, Michael G

2017-09-01

The majority of spinal cord injuries (SCI) occur at the cervical level, which results in significant impairment. Neurologic level and severity of injury are primary endpoints in clinical trials; however, how level-specific damages relate to behavioural performance in cervical injury is incompletely understood. We hypothesized that ascending level of injury leads to worsening forelimb performance, and correlates with loss of neural tissue and muscle-specific neuron pools. A direct comparison of multiple models was made with injury realized at the C5, C6, C7 and T7 vertebral levels using clip compression with sham-operated controls. Animals were assessed for 10weeks post-injury with numerous (40) outcome measures, including: classic behavioural tests, CatWalk, non-invasive MRI, electrophysiology, histologic lesion morphometry, neuron counts, and motor compartment quantification, and multivariate statistics on the total dataset. Histologic staining and T1-weighted MR imaging revealed similar structural changes and distinct tissue loss with cystic cavitation across all injuries. Forelimb tests, including grip strength, F-WARP motor scale, Inclined Plane, and forelimb ladder walk, exhibited stratification between all groups and marked impairment with C5 and C6 injuries. Classic hindlimb tests including BBB, hindlimb ladder walk, bladder recovery, and mortality were not different between cervical and thoracic injuries. CatWalk multivariate gait analysis showed reciprocal and progressive changes forelimb and hindlimb function with ascending level of injury. Electrophysiology revealed poor forelimb axonal conduction in cervical C5 and C6 groups alone. The cervical enlargement (C5-T2) showed progressive ventral horn atrophy and loss of specific motor neuron populations with ascending injury. Multivariate statistics revealed a robust dataset, rank-order contribution of outcomes, and allowed prediction of injury level with single-level discrimination using forelimb performance and neuron counts. Level-dependent models were generated using clip-compression SCI, with marked and reliable differences in forelimb performance and specific neuron pool loss. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-lasting behavioral effects in neonatal mice with multiple exposures to ketamine-xylazine anesthesia

PubMed Central

Huang, Lianyan; Hayes, Scott; Yang, Guang

2016-01-01

Anesthetic agents are often administered in the neonatal period, a time of rapid brain development and synaptogenesis. Mounting evidence suggests that anesthetics can disrupt neurocognitive development, particularly in cases of multiple or prolonged anesthetic exposure. Previous studies have shown that administering multiple doses of ketamine-xylazine (KX) anesthesia to neonatal mice can induce long-term changes to synaptic plasticity in the cortex, but the effect on neurocognitive function remains unclear. In this study, we exposed neonatal mice to single dose and multiple doses of KX anesthesia in the neonatal period (postnatal days 7, 9, 11), and conducted a series of behavioral tests in young adulthood (1 month of age). Mice receiving multiple doses of KX anesthesia showed deficits in novel object recognition, sociability, preference for social novelty and contextual fear response, but no effect on auditory-cued fear response. Single dose of KX anesthesia had no effect on these behaviors except for contextual fear response. We also observed that multiple exposures to KX anesthesia were associated with decreased CaMKII phosphorylation, which is known to play a role in synapse development and long-term potentiation, likely contributing to learning impairment. PMID:27622724

Fluid tagging for CT colonography: effectiveness of a 2-hour iodinated oral preparation after incomplete optical colonoscopy.

PubMed

Chang, Kevin J; Rekhi, Satinder S; Anderson, Stephan W; Soto, Jorge A

2011-01-01

To evaluate the distal extent and attenuation of bowel opacification achieved after administration of a single low volume dose of oral contrast 2 hours before computed tomographic colonography (CTC) after incomplete optical colonoscopy. This retrospective study included 144 patients undergoing CTC after incomplete colonoscopy from April 2006 to July 2008 at 2 separate medical centers. Each patient received 20 to 30 mL of diatrizoate meglumine and diatrizoate sodium solution 2 hours before being scanned. The distalmost extent of opacification was: stomach/small bowel, n = 13; cecum, n = 2; ascending colon, n = 7; transverse colon, n = 19; descending colon, n = 14; sigmoid colon, n = 24; rectum, n = 65. The mean attenuation of each opacified segment was: cecum, 449 Hounsfield units (HU); ascending colon, 474 HU; transverse colon, 468 HU; descending colon, 421 HU; sigmoid colon, 391 HU; and rectum, 382 HU. In 103 (71.5%) patients, oral contrast reached the distal colon (descending colon, sigmoid colon, or rectum). The oral contrast did not reach the colon in only 13 (9.0%) patients. Oral administration of a small volume hyperosmolar oral contrast agent 2 hours before CTC results in satisfactory colonic opacification in the majority of patients. Adding same-day fluid tagging in incomplete colonoscopy patients presenting for completion CTC should result in adequate fluid opacification for most of the colon, especially proximal segments not visualized at the time of incomplete colonoscopy.

Drinking sucrose or saccharin enhances sensitivity of rats to quinpirole-induced yawning

PubMed Central

Serafine, Katherine M; Bentley, Todd A; Kilborn, Dylan J; Koek, Wouter; France, Charles P

2015-01-01

Diet can impact sensitivity of rats to some of the behavioral effects of drugs acting on dopamine systems. The current study tested whether continuous access to sucrose is necessary to increase yawning induced by the dopamine receptor agonist quinpirole, or if intermittent access is sufficient. These studies also tested whether sensitivity to quinpirole-induced yawning increases in rats drinking the non-caloric sweetener saccharin. Dose-response curves (0.0032–0.32 mg/kg) for quinpirole-induced yawning were determined once weekly in rats with free access to standard chow and either continuous access to water, 10% sucrose solution, or 0.1% saccharin solution, or intermittent access to sucrose or saccharin (i.e., 2 days per week with access to water on other days). Cumulative doses of quinpirole increased then decreased yawning, resulting in an inverted U-shaped dose-response curve. Continuous or intermittent access to sucrose enhanced sensitivity to quinpirole-induced yawning. Continuous, but not intermittent, access to saccharin also enhanced sensitivity to quinpirole-induced yawning. In all groups, pretreatment with the selective D3 receptor antagonist PG 01037 shifted the ascending limb of the quinpirole dose-response curve to the right, while pretreatment with the selective D2 receptor antagonist L-741626 shifted the descending limb to the right. These results suggest that even intermittent consumption of diets containing highly palatable substances (e.g. sucrose) alters sensitivity to drugs acting on dopamine systems in a manner that could be important in vulnerability to abuse drugs. PMID:26189020

Study protocol: a dose-escalating, phase-2 study of oral lisdexamfetamine in adults with methamphetamine dependence.

PubMed

Ezard, Nadine; Dunlop, Adrian; Clifford, Brendan; Bruno, Raimondo; Carr, Andrew; Bissaker, Alexandra; Lintzeris, Nicholas

2016-12-01

The treatment of methamphetamine dependence is a continuing global health problem. Agonist type pharmacotherapies have been used successfully to treat opioid and nicotine dependence and are being studied for the treatment of methamphetamine dependence. One potential candidate is lisdexamfetamine, a pro-drug for dexamphetamine, which has a longer lasting therapeutic action with a lowered abuse potential. The purpose of this study is to determine the safety of lisdexamfetamine in this population at doses higher than those currently approved for attention deficit hyperactivity disorder or binge eating disorder. This is a phase 2 dose escalation study of lisdexamfetamine for the treatment of methamphetamine dependence. Twenty individuals seeking treatment for methamphetamine dependence will be recruited at two Australian drug and alcohol services. All participants will undergo a single-blinded ascending-descending dose regime of 100 to 250 mg lisdexamfetamine, dispensed daily on site, over an 8-week period. Participants will be offered counselling as standard care. For the primary objectives the outcome variables will be adverse events monitoring, drug tolerability and regimen completion. Secondary outcomes will be changes in methamphetamine use, craving, withdrawal, severity of dependence, risk behaviour and other substance use. Medication acceptability, potential for non-prescription use, adherence and changes in neurocognition will also be measured. Determining the safety of lisdexamfetamine will enable further research to develop pharmacotherapies for the treatment of methamphetamine dependence. Australian and New Zealand Clinical Trials Registry ACTRN12615000391572 Registered 28 th April 2015.

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis).

PubMed

Sanchez-Migallon Guzman, David; Flammer, Keven; Papich, Mark G; Grooters, Amy M; Shaw, Shannon; Applegate, Jeff; Tully, Thomas N

2010-04-01

To determine the pharmacokinetics and safety of voriconazole administered orally in single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). 15 clinically normal adult Hispaniolan Amazon parrots. Single doses of voriconazole (12 or 24 mg/kg) were administered orally to 15 and 12 birds, respectively; plasma voriconazole concentrations were determined at intervals via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) or water was administered orally to 6 and 4 birds, respectively, every 8 hours for 11 days (beginning day 0); trough plasma voriconazole concentrations were evaluated on 3 days. Birds were monitored daily, and clinicopathologic variables were evaluated before and after the trial. Voriconazole elimination half-life was short (0.70 to 1.25 hours). In the single-dose experiments, higher drug doses yielded proportional increases in the maximum plasma voriconazole concentration (C(max)) and area under the curve (AUC). In the multiple-dose trial, C(max), AUC, and plasma concentrations at 2 and 4 hours were decreased on day 10, compared with day 0 values; however, there was relatively little change in terminal half-life. With the exception of 1 voriconazole-treated parrot that developed polyuria, adverse effects were not evident. In Hispaniolan Amazon parrots, oral administration of voriconazole was associated with proportional kinetics following administration of single doses and a decrease in plasma concentration following administration of multiple doses. Oral administration of 18 mg of voriconazole/kg every 8 hours would require adjustment to maintain therapeutic concentrations during long-term treatment. Safety and efficacy of voriconazole treatment in this species require further investigation.

Pharmacokinetics of opicapone, a third-generation COMT inhibitor, after single and multiple oral administration: A comparative study in the rat

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

Gonçalves, Daniela

Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n = 8 per group) were orally treated with single (30, 60 or 90 mg/kg) or multiple (30 mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24 h post-dosing through amore » cannula introduced in the tail vein of rats. After quantifying opicapone and BIA 9-1079 in plasma, a non-compartmental pharmacokinetic analysis was performed. Opicapone was quickly absorbed (time to reach the maximum plasma concentration ≤ 2 h) in both dosage regimens and the extent of systemic exposure to opicapone increased approximately in a dose-proportional manner after single-dosing within the studied dose range (30–90 mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58–4.50 h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen. - Highlights: • Opicapone is relatively rapid absorbed after oral administration to rats. • Systemic exposure to opicapone increases approximately in a dose-proportional manner. • Opicapone and BIA 9-1079 show a small systemic accumulation after multiple-dosing.« less

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels

PubMed Central

Hyun, Seung Won; Wong, Weng Kee

2016-01-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs. PMID:26565557

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels.

PubMed

Hyun, Seung Won; Wong, Weng Kee

2015-11-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs.

Multiple-, But Not Single-, Dose of Parecoxib Reduces Shoulder Pain after Gynecologic Laparoscopy

PubMed Central

Zhang, Hufei; Shu, Haihua; Yang, Lu; Cao, Minghui; Zhang, Jingjun; Liu, Kexuan; Xiao, Liangcan; Zhang, Xuyu

2012-01-01

Background: The aim of this study was to investigate effect of single- and multiple-dose of parecoxib on shoulder pain after gynecologic laparoscopy. Methods: 126 patients requiring elective gynecologic laparoscopy were randomly allocated to three groups. Group M (multiple-dose): receiving parecoxib 40mg at 30min before the end of surgery, at 8 and 20hr after surgery, respectively; Group S (single-dose): receiving parecoxib 40mg at 30min before the end of surgery and normal saline at the corresponding time points; Group C (control): receiving normal saline at the same three time points. The shoulder pain was evaluated, both at rest and with motion, at postoperative 6, 24 and 48hr. The impact of shoulder pain on patients' recovery (activity, mood, walking and sleep) was also evaluated. Meanwhile, rescue analgesics and complications were recorded. Results: The overall incidence of shoulder pain in group M (37.5%) was lower than that in group C (61.9%) (difference=-24.4%; 95% CI: 3.4~45.4%; P=0.023). Whereas, single-dose regimen (61.0%) showed no significant reduction (difference with control=-0.9%; 95% CI: -21.9~20.0%; P=0.931). Moreover, multiple-dose regimen reduced the maximal intensity of shoulder pain and the impact for activity and mood in comparison to the control. Multiple-dose of parecoxib decreased the consumption of rescue analgesics. The complications were similar among all groups and no severe complications were observed. Conclusions: Multiple-, but not single-, dose of parecoxib may attenuate the incidence and intensity of shoulder pain and thereby improve patients' quality of recovery following gynecologic laparoscopy. PMID:23136538

Initial medical management in acute type A aortic dissection patients with a thrombosed false lumen in the ascending aorta combining intramural hematoma and retrograde dissection from the descending to the ascending aorta.

PubMed

Sadamatsu, Kenji; Takase, Susumu; Sagara, Shuichiro; Ohe, Kensuke; Nishi, Jun-Ichiro; Tashiro, Hideki; Kosuga, Tomokazu; Yasunaga, Hiroshi

2018-05-01

The feasibility of medical management for select patients with acute type A aortic dissection has been reported from a few institutions. In this study, we retrospectively investigated the safety and feasibility of our conservative approach for patients with type A aortic dissection in daily practice. From January 2013 to December 2017, 131 consecutive patients were admitted to our institution for acute aortic dissection, including 58 patients of type A. Initial medical management was attempted in select patients who were clinically stable and had a thrombosed false lumen of the ascending aorta without ulcer-like projections in the ascending aorta. Except for nine patients contraindicated for surgery, urgent surgery was performed in 26 patients (SRG group), while 23 patients (MED group) were treated with the initial medical management. The maximum diameter of the ascending aorta was significantly larger in the SRG group than in the MED group. In the MED group, the heart rate and blood pressures were well-controlled at admission to the intensive-care unit, and the systolic blood pressure was further reduced at 24 h after. The in-hospital mortality rates of the MED and SRG groups were 0% and 15%, respectively. During the follow-up period, the survival rate was significantly higher in the MED group than in the SRG group, and the aortic event-free survival at one year was 80%. The initial medical management for select patients with a thrombosed false lumen in the ascending aorta was a safe and feasible strategy in real-world practice.

Ascending aortic curvature as an independent risk factor for type A dissection, and ascending aortic aneurysm formation: a mathematical model.

PubMed

Poullis, Michael P; Warwick, Richard; Oo, Aung; Poole, Robert J

2008-06-01

To develop a mathematical model to demonstrate that ascending aortic curvature is an independent risk factor for type A dissections, in addition to hypertension, bicuspid aortic valve, aneurysm of ascending aorta, and intrinsic aortic tissue abnormalities, like Marfan's syndrome. A steady state one-dimensional flow analysis was performed, utilising Newton's third law of motion. Five different clinical scenarios were evaluated: (1) effect of aortic curvature; (2) effect of beta-blockers, (3) effect of patient size, (4) forces on a Marfan's aorta, and (5) site of entry flap in aortic dissection. Aortic curvature increases the forces exerted on the ascending aorta by a factor of over 10-fold. Aortic curvature can cause patients with a systolic blood pressure of 8 0mmHg to have greater forces exerted on their aorta despite smaller diameters and lower cardiac outputs, than patients with systolic blood pressures of 120 mmHg. In normal diameter aortas, beta-blockers have minimal effect compared with aortic curvature. Aortic curvature may help to explain why normal diameter aortas can dissect, and also that the point of the entry tear may be potentially predictable. Aortic curvature has major effects on the forces exerted on the aorta in patients with Marfan's syndrome. Aortic curvature is relatively more important that aortic diameter, blood pressure, cardiac output, beta-blocker use, and patient size with regard to the force acting on the aortic wall. This may explain why some patients with normal diameter ascending aortas with or without Marfan's syndrome develop type A dissections and aneurysms. Aortic curvature may also help to explain the site of entry tear in acute type A dissection. Further clinical study is needed to validate this study's finding.

Synchronized epiaortic two-dimensional and color Doppler echocardiographic guidance enables routine ascending aortic cannulation in type A acute aortic dissection.

PubMed

Inoue, Yoshito; Takahashi, Ryuichi; Ueda, Toshihiko; Yozu, Ryohei

2011-02-01

Preference for arterial inflow during surgery for type A acute aortic dissection remains controversial. Antegrade central perfusion prevents malperfusion and retrograde embolism, and the ascending aorta provides arterial access for rapid establishment of systemic perfusion, especially if there is hemodynamic instability. It has not been used routinely, however, because of the disruption caused to the aorta. We evaluated the safety and efficacy of routine cannulation of the dissected aorta for the repair of type A dissection. Surgical results were analyzed for 83 consecutive patients with type A acute aortic dissection between 2002 and 2009. They were treated surgically by prosthetic graft replacement under hypothermic circulatory arrest. The ascending aorta was routinely cannulated using the Seldinger technique with epiaortic echocardiographic guidance; antegrade systemic perfusion was evaluated by color Doppler ultrasound. Systemic antegrade perfusion via the dissected ascending aorta was performed safely in all cases. There was no malperfusion or thromboembolism as a result of ascending aortic cannulation. Epiaortic 2-dimensional and color Doppler imaging provided real-time monitoring adequate for the placement and for proper systemic perfusion. There were 5 in-hospital deaths (5/83=6.0%) and 8 strokes (preoperative 6/83=7.2%, postoperative 2/83=2.4%). A total of 78 patients (78/83=94%) were discharged and have been followed up without major adverse cardiac events for a mean duration of 31.8 months. Ascending aortic cannulation is a simple and safe technique that provides a rapid and reliable route of antegrade central systemic perfusion in type A aortic dissection. Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Aneurysmal subarachnoid hemorrhage causes injury of the ascending reticular activating system: relation to consciousness.

PubMed

Jang, S H; Kim, H S

2015-04-01

Little is known about the pathogenetic mechanism of impaired consciousness following subarachnoid hemorrhage. Using diffusion tensor imaging, we attempted to investigate the presence of injury of the lower portion of the ascending reticular activating system between the pontine reticular formation and the intralaminar thalamic nuclei, and the relation between this injury and consciousness level in patients with SAH. We recruited 24 consecutive patients with spontaneous SAH following aneurysmal rupture and 21 healthy control subjects. Consciousness level was rated by using the Glasgow Coma Scale. Using diffusion tensor tractography, we reconstructed the lower portion of the ascending reticular activating system between the pontine reticular formation and the intralaminar thalamic nuclei. Values of fractional anisotropy, apparent diffusion coefficient, and tract number of the ascending reticular activating system were measured. A significant difference in the tract number was observed between the patient and control groups (P < .05); however, there was no significant difference in terms of fractional anisotropy and apparent diffusion coefficient values (P > .05). In addition, regarding the tract number of the patient group, the Glasgow Coma Scale showed strong positive correlations with the tract number on the more affected side (r = 0.890, P < .05), the less affected side (r = 0.798, P < .05), and both sides (r = 0.919, P < .05), respectively. We found injury of the lower portion of the ascending reticular activating system between the pontine reticular formation and the thalamus in patients with SAH. In addition, we observed a close association between injury of the lower portion of the ascending reticular activating system and impaired consciousness in patients with SAH. © 2015 by American Journal of Neuroradiology.

Brain protection by methylprednisolone in rats with spinal cord injury.

PubMed

Chang, Chia-Mao; Lee, Ming-Hsueh; Wang, Ting-Chung; Weng, Hsu-Huei; Chung, Chiu-Yen; Yang, Jen-Tsung

2009-07-01

Traumatic spinal cord injury is clinically treated by high doses of methylprednisolone. However, the effect of methylprednisolone on the brain in spinal cord injury patients has been little investigated. This experimental study examined Bcl-2 and Bax protein expression and Nissl staining to evaluate an apoptosis-related intracellular signaling event and final neuron death, respectively. Spinal cord injury produced a significant apoptotic change and cell death not only in the spinal cord but also in the supraventricular cortex and hippocampal cornu ammonis 1 region in the rat brains. The treatment of methylprednisolone increased the Bcl-2/Bax ratio and prevented neuron death for 1-7 days after spinal cord injury. These findings suggest that rats with spinal cord injury show ascending brain injury that could be restricted through methylprednisolone management.

Comparative pharmacokinetics of oxytetracycline in blunt-snout bream (Megalobrama amblycephala) with single and multiple-dose oral administration.

PubMed

Li, Ru-Qin; Ren, Yu-Wei; Li, Jing; Huang, Can; Shao, Jun-Hui; Chen, Xiao-Xuan; Wu, Zhi-Xin

2015-06-01

Research into the pharmacokinetics and residue elimination of oxytetracycline (OTC) is important both to determine the optimal dosage regimens and to establish a safe withdrawal time in fish. A depletion study is presented here for OTC in Megalobrama amblycephala with a single-dose (100 mg/kg) and multiple-dose (100 mg/kg for five consecutive days) oral administration. The study was conducted at 25 °C. As a result, a one-compartment model was developed. For the single dose, the absorption half-life was 5.79, 9.40, 6.96, and 8.06 h in the plasma, liver, kidney, and muscle, respectively. However, the absorption half-life was 3.62, 7.33, 4.59, and 6.02 h with multiple-dose oral administration. The elimination half-time in the plasma, liver, kidney, and muscle was 58.63, 126.43, 65.1, and 58.85 h when M. amblycephala was treated with a single dose. However, the elimination half-time changed to 91.75, 214.87, 126.22, and 135.84 h with multiple-dose oral administration.

Pharmacokinetics interaction between imatinib and genistein in rats.

PubMed

Wang, Zhe; Wang, Li; Xia, Meng-Ming; Sun, Wei; Huang, Cheng-Ke; Cui, Xiao; Hu, Guo-Xin; Lian, Qing-Quan; Wang, Zeng-Shou

2015-01-01

The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly (P < 0.05) decreased the AUC0-t and C max of imatinib. AUC0-t and the C max of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect.

Statistical strategies for averaging EC50 from multiple dose-response experiments.

PubMed

Jiang, Xiaoqi; Kopp-Schneider, Annette

2015-11-01

In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.

Roof Plate-Derived Radial Glial-like Cells Support Developmental Growth of Rapidly Adapting Mechanoreceptor Ascending Axons.

PubMed

Kridsada, Kim; Niu, Jingwen; Haldipur, Parthiv; Wang, Zhiping; Ding, Long; Li, Jian J; Lindgren, Anne G; Herrera, Eloisa; Thomas, Gareth M; Chizhikov, Victor V; Millen, Kathleen J; Luo, Wenqin

2018-06-05

Spinal cord longitudinal axons comprise some of the longest axons in our body. However, mechanisms that drive this extra long-distance axonal growth are largely unclear. We found that ascending axons of rapidly adapting (RA) mechanoreceptors closely abut a previously undescribed population of roof plate-derived radial glial-like cells (RGLCs) in the spinal cord dorsal column, which form a network of processes enriched with growth-promoting factors. In dreher mutant mice that lack RGLCs, the lengths of ascending RA mechanoreceptor axon branches are specifically reduced, whereas their descending and collateral branches, and other dorsal column and sensory pathways, are largely unaffected. Because the number and intrinsic growth ability of RA mechanoreceptors are normal in dreher mice, our data suggest that RGLCs provide critical non-cell autonomous growth support for the ascending axons of RA mechanoreceptors. Together, our work identifies a developmental mechanism specifically required for long-range spinal cord longitudinal axons. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Development and Implementation for Calculation Model of Measuring Co-Seismic Deformation Field by Using Ascending and Descending Orbit SAR Data

NASA Astrophysics Data System (ADS)

Xue, Tengfei; Chang, Zhanqiang; Zhang, Jingfa

2016-08-01

Interferometry Synthetic Aperture Radar (InSAR)can only measure one component of the surface deformation in the satellite's line of sight (LOS) instead of that in vertical and horizontal directions, i.e. LOS Amphibious. In view of this problem, we analyzed and summarized some methods that can measure the three-dimensional deformation of ground surface by using D-InSAR, developed the calculation model of measuring the three-dimensional co-seismic deformation filed by using the ascending and descending orbit SAR data. The Formula of left-looking (both ascending and descending orbit data), right-looking (both ascending and descending orbit data) and general expression were proposed. The model was applied on L'Aquila earthquake, and the results reveal that the earthquake has caused displacement in both vertical and horizontal directions, and the earthquake made the area down lift 16.8cm along the vertical direction. The characters of the surface reflected by the results are very consistent with the geological exploration.

Epiaortic fat pad area: A novel index for the dimensions of the ascending aorta.

PubMed

Toufan, Mehrnoush; Pourafkari, Leili; Boudagh, Shabnam; Nader, Nader D

2016-06-01

We sought to investigate the possible association between the area of the epiaortic fat pad (EAFP) and dimensions of the ascending aorta. A total of 193 individuals underwent transthoracic echocardiography (TTE) prospectively. The area of the EAFP was traced anterior to the aortic root and correlated with the diameter of the aorta. The mean area of the EAFP was 5.16 ± 2.28 cm(2) Absolute and indexed dimensions of the ascending aorta had a significant correlation with the area of the EAFP (p <0.001 for all). In a multivariate linear regression model, age >65 (p <0.001), body mass index >30 kg/m(2) (p = 0.02) and a history of hyperlipidemia (p = 0.003) were identified as independent predictors of the area for EAFP. In conclusion, both the absolute and indexed diameters of the ascending aorta at the different segments that directly come into contact with the EAFP linearly correlate with the area of the EAFP measured by TTE. © The Author(s) 2016.

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers

PubMed Central

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-01-01

Aim The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Methods Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. Results ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Conclusions Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. PMID:23016924

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.

PubMed

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-05-01

The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. © 2012 Abbott Laboratories. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

[Graft Pseudoaneurysm after Ascending to Abdominal Aorta Bypass for Atypical Coarctation Due to Aortitis Syndrome;Report of a Case].

PubMed

Yada, Masashi; Yamanaka, Kazuo; Miwa, Senri; Hirose, Keiichi; Sakaguchi, Hisashi; Yoshida, Yukiyo; Onga, Youhei; Tara, Yuichi

2017-05-01

We present a case of a 44-year-old woman, with pseudoaneurysm formation at the middle of the prosthetic graft, 60 mm in diameter. She had been diagnosed with atypical coarctation due to aortitis 27 years before, and had undergone a bypass operation with 14 mm-diameter Cooley double velour graft from the ascending aorta to the abdominal aorta. This time, endovascular aortic repair was performed to prevent rupture of the pseudoaneurysm. Though a knitted Dacron graft has a risk of psuedaneurysm formation long patency could be obtained when used in ascending aorta-abdominal aorta bypass.

Monozygotic twins with Marfan's syndrome and ascending aortic aneurysm.

PubMed

Redruello, Héctor Jorge; Cianciulli, Tomas Francisco; Rostello, Eduardo Fernandez; Recalde, Barbara; Lax, Jorge Alberto; Picone, Victorio Próspero; Belforte, Sandro Mario; Prezioso, Horacio Alberto

2007-08-01

Marfan's syndrome is a hereditary connective tissue disease, in which cardiovascular abnormalities (especially aortic root dilatation) are the most important cause of morbidity and mortality. In this report, we describe two 24-year-old twins, with a history of surgery for lens subluxation and severe cardiovascular manifestations secondary to Marfan's syndrome. One of the twins suffered a type A aortic dissection, which required replacement of the ascending aorta, and the other twin had an aneurysmal dilatation of the ascending aorta (46mm) and was prescribed medical treatment with atenolol and periodic controls to detect the presence of a critical diameter (50mm) that would indicate the need for prophylactic surgery.

[Re-operation for Saccular Aneurysm after Ascending Aortic Replacement with Homograft;Report of a Case].

PubMed

Ikeda, Masahiro; Asakura, Toshihisa; Uwabe, Kazuhiko; Morita, Kozo; Iguchi, Atsushi; Niinami, Hiroshi

2017-09-01

A 62-years-old female had undergone ascending aortic replacement with homograft for graft infection and mediastinitis after initial replacement of ascending aorta due to acute type A dissection. Ten years after homograft replacement, follow up computed tomography showed acute growing saccular aneurysm of the homograft without infectious symptoms. We urgently performed Bentall procedure and hemiarch replacement successfully. Pathological diagnosis was true aneurysm of the homograft. She was discharged from hospital without any complication and has been quite uneventful 7 years after surgery. True aneurysm of the homograft is very rare and our case is the 1st report of successful reoperation.

Aortic annulus and ascending aorta: comparison of preoperative and periooperative measurement in patients with aortic stenosis.

PubMed

Smíd, Michal; Ferda, Jirí; Baxa, Jan; Cech, Jakub; Hájek, Tomás; Kreuzberg, Boris; Rokyta, Richard

2010-04-01

Precise determination of the aortic annulus size constitutes an integral part of the preoperative evaluation prior to aortic valve replacement. It enables the estimation of the size of prosthesis to be implanted. Knowledge of the size of the ascending aorta is required in the preoperative analysis and monitoring of its dilation enables the precise timing of the operation. Our goal was to compare the precision of measurement of the aortic annulus and ascending aorta using magnetic resonance (MR), multidetector-row computed tomography (MDCT), transthoracic echocardiography (TTE), and transoesophageal echocardiography (TEE) in patients with degenerative aortic stenosis. A total of 15 patients scheduled to have aortic valve replacement were enrolled into this prospective study. TTE was performed in all patients and was supplemented with TEE, CT and MR in the majority of patients. The values obtained were compared with perioperative measurements. For the measurement of aortic annulus, MR was found to be the most precise technique, followed by MDCT, TTE, and TEE. For the measurement of ascending aorta, MR again was found to be the most precise technique, followed by MDCT, TEE, and TTE. In our study, magnetic resonance was found to be the most precise technique for the measurement of aortic annulus and ascending aorta in patients with severe degenerative aortic stenosis. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Effects of ascending and descending climbers on space elevator cable dynamics

NASA Astrophysics Data System (ADS)

Ishikawa, Yoji; Otsuka, Kiyotoshi; Yamagiwa, Yoshiki; Doi, Hinata

2018-04-01

Based on a mass-point model, the cable dynamics of a space elevator during a climber's travel motion are examined. The cable response during a single operation of one ascending or descending climber is analyzed first, and then, based on the results, the cable dynamics for simultaneous operation of an ascending and a descending climber are evaluated. For the single operation, bending is significant when the climber is traveling near the Earth's surface. The cable also inclines with periodic oscillation as a result of a Coriolis force corresponding to the climber velocity. However, simultaneous operation of ascending and descending climbers can suppress the inclination of the cable by almost a factor of ten. In simultaneous operation, compared to single operation, a descending climber has a smaller amplitude of libration angle and less cable bending, while an ascending climber has a smaller amplitude when the climber is traveling at a higher altitude with climber velocities of 200 km/h and 400 km/h. The phase of the oscillation of the overall cable is found to be close to that of the descending climber. Cable bending is suppressed for any examined climber velocity, but the dependency of this suppression of displacement on climber velocity is not found. In summary, simultaneous operation can surely suppress the inclination of the cable via the cancellation of Coriolis forces by the two climbers.

The effect of a probiotic drink with Lactobacillus plantarum 299v on the bacterial composition in faeces and mucosal biopsies of rectum and ascending colon.

PubMed

Goossens, D A M; Jonkers, D M A E; Russel, M G V M; Stobberingh, E E; Stockbrügger, R W

2006-01-15

Studies on probiotics mainly base their results on faecal samples, which may not represent the situation in the mucosa of distal and proximal colon. In a placebo-controlled study, to assess the effect of Lactobacillus plantarum 299v on the bacterial composition of faecal vs. mucosal samples. Twenty-nine patients undergoing colonoscopic examination for polyps consumed a twice-daily drink with or without L. plantarum 299v (10(11) CFU/day) for 2 weeks. Faecal samples were collected before and after consumption. During colonoscopy, biopsies were collected from the ascending colon and rectum. The faecal and mucosal bacterial concentrations and prevalence were determined. L. plantarum 299v significantly increased the concentration of faecal lactic acid bacteria, lactobacilli and clostridia, and was identified in two rectal biopsies but not in the ascending colon biopsies of probiotic-treated subjects. Concentrations and prevalence in ascending colon and rectum biopsies were comparable, but were significantly lower compared with faecal samples. After probiotic consumption, a significant increase in the faecal concentration of lactobacilli was found but concentrations were low in biopsies. The bacterial composition in biopsies of the ascending colon and rectum did not differ based on culture techniques. To further elucidate the modes of action of probiotics, it might be necessary to study differences in colonization with molecular techniques.

Gross anatomy of the intestine and its mesentery in the nutria (Myocastor coypus).

PubMed

Pérez, W; Lima, M; Bielli, A

2008-11-01

The intestines and mesentery of the nutria (Myocastor coypus) have not been fully described. In the present study 30 adult nutrias were studied using gross dissection. The small intestine was divided into the duodenum, jejunum and ileum as usual. The duodenum started at the pylorus with a cranial portion, which dilated forming a duodenal ampulla. The ileum was located within the concavity of the caecum and attached to the coiled caecum by means of the iliocaecal fold. The ascending colon had two ansae, one proximal and one distal. The proximal ansa was fixed to the caecum by the caecocolic fold. The base of the caecum and a short proximal part of the ascending colon belonging to the proximal ansa were attached to the mesoduodenum descendens. The distal ansa of the ascending colon had a proximal part which was sacculated and a distal part which was smooth. The two parts of the distal ansa of the ascending colon were parallel and joined by a flexure of variable localisation. The smooth part of the distal ansa of the ascending colon was attached to the initial portion of the descending colon by a peritoneal fold. The short transverse colon was directly attached to the mesoduodenum and greater omentum. In conclusion, we have described the anatomy of the intestines of the nutria and its mesentery in detail, and provided a nomenclature list adapted to the Nomina Anatomica Veterinaria.

Observations on the macroscopic anatomy of the intestinal tract and its mesenteric folds in the pampas deer (Ozotoceros bezoarticus, Linnaeus 1758).

PubMed

Pérez, W; Clauss, M; Ungerfeld, R

2008-08-01

We described the macroscopic anatomy of the intestines and their peritoneal folds of five adult pampas deer (Ozotoceros bezoarticus), a cervid species considered to ingest a high proportion of grass in its natural diet. The mean (+/-SD) body weight was 17 (+/-2) kg. The small intestine and the caecocolon measured 495 (+/-37) cm and 237 (+/-24) cm in length, respectively, with an average ratio (small intestine:caecocolon) of 1.9 (+/-0.1). The ascending colon had two and a half centripetal gyri, a central flexure and two centrifugal gyri. The spiral ansa, which was similar to an ellipse, was fixed to the whole left face of the mesenterium. Apart from the peritoneal folds described in the Nomina Anatomica Veterinaria, three additional, hitherto not described folds were found: a fold that fixed the caecum to the proximal ansa of the ascending colon, one that joined the terminal part of the proximal ansa to the last centrifugal gyrus of the spiral ansa of the ascending colon, and one that linked the ascending duodenum to the proximal ansa of the ascending colon. When compared with published data from other cervids of different feeding niches, it appears that, among cervids, the ratio of small intestine to the caecocolon length does not reflect the natural diet.

Orexin A affects ascending contraction depending on downstream cholinergic neurons and descending relaxation through independent pathways in mouse jejunum.

PubMed

Satoh, Yuji; Okishio, Yutaka; Azuma, Yasu-Taka; Nakajima, Hidemitsu; Hata, Fumiaki; Takeuchi, Tadayoshi

2006-09-01

The involvement of orexin in neural pathways for peristalsis was examined in mouse jejunal segments. Localized distension of the segments using a small balloon resulted in ascending contraction and descending relaxation. Ascending contraction was abolished by atropine and tetrodotoxin. Desensitization to orexin A (OXA) and SB-334867-A, an orexin-1 receptor antagonist, significantly inhibited ascending contraction. Hexamethonium also produced a significant inhibition. Exogenous administration of either OXA or nicotine induced a transient contraction that was completely inhibited by atropine and tetrodotoxin. The OXA-induced contraction was significantly inhibited by hexamethonium and SB-334867-A, whereas the nicotine-induced contraction was not inhibited by SB-334867-A. Descending relaxation was either partially or completely inhibited by l-nitroarginine and tetrodotoxin, respectively. Both SB-334867-A and hexamethonium partially inhibited descending relaxation. A combination of SB-334867-A and hexamethonium had an additive inhibitory effect on descending relaxation. Exogenous OXA, in the presence of atropine, induced a relaxation that was significantly inhibited by both l-nitroarginine and SB-334867-A, but not by hexamethonium. Nicotine in the presence of atropine relaxed the jejunal segment. SB-334867-A, unlike hexamethonium, did not affect nicotine-induced relaxation. These results suggest that OXA plays an important role in the ascending and descending neural reflexes in the mouse jejunum.

The Effects on Muscle Activation of Flatfoot during Gait According to the Velocity on an Ascending Slope.

PubMed

Lee, Chang-Ryeol; Kim, Myoung-Kwon

2014-05-01

[Purpose] This study determined the difference between flatfeet and normal feet in humans on an ascending slope using electromyography (EMG). [Subjects] This study was conducted on 30 adults having normal feet (n=15) and flatfeet (n=15), all of whom were 21 to 30 years old. [Methods] A treadmill (AC5000M, SCIFIT,) was used to analyze kinematic features during gait. These features were analyzed at slow, normal, and fast gait velocities on an ascending slope. A surface electromyogram (TeleMyo 2400T, Noraxon Co., USA) was used to measure muscle activity changes. [Results] The activities of most muscles in the subjects with flatfeet were significantly different from the muscle activities in the subjects with normal feet at different gait velocities on an ascending slope. There were significant differences in the vastus medialis and abductor hallucis muscles. [Conclusion] Because muscle activation of the vastus medialis in relation to stability of the lower extremity has a tendency to increase with an increase in gait velocity on an ascending slope, we hypothesized that higher impact transfer to the knee joints occurs in subjects with flatfeet due to the lack of a medial longitudinal arch and that the abductor halluces muscles, which provide dynamic stability to the medial longitudinal arches, do not activate well when they are needed in subjects with flatfeet.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects.

PubMed

Li, Xiaojiao; Liu, Chang; Wu, Min; Zhang, Hong; Sun, Yanfu; Cheng, Longmei; Chen, Hong; Liu, Chengjiao; Yang, Lizhi; Zhang, Qi; Cao, Yuchen; Gu, Jingkai; Ding, Yanhua

2016-08-01

Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a κ-Opioid Agonist in THC-Treated Mice.

PubMed

Chopda, Girish R; Parge, Viraj; Thakur, Ganesh A; Gatley, S John; Makriyannis, Alexandros; Paronis, Carol A

2016-08-01

Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of Δ(9)-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the κ-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% of maximal possible effect. Treatment with THC produced 9- and 7-fold rightward shifts of the diuresis and antinociception dose-response curves for THC and, respectively, 7- and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to >35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the Bmax value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis dose-effect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Respiration Induced Heart Motion and Indications of Gated Delivery for Left-Sided Breast Irradiation

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

Qi, X. Sharon, E-mail: xiangrong.qi@ucdenver.edu; Hu, Angela; Wang Kai

Purpose: To investigate respiration-induced heart motion for left-sided breast irradiation using a four-dimensional computed tomography (4DCT) technique and to determine novel indications to assess heart motion and identify breast patients who may benefit from a gated treatment. Methods and Materials: Images of 4DCT acquired during free breathing for 20 left-sided breast cancer patients, who underwent whole breast irradiation with or without regional nodal irradiation, were analyzed retrospectively. Dose distributions were reconstructed in the phases of 0%, 20%, and 50%. The intrafractional heart displacement was measured in three selected transverse CT slices using D{sub LAD} (the distance from left ascending aortamore » to a fixed line [connecting middle point of sternum and the body] drawn on each slice) and maximum heart depth (MHD, the distance of the forefront of the heart to the line). Linear regression analysis was used to correlate these indices with mean heart dose and heart dose volume at different breathing phases. Results: Respiration-induced heart displacement resulted in observable variations in dose delivered to the heart. During a normal free-breathing cycle, heart-induced motion D{sub LAD} and MHD changed up to 9 and 11 mm respectively, resulting in up to 38% and 39% increases of mean doses and V{sub 25.2} for the heart. MHD and D{sub LAD} were positively correlated with mean heart dose and heart dose volume. Respiratory-adapted gated treatment may better spare heart and ipsilateral-lung compared with the conventional non-gated plan in a subset of patients with large D{sub LAD} or MHD variations. Conclusion: Proposed indices offer novel assessment of heart displacement based on 4DCT images. MHD and D{sub LAD} can be used independently or jointly as selection criteria for respiratory gating procedure before treatment planning. Patients with great intrafractional MHD variations or tumor(s) close to the diaphragm may particularly benefit from the gated treatment.« less

Safety, Tolerability and Pharmacokinetics of Single Doses of Oxytocin Administered via an Inhaled Route in Healthy Females: Randomized, Single-blind, Phase 1 Study.

PubMed

Fernando, Disala; Siederer, Sarah; Singh, Sunita; Schneider, Ian; Gupta, Ashutosh; Powell, Marcy; Richards, Duncan; McIntosh, Michelle P; Lambert, Peter; Fowles, Susan

2017-08-01

The utility of intramuscular (IM) oxytocin for the prevention of postpartum hemorrhage in resource-poor settings is limited by the requirement for temperature-controlled storage and skilled staff to administer the injection. We evaluated the safety, tolerability and pharmacokinetics (PK) of a heat-stable, inhaled (IH) oxytocin formulation. This phase 1, randomized, single-center, single-blind, dose-escalation, fixed-sequence study (NCT02542813) was conducted in healthy, premenopausal, non-pregnant, non-lactating women aged 18-45years. Subjects initially received IM oxytocin 10 international units (IU) on day 1, IH placebo on day 2, and IH oxytocin 50μg on day 3. Subjects were then randomized 4:1 using validated GSK internal software to IH placebo or ascending doses of IH oxytocin (200, 400, 600μg). PK was assessed by comparing systemic exposure (maximum observed plasma concentration, area under the concentration-time curve, and plasma concentrations at 10 and 30min post dose) for IH versus IM oxytocin. Adverse events (AEs), spirometry, laboratory tests, vital signs, electrocardiograms, physical examinations, and cardiac telemetry were assessed. Subjects were recruited between September 14, 2015 and October 12, 2015. Of the 16 subjects randomized following initial dosing, 15 (IH placebo n=3; IH oxytocin n=12) completed the study. IH (all doses) and IM oxytocin PK profiles were comparable in shape. However, systemic exposure with IH oxytocin 400μg most closely matched IM oxytocin 10IU. Systemic exposure was approximately dose proportional for IH oxytocin. No serious AEs were reported. No clinically significant findings were observed for any safety parameters. These data suggest that similar oxytocin systemic exposure can be achieved with IM and IH administration routes, and no safety concerns were identified with either route. The inhalation route may offer the opportunity to increase access to oxytocin for women giving birth in resource-poor settings. Copyright © 2017. Published by Elsevier B.V.

Pomalidomide for Multiple Myeloma

Cancer.gov

A summary of results from a phase III trial that compared the combination of pomalidomide (Pomalyst®) and low-dose dexamethasone versus high-dose dexamethasone alone in patients with multiple myeloma that has progressed despite other treatments.

Herpes simplex virus meningitis complicated by ascending paralysis

PubMed Central

Benjamin, Mina M.; Gummelt, Kyle L.; Zaki, Rabeea; Afzal, Aasim; Sloan, Louis

2013-01-01

A case of herpes simplex virus (HSV) meningitis complicated by ascending paralysis with almost complete recovery following antiviral treatment is reported. We present this case to illustrate the importance of including HSV-induced neuropathy in the differential diagnosis of acute neurologic symptoms following the viral illness. PMID:23814385

New approach to CT pixel-based photon dose calculations in heterogeneous media

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

Wong, J.W.; Henkelman, R.M.

The effects of small cavities on dose in water and the dose in a homogeneous nonunit density medium illustrate that inhomogeneities do not act independently in photon dose perturbation, and serve as two constraints which should be satisfied by approximate methods of computed tomography (CT) pixel-based dose calculations. Current methods at best satisfy only one of the two constraints and show inadequacies in some intermediate geometries. We have developed an approximate method that satisfies both these constraints and treats much of the synergistic effect of multiple inhomogeneities correctly. The method calculates primary and first-scatter doses by first-order ray tracing withmore » the first-scatter contribution augmented by a component of second scatter that behaves like first scatter. Multiple-scatter dose perturbation values extracted from small cavity experiments are used in a function which approximates the small residual multiple-scatter dose. For a wide range of geometries tested, our method agrees very well with measurements. The average deviation is less than 2% with a maximum of 3%. In comparison, calculations based on existing methods can have errors larger than 10%.« less

Reduced Sodium Transport With Nasal Administration of the Prostasin Inhibitor Camostat in Subjects With Cystic Fibrosis

PubMed Central

Reeves, Ginger; Hathorne, Heather; Solomon, G. Martin; Abbi, Smita; Renard, Didier; Lock, Ruth; Zhou, Ping; Danahay, Henry; Clancy, John P.; Waltz, David A.

2013-01-01

Background: Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF). Methods: To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing Na+ transport in the CF airway, we conducted a two-part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered through a nasal spray pump in subjects with CF. Nasal potential difference (PD) was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach. Results: In part 1, nine subjects were enrolled, and six completed crossover dosing at the maximally tolerated dose. The change in maximal (most polarizing) basal PD 2 h following administration of camostat was +13.1 mV (1.6-mg dose group) compared with −8.6 mV following placebo (P < .005). Intrasubject change in Ringer and amiloride-sensitive PDs exhibited similar and consistent responses. Bayesian analysis in an additional six subjects in part 2 estimated a dose of 18 μg/mL to provide 50% of the maximum effect. There was no significant change in chloride transport or total nasal symptom score, nasal examination rating, and laboratory parameters. Conclusions: This study establishes the proof of concept that a reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease. Trial registration: ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov PMID:23412700

Comparison of buprenorphine and methadone effects on opiate self-administration in primates.

PubMed

Mello, N K; Bree, M P; Mendelson, J H

1983-05-01

The effects of ascending and descending doses of buprenorphine (0.014-0.789 mg/kg/day) and methadone (0.179-11.86 mg/kg/day) on opiate and food intake were studied in Macaque monkeys over 195 to 245 days. Food (1-g banana pellets) and i.v. drug self-administration (heroin 0.01 or 0.02 mg/kg/injection or Dilaudid 0.02 mg/kg/injection) were maintained on a second-order schedule of reinforcement [FR 4 (VR 16:S)]. Buprenorphine (0.282-0.789 mg/kg/day) produced a significant suppression of opiate self-administration at 2.5 to 7 times the dose shown to be effective in human opiate abusers (P less than .05-.001). Methadone (1.43-11.86 mg/kg/day) did not suppress opiate self-administration in four of five monkeys across a dose range equivalent to 100 to 800 mg/day in man. The distribution of opiate self-administration across drug sessions did not account for the absence of methadone suppression as monkeys took 43% of the total daily opiate injections during the first daily drug session, 2.5 hr after methadone administration. During buprenorphine maintenance, food intake remained stable or increased significantly above base-line levels. Methadone maintenance was associated with significant decrements in food intake in four of five monkeys. Buprenorphine appeared to be significantly more effective in suppressing opiate self-administration than methadone across the dose range studied. Buprenorphine had none of the toxic side effects (seizures, respiratory depression, profound psychomotor retardation) associated with high doses of methadone over 6 to 8 months of daily drug treatment. These data are consistent with clinical studies of buprenorphine effects on heroin self-administration in human opiate addicts.

Aripiprazole effects on self-administration and pharmacodynamics of intravenous cocaine and cigarette smoking in humans.

PubMed

Lofwall, Michelle R; Nuzzo, Paul A; Campbell, Charles; Walsh, Sharon L

2014-06-01

Aripiprazole is a partial agonist at dopamine (D2) and serotonin (5-HT1a) receptors and 5-HT2 antagonist. Because cocaine affects dopamine and serotonin, this study assessed whether aripiprazole could diminish the reinforcing efficacy of cocaine. Secondary aims evaluated aripiprazole on ad lib cigarette smoking and with a novel 40-hr smoking abstinence procedure. Adults with regular cocaine and cigarette use completed this inpatient double blind, randomized, placebo-controlled mixed-design study. A placebo lead-in was followed by randomization to aripiprazole (0, 2 or 10 mg/day/p.o.; n = 7 completed/group). Three sets of test sessions, each consisting of 3 cocaine sample-choice (i.e., self-administration) sessions and 1 dose-response session, were conducted (once during the lead-in and twice after randomization). Sample sessions tested each cocaine dose (0, 20 and 40 mg/70 kg, i.v.) in random order; subjective, observer-rated and physiologic outcomes were collected. Later that day, participants chose between the morning's sample dose or descending amounts of money over 7 trials. In dose response sessions, all doses were given 1 hr apart in ascending order for pharmacodynamic and pharmacokinetic assessment. Two sets of smoking topography sessions were conducted during the lead-in and after randomization; 1 with and 1 without 40 hr of smoking abstinence. Number of ad lib cigarettes smoked during non-session days was collected. Cocaine produced prototypic effects, but aripiprazole did not significantly alter these effects or smoking outcomes. The smoking abstinence procedure reliably produced nicotine withdrawal and craving and increased smoking modestly. These data do not support further investigation of aripiprazole for cocaine or tobacco use disorder treatment. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Is high–dose rate RapidArc-based radiosurgery dosimetrically advantageous for the treatment of intracranial tumors?

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

Zhao, Bo; Yang, Yong, E-mail: yangy2@upmc.edu; Li, Xiang

In linac-based stereotactic radiosurgery (SRS) and radiotherapy (SRT), circular cone(s) or conformal arc(s) are conventionally used to treat intracranial lesions. However, when the target is in close proximity to critical structures, it is frequently quite challenging to generate a quality plan using these techniques. In this study, we investigated the dosimetric characteristics of using high–dose rate RapidArc (RA) technique for radiosurgical treatment of intracranial lesions. A total of 10 intracranial SRS/SRT cases previously planned using dynamic conformal arc (DCA) or cone-based techniques have been included in this study. For each case, 3 treatment plans were generated: (1) a DCA planmore » with multiple noncoplanar arcs, (2) a high–dose rate RA plan with arcs oriented the same as DCA (multiple-arc RA), and 3) a high–dose rate RA plan with a single coplanar arc (single-arc RA). All treatment plans were generated under the same prescription and similar critical structure dose limits. Plan quality for different plans was evaluated by comparing various dosimetric parameters such as target coverage, conformity index (CI), homogeneity index (HI), critical structures, and normal brain tissue doses as well as beam delivery time. With similar critical structure sparing, high–dose rate RA plans can achieve much better target coverage, dose conformity, and dose homogeneity than the DCA plans can. Plan quality indices CI and HI, for the DCA, multiple-arc RA, and single-arc RA techniques, were measured as 1.67 ± 0.39, 1.32 ± 0.28, and 1.38 ± 0.30 and 1.24 ± 0.11, 1.10 ± 0.04, and 1.12 ± 0.07, respectively. Normal brain tissue dose (V{sub 12} {sub Gy}) was found to be similar for DCA and multiple-arc RA plans but much larger for the single-arc RA plans. Beam delivery was similar for DCA and multiple-arc RA plans but shorter with single-arc RA plans. Multiple-arc RA SRS/SRT can provide better treatment plans than conventional DCA plans, especially for complex cases.« less

Pharmacokinetics of opicapone, a third-generation COMT inhibitor, after single and multiple oral administration: A comparative study in the rat.

PubMed

Gonçalves, Daniela; Alves, Gilberto; Fortuna, Ana; Soares-da-Silva, Patrício; Falcão, Amílcar

2017-05-15

Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n=8 per group) were orally treated with single (30, 60 or 90mg/kg) or multiple (30mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24h post-dosing through a cannula introduced in the tail vein of rats. After quantifying opicapone and BIA 9-1079 in plasma, a non-compartmental pharmacokinetic analysis was performed. Opicapone was quickly absorbed (time to reach the maximum plasma concentration≤2h) in both dosage regimens and the extent of systemic exposure to opicapone increased approximately in a dose-proportional manner after single-dosing within the studied dose range (30-90mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58-4.50h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen. Copyright © 2017 Elsevier Inc. All rights reserved.

Estimation of effective dose and lifetime attributable risk from multiple head CT scans in ventriculoperitoneal shunted children.

PubMed

Aw-Zoretic, J; Seth, D; Katzman, G; Sammet, S

2014-10-01

The purpose of this review is to determine the averaged effective dose and lifetime attributable risk factor from multiple head computed tomography (CT) dose data on children with ventriculoperitoneal shunts (VPS). A total of 422 paediatric head CT exams were found between October 2008 and January 2011 and retrospectively reviewed. The CT dose data was weighted with the latest IRCP 103 conversion factor to obtain the effective dose per study and the averaged effective dose was calculated. Estimates of the lifetime attributable risk were also calculated from the averaged effective dose using a conversion factor from the latest BEIR VII report. Our study found the highest effective doses in neonates and the lowest effective doses were observed in the 10-18 years age group. We estimated a 0.007% potential increase risk in neonates and 0.001% potential increased risk in teenagers over the base risk. Multiple head CTs in children equates to a slight potential increase risk in lifetime attributable risk over the baseline risk for cancer, slightly higher in neonates relative to teenagers. The potential risks versus clinical benefit must be assessed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Standardized ileal digestible valine:lysine dose response effects in 25- to 45-kg pigs under commercial conditions.

PubMed

Gonçalves, Marcio A D; Tokach, Mike D; Dritz, Steve S; Bello, Nora M; Touchette, Kevin J; Goodband, Robert D; DeRouchey, Joel M; Woodworth, Jason C

2018-03-06

Two experiments were conducted to estimate the standardized ileal digestible valine:lysine (SID Val:Lys) dose response effects in 25- to 45-kg pigs under commercial conditions. In experiment 1, a total of 1,134 gilts (PIC 337 × 1050), initially 31.2 kg ± 2.0 kg body weight (BW; mean ± SD) were used in a 19-d growth trial with 27 pigs per pen and seven pens per treatment. In experiment 2, a total of 2,100 gilts (PIC 327 × 1050), initially 25.4 ± 1.9 kg BW were used in a 22-d growth trial with 25 pigs per pen and 12 pens per treatment. Treatments were blocked by initial BW in a randomized complete block design. In experiment 1, there were a total of six dietary treatments with SID Val at 59.0, 62.5, 65.9, 69.6, 73.0, and 75.5% of Lys and for experiment 2 there were a total of seven dietary treatments with SID Val at 57.0, 60.6, 63.9, 67.5, 71.1, 74.4, and 78.0% of Lys. Experimental diets were formulated to ensure that Lys was the second limiting amino acid throughout the experiments. Initially, linear mixed models were fitted to data from each experiment. Then, data from the two experiments were combined to estimate dose-responses using a broken-line linear ascending (BLL) model, broken-line quadratic ascending (BLQ) model, or quadratic polynomial (QP). Model fit was compared using Bayesian information criterion (BIC). In experiment 1, ADG increased linearly (P = 0.009) with increasing SID Val:Lys with no apparent significant impact on G:F. In experiment 2, ADG and ADFI increased in a quadratic manner (P < 0.002) with increasing SID Val:Lys whereas G:F increased linearly (P < 0.001). Overall, the best-fitting model for ADG was a QP, whereby the maximum mean ADG was estimated at a 73.0% (95% CI: [69.5, >78.0%]) SID Val:Lys. For G:F, the overall best-fitting model was a QP with maximum estimated mean G:F at 69.0% (95% CI: [64.0, >78.0]) SID Val:Lys ratio. However, 99% of the maximum mean performance for ADG and G:F were achieved at, 68% and 63% SID Val:Lys ratio, respectively. Therefore, the SID Val:Lys requirement ranged from73.0% for maximum ADG to 63.2% SID Val:Lys to achieve 99% of maximum G:F in 25- to 45-kg BW pigs.

Impact of peripheral hearing loss on top-down auditory processing.

PubMed

Lesicko, Alexandria M H; Llano, Daniel A

2017-01-01

The auditory system consists of an intricate set of connections interposed between hierarchically arranged nuclei. The ascending pathways carrying sound information from the cochlea to the auditory cortex are, predictably, altered in instances of hearing loss resulting from blockage or damage to peripheral auditory structures. However, hearing loss-induced changes in descending connections that emanate from higher auditory centers and project back toward the periphery are still poorly understood. These pathways, which are the hypothesized substrate of high-level contextual and plasticity cues, are intimately linked to the ascending stream, and are thereby also likely to be influenced by auditory deprivation. In the current report, we review both the human and animal literature regarding changes in top-down modulation after peripheral hearing loss. Both aged humans and cochlear implant users are able to harness the power of top-down cues to disambiguate corrupted sounds and, in the case of aged listeners, may rely more heavily on these cues than non-aged listeners. The animal literature also reveals a plethora of structural and functional changes occurring in multiple descending projection systems after peripheral deafferentation. These data suggest that peripheral deafferentation induces a rebalancing of bottom-up and top-down controls, and that it will be necessary to understand the mechanisms underlying this rebalancing to develop better rehabilitation strategies for individuals with peripheral hearing loss. Copyright © 2016 Elsevier B.V. All rights reserved.

[Pain information pathways from the periphery to the cerebral cortex].

PubMed

Kuroda, Ryotaro; Kawabata, Atsufumi

2003-07-01

A recent PET study revealed that the first and second somatosensory cortices (SI, SII), and the anterior cingulate cortex are activated by painful peripheral stimulation in humans. It has become clear that painful signals (nociceptive information) evoked at the periphery are transmitted via various circuits to the multiple cerebral cortices where pain signals are processed and perceived. Human or clinical pain is not merely a modality of somatic sensation, but associated with the affect that accompanies sensation. Consequently, pain has a somatosensory-discriminative aspect and an affective-cognitive aspect that are processed in different but correlated brain structures in the ascending circuits. Considering the physiologic characteristics and fiber connections, the SI and SII cortices appear to be involved in somatosensory-discriminative pain, and the anterior cingulate cortex (area 24) in the affective-cognitive aspect of pain. This paper deals with the ascending pain pathways from the periphery to these cortices and their interconnections. Our recent findings on the protease-activated receptors 1 and 2 (PAR-1, and -2), which are confirmed to exist in the dorsal root ganglion cells, are also described. Activation of PAR-2 during inflammation or tissue injury at the periphery is pronociceptive, while PAR-1 appears to be antinociceptive. Based on the these findings, PAR-1 and PAR-2 are attracting interest as target molecules for new drug development.

Emplacement of the Kodiak batholith and slab-window migration

USGS Publications Warehouse

Farris, David W.; Haeussler, Peter J.; Friedman, Richard; Paterson, Scott R.; Saltus, R.W.; Ayuso, Robert A.

2006-01-01

The Kodiak batholith is one of the largest, most elongate intrusive bodies in the forearc Sanak-Baranof plutonic belt located in southern Alaska. This belt is interpreted to have formed during the subduction of an oceanic spreading center and the associated migration of a slab window. Individual plutons of the Kodiak batholith track the location and evolution of the underlying slab window. Six U/Pb zircon ages from the axis of the batholith exhibit a northeastward-decreasing age progression of 59.2 ± 0.2 Ma at the southwest end to 58.4 ± 0.2 Ma at the northeast tip. The trench-parallel rate of age progression is within error of the average slab-window migration rate for the entire Sanak-Baranof belt (~19 cm/yr). Structural relationships, U/Pb ages, and a model of new gravity data indicate that magma from the Kodiak batholith ascended 5-10 km as a northeastward-younging series of 1-8-km-diameter viscoelastic diapirs. Individual plutons ascended by multiple emplacement mechanisms including downward flow, collapse of wall rock, stoping, and diking. Stokes flow xenolith calculations suggest ascent rates of 5-100 m/yr and an effective magmatic viscosity of 107-108 Pa s. Pre-existing structural or lithologic heterogeneities did not dominantly control the location of the main batholith. Instead, its location was determined by migration of the slab window at depth. 

Finite element analysis of helical flows in human aortic arch: A novel index

PubMed Central

Lee, Cheng-Hung; Liu, Kuo-Sheng; Jhong, Guan-Heng; Liu, Shih-Jung; Hsu, Ming-Yi; Wang, Chao-Jan; Hung, Kuo-Chun

2014-01-01

This study investigates the helical secondary flows in the aortic arch using finite element analysis. The relationship between helical flow and the configuration of the aorta in patients of whose three-dimensional images constructed from computed tomography scans was examined. A finite element model of the pressurized root, arch, and supra-aortic vessels was developed to simulate the pattern of helical secondary flows. Calculations indicate that most of the helical secondary flow was formed in the ascending aorta. Angle α between the zero reference point and the aortic ostium (correlation coefficient (r) = −0.851, P = 0.001), the dispersion index of the cross section of the ascending (r = 0.683, P = 0.021) and descending aorta (r = 0.732, P = 0.010), all correlated closely with the presence of helical flow (P < 0.05). Stepwise multiple linear regression analysis confirmed angel α to be independently associated with the helical flow pattern in therein (standardized coefficients = −0.721, P = 0.023). The presence of helical fluid motion based on the atherosclerotic risks of patients, including those associated with diabetes, hypertension, hyperlipidemia, or renal insufficiency, was also evaluated. Numerical simulation of the flow patterns in aortas incorporating the atherosclerotic risks may better explain the mechanism of formation of helical flows and provide insight into causative factors that underlie them. PMID:24803960

Improvements of CO2 and O2 Transmission Modeling for ASCENDS Mission Applications

NASA Technical Reports Server (NTRS)

Pliutau, Denis; Prasad, Narashimha S.

2011-01-01

Simulations using the HITRAN database and other data have been carried out to select the optimum laser wavelengths for the measurements of CO2 and O2 concentrations with the application to the ASCENDS mission. The accuracy set forth for the ASCENDS mission requires accurate line-by-line calculations involving the use of non-Voigt line shapes. To aid in achieving this goal, improved CO2 and O2 transmission calculation methods are being developed. In particular, line-by-line transmission modeling of CO2 was improved by implementing non-Voigt spectral lineshapes. Ongoing work involves extending this approach to the O2 molecule 1.26-1.27micron spectral band.

Comparison of trunk acceleration ratios during stair negotiation in old-old females.

PubMed

Shin, Sun-Shil; Yoo, Won-Gyu

2016-06-01

[Purpose] This study compared trunk acceleration ratios in old-old adult females during stair negotiation. [Subjects and Methods] Twelve old-old adult females who could walk independently volunteered for this study. This study measured gait time and trunk acceleration ratios using an accelerometer during ascending and descending stairs [Results] The trunk acceleration ratio when descending stairs was significantly higher than that when ascending stairs. [Conclusion] These findings suggest that old-old females have greater deterioration of upper trunk control function for descending than for ascending stairs, regardless of task time. In addition, the trunk acceleration ratio during stair negotiation is a useful clinical marker to predict function and balance control ability in old-old females.

Chronic antihypertensive treatment improves pulse pressure but not large artery mechanics in a mouse model of congenital vascular stiffness.

PubMed

Halabi, Carmen M; Broekelmann, Thomas J; Knutsen, Russell H; Ye, Li; Mecham, Robert P; Kozel, Beth A

2015-09-01

Increased arterial stiffness is a common characteristic of humans with Williams-Beuren syndrome and mouse models of elastin insufficiency. Arterial stiffness is associated with multiple negative cardiovascular outcomes, including myocardial infarction, stroke, and sudden death. Therefore, identifying therapeutic interventions that improve arterial stiffness in response to changes in elastin levels is of vital importance. The goal of this study was to determine the effect of chronic pharmacologic therapy with different classes of antihypertensive medications on arterial stiffness in elastin insufficiency. Elastin-insufficient mice 4-6 wk of age and wild-type littermates were subcutaneously implanted with osmotic micropumps delivering a continuous dose of one of the following: vehicle, losartan, nicardipine, or propranolol for 8 wk. At the end of treatment period, arterial blood pressure and large artery compliance and remodeling were assessed. Our results show that losartan and nicardipine treatment lowered blood pressure and pulse pressure in elastin-insufficient mice. Elastin and collagen content of abdominal aortas as well as ascending aorta and carotid artery biomechanics were not affected by any of the drug treatments in either genotype. By reducing pulse pressure and shifting the working pressure range of an artery to a more compliant region of the pressure-diameter curve, antihypertensive medications may mitigate the consequences of arterial stiffness, an effect that is drug class independent. These data emphasize the importance of early recognition and long-term management of hypertension in Williams-Beuren syndrome and elastin insufficiency. Copyright © 2015 the American Physiological Society.

Temporal aspects of tumorigenic response to individual and mixed carcinogens. [Response of mouse skin to benzo(a)pyrene

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

Albert, R.E.; Burns, F.J.

1976-02-01

Results are reported from experiments that involved either single or multiple doses of benzo(a)pyrene in mouse skin followed by prolonged observation. Preliminary results indicate linearity in dose and time and no evidence of recovery or enhancement for multiple doses of initiator given for extended periods of time. (auth)

Triple dose of gadolinium-DTPA and delayed MRI in patients with benign multiple sclerosis.

PubMed Central

Filippi, M; Capra, R; Campi, A; Colombo, B; Prandini, F; Marcianò, N; Gasparotti, R; Comi, G

1996-01-01

OBJECTIVES--To evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) or delayed MRI increase the number, size, and conspicuousness of enhancing lesions in patients with benign multiple sclerosis. METHODS--T1 weighted brain MRI was carried out on 20 patients with benign multiple sclerosis (expanded disability status scale < 3 with a disease duration > 10 years) in two sessions. In the first session, one scan was obtained before and two scans five to seven minutes and 20-30 minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, the same procedure was repeated with 0.3 mmol/kg Gd-DTPA (triple dose). RESULTS--Nine enhancing lesions were found in seven patients (35%) using the standard dose of Gd-DTPA. The numbers of enhancing lesions increased to 13 (P = 0.03) and the number of patients with such lesions to eight (40%) on the delayed standard dose scans. On the early triple dose scans, we found 19 enhancing lesions in 10 patients (50%). The number of enhancing lesions was significantly higher (P = 0.01) than that obtained with the early standard dose. The number of enhancing lesions was 18 and the number of "active" patients 11 (55%) on the delayed triple dose scans. The enhancing areas increased progressively from the early standard dose scans to the delayed triple dose scans. The contrast ratios of the lesions detected in early standard dose scans was lower than those of lesions present in the early (P = 0.01) and delayed (P = 0.04) triple dose scans. CONCLUSIONS--More enhancing lesions were detected in patients with benign multiple sclerosis with both delay of MRI and the use of triple dose of Gd-DTPA suggesting that the amount of inflammation in the lesions of such patients is mild and heterogeneous. Images PMID:8778257

Quantitative comparison of the results obtained by the multiple-dose guinea pig maximization test and the non-radioactive murine local lymph-node assay for various biocides.

PubMed

Yamano, Tetsuo; Shimizu, Mitsuru; Noda, Tsutomu

2005-07-01

We compared the results of the multiple-dose guinea pig maximization test (GPMT) and the non-radioactive murine local lymph-node assay (LLNA) for various biocides. Thirteen out of 17 positive biocides in the GPMT gave positive results in the LLNA. In the GPMT, the minimum first induction doses ranged over four orders (0.00005-0.5%), while elicitation-threshold doses, which were evaluated using an optimally sensitized group of animals in the multiple-dose studies, ranged over five orders (0.00006-2.8%). In the LLNA, minimum induction doses ranged over more than three orders (0.01-30%). With respect to 13 biocides that were positive in both the GPMT and the LLNA, results were quantitatively compared. When compared after conversion to corresponding area doses (microg/cm), the minimum doses required to elicit skin reaction in guinea pigs were always lower than that for induction in mice with all biocides. Correlation between minimum induction doses from the GPMT and the LLNA seemed poor (r=0.57), while that between minimum induction doses in the LLNA and elicitation-threshold doses in the GPMT was relatively good (r=0.73). The results suggest the possibility to estimate human elicitation-threshold doses, which are definitely lacking in the process of risk assessment for skin-sensitizers, from the data of the LLNA.

Pathogenetic Basis of Aortopathy and Aortic Valve Disease

ClinicalTrials.gov

2018-02-19

Aortopathies; Thoracic Aortic Aneurysm; Aortic Valve Disease; Thoracic Aortic Disease; Thoracic Aortic Dissection; Thoracic Aortic Rupture; Ascending Aortic Disease; Descending Aortic Disease; Ascending Aortic Aneurysm; Descending Aortic Aneurysm; Marfan Syndrome; Loeys-Dietz Syndrome; Ehlers-Danlos Syndrome; Shprintzen-Goldberg Syndrome; Turner Syndrome; PHACE Syndrome; Autosomal Recessive Cutis Laxa; Congenital Contractural Arachnodactyly; Arterial Tortuosity Syndrome

Dual-task interference effects on cross-modal numerical order and sound intensity judgments: the more the louder?

PubMed

Alards-Tomalin, Doug; Walker, Alexander C; Nepon, Hillary; Leboe-McGowan, Launa C

2017-09-01

In the current study, cross-task interactions between number order and sound intensity judgments were assessed using a dual-task paradigm. Participants first categorized numerical sequences composed of Arabic digits as either ordered (ascending, descending) or non-ordered. Following each number sequence, participants then had to judge the intensity level of a target sound. Experiment 1 emphasized processing the two tasks independently (serial processing), while Experiments 2 and 3 emphasized processing the two tasks simultaneously (parallel processing). Cross-task interference occurred only when the task required parallel processing and was specific to ascending numerical sequences, which led to a higher proportion of louder sound intensity judgments. In Experiment 4 we examined whether this unidirectional interaction was the result of participants misattributing enhanced processing fluency experienced on ascending sequences as indicating a louder target sound. The unidirectional finding could not be entirely attributed to misattributed processing fluency, and may also be connected to experientially derived conceptual associations between ascending number sequences and greater magnitude, consistent with conceptual mapping theory.

Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population.

PubMed

Li, Xueqing; Wang, Rutao; Liu, Yang; Liu, Yun; Zheng, Heng; Feng, Yabo; Zhao, Na; Geng, Hongbin; Zhang, Wanzhi; Wen, Aidong

2017-11-16

Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C max showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t max of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed. Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The t max of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).

Asymmetric variations in the tropical ascending branches of Hadley circulations and the associated mechanisms and effects

NASA Astrophysics Data System (ADS)

Sun, Bo

2018-03-01

This study investigates the variations in the tropical ascending branches (TABs) of Hadley circulations (HCs) during past decades, using a variety of reanalysis datasets. The northern tropical ascending branch (NTAB) and the southern tropical ascending branch (STAB), which are defined as the ascending branches of the Northern Hemisphere HC and Southern Hemisphere HC, respectively, are identified and analyzed regarding their trends and variability. The reanalysis datasets consistently show a persistent increase in STAB during past decades, whereas they show less consistency in NTAB regarding its decadalto multidecadal variability, which generally features a decreasing trend. These asymmetric trends in STAB and NTAB are attributed to asymmetric trends in the tropical SSTs. The relationship between STAB/NTAB and tropical SSTs is further examined regarding their interannual and decadal- to multidecadal variability. On the interannual time scale, the STAB and NTAB are essentially modulated by the eastern-Pacific type of ENSO, with a strengthened (weakened) STAB (NTAB) under an El Niño condition. On the decadal- to multidecadal time scale, the variability of STAB and NTAB is closely related to the southern tropical SSTs and the meridional asymmetry of global tropical SSTs, respectively. The tropical eastern Pacific SSTs (southern tropical SSTs) dominate the tropical SST-NTAB/STAB relationship on the interannual (decadal- to multidecadal) scale, whereas the NTAB is a passive factor in this relationship. Moreover, a cross-hemispheric relationship between the NTAB/STAB and the HC upper-level meridional winds is revealed.

Alcohol affects executive cognitive functioning differentially on the ascending versus descending limb of the blood alcohol concentration curve.

PubMed

Pihl, Robert O; Paylan, Sheila S; Gentes-Hawn, Alyson; Hoaken, Peter N S

2003-05-01

Executive cognitive functioning (ECF), a construct that includes cognitive abilities such as planning, abstract reasoning, and the capacity to govern self-directed behavior, has been recently researched as an antecedent to many forms of psychopathology and has been implicated in alcohol-related aggression. This study was designed to examine whether differential ECF impairments can be noted on the ascending versus the descending limbs of the blood alcohol concentration curve. Forty-one male university students participated in this study. Twenty-one subjects were given 1.32 ml of 95% alcohol per kilogram of body weight, mixed with orange juice, and the remaining 20 were given a placebo. Participants were randomly assigned to either an ascending or descending blood alcohol group and were tested on six tests of ECF on their assigned limb. Subjective mood data were also collected. Intoxicated participants on both limbs demonstrated ECF impairment; the descending-limb group showed greater impairment than their ascending-limb counterparts. Intoxicated subjects were significantly more anxious at baseline than placebo subjects. The introduction of this covariate nullified any significant differences in subjective mood found on either limb of the blood alcohol concentration curve, but ECF impairments remained robust. Our results support the conclusion that alcohol negatively affects cognitive performance and has a differential effect on the descending versus the ascending limb of the blood alcohol concentration curve. The latter finding may have important ramifications relating to the detrimental consequences of alcohol intoxication.

Regional Differences in Stem and Transit Cell Proliferation and Apoptosis in the Terminal Ileum and Colon of Mice After 12 Gy

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

Gandara, Ricardo M.C.; Mahida, Yashwant R., E-mail: yash.mahida@nottingham.ac.uk; Potten, Christopher S.

2012-03-01

Purpose: The intestinal epithelium has a high rate of cell turnover, which is regulated by stem cells located near the base of crypts. We aimed to investigate stem cell-dependent characteristics of cell proliferation, apoptosis, and crypt size in terminal ileum and different regions of the colon. Methods and Materials: Mice were studied under steady-state conditions and after radiation-induced stem cell apoptosis. Percentage of proliferating or apoptotic cells at a particular cell position (cp) along the crypt axis was expressed as labeling or apoptotic index. Results: Under steady-state conditions: crypt size was smallest in the ascending colon. In contrast to othermore » regions of the colon, the distribution profile of proliferating cells in ascending colon showed some similarity to that in the terminal ileum. Postirradiation: apoptotic cells were prominent at the bottom of the crypt of mid- and descending colon but in the ascending colon, they were seen with similar frequency from cp 1 to 4. During regeneration, a constant proliferative capacity was seen above Paneth cells in the terminal ileum. In the ascending (but not mid- or descending) colon, the profile of proliferating cells over the first 4 days after irradiation showed a similarity to that in the terminal ileum. Conclusions: Profiles of proliferating epithelial cells (under steady-state conditions and postirradiation) and apoptotic cells (postirradiation) suggest similarities in the location of stem cells in the ascending colon and terminal ileum.« less

In Vivo Patellar Tracking and Patellofemoral Cartilage Contacts during Dynamic Stair Ascending

PubMed Central

Suzuki, Takashi; Hosseini, Ali; Li, Jing-Sheng; Gill, Thomas J; Li, Guoan

2012-01-01

The knowledge of normal patellar tracking is essential for understanding of the knee joint function and for diagnosis of patellar instabilities. This paper investigated the patellar tracking and patellofemoral joint contact locations during a stair ascending activity using a validated dual-fluoroscopic imaging system. The results showed that the patellar flexion angle decreased from 41.9° to 7.5° with the knee extension during stair ascending. During first 80% of the activity, the patella shifted medially about 3.9 mm and then slightly shifted laterally during the last 20% of the ascending activity. Anterior translation of 13 mm of the patella was measured at the early 80% of the activity and then slightly moved posteriorly by about 2 mm at the last 20% of the activity. The path of the cartilage contact points was slightly lateral on the cartilage surfaces of patella and femur. On the patellar cartilage surface, the cartilage contact locations were about 2 mm laterally from heel strike to 60% of the stair ascending activity and moved laterally and reached 5.3 mm at full extension. However, the cartilage contact locations were relatively constant on the femoral cartilage surface (~5 mm lateral). The patellar tracking pattern was consistent with the patellofemoral cartilage contact location pattern. These data could provide baseline knowledge for understanding of normal physiology of the patellofemoral joint and can be used as a reference for clinical evaluation of patellofemoral disorder symptoms. PMID:22840488

Transcardiac endograft delivery for endovascular treatment of the ascending aorta: a feasibility study in pigs.

PubMed

Wipper, Sabine; Lohrenz, Christina; Ahlbrecht, Oliver; Carpenter, Sebastian W; Tsilimparis, Nikolaos; Kersten, Jan Felix; Detter, Christian; Debus, Eike S; Kölbel, Tilo

2015-06-01

To compare the technical feasibility and hemodynamic alterations during antegrade transcardiac access routes vs conventional transfemoral access (TFA) for endovascular treatment of the ascending aorta in a porcine model. Antegrade transseptal access (TSA), transapical access (TAA), and TFA were used for implantation of custom-made endografts into the ascending aorta under fluoroscopy (6 pigs each). Hemodynamic parameters, myocardial and cerebral blood flow, and carotid artery blood flow were evaluated during baseline (T1), sheath advancement (T2), after sheath retraction (T3), and after endograft deployment (T4). Endograft deployment was feasible in all animals; all coronary arteries remained patent. Hemodynamic parameters were comparable in all 3 study groups during all measurements. During T2, transient hemodynamic alteration occurred in all groups, with transient severe valve insufficiency in TSA and TAA reflected by the higher pulmonary to mean arterial pressure ratio (p<0.05) as compared with TFA. Values stabilized again at T3 and remained stable until T4. The innominate artery was partially occluded in 4 (TSA), 3 (TAA), and 5 (TFA) animals. There was no deterioration of myocardial or cerebral perfusion during the procedures. Endograft deployment and fluoroscopy times during TAA were shorter than in TSA and TFA. TSA, TFA, and TAA to the ascending aorta are feasible for endograft delivery to the ascending aorta in a porcine model. Transient hemodynamic instability in TSA and TAA recovered to near preoperative values. TAA appeared technically easier. © The Author(s) 2015.

Eating high fat chow increases the sensitivity of rats to quinpirole-induced discriminative stimulus effects and yawning

PubMed Central

Baladi, Michelle G; France, Charles P

2010-01-01

Discriminative stimulus effects of directly-acting dopamine receptor agonists (e.g. quinpirole) appear to be mediated by D3 receptors in free-feeding rats. Free access to high fat chow increases sensitivity to quinpirole-induced yawning and the current study examined whether eating high fat chow increases sensitivity to the discriminative stimulus effects of quinpirole. Five rats discriminated between 0.032 mg/kg quinpirole and vehicle while responding under a continuous reinforcement schedule of stimulus shock termination. When rats had free access to high fat chow (discrimination training was suspended), the quinpirole discrimination dose-response curve shifted leftward, possibly indicating enhanced sensitivity at D3 receptors. In the same rats, both the ascending (mediated by D3 receptors) and descending (mediated by D2 receptors) limbs of the dose- response curve for quinpirole-induced yawning shifted leftward. When rats had free access to a standard chow (discrimination training was suspended), the quinpirole discrimination and yawning dose-response curves did not change. Together with published data showing that the discriminative stimulus effects of quinpirole in free- feeding rats are mediated by D3 receptors and the insensitivity of this effect of quinpirole to food restriction (shown to increase sensitivity to D2 but not D3-mediated effects), these results suggest that the leftward shift of the discrimination dose-response curve when rats eat high fat chow is likely due to enhanced sensitivity at D3 receptors. Thus, eating high fat food enhances drug effects in a manner that might impact clinical effects of drugs or vulnerability to drug abuse. PMID:20729718

Eating high-fat chow increases the sensitivity of rats to quinpirole-induced discriminative stimulus effects and yawning.

PubMed

Baladi, Michelle G; France, Charles P

2010-10-01

Discriminative stimulus effects of direct acting dopamine receptor agonists (e.g. quinpirole) appear to be mediated by D3 receptors in free-feeding rats. Free access to high-fat chow increases sensitivity to quinpirole-induced yawning, and this study examined whether eating high-fat chow increases sensitivity to the discriminative stimulus effects of quinpirole. Five rats discriminated between 0.032 mg/kg quinpirole and vehicle while responding under a continuous reinforcement schedule of stimulus shock termination. When rats had free access to high-fat chow (discrimination training was suspended), the quinpirole discrimination dose-response curve shifted leftward, possibly indicating enhanced sensitivity at D3 receptors. In the same rats, both the ascending (mediated by D3 receptors) and descending (mediated by D2 receptors) limbs of the dose-response curve for quinpirole-induced yawning shifted leftward. When rats had free access to a standard chow (discrimination training was suspended), the quinpirole discrimination and yawning dose-response curves did not change. Together with published data showing that the discriminative stimulus effects of quinpirole in free-feeding rats are mediated by D3 receptors and the insensitivity of this effect of quinpirole to food restriction (shown to increase sensitivity to D2 but not D3-mediated effects), these results suggest that the leftward shift of the discrimination dose-response curve when rats eat high-fat chow is likely because of enhanced sensitivity at D3 receptors. Thus, eating high-fat food enhances drug effects in a manner that might impact clinical effects of drugs or vulnerability to drug abuse.

Perioperative pharmacokinetics of methadone in adolescents.

PubMed

Sharma, Anshuman; Tallchief, Danielle; Blood, Jane; Kim, Thomas; London, Amy; Kharasch, Evan D

2011-12-01

Methadone is frequently administered to adults experiencing anesthesia and receiving pain treatment. Methadone pharmacokinetics in adults are well characterized, including the perioperative period. Methadone is also used in children. There is, however, no information on methadone pharmacokinetics in children of any age. The purpose of this investigation was to determine the pharmacokinetics of intravenous methadone in children undergoing surgery. Perioperative opioid-sparing effects were also assessed. Eligible subjects were children 5-18 yr undergoing general anesthesia and surgery, with an anticipated postoperative inpatient stay exceeding 3 days. Three groups of 10 to 11 patients each received intravenous methadone hydrochloride after anesthetic induction in ascending dose groups of 0.1, 0.2, and 0.3 mg/kg (up to 20 mg). Anesthetic care was not otherwise changed. Venous blood was obtained for 4 days, for stereoselective determination of methadone and metabolites. Pain assessments were made each morning. Daily and total opioid consumption was determined. Perioperative opioid consumption and pain was determined in a second cohort, which was matched to age, sex, race, ethnicity, surgical procedure, and length of stay, but not receiving methadone. The final methadone study cohort was 31 adolescents (14 ± 2 yr, range 10-18) undergoing major spine surgery for a diagnosis of scoliosis. Methadone pharmacokinetics were linear over the dose range 0.1-0.3 mg/kg. Disposition was stereoselective. Methadone administration did not dose-dependently affect postoperative pain scores, and did not dose-dependently decrease daily or total postoperative opioid consumption in spinal fusion patients. Methadone enantiomer disposition in adolescents undergoing surgery was similar to that in healthy adults.

Cardiovascular effects of 3,4-methylenedioxymethamphetamine. A double-blind, placebo-controlled trial.

PubMed

Lester, S J; Baggott, M; Welm, S; Schiller, N B; Jones, R T; Foster, E; Mendelson, J

2000-12-19

The psychoactive stimulant 3, 4-methylenedioxymethamphetamine (MDMA), also known as "ecstasy," is widely used in nonmedical settings. Little is known about its cardiovascular effects. To evaluate the acute cardiovascular effects of MDMA by using transthoracic two-dimensional and Doppler echocardiography. Four-session, ascending-dose, double-blind, placebo-controlled trial. Urban hospital. Eight healthy adults who self-reported MDMA use. Echocardiographic effects of dobutamine (5, 20, and 40 microg/kg of body weight per minute) were measured in a preliminary session. Oral MDMA (0.5 and 1.5 mg/kg of body weight) or placebo was administered 1 hour before echocardiographic measurements in three weekly sessions. Heart rate and blood pressure were measured at regular intervals before and after MDMA administration. Echocardiographic measures of stroke volume, ejection fraction, cardiac output, and meridional wall stress were obtained 1 hour after MDMA administration and during dobutamine infusions. At a dose of 1.5 mg/kg, MDMA increased mean heart rate (by 28 beats/min), systolic blood pressure (by 25 mm Hg), diastolic blood pressure (by 7 mm Hg), and cardiac output (by 2 L/min). The effects of MDMA were similar to those of dobutamine, 20 and 40 microg/kg per minute. Inotropism, measured by using meridional wall stress corrected for ejection fraction, decreased after administration of dobutamine, 40 microg/kg per minute, but did not change after either dose of MDMA. Modest oral doses of MDMA increase heart rate, blood pressure, and myocardial oxygen consumption in a magnitude similar to dobutamine, 20 to 40 microg/kg per minute. In contrast to dobutamine, MDMA has no measurable inotropic effects.

Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy.

PubMed

Chiriboga, Claudia A; Swoboda, Kathryn J; Darras, Basil T; Iannaccone, Susan T; Montes, Jacqueline; De Vivo, Darryl C; Norris, Daniel A; Bennett, C Frank; Bishop, Kathie M

2016-03-08

To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. Results from this study support continued development of nusinersen for treatment of SMA. This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns. © 2016 American Academy of Neurology.

Usefulness of simultaneous and sequential monitoring of glucose level and electrocardiogram in monkeys treated with gatifloxacin under conscious and nonrestricted conditions.

PubMed

Yoshimatsu, Yu; Ishizaka, Tomomichi; Chiba, Katsuyoshi; Mori, Kazuhiko

2018-05-10

Drug-induced cardiac electrophysiological abnormalities accompanied by hypoglycemia or hyperglycemia increase the risk for life-threatening arrhythmia. To assess the drug-induced cardiotoxic potential associated with extraordinary blood glucose (GLU) levels, the effect of gatifloxacin (GFLX) which was frequently associated with GLU abnormality and QT/QTc prolongations in the clinic on blood GLU and electrocardiogram (ECG) parameters was investigated in cynomolgus monkeys (n=4) given GFLX orally in an ascending dose regimen (10, 30, 60 and 100 mg/kg). Simultaneous and sequential GLU and ECG monitoring with a continuous GLU monitoring system and Holter ECG, respectively, were conducted for 24 h under free-moving conditions. Consequently, GFLX at 30 and 60 mg/kg dose-dependently induced a transient decrease in GLU without any ECG abnormality 2-4 h postdose. Highest dose of 100 mg/kg caused severe hypoglycemia with a mean GLU of <30 mg/dL, accompanied by remarkable QT/QTc prolongations by 20-30% in all animals. In contrast, hyperglycemia without QT/QTc prolongations was noted 24 h after dosing in one animal. A close correlation between GLU and QTc values was observed in animals treated with 100 mg/kg, suggesting that GFLX-induced hypoglycemia enhanced QT/QTc prolongations. Furthermore, the 24-h sequential GLU monitoring data clearly distinguished between GFLX-induced GLU abnormality and physiological GLU changes influenced by feeding throughout the day. In conclusion, the combined assessment of continuous GLU and ECG monitoring is valuable in predicting the drug-induced cardio-electrophysiological risk associated with both GLU and ECG abnormalities.

Sex differences in novelty- and psychostimulant-induced behaviors of C57BL/6 mice

PubMed Central

Van Swearingen, Amanda E. D.; Walker, Q. David; Kuhn, Cynthia M.

2012-01-01

Rationale Women are more sensitive than men to psychostimulants and progress from initial use to drug addiction more quickly. The mouse has been an under-utilized model to study sex differences in psychostimulant action. Mice could serve as an ideal genetically-tractable model for mechanistic studies into sex and hormone effects on psychostimulant behavior. Objectives To characterize psychostimulant effects in male and female mice with a combination of automated data collection and behavioral observation. Methods Male and female C57BL/6 mice (Charles River) were given a single dose or sequential ascending binge doses of d-amphetamine (AMPH) or cocaine (COC). Behavior was assessed in open field chambers using both automated photobeam interruptions and behavioral observations. Brain psychostimulant concentrations were determined at the time of maximum behavioral stimulation. Results Psychostimulants induced behavioral activation in mice including both increased locomotion as detected with an automated system and a sequence of behaviors progressing from stereotyped sniffing at low doses to patterned locomotion and rearing at high doses. Females exhibited more patterned locomotion and a shift towards higher behavior scores after either psychostimulant despite having lower AMPH and equivalent COC brain levels as males. Conclusions Female C57BL/6 mice exhibit enhanced psychostimulant-induced behavior compared to males, similar to reports in rats. The combination of automated behavioral measures and behavioral observation was essential for verifying the existence of these differences. These results indicate the importance of testing both sexes when characterizing genetically manipulated mice to control for potential sex-specific effects. PMID:22975726

A case control study of multiple myeloma at four nuclear facilities.

PubMed

Wing, S; Richardson, D; Wolf, S; Mihlan, G; Crawford-Brown, D; Wood, J

2000-04-01

Reported elevations of multiple myeloma among nuclear workers exposed to external penetrating ionizing radiation, based on small numbers of cases, prompted this multi-facility study of workers at US Department of Energy facilities. Ninety-eight multiple myeloma deaths and 391 age-matched controls were selected from the combined roster of 115,143 workers hired before 1979 at Hanford, Los Alamos National Laboratory, Oak Ridge National Laboratory, and the Savannah River site. These workers were followed for vital status through 1990 (1986 for Hanford). Demographic, work history, and occupational exposure data were derived from personnel, occupational medicine, industrial hygiene, and health physics records. Exposure-disease associations were evaluated using conditional logistic regression. Cases were disproportionately African American, male, and hired prior to 1948. Lifetime cumulative whole body ionizing radiation dose was not associated with multiple myeloma, however, there was a significant effect of age at exposure, with positive associations between multiple myeloma and doses received at older ages. Dose response associations increased in magnitude with exposure age (from 40 to 50) and lag assumption (from 5 to 15 years), while a likelihood ratio goodness of fit test reached the highest value for cumulative doses received at ages above 45 with a 5-year lag (X2=5.43,1 df; relative risk = 6.9% per 10 mSv). Dose response associations persisted with adjustment for potential confounders. Multiple myeloma was associated with low level whole body penetrating ionizing radiation doses at older ages. The exposure age effect is at odds with interpretations of A-bomb survivor studies but in agreement with several studies of cancer among nuclear workers.

Shear stress increases nitric oxide production in thick ascending limbs

PubMed Central

Cabral, Pablo D.; Hong, Nancy J.

2010-01-01

We showed that luminal flow stimulates nitric oxide (NO) production in thick ascending limbs. Ion delivery, stretch, pressure, and shear stress all increase when flow is enhanced. We hypothesized that shear stress stimulates NO in thick ascending limbs, whereas stretch, pressure, and ion delivery do not. We measured NO in isolated, perfused rat thick ascending limbs using the NO-sensitive dye DAF FM-DA. NO production rose from 21 ± 7 to 58 ± 12 AU/min (P < 0.02; n = 7) when we increased luminal flow from 0 to 20 nl/min, but dropped to 16 ± 8 AU/min (P < 0.02; n = 7) 10 min after flow was stopped. Flow did not increase NO in tubules from mice lacking NO synthase 3 (NOS 3). Flow stimulated NO production by the same extent in tubules perfused with ion-free solution and physiological saline (20 ± 7 vs. 24 ± 6 AU/min; n = 7). Increasing stretch while reducing shear stress and pressure lowered NO generation from 42 ± 9 to 17 ± 6 AU/min (P < 0.03; n = 6). In the absence of shear stress, increasing pressure and stretch had no effect on NO production (2 ± 8 vs. 8 ± 8 AU/min; n = 6). Similar results were obtained in the presence of tempol (100 μmol/l), a O2− scavenger. Primary cultures of thick ascending limb cells subjected to shear stresses of 0.02 and 0.55 dyne/cm2 produced NO at rates of 55 ± 10 and 315 ± 93 AU/s, respectively (P < 0.002; n = 7). Pretreatment with the NOS inhibitor l-NAME (5 mmol/l) blocked the shear stress-induced increase in NO production. We concluded that shear stress rather than pressure, stretch, or ion delivery mediates flow-induced stimulation of NO by NOS 3 in thick ascending limbs. PMID:20719980

Aortic Dissection in Patients With Bicuspid Aortic Valve–Associated Aneurysms

PubMed Central

Wojnarski, Charles M.; Svensson, Lars G.; Roselli, Eric E.; Idrees, Jay J.; Lowry, Ashley M.; Ehrlinger, John; Pettersson, Gösta B.; Gillinov, A. Marc; Johnston, Douglas R.; Soltesz, Edward G.; Navia, Jose L.; Hammer, Donald F.; Griffin, Brian; Thamilarasan, Maran; Kalahasti, Vidyasagar; Sabik, Joseph F.; Blackstone, Eugene H.; Lytle, Bruce W.

2016-01-01

Background Data regarding the risk of aortic dissection in patients with bicuspid aortic valve and large ascending aortic diameter are limited, and appropriate timing of prophylactic ascending aortic replacement lacks consensus. Thus our objectives were to determine the risk of aortic dissection based on initial cross-sectional imaging data and clinical variables and to isolate predictors of aortic intervention in those initially prescribed serial surveillance imaging. Methods From January 1995 to January 2014, 1,181 patients with bicuspid aortic valve underwent cross-sectional computed tomography (CT) or magnetic resonance imaging (MRI) to ascertain sinus or tubular ascending aortic diameter greater than or equal to 4.7 cm. Random Forest classification was used to identify risk factors for aortic dissection, and among patients undergoing surveillance, time-related analysis was used to identify risk factors for aortic intervention. Results Prevalence of type A dissection that was detected by imaging or was found at operation or on follow-up was 5.3% (n = 63). Probability of type A dissection increased gradually at a sinus diameter of 5.0 cm—from 4.1% to 13% at 7.2 cm—and then increased steeply at an ascending aortic diameter of 5.3 cm—from 3.8% to 35% at 8.4 cm—corresponding to a cross-sectional area to height ratio of 10 cm2/m for sinuses of Valsalva and 13 cm2/m for the tubular ascending aorta. Cross-sectional area to height ratio was the best predictor of type A dissection (area under the curve [AUC] = 0.73). Conclusions Early prophylactic ascending aortic replacement in patients with bicuspid aortic valve should be considered at high-volume aortic centers to reduce the high risk of preventable type A dissection in those with aortas larger than approximately 5.0 cm or with a cross-sectional area to height ratio greater than approximately 10 cm2/m. PMID:26209494

Aortic elongation and the risk for dissection: the Tübingen Aortic Pathoanatomy (TAIPAN) project†.

PubMed

Krüger, Tobias; Oikonomou, Alexandre; Schibilsky, David; Lescan, Mario; Bregel, Katharina; Vöhringer, Luise; Schneider, Wilke; Lausberg, Henning; Blumenstock, Gunnar; Bamberg, Fabian; Schlensak, Christian

2017-06-01

We measured aortic dimensions, particularly length parameters, using 3D imaging with the aim of refining the risk-morphology for Stanford type A aortic dissection (TAD). Computer tomography angiography studies were analysed using the curved multiplanar reformats. At defined landmarks, the diameters and lengths of aortic segments were recorded. Three groups were compared retrospectively: patients actually suffering from a TAD (TAD-group; n  = 150), patients before suffering a TAD (preTAD-group n  = 15) and a healthy control group ( n  = 215). Receiver operating characteristic curves (ROCs) were analysed (control versus preTAD) to study the diagnostic value of the individual variables. Median diameters of preTAD (43 mm) and TAD (50 mm) aortas were significantly ( P  < 0.001) larger than those of the control group (35 mm). Ninety-three percent of preTAD and 68% of TAD aortas were less than 55 mm in the mid-ascending aorta. The ascending aorta and the aortic arch were significantly longer in both preTAD and TAD aortas compared to control aortas ( P  < 0.001); in the control aortas the central line distance from the aortic valve to the brachiocephalic trunk was 93 mm. In preTAD aortas, it was 111 mm, and it was 117 mm in TAD aortas ( P  < 0.001). In ROC analysis, the area under the curve was 0.912 for the ascending diameter and 0.787 for the ascending and arch lengths. TAD-prediction based on the aortic diameter is ineffective. Besides circumferential dilatation, ascending aorta elongation precedes TAD and appears to be a useful additional parameter for prognostication. We propose a diagnostic score involving ascending aorta diameter and length. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Aortic elongation in aortic aneurysm and dissection: the Tübingen Aortic Pathoanatomy (TAIPAN) project.

PubMed

Krüger, Tobias; Sandoval Boburg, Rodrigo; Lescan, Mario; Oikonomou, Alexandre; Schneider, Wilke; Vöhringer, Luise; Lausberg, Henning; Bamberg, Fabian; Blumenstock, Gunnar; Schlensak, Christian

2018-01-24

To study the lengths and diameters of aortic segments in healthy and diseased aortas and to assess the role of aortic elongation in Type A aortic dissection (TAD) prediction. Ectasia and aneurysm were defined by ascending aorta diameters of 45-54 mm and ≥55 mm, respectively. Computed tomography angiography studies of 256 healthy, 102 ectasia, 38 aneurysm, 17 pre-TAD and 166 TAD aortas were analysed using curved multiplanar reformats. The study groups were structurally equal. The diameter of the ascending aorta was 35 mm in the control group and was larger (P < 0.001) in the pre-TAD (43 mm) and TAD (56 mm) groups. The length of the ascending aorta from the aortic annulus to the brachiocephalic trunk was 92 mm in the control group, 113 mm in the ectasia group, 120 mm in the aneurysm group and 111 mm and 118 mm in the pre-TAD and TAD groups (all P < 0.001 compared with the control group). An ascending aorta length of 120 mm was exceeded in 2% of the control group, 31% of the ectasia group, 50% of the aneurysm group, 24% of the pre-TAD group and 48% of the TAD group. The correlation between the diameter and the length of the ascending aorta was r = 0.752; therefore, both parameters must be examined separately. A score considering both parameters identified 23.5% of pre-TAD patients, significantly more than the diameter alone, and 31.4% of ectasia aortas were elongated. Patients with ectatic (45-54 mm diameter) and elongated (≥120 mm) ascending aortas represent a high-risk subpopulation for TAD. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Angiotensin II-induced hypertension blunts thick ascending limb NO production by reducing NO synthase 3 expression and enhancing threonine 495 phosphorylation

PubMed Central

Ramseyer, Vanesa D.; Gonzalez-Vicente, Agustin; Carretero, Oscar A.

2014-01-01

Thick ascending limbs reabsorb 30% of the filtered NaCl load. Nitric oxide (NO) produced by NO synthase 3 (NOS3) inhibits NaCl transport by this segment. In contrast, chronic angiotensin II (ANG II) infusion increases net thick ascending limb transport. NOS3 activity is regulated by changes in expression and phosphorylation at threonine 495 (T495) and serine 1177 (S1177), inhibitory and stimulatory sites, respectively. We hypothesized that NO production by thick ascending limbs is impaired by chronic ANG II infusion, due to reduced NOS3 expression, increased phosphorylation of T495, and decreased phosphorylation of S1177. Rats were infused with 200 ng·kg−1·min−1 ANG II or vehicle for 1 and 5 days. ANG II infusion for 5 days decreased NOS3 expression by 40 ± 12% (P < 0.007; n = 6) and increased T495 phosphorylation by 147 ± 26% (P < 0.008; n = 6). One-day ANG II infusion had no significant effect. NO production in response to endothelin-1 was blunted in thick ascending limbs from ANG II-infused animals [ANG II −0.01 ± 0.06 arbitrary fluorescence units (AFU)/min vs. 0.17 ± 0.02 AFU/min in controls; P < 0.01]. This was not due to reduced endothelin-1 receptor expression. Phosphatidylinositol 3,4,5-triphosphate (PIP3)-induced NO production was also reduced in ANG II-infused rats (ANG II −0.07 ± 0.06 vs. 0.13 ± 0.04 AFU/min in controls; P < 0.03), and this correlated with an impaired ability of PIP3 to increase S1177 phosphorylation. We conclude that in ANG II-induced hypertension NO production by thick ascending limbs is impaired due to decreased NOS3 expression and altered phosphorylation. PMID:25377910

Angiotensin II-induced hypertension blunts thick ascending limb NO production by reducing NO synthase 3 expression and enhancing threonine 495 phosphorylation.

PubMed

Ramseyer, Vanesa D; Gonzalez-Vicente, Agustin; Carretero, Oscar A; Garvin, Jeffrey L

2015-01-15

Thick ascending limbs reabsorb 30% of the filtered NaCl load. Nitric oxide (NO) produced by NO synthase 3 (NOS3) inhibits NaCl transport by this segment. In contrast, chronic angiotensin II (ANG II) infusion increases net thick ascending limb transport. NOS3 activity is regulated by changes in expression and phosphorylation at threonine 495 (T495) and serine 1177 (S1177), inhibitory and stimulatory sites, respectively. We hypothesized that NO production by thick ascending limbs is impaired by chronic ANG II infusion, due to reduced NOS3 expression, increased phosphorylation of T495, and decreased phosphorylation of S1177. Rats were infused with 200 ng·kg(-1)·min(-1) ANG II or vehicle for 1 and 5 days. ANG II infusion for 5 days decreased NOS3 expression by 40 ± 12% (P < 0.007; n = 6) and increased T495 phosphorylation by 147 ± 26% (P < 0.008; n = 6). One-day ANG II infusion had no significant effect. NO production in response to endothelin-1 was blunted in thick ascending limbs from ANG II-infused animals [ANG II -0.01 ± 0.06 arbitrary fluorescence units (AFU)/min vs. 0.17 ± 0.02 AFU/min in controls; P < 0.01]. This was not due to reduced endothelin-1 receptor expression. Phosphatidylinositol 3,4,5-triphosphate (PIP3)-induced NO production was also reduced in ANG II-infused rats (ANG II -0.07 ± 0.06 vs. 0.13 ± 0.04 AFU/min in controls; P < 0.03), and this correlated with an impaired ability of PIP3 to increase S1177 phosphorylation. We conclude that in ANG II-induced hypertension NO production by thick ascending limbs is impaired due to decreased NOS3 expression and altered phosphorylation. Copyright © 2015 the American Physiological Society.

Modeling Environment for Total Risk-4M

EPA Science Inventory

MENTOR-4M uses an integrated, mechanistically consistent, source-to-dose modeling framework to quantify simultaneous exposures and doses of individuals and populations to multiple contaminants. It is an implementation of the MENTOR system for exposures to Multiple contaminants fr...

Group B Streptococcus Induces Neutrophil Recruitment to Gestational Tissues and Elaboration of Extracellular Traps and Nutritional Immunity.

PubMed

Kothary, Vishesh; Doster, Ryan S; Rogers, Lisa M; Kirk, Leslie A; Boyd, Kelli L; Romano-Keeler, Joann; Haley, Kathryn P; Manning, Shannon D; Aronoff, David M; Gaddy, Jennifer A

2017-01-01

Streptococcus agalactiae , or Group B Streptococcus (GBS), is a gram-positive bacterial pathogen associated with infection during pregnancy and is a major cause of morbidity and mortality in neonates. Infection of the extraplacental membranes surrounding the developing fetus, a condition known as chorioamnionitis, is characterized histopathologically by profound infiltration of polymorphonuclear cells (PMNs, neutrophils) and greatly increases the risk for preterm labor, stillbirth, or neonatal GBS infection. The advent of animal models of chorioamnionitis provides a powerful tool to study host-pathogen relationships in vivo and ex vivo . The purpose of this study was to evaluate the innate immune response elicited by GBS and evaluate how antimicrobial strategies elaborated by these innate immune cells affect bacteria. Our work using a mouse model of GBS ascending vaginal infection during pregnancy reveals that clinically isolated GBS has the capacity to invade reproductive tissues and elicit host immune responses including infiltration of PMNs within the choriodecidua and placenta during infection, mirroring the human condition. Upon interacting with GBS, murine neutrophils elaborate DNA-containing extracellular traps, which immobilize GBS and are studded with antimicrobial molecules including lactoferrin. Exposure of GBS to holo- or apo-forms of lactoferrin reveals that the iron-sequestration activity of lactoferrin represses GBS growth and viability in a dose-dependent manner. Together, these data indicate that the mouse model of ascending infection is a useful tool to recapitulate human models of GBS infection during pregnancy. Furthermore, this work reveals that neutrophil extracellular traps ensnare GBS and repress bacterial growth via deposition of antimicrobial molecules, which drive nutritional immunity via metal sequestration strategies.

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

PubMed

Rao, Shripada C; Srinivasjois, Ravisha; Moon, Kwi

2016-12-06

Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups (typical RR 1.69, 95% CI 0.18 to 16.25; typical RD 0.01, 95% CI -0.04 to 0.05; 5 trials; N = 214). Nephrotoxicity was not noted with either of the treatment regimens. Overall, the quality of evidence was considered to be moderate on GRADE analysis, given the small sample size and unclear/high risk of bias in some of the domains in a few of the included studies. There is insufficient evidence from the currently available RCTs to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggest that pharmacokinetic properties of a 'once a day' gentamicin regimen are superior to a 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There was no change in nephrotoxicity or auditory toxicity. Based on the assessment of pharmacokinetics, a 'once a day regimen' may be superior in treating sepsis in neonates of more than 32 weeks' gestation.

Submillisievert coronary CT angiography with adaptive prospective ECG-triggered sequence acquisition and iterative reconstruction in patients with high heart rate on the dual-source CT.

PubMed

Tang, Pei-Hua; Du, Ben-Jun; Fang, Xiang-Ming; Hu, Xiao-Yun; Qian, Ping-Yan; Gao, Quan-Sheng

2016-11-22

To assess the application value of submillisievert coronary CT angiography (CCTA) in patients with a high heart rate (HR) acquired with adaptive prospective ECG-triggered sequence acquisition and iterative reconstruction on the secondary generation dual-source CT. A total of 120 consecutive high-HR patients suspected with coronary artery disease underwent CCTA and invasive coronary angiography (ICA) within two weeks. Patients were randomly assigned into three groups: group A (n = 40), where the patients underwent retrospectively ECG-triggered acquisition CCTA at 100 kVp; group B (n = 40), where the patients received adaptive prospective ECG-triggered sequence acquisition at 100 kVp; and group C (n = 40), where the patients performed adaptive prospective ECG-triggered sequence acquisition at 80 kVp with iterative reconstruction. The mean CT values, signal noise ratios (SNR) and contrast noise ratios (CNR) in the ascending aorta and coronary arteries of the three groups were measured and compared. The image quality and radiation dose among the three groups were compared. The consistency of displaying the coronary stenosis of each group was assessed compared with the results of ICA as the gold standard. There was no significant difference in gender, age and body mass index (BMI) (all P > 0.05). The mean attenuations, SNRs and CNRs in the ascending aorta and coronary artery were not significantly different between group A and group B (P > 0.05). The mean attenuations of group C were significantly higher than group A and group B (P < 0.01), but the image noise and CNR were significantly lower in group C (P < 0.01). The number of appreciable segments among the three groups was not significantly different on a per-segment and per-vessel basis (P > 0.05). The subjective image quality among the three groups was not significantly different (P > 0.05). With the ICA result as a reference standard, there was good consistency in the evaluation of the coronary stenosis degree between CCTA and ICA (r > 0.75), as well as in the assessment of the coronary stenosis rate using the Bland- Altman analysis. The mean radiation dose in group B was half of that in group A. Moreover, the mean radiation dose in group C was less than one sixth of that in group A and less than 1 mSv (0.7±0.2 mSv). For patients with high HR, adaptive prospective ECG-triggered sequence acquisition on the FLASH dual-source CT results in equal image quality and half of the radiation dose reduction compared with retrospectively ECG-triggered spiral acquisition at the same tube voltage (100 kVp) and same R-R interval of exposure. In addition, adaptive prospective ECG-triggered sequence acquisition combined with low tube voltage and iterative reconstruction can further reduce the radiation dose to the submillisievert level without compromising image quality and the accuracy of assessing the coronary stenosis degree, and can be popularized as a routine technique.

Pharmacokinetics of isotretinoin during repetitive dosing to patients.

PubMed

Brazzell, R K; Vane, F M; Ehmann, C W; Colburn, W A

1983-01-01

The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.

Rectal Bleeding After High-Dose-Rate Brachytherapy Combined With Hypofractionated External-Beam Radiotherapy for Localized Prostate Cancer: The Relationship Between Dose-Volume Histogram Parameters and the Occurrence Rate

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

Okamoto, Masahiko, E-mail: masaoka@showa.gunma-u.ac.jp; Ishikawa, Hitoshi; Ebara, Takeshi

2012-02-01

Purpose: To determine the predictive risk factors for Grade 2 or worse rectal bleeding after high-dose-rate brachytherapy (HDR-BT) combined with hypofractionated external-beam radiotherapy (EBRT) for prostate cancer using dose-volume histogram analysis. Methods and Materials: The records of 216 patients treated with HDR-BT combined with EBRT were analyzed. The treatment protocols for HDR-BT were 5 Gy Multiplication-Sign five times in 3 days or 7 Gy Multiplication-Sign three, 10.5 Gy Multiplication-Sign two, or 9 Gy Multiplication-Sign two in 2 days. The EBRT doses ranged from 45 to 51 Gy with a fractional dose of 3 Gy. Results: In 20 patients Grade 2more » or worse rectal bleeding developed, and the cumulative incidence rate was 9% at 5 years. By converting the HDR-BT and EBRT radiation doses into biologic effective doses (BED), the BED{sub 3} at rectal volumes of 5% and 10% in the patients who experienced bleeding were significantly higher than those in the remaining 196 patients. Univariate analysis showed that a higher rectal BED{sub 3-5%} and the use of fewer needles in brachytherapy were correlated with the incidence of bleeding, but BED{sub 3-5%} was found to be the only significant factor on multivariate analysis. Conclusions: The radiation dose delivered to small rectal lesions as 5% is important for predicting Grade 2 or worse rectal bleeding after HDR-BT combined with EBRT for prostate cancer.« less

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

PubMed Central

Cui, Yimin; Song, Yan; Wang, Jessie; Yu, Zhigang; Schuster, Alan; Barrett, Yu Chen; Frost, Charles

2013-01-01

Background The pharmacokinetics (PK), pharmacodynamics (PD), and safety of apixaban were assessed in healthy Chinese subjects in this randomized, placebo-controlled, double-blind, single-sequence, single- and multiple-dose study. Subjects and methods Eighteen subjects 18–45 years of age were randomly assigned (2:1 ratio) to receive apixaban or matched placebo. Subjects received a single 10 mg dose of apixaban or placebo on day 1, followed by 10 mg apixaban or placebo twice daily for 6 days (days 4–9). The PK and PD of apixaban were assessed by collecting plasma samples for 72 hours following the dose on day 1 and the morning dose on day 9, and measuring apixaban concentration and anti-Xa activity. Safety was assessed via physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory evaluations. Results PK analysis showed similar characteristics of apixaban after single and multiple doses, including a median time to maximum concentration of ~3 hours, mean elimination half-life of ~11 hours, and renal clearance of ~1.2 L/hour. The accumulation index was 1.7, consistent with twice-daily dosing and the observed elimination half-life. Single-dose data predict multiple-dose PK, therefore apixaban PK are time-independent. The relationship between anti-Xa activity and plasma apixaban concentrations appears to be linear. Apixaban was safe and well tolerated, with no bleeding-related adverse events reported. Conclusion Apixaban was safe and well tolerated in healthy Chinese subjects. Apixaban PK and PD were predictable and consistent with findings from previous studies in Asian and non-Asian subjects. The administration of apixaban does not require any dose modification based on race. PMID:24353445

Steady-state pharmacokinetics of fluvastatin in healthy subjects following a new extended release fluvastatin tablet, Lescol XL.

PubMed

Barilla, Denise; Prasad, Pratapa; Hubert, Martine; Gumbhir-Shah, Kavita

2004-03-01

This was an open-label, randomized, three-period, three-treatment, multiple dose, crossover study in 12 healthy male and female subjects. This study evaluated single dose and steady-state pharmacokinetics of fluvastatin following single and multiple dose administrations of a new extended release fluvastatin 8 h matrix tablet, Lescol XL 80 mg and 160 mg doses once a day. The study also included a twice a day administration of an immediate release (IR) form of fluvastatin capsule, Lescol, for comparative purposes. All doses were administered for 7 days. The safety and tolerability were also assessed. The pharmacokinetics of fluvastatin were evaluated on days 1 and 7 following each treatment. Fluvastatin systemic exposure was 50% less when administered as Lescol XL 80 mg qd compared with Lescol IR 40 mg bid. Conversely, fluvastatin systemic exposure was 22% higher when administered as Lescol XL 160 mg qd compared with Lescol IR 40 mg bid. Single doses of Lescol XL 80 mg and 160 mg were dose proportional but, deviation (30%) from dose proportionality was observed for the Lescol XL 160 mg at steady-state. There appeared to be moderate (20%-40%) accumulation of serum fluvastatin maximal concentrations and exposure after multiple doses of Lescol XL tablets. Both Lescol XL 80 mg and 160 mg showed delayed absorption and longer apparent elimination half-life compared with fluvastatin IR capsule. Single and multiple doses of fluvastatin were generally well tolerated in this healthy volunteer population. Adverse event profiles were consistent with the published safety profile of the marketed formulations. Aside from one incidence of creatine phosphokinase (CPK) elevation (following Lescol XL 160 mg qd treatment), there were no safety concerns with any of the treatments when administered acutely (7 days). Copyright 2004 John Wiley & Sons, Ltd.

Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects

PubMed Central

Frost, Charles; Nepal, Sunil; Wang, Jessie; Schuster, Alan; Byon, Wonkyung; Boyd, Rebecca A; Yu, Zhigang; Shenker, Andrew; Barrett, Yu Chen; Mosqueda-Garcia, Rogelio; LaCreta, Frank

2013-01-01

Aim Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. Method This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily– with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). Results Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3–1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile. Conclusion Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures. PMID:23451769

Response of the Cardiovascular System to Vibration and Combined Stresses

DTIC Science & Technology

1975-08-31

Canines were chronically instrumented for continuous measurements of ascending aortic flow ( Zepeda ), left ventricular pressure (Konigsberg), circum- flex...different animals. Each dog was chronically instrumented for continuous measuremernt of ascending aortic flow ( Zepeda ), left ventricular pressure...vibration protocol as those animals restrained vertically. METHODS Canines (16 to 22 kg) were chronically instrumented with electromagnetic flow cuffs ( Zepeda

Draft Genome Sequences of Three Escherichia coli Strains with Different In Vivo Pathogenicities in an Avian (Ascending) Infection Model of the Oviduct

PubMed Central

Thøfner, Ida Cecilie Naundrup; Pors, Susanne Elisabeth; Christensen, Henrik; Bisgaard, Magne; Christensen, Jens Peter

2015-01-01

Here, we present three draft genome sequences of Escherichia coli strains that experimentally were proven to possess low (strain D2-2), intermediate (Chronic_salp), or high virulence (Cp6salp3) in an avian (ascending) infection model of the oviduct. PMID:25953185

Analytical Description of Ascending Motion of Rockets in the Atmosphere

ERIC Educational Resources Information Center

Rodrigues, H.; de Pinho, M. O.; Portes, D., Jr.; Santiago, A.

2009-01-01

In continuation of a previous work, we present an analytic study of ascending vertical motion of a rocket subjected to a quadratic drag for the case where the mass-variation law is a linear function of time. We discuss the detailed analytical solution of the model differential equations in closed form. Examples of application are presented and…

Case report of an unusual combination of purulent pericarditis and false aneurysm of the ascending aorta.

PubMed

Meier, David; Kirsch, Matthias; Qanadli, Salah Dine; Muller, Olivier; Fishman, Daniel; Trana, Catalina

2018-01-29

Purulent pericarditis is an uncommon entity, which is, in very rare cases, associated to infection of the aorta. We present the case of a 42-year-old male patient, who was admitted to hospital complaining of tiredness, diarrhea and leg edema. Clinical examination revealed a hypotensive and obviously shocked patient. He was ultimately diagnosed with a rare combination of purulent pericarditis followed by false aneurysm of the ascending aorta. He was successfully treated by surgical pericardial drainage, replacement of the ascending aorta and antibiotics. Mycotic aneurysms can rarely be associated with purulent pericarditis. Our literature review shows that there are two mechanisms explaining this association and that in most of the published cases infective endocarditis could not be demonstrated.

Laboratory measures of methylphenidate effects in cocaine-dependent patients receiving treatment.

PubMed

Roache, J D; Grabowski, J; Schmitz, J M; Creson, D L; Rhoades, H M

2000-02-01

Two experiments examined the effects of methylphenidate in male and female patients enrolled in an outpatient treatment program for primary cocaine dependence. The first study was a component of a double-blind efficacy trial wherein 57 patients were first tested in a human laboratory for their initial responsiveness to medication. Patients were randomly assigned to receive either placebo or methylphenidate treatment and received their first dose in the human laboratory environment before continuing in outpatient treatment. Methylphenidate was given as a 20-mg sustained-release dose (twice daily) plus an additional 5-mg immediate-release dose combined with the morning dose. Methylphenidate increased heart rate and subjective ratings; however, the subjective effects were primarily of a "dysphoric" nature, and significant effects were limited to increases in anxiety, depression, and anger on the Profile of Mood States; shaky/jittery ratings on a visual analog scale; and dysphoria on the lysergic acid diethylamide (LSD) scale of the Addiction Research Center Inventory. Methylphenidate did not increase cocaine craving nor ratings suggesting abuse potential (i.e., Morphine-Benzedrine Group or drug-liking scores, etc.). None of the drug effects observed in the human laboratory was of clinical concern, and no subject was precluded from continuing in the outpatient study. After outpatient treatment completion, 12 patients were brought back into a second double-blind human laboratory study in which three doses (15, 30, and 60 mg) of immediate-release methylphenidate were administered in an ascending series preceded and followed by placebo. Methylphenidate produced dose-related increases in heart rate, subjective ratings of shaky/jittery, and LSD/dysphoria without significantly altering cocaine craving or stimulant euphoria ratings. These results suggest that stimulant substitution-type approaches to the treatment of cocaine dependence are not necessarily contraindicated because of cardiovascular toxicity or medication abuse potential. However, they also suggest that the subjective effects of methylphenidate may not be positive enough for an adequate replacement approach.

The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H₃ receptor antagonist in patients with mild to moderate Alzheimer's disease: a preliminary investigation.

PubMed

Nathan, Pradeep J; Boardley, Rebecca; Scott, Nicola; Berges, Alienor; Maruff, Paul; Sivananthan, Tharani; Upton, Neil; Lowy, Martin T; Nestor, Peter J; Lai, Robert

2013-03-01

The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects in pre-clinical models. GSK239512 is a potent and selective H₃ receptor antagonist developed for the treatment of cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimer's disease using ascending dose titration regimens. The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients. Overall, the 5/10/20/40 μg and 10/20/40/80 μg regimens were well-tolerated. The regimen of 20/40/80/150 μg showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects on tasks of attention and memory with effect sizes between 0.56 and 1.37. GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer's disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 μg and a maximum dose of 80 μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer's disease. These findings await replication in a larger study.

Catalogue of Exoplanets in Multiple-Star-Systems

NASA Astrophysics Data System (ADS)

Schwarz, Richard; Funk, Barbara; Bazsó, Ákos; Pilat-Lohinger, Elke

2017-07-01

Cataloguing the data of exoplanetary systems becomes more and more important, due to the fact that they conclude the observations and support the theoretical studies. Since 1995 there is a database which list most of the known exoplanets (The Extrasolar Planets Encyclopaedia is available at http://exoplanet.eu/ and described at Schneider et al. 2011). With the growing number of detected exoplanets in binary and multiple star systems it became more important to mark and to separate them into a new database. Therefore we started to compile a catalogue for binary and multiple star systems. Since 2013 the catalogue can be found at http://www.univie.ac.at/adg/schwarz/multiple.html (description can be found at Schwarz et al. 2016) which will be updated regularly and is linked to the Extrasolar Planets Encyclopaedia. The data of the binary catalogue can be downloaded as a file (.csv) and used for statistical purposes. Our database is divided into two parts: the data of the stars and the planets, given in a separate list. Every columns of the list can be sorted in two directions: ascending, meaning from the lowest value to the highest, or descending. In addition an introduction and help is also given in the menu bar of the catalogue including an example list.

[A sixty-year-old man suffering from multiple system atrophy with pneumatosis intestinalis].

PubMed

Shimizu, Fumitaka; Kawai, Motoharu; Ogasawara, Jun-Ichi; Negoro, Kiyoshi; Kanda, Takashi

2007-01-01

We herein report a 60-year-old man demonstrating multiple system atrophy of the cerebellar type (MSA-C) with a five-year of clinical history, who developed severe constipation followed by watery diarrhea. An abdominal CT scan showed free air in the abdominal cavity and extensive pericolic gas accumulation in the ascending and transverse colon. He was diagnosed to have pneumatosis intestinalis (PI). The air in the abdominal cavity as well as in the wall of the colon thereafter disappeared after nine days' of conservative therapy. The presense of chronic idiopathic intestinal pseudo-obstruction due to severe dysautonomia and a longstanding bed-ridden state may have been the cause of PI in this patient. This is the first case report of PI associated with MSA; however, the association of PI may have been overlooked in this disorder because of severe constipation and diarrhea, the two cardinal symptoms of PI, which happen to also be two of the typical symptoms of MSA itself.

Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer

NASA Astrophysics Data System (ADS)

Anderle, Kristjan; Stroom, Joep; Vieira, Sandra; Pimentel, Nuno; Greco, Carlo; Durante, Marco; Graeff, Christian

2018-01-01

Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.

Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and Patch Administration in Rats.

PubMed

Lee, Soo-Han; Kim, Seung-Hyun; Noh, Yook-Hwan; Choi, Byung-Moon; Noh, Gyu-Jeong; Park, Woo-Dae; Kim, Eun-Jung; Cho, Ik-Hyun; Bae, Chun-Sik

2016-02-01

Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Pharmacokinetic Properties and Tolerability of Cycloserine Following Oral Administration in Healthy Chinese Volunteers: A Randomized, Open-Label, Single- and Multiple-Dose 3-Way Crossover Study.

PubMed

Zhou, Huili; Wu, Guolan; Hu, Xingjiang; Zhu, Meixiang; Zhai, You; Liu, Jian; Shentu, Jianzhong; Wu, Lihua

2015-06-01

A new generic formulation of cycloserine has been developed in China but the pharmacokinetic properties of cycloserine in the Chinese population have not been reported. The aim of our study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of cycloserine capsules in healthy Chinese volunteers. This open-label, single- and multiple-dose 3-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of cycloserine (250, 500, or 1000 mg) in separate trial periods, with a 1-week washout between periods. Those allocated to the 250-mg dose continued into the multiple-dose phase, in which they received 250 mg BID for 5 consecutive days. During the single-dose phase, blood samples were collected at regular intervals from 0 to 72 hours after drug administration and the concentrations of cycloserine were determined using LC-MS/MS. During the multiple-dose phase, blood samples were obtained before drug administration on Days 4, 5, and 6 to determine the Cmin at steady state. On Day 6, blood samples were also collected from 0 to 72 hours after drug administration. Pharmacokinetic parameters were estimated using noncompartmental methods. Tolerability was determined using clinical evaluation and monitoring of adverse events. The study enrolled 12 healthy Chinese volunteers (6 men: mean [SD] age = 23.0 [2.6] years, weight = 60.2 [6.2] kg, height = 170.0 [3.0] cm, and body mass index = 20.7 [1.7]; 6 women: mean [SD] age = 25.3 [1.4] years, weight = 51.5 [3.3] kg, height = 160.0 [4.0] cm, and body mass index = 20.1 [0.9]). After administration of a single dose, cycloserine was rapidly absorbed, reaching peak plasma concentrations approximately 0.84 hours after oral administration, and t½ in plasma was about 13.0 hours. The geometric mean (SD) Cmax value increased in proportion to cycloserine dose, from 19.42 (5.89) to 84.76 (21.74) mg/L, and the geometric mean (SD) AUC0-72h value increased from 264.16 (133.37) to 1153.87 (522.16) mg·h/L in the range of a 250- to 1000-mg dose. After administration of multiple doses of cycloserine 250 mg BID, the mean (SD) t½ was 13.56 (4.38) hours, the apparent total clearance of the drug from plasma after oral administration was 1.02 (0.42) L/h, and the apparent volume of distribution was 18.22 (5.25) L, which were comparable with those after single dosing. The accumulation index was 2.19 (0.51), and the fluctuation was 1.05 (0.35). Results of the t tests of Cmax and AUC found no significant differences between the male and female groups. No serious adverse events were reported, and there were no discontinuations due to adverse events. The pharmacokinetic properties of cycloserine were linear at doses from 250 mg to 1000 mg. After multiple doses, the pharmacokinetic properties of cycloserine were consistent with those after single doses. At the doses studied, cycloserine appears to be well tolerated in these healthy volunteers. Chinese Clinical Trials registration: ChiCTR-TTRCC-13003982. Copyright © 2015. Published by Elsevier Inc.

Ascending Aortic Dimensions in Former National Football League Athletes.

PubMed

Gentry, James L; Carruthers, David; Joshi, Parag H; Maroules, Christopher D; Ayers, Colby R; de Lemos, James A; Aagaard, Philip; Hachamovitch, Rory; Desai, Milind Y; Roselli, Eric E; Dunn, Reginald E; Alexander, Kezia; Lincoln, Andrew E; Tucker, Andrew M; Phelan, Dermot M

2017-11-01

Ascending aortic dimensions are slightly larger in young competitive athletes compared with sedentary controls, but rarely >40 mm. Whether this finding translates to aortic enlargement in older, former athletes is unknown. This cross-sectional study involved a sample of 206 former National Football League (NFL) athletes compared with 759 male subjects from the DHS-2 (Dallas Heart Study-2; mean age of 57.1 and 53.6 years, respectively, P <0.0001; body surface area of 2.4 and 2.1 m 2 , respectively, P <0.0001). Midascending aortic dimensions were obtained from computed tomographic scans performed as part of a NFL screening protocol or as part of the DHS. Compared with a population-based control group, former NFL athletes had significantly larger ascending aortic diameters (38±5 versus 34±4 mm; P <0.0001). A significantly higher proportion of former NFL athletes had an aorta of >40 mm (29.6% versus 8.6%; P <0.0001). After adjusting for age, race, body surface area, systolic blood pressure, history of hypertension, current smoking, diabetes mellitus, and lipid profile, the former NFL athletes still had significantly larger ascending aortas ( P <0.0001). Former NFL athletes were twice as likely to have an aorta >40 mm after adjusting for the same parameters. Ascending aortic dimensions were significantly larger in a sample of former NFL athletes after adjusting for their size, age, race, and cardiac risk factors. Whether this translates to an increased risk is unknown and requires further evaluation. © 2017 American Heart Association, Inc.

Over length quantification of the multiaxial mechanical properties of the ascending, descending and abdominal aorta using Digital Image Correlation.

PubMed

Peña, Juan A; Corral, Victoria; Martínez, Miguel A; Peña, Estefanía

2018-01-01

In this paper, we hypothesize that the biaxial mechanical properties of the aorta may be dependent on arterial location. To demonstrate any possible position-related difference, our study analyzed and compared the biaxial mechanical properties of the ascending thoracic aorta, descending thoracic aorta and infrarenal abdominal aorta stemming from the same porcine subjects, and reported values of constitutive parameters for well-known strain energy functions, showing how these mechanical properties are affected by location along the aorta. When comparing ascending thoracic aorta, descending thoracic aorta and infrarenal abdominal aorta, abdominal tissues were found to be stiffer and highly anisotropic. We found that the aorta changed from a more isotropic to a more anisotropic tissue and became progressively less compliant and stiffer with the distance to the heart. We observed substantial differences in the anisotropy parameter between aortic samples where abdominal samples were more anisotropic and nonlinear than the thoracic samples. The phenomenological model was not able to capture the passive biaxial properties of each specific porcine aorta over a wide range of biaxial deformations, showing the best prediction root mean square error ε=0.2621 for ascending thoracic samples and, especially, the worst for the infrarenal abdominal samples ε=0.3780. The micro-structured model with Bingham orientation density function was able to better predict biaxial deformations (ε=0.1372 for ascending thoracic aorta samples). The root mean square error of the micro-structural model and the micro-structured model with von Mises orientation density function were similar for all positions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Kinematic alterations of the lower limbs and pelvis during an ascending stairs task are associated with the degree of knee osteoarthritis severity.

PubMed

Gonçalves, Glaucia Helena; Selistre, Luiz Fernando Approbato; Petrella, Marina; Mattiello, Stela Márcia

2017-03-01

Individuals with knee osteoarthritis (OA) generally demonstrate great difficulty in ascending stairs. The strategies and compensations used by these individuals in stair activities have not been fully established. The purpose of this study was to investigate the joint kinematics of the pelvis, hip, knee and ankle throughout the gait cycle, in the sagittal and frontal planes, in individuals with mild and moderate knee OA, during an ascending stairs task. Thirty-one individuals with knee OA and 19 controls were subjected to clinical and radiographic analysis, divided into three groups: control, mild knee OA, and moderate knee OA. Participants answered a self-reported questionnaire, carried out performance-based tests, and their kinematic data were recorded during an ascending stairs task using an eight-camera Qualisys 3D-Motion analysis system. The individuals with moderate degrees of knee OA demonstrated kinematic alterations in the pelvis, hip, knee, and ankle in the sagittal plane. The individuals with mild degrees of knee OA demonstrated kinematic alterations of the hip in the frontal plane, and kinematic alterations of the ankle in the sagittal plane. The ascending stairs task allowed verification of meaningful information regarding gait strategies used by individuals with mild and moderate knee OA. The strategies of these two groups of individuals are different for this task, although more pronounced in individuals with moderate knee OA. The findings should be taken into account in the development of rehabilitation programs. Copyright © 2017 Elsevier B.V. All rights reserved.

An automated multi-modal object analysis approach to coronary calcium scoring of adaptive heart isolated MSCT images

NASA Astrophysics Data System (ADS)

Wu, Jing; Ferns, Gordon; Giles, John; Lewis, Emma

2012-02-01

Inter- and intra- observer variability is a problem often faced when an expert or observer is tasked with assessing the severity of a disease. This issue is keenly felt in coronary calcium scoring of patients suffering from atherosclerosis where in clinical practice, the observer must identify firstly the presence, followed by the location of candidate calcified plaques found within the coronary arteries that may prevent oxygenated blood flow to the heart muscle. This can be challenging for a human observer as it is difficult to differentiate calcified plaques that are located in the coronary arteries from those found in surrounding anatomy such as the mitral valve or pericardium. The inclusion or exclusion of false positive or true positive calcified plaques respectively will alter the patient calcium score incorrectly, thus leading to the possibility of incorrect treatment prescription. In addition to the benefits to scoring accuracy, the use of fast, low dose multi-slice CT imaging to perform the cardiac scan is capable of acquiring the entire heart within a single breath hold. Thus exposing the patient to lower radiation dose, which for a progressive disease such as atherosclerosis where multiple scans may be required, is beneficial to their health. Presented here is a fully automated method for calcium scoring using both the traditional Agatston method, as well as the Volume scoring method. Elimination of the unwanted regions of the cardiac image slices such as lungs, ribs, and vertebrae is carried out using adaptive heart isolation. Such regions cannot contain calcified plaques but can be of a similar intensity and their removal will aid detection. Removal of both the ascending and descending aortas, as they contain clinical insignificant plaques, is necessary before the final calcium scores are calculated and examined against ground truth scores of three averaged expert observer results. The results presented here are intended to show the requirement and feasibility for an automated scoring method that reduces the subjectivity and reproducibility error inherent with manual clinical calcium scoring.

Acute symptomatic sinus bradycardia in a woman treated with pulse dose steroids for multiple sclerosis: a case report.

PubMed

Kundu, Amartya; Fitzgibbons, Timothy P

2015-09-24

Sinus bradycardia has been reported after administration of pulse dose steroids, although most cases have occurred in children and are asymptomatic. We report a case of acute symptomatic sinus bradycardia due to pulse dose steroids in a woman with multiple sclerosis. Interestingly, this patient also suffered from inappropriate sinus tachycardia due to autonomic involvement of multiple sclerosis. A 48-year-old Caucasian woman with multiple sclerosis and chronic palpitations due to inappropriate sinus tachycardia was prescribed a 5-day course of intravenous methylprednisolone for treatment of an acute flare. Immediately following the fourth dose of intravenous methylprednisolone, she developed dyspnea, chest heaviness, and lightheadedness. She was referred to the emergency department where an electrocardiogram showed marked sinus bradycardia (40 beats per minute). Initial laboratory test results, including a complete blood count, basic metabolic profile and cardiac biomarkers, were normal. She was admitted for observation on telemetry monitoring. Her heart rate gradually increased and her symptoms resolved. Her outpatient dose of atenolol, taken for symptomatic inappropriate sinus tachycardia, was resumed. Our patient's acute symptoms were attributed to symptomatic sinus bradycardia due to pulse dose steroid treatment. Although several theories have been suggested to explain this phenomenon, the exact mechanism still remains unknown. It does not warrant any specific treatment, as it is a self-limiting side effect that resolves after discontinuing steroid infusion. Young patients who are free of any active cardiac conditions can safely be administered pulse dose steroids without monitoring. However, older patients with active cardiac conditions should have heart rate and blood pressure monitoring during infusion. Our patient also suffered from inappropriate sinus tachycardia, a manifestation of autonomic involvement of multiple sclerosis that has not been previously described. This case has implications for the pathogenesis and treatment of dysautonomia in patients with multiple sclerosis.

Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model

PubMed Central

Barnewall, Roy E.; Comer, Jason E.; Miller, Brian D.; Gutting, Bradford W.; Wolfe, Daniel N.; Director-Myska, Alison E.; Nichols, Tonya L.; Taft, Sarah C.

2012-01-01

Repeated low-level exposures to biological agents could occur before or after the remediation of an environmental release. This is especially true for persistent agents such as B. anthracis spores, the causative agent of anthrax. Studies were conducted to examine aerosol methods needed for consistent daily low aerosol concentrations to deliver a low-dose (less than 106 colony forming units (CFU) of B. anthracis spores) and included a pilot feasibility characterization study, acute exposure study, and a multiple 15 day exposure study. This manuscript focuses on the state-of-the-science aerosol methodologies used to generate and aerosolize consistent daily low aerosol concentrations and resultant low inhalation doses to rabbits. The pilot feasibility characterization study determined that the aerosol system was consistent and capable of producing very low aerosol concentrations. In the acute, single day exposure experiment, targeted inhaled doses of 1 × 102, 1 × 103, 1 × 104, and 1 × 105 CFU were used. In the multiple daily exposure experiment, rabbits were exposed multiple days to targeted inhaled doses of 1 × 102, 1 × 103, and 1 × 104 CFU. In all studies, targeted inhaled doses remained consistent from rabbit-to-rabbit and day-to-day. The aerosol system produced aerosolized spores within the optimal mass median aerodynamic diameter particle size range to reach deep lung alveoli. Consistency of the inhaled dose was aided by monitoring and recording respiratory parameters during the exposure with real-time plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over multiple exposure days. PMID:22919662

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study.

PubMed

Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Schachtel, Emily

2014-07-03

The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Adults (n=198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n=101) or matching placebo lozenges (n=97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P<0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P<0.01). There were no serious adverse events. Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010.

It's Lonely at the Top: Winning Climbing Fibers Ascend Dendrites Solo

PubMed Central

Draft, Ryan W.; Lichtman, Jeff W.

2009-01-01

In mammals, climbing fiber axons compete for sole innervation at each Purkinje cell. At the same time, synapses disappear from Purkinje somata and appear in great numbers on the dendrites. In this issue of Neuron, Hashimoto et al. show that, by the time climbing fibers ascend the dendrites, the winner and losers are already decided. PMID:19607787

Sustainability, Participatory Culture, and the Performance of Democracy: Ascendant Sites of Theory and Practice in Art Education

ERIC Educational Resources Information Center

Blandy, Doug

2011-01-01

Art education is a systemic and extensive network within which children, youth, and adults make and learn about material culture. This lecture considers three sites of theory and practice that I see as ascendant in circulating through this network. These sites are sustainability, participatory culture, and performing democracy. I argue that…

Draft Genome Sequences of Three Escherichia coli Strains with Different In Vivo Pathogenicities in an Avian (Ascending) Infection Model of the Oviduct.

PubMed

Olsen, Rikke Heidemann; Thøfner, Ida Cecilie Naundrup; Pors, Susanne Elisabeth; Christensen, Henrik; Bisgaard, Magne; Christensen, Jens Peter

2015-05-07

Here, we present three draft genome sequences of Escherichia coli strains that experimentally were proven to possess low (strain D2-2), intermediate (Chronic_salp), or high virulence (Cp6salp3) in an avian (ascending) infection model of the oviduct. Copyright © 2015 Olsen et al.

An Exploratory Study of the Ascendancy of Women to the Position of K-12 Superintendent

ERIC Educational Resources Information Center

Hanson, Karen M.

2011-01-01

Despite earning over half of the doctoral degrees in education, women are underrepresented in the position of K-12 superintendent. In 2000, although 72% of all classroom teachers were female, only 14% of all superintendents in the United States were women. Research indicates that women experience barriers in their ascendancy to superintendent.…

Retrograde Ascending Dissection After Thoracic Endovascular Aortic Repair Combined With the Chimney Technique and Successful Open Repair Using the Frozen Elephant Trunk Technique.

PubMed

Hirano, Koji; Tokui, Toshiya; Nakamura, Bun; Inoue, Ryosai; Inagaki, Masahiro; Maze, Yasumi; Kato, Noriyuki

2018-01-01

The chimney technique can be combined with thoracic endovascular aortic repair (TEVAR) to both obtain an appropriate landing zone and maintain blood flow of the arch vessels. However, surgical repair becomes more complicated if retrograde type A aortic dissection occurs after TEVAR with the chimney technique. We herein report a case involving a 73-year-old woman who developed a retrograde ascending dissection 3 months after TEVAR for acute type B aortic dissection. To ensure an adequate proximal sealing distance, the proximal edge of the stent graft was located at the zone 2 level and an additional bare stent was placed at the left subclavian artery (the chimney technique) at the time of TEVAR. Enhanced computed tomography revealed an aortic dissection involving the ascending aorta and aortic arch. Surgical aortic repair using the frozen elephant trunk technique was urgently performed. The patient survived without stroke, paraplegia, renal failure, or other major complications. Retrograde ascending dissection can occur after TEVAR combined with the chimney technique. The frozen elephant trunk technique is useful for surgical repair in such complicated cases.

SU-F-T-349: Dosimetric Comparison of Three Different Simultaneous Integrated Boost Irradiation Techniques for Multiple Brain Metastases: Intensity-Modulatedradiotherapy, Hybrid Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy

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

Lin, X; Sun, T; Yin, Y

Purpose: To study the dosimetric impact of intensity-modulated radiotherapy (IMRT), hybrid intensity-modulated radiotherapy (h-IMRT) and volumetric modulated arc therapy(VMAT) for whole-brain radiotherapy (WBRT) with simultaneous integrated boost in patients with multiple brain metastases. Methods: Ten patients with multiple brain metastases were included in this analysis. The prescribed dose was 45 Gy to the whole brain (PTVWBRT) and 55 Gy to individual brain metastases (PTVboost) delivered simultaneously in 25 fractions. Three treatment techniques were designed: the 7 equal spaced fields IMRT plan, hybrid IMRT plan and VMAT with two 358°arcs. In hybrid IMRT plan, two fields(90°and 270°) were planned to themore » whole brain. This was used as a base dose plan. Then 5 fields IMRT plan was optimized based on the two fields plan. The dose distribution in the target, the dose to the organs at risk and total MU in three techniques were compared. Results: For the target dose, conformity and homogeneity in PTV, no statistically differences were observed in the three techniques. For the maximum dose in bilateral lens and the mean dose in bilateral eyes, IMRT and h-IMRT plans showed the highest and lowest value respectively. No statistically significant differences were observed in the dose of optic nerve and brainstem. For the monitor units, IMRT and VMAT plans showed the highest and lowest value respectively. Conclusion: For WBRT with simultaneous integrated boost in patients with multiple brain metastases, hybrid IMRT could reduce the doses to lens and eyes. It is feasible for patients with brain metastases.« less

Dynamically accumulated dose and 4D accumulated dose for moving tumors

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

Li Heng; Li Yupeng; Zhang Xiaodong

2012-12-15

Purpose: The purpose of this work was to investigate the relationship between dynamically accumulated dose (dynamic dose) and 4D accumulated dose (4D dose) for irradiation of moving tumors, and to quantify the dose uncertainty induced by tumor motion. Methods: The authors established that regardless of treatment modality and delivery properties, the dynamic dose will converge to the 4D dose, instead of the 3D static dose, after multiple deliveries. The bounds of dynamic dose, or the maximum estimation error using 4D or static dose, were established for the 4D and static doses, respectively. Numerical simulations were performed (1) to prove themore » principle that for each phase, after multiple deliveries, the average number of deliveries for any given time converges to the total number of fractions (K) over the number of phases (N); (2) to investigate the dose difference between the 4D and dynamic doses as a function of the number of deliveries for deliveries of a 'pulsed beam'; and (3) to investigate the dose difference between 4D dose and dynamic doses as a function of delivery time for deliveries of a 'continuous beam.' A Poisson model was developed to estimate the mean dose error as a function of number of deliveries or delivered time for both pulsed beam and continuous beam. Results: The numerical simulations confirmed that the number of deliveries for each phase converges to K/N, assuming a random starting phase. Simulations for the pulsed beam and continuous beam also suggested that the dose error is a strong function of the number of deliveries and/or total deliver time and could be a function of the breathing cycle, depending on the mode of delivery. The Poisson model agrees well with the simulation. Conclusions: Dynamically accumulated dose will converge to the 4D accumulated dose after multiple deliveries, regardless of treatment modality. Bounds of the dynamic dose could be determined using quantities derived from 4D doses, and the mean dose difference between the dynamic dose and 4D dose as a function of number of deliveries and/or total deliver time was also established.« less

Ceruletide intravenous dose-response study by a simplified scintigraphic technique

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

Krishnamurthy, G.T.; Turner, F.E.; Mangham, D.

1985-04-01

The intravenous dose response of a ceruletide diethylamine (ceruletide) was established by a simplified scintigraphic technique where multiple graded doses were given sequentially on a single occasion. The gallbladder volume was presented nongeometrically by /sup 99m/Tc-IDA counts. The mean latent period, ejection period, and ejection rate were similar for all four groups of subjects given 1-20 ng/kg of ceruletide. The ejection fractions were similar to the values when the identical dose of ceruletide was administered sequentially either before or after another dose. A dose of 5 ng/kg produced the most physiologic type of emptying. Intravenous doses of 10 ng/kg andmore » larger caused adverse reactions in 42% of the total doses in the form of abdominal pain, nausea, systolic and diastolic hypotension, or bradycardia. It is concluded that the dose response of a cholecystokininlike agent (ceruletide) can be established reliably by a scintigraphic technique where multiple graded doses are given on a single occasion.« less

SU-E-T-540: Volumetric Modulated Total Body Irradiation Using a Rotational Lazy Susan-Like Immobilization System

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

Gu, X; Hrycushko, B; Lee, H

2014-06-01

Purpose: Traditional extended SSD total body irradiation (TBI) techniques can be problematic in terms of patient comfort and/or dose uniformity. This work aims to develop a comfortable TBI technique that achieves a uniform dose distribution to the total body while reducing the dose to organs at risk for complications. Methods: To maximize patient comfort, a lazy Susan-like couch top immobilization system which rotates about a pivot point was developed. During CT simulation, a patient is immobilized by a Vac-Lok bag within the body frame. The patient is scanned head-first and then feet-first following 180° rotation of the frame. The twomore » scans are imported into the Pinnacle treatment planning system and concatenated to give a full-body CT dataset. Treatment planning matches multiple isocenter volumetric modulated arc (VMAT) fields of the upper body and multiple isocenter parallel-opposed fields of the lower body. VMAT fields of the torso are optimized to satisfy lung dose constraints while achieving a therapeutic dose to the torso. The multiple isocenter VMAT fields are delivered with an indexed couch, followed by body frame rotation about the pivot point to treat the lower body isocenters. The treatment workflow was simulated with a Rando phantom, and the plan was mapped to a solid water slab phantom for point- and film-dose measurements at multiple locations. Results: The treatment plan of 12Gy over 8 fractions achieved 80.2% coverage of the total body volume within ±10% of the prescription dose. The mean lung dose was 8.1 Gy. All ion chamber measurements were within ±1.7% compared to the calculated point doses. All relative film dosimetry showed at least a 98.0% gamma passing rate using a 3mm/3% passing criteria. Conclusion: The proposed patient comfort-oriented TBI technique provides for a uniform dose distribution within the total body while reducing the dose to the lungs.« less

Simulating maar-diatreme volcanic systems in bench-scale experiments

NASA Astrophysics Data System (ADS)

Andrews, R. G.; White, J. D. L.; Dürig, T.; Zimanowski, B.

2015-12-01

Maar-diatreme eruptions are incompletely understood, and explanations for the processes involved in them have been debated for decades. This study extends bench-scale analogue experiments previously conducted on maar-diatreme systems and attempts to scale the results up to both field-scale experimentation and natural volcanic systems in order to produce a reconstructive toolkit for maar volcanoes. These experimental runs produced via multiple mechanisms complex deposits that match many features seen in natural maar-diatreme deposits. The runs include deeper single blasts, series of descending discrete blasts, and series of ascending blasts. Debris-jet inception and diatreme formation are indicated by this study to involve multiple types of granular fountains within diatreme deposits produced under varying initial conditions. The individual energies of blasts in multiple-blast series are not possible to infer from the final deposits. The depositional record of blast sequences can be ascertained from the proportion of fallback sedimentation versus maar ejecta rim material, the final crater size and the degree of overturning or slumping of accessory strata. Quantitatively, deeper blasts involve a roughly equal partitioning of energy into crater excavation energy versus mass movement of juvenile material, whereas shallower blasts expend a much greater proportion of energy in crater excavation.

Laparoscopic resection of adult colon duplication causing intussusception

PubMed Central

Kyo, Kennoki; Azuma, Masaki; Okamoto, Kazuya; Nishiyama, Motohiro; Shimamura, Takahiro; Maema, Atsushi; Shirakawa, Motoaki; Nakamura, Toshio; Koda, Kenji; Yokoyama, Hidetaro

2016-01-01

Gastrointestinal duplications are uncommon congenital malformations that can occur anywhere along the gastrointestinal tract. Most cases are recognized before the age of 2 years, and those encountered in adults are rare. We describe here a case of ascending colon duplication in a 20-year-old male that caused intussusception and was treated laparoscopically. Although computed tomography revealed a cystic mass filled with stool-like material, the preoperative diagnosis was a submucosal tumor of the ascending colon. We performed a laparoscopic right colectomy, and the postoperative pathological diagnosis was duplication of the ascending colon, both cystic and tubular components. We conclude that gastrointestinal duplications, although rare, should be considered in the differential diagnosis of all abdominal and submucosal cystic lesions and that laparoscopy is a preferred approach for the surgical treatment of gastrointestinal duplications. PMID:26900303

Rupture of an ascending and descending thoracic aortic aneurysm causing tension hemothorax: a case report.

PubMed

Pizon, Anthony; Bissell, Brad J; Gilmore, Nathan

2012-10-01

A ruptured thoracic aortic aneurysm is a life-threatening condition and can lead to a tension hemothorax. To describe the presentation and management of a case of a tension hemothorax. An 84-year-old woman presented in respiratory distress and was found to have a tension hemothorax. The cause was the rupture of an ascending and descending thoracic aortic aneurysm. She was managed with intubation, mechanical ventilation, and chest tube placement with stabilization. Definitive operative repair was deferred due to the patient's comorbidities and wishes of the family. A tension hemothorax can result from an ascending and descending thoracic aneurysm, as this case describes. Emergent therapy is necessary as this is a life-threatening condition. Copyright © 2012 Elsevier Inc. All rights reserved.

Ascending Aortic Stenting for Acute Supraaortic Stenosis From Graft Collapse.

PubMed

Lader, Joshua M; Smith, Deane E; Staniloae, Cezar; Fallahi, Arzhang; Iqbal, Sohah N; Galloway, Aubrey C; Williams, Mathew R

2018-06-01

A 78-year-old man with remote type-A dissection presented with acute-onset dyspnea. Twenty-two years prior, treatment for his aortic disease required replacement of ascending and arch aneurysms with a polyester graft (Dacron) using the graft inclusion technique. He presented currently in cardiogenic shock. Echocardiography demonstrated new severe hypokinesis of all apical segments. Left-heart catheterization revealed a 120 mm Hg intragraft gradient. Computed tomography arteriography was unrevealing, but intraaortic ultrasound demonstrated critical intragraft stenosis. A balloon expandable stent (Palmaz stent, Cordis, Milpitas, CA) was deployed in the stenotic region with gradient resolution. The patient later underwent aortic root replacement and ascending aneurysm repair (Bio-Bentall technique) and is doing well at 24 months. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

A Multicenter, Randomized, Open-Label, Pharmacokinetics and Safety Study of Pantoprazole Tablets in Children and Adolescents Aged 6 Through 16 Years With GERD

PubMed Central

Ward, Robert M.; Kearns, Gregory L.; Tammara, Brinda; Bishop, Phyllis; O’Gorman, Molly A.; James, Laura P.; Katz, Mitchell H.; Maguire, Mary K.; Rath, Natalie; Meng, Xu; Comer, Gail M.

2011-01-01

SUMMARY Children with GERD may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drug’s kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed-release tablets in pediatric patients with GERD aged ≥6 through 11 years (study 1) and 12 through 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose, and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar toPK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug-associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults. PMID:20852004

Elucidating Rifampin’s Inducing and Inhibiting Effects on Glyburide Pharmacokinetics and Blood Glucose in Healthy Volunteers: Unmasking the Differential Effect of Enzyme Induction and Transporter Inhibition for a Drug and Its Primary Metabolite

PubMed Central

Zheng, HX; Huang, Y; Frassetto, LA; Benet, LZ

2013-01-01

The effects of single doses of intravenous ciprofloxacin and rifampin, multiple doses of rifampin, on glyburide exposure and effect on blood glucose levels in 9 healthy volunteers were investigated. The single intravenous dose of rifampin significantly increased the AUCs of glyburide and metabolite. Blood glucose levels dropped significantly in comparison to when glyburide was dosed alone. Multiple doses of rifampin induced liver enzymes leading to a marked decrease in glyburide exposure and in blood glucose measurements. When intravenous rifampin was given after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect, however, relative changes in AUC for glyburide and its hydroxyl metabolite were the same as that seen under non-induced conditions. The studies reported here demonstrate how measurements of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and characterizing enzymatic versus transporter mechanisms. PMID:18843263

Elucidating rifampin's inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite.

PubMed

Zheng, H X; Huang, Y; Frassetto, L A; Benet, L Z

2009-01-01

The effects of single doses of intravenous (IV) ciprofloxacin and rifampin and of multiple doses of rifampin on glyburide exposure and blood glucose levels were investigated in nine healthy volunteers. A single IV dose of rifampin significantly increased the area under the concentration-time curve (AUC) of glyburide and its metabolite. Blood glucose levels were significantly lower than those observed after dosing with glyburide alone. Multiple doses of rifampin induced an increase in liver enzyme levels, leading to a marked decrease in glyburide exposure and blood glucose levels. When IV rifampin was administered after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect; however, the relative changes in AUC for glyburide and its hydroxyl metabolite were similar to those seen under noninduced conditions. The studies reported here demonstrate how measurements of the levels of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and in characterizing enzymatic vs. transporter mechanisms.

Shared Dosimetry Error in Epidemiological Dose-Response Analyses

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

Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail

2015-03-23

Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takesmore » up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. Use of these methods for several studies, including the Mayak Worker Cohort and the U.S. Atomic Veterans Study, is discussed.« less

Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers▿

PubMed Central

Di Stefano, A. F. D.; Rusca, A.; Loprete, L.; Dröge, M. J.; Moro, L.; Assandri, A.

2011-01-01

The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fecal elimination of rifamycin SV after single- and multiple-dose regimens of the new formulation were investigated. Concentrations in plasma of >2 ng/ml were infrequently and randomly quantifiable after single and multiple oral doses. The systemic exposure to rifamycin SV after single and multiple oral doses of MMX tablets under fasting and fed conditions or following a four-times-a-day (q.i.d.) or a twice-a-day (b.i.d.) regimen could be considered negligible. With both oral regimens, the drug was confirmed to be very poorly absorbable systemically. The amount of systemically absorbed antibiotic excreted by the renal route is far lower than 0.01% of the administered dose after both the single- and multiple-dose regimens. The absolute bioavailability, calculated as the mean percent ratio between total urinary excretion amounts (ΣXu) after a single intravenous injection and after a single oral dose under fasting conditions, was 0.0410 ± 0.0617. The total elimination of the unchanged rifamycin SV with feces was 87% of the administered oral dose. No significant effect of rifamycin SV on vital signs, electrocardiograms, or laboratory parameters was observed. PMID:21402860

Investigation of dose characteristics in three-dimensional MAGAT-type polymer gel dosimetry with MSE MR imaging

NASA Astrophysics Data System (ADS)

Lee, Jason J. S.; Tsai, Chia-Jung; Lo, Man-Kuok; Huang, Yung-Hui; Chen, Chien-Chuan; Wu, Jay; Tyan, Yeu-Sheng; Wu, Tung-Hsin

2008-05-01

A new type of normoxic polymer gel dosimeter, named MAGAT responses well to absorbed dose even when manufacturing in the presence of normal levels of oxygen. The aim of this study was to evaluate dose response, diffusion effect and cumulated dose response under multiple fractional irradiations of the MAGAT gel dosimeter using Multiple Spin-Echo (MSE) Magnetic Resonance (MR) sequence. Dose response was performed by irradiating MAGAT-gel-filled testing vials with a 6 MV linear accelerator and a linear relationship was present with doses from 0 to 6 Gy, but gradually, a bi-exponential function result was obtained with given doses up to 20 Gy. No significant difference in dose response was present between single and cumulated doses (p > 0.05). For study of diffusion effect, edge sharpness of the R2 map imaging between two split doses was smaller than 1 cm of dose profile penumbra between 20% and 80%. In conclusion, the MAGAT polymer gel dosimeter with MSE MR imaging is a promising method for dose verification in clinical radiation therapy practice.

Sodium Chloride and Water Transport in the Medullary Thick Ascending Limb of Henle. EVIDENCE FOR ACTIVE CHLORIDE TRANSPORT

PubMed Central

Rocha, Antonino S.; Kokko, Juha P.

1973-01-01

Transport of NaCl and water was examined in the rabbit medullary thick ascending limb of Henle (ALH) by perfusing isolated segments of these nephrons in vitro. Osmotic water permeability was evaluated by perfusing tubules against imposed osmotic gradients. In these experiments the net transport of fluid remained at zero when segments of thick ALH were perfused with isotonic ultrafiltrate in a bath of rabbit serum in which the serum osmolality was increased by the addition of either 239±8 mosmol/liter of raffinose or 232±17 mosmol of NaCl indicating that the thick ascending limb of Henle is impermeant to osmotic flow of water. When these tubules were perfused at slow rates with isosmolal ultrafiltrate of same rabbit serum as used for the bath, the effluent osmolality was consistently lowered to concentrations less than the perfusate and the bath. That this decrease in collected fluid osmolality represented salt transport was demonstrated in a separate set of experiments in which it was shown that the sodium and chloride concentrations decreased to 0.79±0.02 and 0.77±0.02 respectively when compared with the perfusion fluid concentrations. In each instance the simultaneously determined transtubular potential difference (PD) revealed the lumen to be positive with the magnitude dependent on the perfusion rate. At flow rates above 2 nl·min-1, the mean transtubular PD was stable and equal to 6.70±0.34 mv. At stop-flow conditions this PD became more positive. Ouabain and cooling reversibly decreased the magnitude of this PD. The transtubular PD remained positive, 3.3±0.2 mV, when complete substitution of Na by choline was carried out in both the perfusion fluid and the bathing media. These results are interpreted to indicate that the active transport process is primarily an electrogenic chloride mechanism. The isotopic permeability coefficient for Na was 6.27±0.38 × 10-5 cm·s-1 indicating that the thick ALH is approximately as permeable to Na as the proximal convoluted tubule. The chloride permeability coefficient for the thick ALH was 1.06±0.12 × 10-5 cm·s-1 which is significantly less than the chloride permeability of the proximal tubule. These data demonstrate that the medullary thick ascending limb of Henle is water impermeable while having the capacity for active outward solute transport as a consequence of an electrogenic chloride pump. The combination of these characteristics allows this segment to generate a dilute tubular fluid and participate as the principal energy source for the overall operation of the countercurrent multiplication system. Images PMID:4685086

Validation and reconstruction of FY-3B/MWRI soil moisture using an artificial neural network based on reconstructed MODIS optical products over the Tibetan Plateau

NASA Astrophysics Data System (ADS)

Cui, Yaokui; Long, Di; Hong, Yang; Zeng, Chao; Zhou, Jie; Han, Zhongying; Liu, Ronghua; Wan, Wei

2016-12-01

Soil moisture is a key variable in the exchange of water and energy between the land surface and the atmosphere, especially over the Tibetan Plateau (TP) which is climatically and hydrologically sensitive as the Earth's 'third pole'. Large-scale spatially consistent and temporally continuous soil moisture datasets are of great importance to meteorological and hydrological applications, such as weather forecasting and drought monitoring. The Fengyun-3B Microwave Radiation Imager (FY-3B/MWRI) soil moisture product is a relatively new passive microwave product, with the satellite being launched on November 5, 2010. This study validates and reconstructs FY-3B/MWRI soil moisture across the TP. First, the validation is performed using in situ measurements within two in situ soil moisture measurement networks (1° × 1° and 0.25° × 0.25°), and also compared with the Essential Climate Variable (ECV) soil moisture product from multiple active and passive satellite soil moisture products using new merging procedures. Results show that the ascending FY-3B/MWRI product outperforms the descending product. The ascending FY-3B/MWRI product has almost the same correlation as the ECV product with the in situ measurements. The ascending FY-3B/MWRI product has better performance than the ECV product in the frozen season and under the lower NDVI condition. When the NDVI is higher in the unfrozen season, uncertainty in the ascending FY-3B/MWRI product increases with increasing NDVI, but it could still capture the variability in soil moisture. Second, the FY-3B/MWRI soil moisture product is subsequently reconstructed using the back-propagation neural network (BP-NN) based on reconstructed MODIS products, i.e., LST, NDVI, and albedo. The reconstruction method of generating the soil moisture product not only considers the relationship between the soil moisture and NDVI, LST, and albedo, but also the relationship between the soil moisture and four-dimensional variations using the longitude, latitude, DEM and day of year (DOY). Results show that the soil moisture could be well reconstructed with R2 higher than 0.56, RMSE less than 0.1 cm3 cm-3, and Bias less than 0.07 cm3 cm-3 for both frozen and unfrozen seasons, compared with the in situ measurements at the two networks. Third, the reconstruction method is applied to generate surface soil moisture over the TP. Both original and reconstructed FY-3B/MWRI soil moisture products could be valuable in studying meteorology, hydrology, and ecosystems over the TP.

Breast Cancer Metastases to the Gastrointestinal Tract Presenting with Anemia and Intra-abdominal Bleed.

PubMed

Khan, Idrees; Malik, Rehan; Khan, Amina; Assad, Salman; Zahid, Mehr; Sohail, Muhammad Saad; Yasin, Faizan; Qavi, Ahmed H

2017-07-06

Signet ring adenocarcinoma of the breast with synchronous metastasis to the gastrointestinal (GI) tract is a rare occurrence, typically presenting with abdominal pain, dyspepsia, or GI bleed. We report a case of metastatic breast cancer presenting with a complaint of anemia. A further diagnostic evaluation revealed generalized lymphadenopathy, nodular thickening of the urinary bladder wall, bone lesions, and enlarged pancreas. Biopsies from the lymph nodes, pancreatic biopsy, and bladder nodule all revealed a signet cell carcinoma. An upper and lower GI endoscopy revealed multiple ulcerated gastric mucosal nodules and polypoid folds in the cecum and proximal ascending colon; the biopsies from these lesions were also positive for signet ring cell adenocarcinoma.

Mid-term results of zone 0 thoracic endovascular aneurysm repair after ascending aorta wrapping and supra-aortic debranching in high-risk patients.

PubMed

Pecoraro, Felice; Lachat, Mario; Hofmann, Michael; Cayne, Neal S; Chaykovska, Lyubov; Rancic, Zoran; Puippe, Gilbert; Pfammatter, Thomas; Mangialardi, Nicola; Veith, Frank J; Bettex, Dominique; Maisano, Francesco; Neff, Thomas A

2017-06-01

Surgical repair of aneurysmal disease involving the ascending aorta, aortic arch and eventually the descending aorta is generally associated with significant morbidity and mortality. A less invasive approach with the ascending wrapping technique (WT), supra-aortic vessel debranching (SADB) and thoracic endovascular aneurysm repair (TEVAR) in zone 0 was developed to reduce the associated risk in these patients. During a 10-year period, consecutive patients treated by the ascending WT, SADB and TEVAR in zone 0 were included. All patients were considered at high risk for conventional surgery. Measured outcomes included perioperative deaths and morbidity, maximal aortic transverse diameter (TD) and its postoperative evolution, endoleak, survival, freedom from cardiovascular reinterventions, SADB freedom from occlusion and aortic valve function during follow-up. Median follow-up was 37.4 [mean = 34; range, 0-65; standard deviation (SD) = 20] months. Twenty-six cases were included with a mean age of 71.88 ( r  = 56-87; SD = 8) years. A mean of 2.9 supra-aortic vessels (75) per patient was debranched from the ascending aorta. The mean time interval from WT/SADB and TEVAR was 29 ( r  = 0-204; SD = 48) days. TEVAR was associated with chimney and/or periscope grafts in 6 (23%) patients, and extra-anatomical supra-aortic bypasses were performed in 6 (23%) patients. Perioperative mortality was 7.7% (2/26). Neurological events were registered in 3 (11.5%) cases, and a reintervention was required in 3 (11.5%) cases. After the WT, the ascending diameter remained stable during the follow-up period in all cases. At mean follow-up, significant shrinkage of the arch/descending aorta diameter was observed. A type I/III endoleak occurred in 3 cases. At 5 years, the rates of survival, freedom from cardiovascular reinterventions and SADB freedom from occlusion were 71.7, 82.3 and 96%, respectively. The use of the ascending WT, SADB and TEVAR in selected patients with complex thoracic aorta disease is safe and shows promising mid-term results at 3 years. The combination of these techniques could represent an alternative to the standard open surgical repair, especially in older patients or in patients unfit for cardiopulmonary bypass. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

PubMed Central

Weisel, Katja C.; Dimopoulos, Meletios A.; Moreau, Philippe; Lacy, Martha Q.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Banos, Anne; Oriol, Albert; Alegre, Adrian; Chen, Christine; Cavo, Michele; Garderet, Laurent; Ivanova, Valentina; Martinez-Lopez, Joaquin; Knop, Stefan; Yu, Xin; Hong, Kevin; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Miguel, Jesus San

2016-01-01

Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 − < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 − < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30. PMID:27081177

Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone.

PubMed

Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J

2017-09-01

Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met 5 ]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met 5 ]-enkephalin or β-endorphin in normal mice. Thus, [Met 5 ]-enkephalin (i.e. opioid growth factor) may be a reasonable candidate biomarker for multiple sclerosis, and may signal new pathways for treatment of autoimmune disorders. Impact statement This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met 5 ]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG 35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. β-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy.

Paraquat detoxication with multiple emulsions.

PubMed

Frasca, S; Couvreur, P; Seiller, M; Pareau, D; Lacour, B; Stambouli, M; Grossiord, J L

2009-10-01

In this study, we show that detoxifying W/O/W multiple emulsions, prepared with an appropriate extractant/trapping couple, represent a promising technology for quick and safe poisoning treatments, with application to the highly toxic herbicide Paraquat, responsible of poisonings from low-dose exposure leading to several deaths every year. In vitro tests led to the choice of an appropriate extractant/trapping couple system with significant detoxication performance. In vivo tests showed (i) that rats receiving high doses of Paraquat, then a detoxifying emulsion, presented an increase from 50% to 100% of the MST (median survival time) and (ii) that no mortality was observed during 30 days with rats dosed with emulsions initially loaded with Paraquat at a concentration much higher than the lethal dose, proving the stability and the inocuity of the detoxifying multiple emulsion in the gastrointestinal tract.

Perforated Solitary Diverticulitis of the Ascending Colon

DTIC Science & Technology

2005-06-01

postoperative day 6. DISCUSSION Diverticuli of the right colon exist in approximately 1% to 5% of patients with diverticular disease .1-3 They are...ORIGINAL REPORTS Perforated Solitary Diverticulitis of the Ascending Colon CPT David S. Kauvar, MC, USA, MAJ, Jayson Aydelotte, MC, USA, and MAJ...Michael Harnisch, MC, USA Department of Surgery, Brooke Army Medical Center, Fort Sam Houston, Texas KEY WORDS: solitary colon diverticulum

Multidimensional Characterization and Differentiation of Neurons in the Anteroventral Cochlear Nucleus

PubMed Central

Typlt, Marei; Englitz, Bernhard; Sonntag, Mandy; Dehmel, Susanne; Kopp-Scheinpflug, Cornelia; Ruebsamen, Rudolf

2012-01-01

Multiple parallel auditory pathways ascend from the cochlear nucleus. It is generally accepted that the origin of these pathways are distinct groups of neurons differing in their anatomical and physiological properties. In extracellular in vivo recordings these neurons are typically classified on the basis of their peri-stimulus time histogram. In the present study we reconsider the question of classification of neurons in the anteroventral cochlear nucleus (AVCN) by taking a wider range of response properties into account. The study aims at a better understanding of the AVCN's functional organization and its significance as the source of different ascending auditory pathways. The analyses were based on 223 neurons recorded in the AVCN of the Mongolian gerbil. The range of analysed parameters encompassed spontaneous activity, frequency coding, sound level coding, as well as temporal coding. In order to categorize the unit sample without any presumptions as to the relevance of certain response parameters, hierarchical cluster analysis and additional principal component analysis were employed which both allow a classification on the basis of a multitude of parameters simultaneously. Even with the presently considered wider range of parameters, high number of neurons and more advanced analytical methods, no clear boundaries emerged which would separate the neurons based on their physiology. At the current resolution of the analysis, we therefore conclude that the AVCN units more likely constitute a multi-dimensional continuum with different physiological characteristics manifested at different poles. However, more complex stimuli could be useful to uncover physiological differences in future studies. PMID:22253838

Determinants and Normal Values of Ascending Aortic Diameter by Age, Gender and Race/Ethnicity in the Multi-Ethnic Study of Atherosclerosis (MESA)

PubMed Central

Turkbey, Evrim B.; Jain, Aditya; Johnson, Craig; Redheuil, Alban; Arai, Andrew E.; Gomes, Antoinette S.; Carr, James; Hundley, W. Gregory; Teixido-Tura, Gisela; Eng, John; Lima, Joao A.C.; Bluemke, David A.

2013-01-01

PURPOSE To determine the normal size and wall thickness of the ascending thoracic aorta (AA) and its relationship with cardiovascular risk factors in a large population-based study. MATERIALS AND METHODS The mean AA luminal diameter was measured in 3573 Multi-Ethnic Study of Atherosclerosis (MESA) participants (age: 45–84 years), using gradient echo phase contrast cine MRI. Multiple linear regression models were used to evaluate the associations between risk factors and AA diameter. The median and upper normal limit (95th percentile) was defined in a “healthy” subgroup as well as AA wall thickness. RESULTS The upper limits of body surface area indexed AA luminal diameter for age categories of 45–54, 55–64, 65–74, and 75–84 years are 21, 22, 22, and 28 mm/m2 in women and 20, 21, 22, 23 mm/m2 in men, respectively. The mean AA wall thickness was 2.8 mm. Age, gender and body surface area were major determinants of AA luminal diameter (~+1 mm/10 years; ~+1.9 mm in men than women; ~+1 mm/ 0.23 m2; p<0.001). The AA diameter in hypertensive subjects was +0.9 mm larger than in normotensives (p<0.001). CONCLUSION AA diameter increases gradually with aging for both genders, among all race/ethnicities. Normal value of AA diameter is provided. PMID:23681649

Ascending and Descending in Virtual Reality: Simple and Safe System Using Passive Haptics.

PubMed

Nagao, Ryohei; Matsumoto, Keigo; Narumi, Takuji; Tanikawa, Tomohiro; Hirose, Michitaka

2018-04-01

This paper presents a novel interactive system that provides users with virtual reality (VR) experiences, wherein users feel as if they are ascending/descending stairs through passive haptic feedback. The passive haptic stimuli are provided by small bumps under the feet of users; these stimuli are provided to represent the edges of the stairs in the virtual environment. The visual stimuli of the stairs and shoes, provided by head-mounted displays, evoke a visuo-haptic interaction that modifies a user's perception of the floor shape. Our system enables users to experience all types of stairs, such as half-turn and spiral stairs, in a VR setting. We conducted a preliminary user study and two experiments to evaluate the proposed technique. The preliminary user study investigated the effectiveness of the basic idea associated with the proposed technique for the case of a user ascending stairs. The results demonstrated that the passive haptic feedback produced by the small bumps enhanced the user's feeling of presence and sense of ascending. We subsequently performed an experiment to investigate an improved viewpoint manipulation method and the interaction of the manipulation and haptics for both the ascending and descending cases. The experimental results demonstrated that the participants had a feeling of presence and felt a steep stair gradient under the condition of haptic feedback and viewpoint manipulation based on the characteristics of actual stair walking data. However, these results also indicated that the proposed system may not be as effective in providing a sense of descending stairs without an optimization of the haptic stimuli. We then redesigned the shape of the small bumps, and evaluated the design in a second experiment. The results indicated that the best shape to present haptic stimuli is a right triangle cross section in both the ascending and descending cases. Although it is necessary to install small protrusions in the determined direction, by using this optimized shape the users feeling of presence of the stairs and the sensation of walking up and down was enhanced.

Calpain-2 Compensation Promotes Angiotensin II-Induced Ascending and Abdominal Aortic Aneurysms in Calpain-1 Deficient Mice

PubMed Central

Subramanian, Venkateswaran; Moorleghen, Jessica J.; Balakrishnan, Anju; Howatt, Deborah A.; Chishti, Athar H.; Uchida, Haruhito A.

2013-01-01

Background and Objective Recently, we demonstrated that angiotensin II (AngII)-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA) in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2) in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development. Methodology/Results To investigate the relative contribution of calpain-1 and -2 in development of AngII-induced AAs, male LDLr −/− mice that were either calpain-1 +/+ or −/− were fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min) for 4 weeks. Calpain-1 deficiency had no significant effect on body weight or blood pressure during AngII infusion. Moreover, calpain-1 deficiency showed no discernible effects on AngII-induced ascending and abdominal AAs. Interestingly, AngII infusion induced increased expression of calpain-2 protein, thus compensating for total calpain activity in aortas of calpain-1 deficient mice. Oral administration of BDA-410, a calpain inhibitor, along with AngII-infusion significantly attenuated AngII-induced ascending and abdominal AA formation in both calpain-1 +/+ and −/− mice as compared to vehicle administered mice. Furthermore, BDA-410 administration attenuated AngII-induced aortic medial hypertrophy and macrophage accumulation. Western blot and immunostaining analyses revealed BDA-410 administration attenuated AngII-induced C-terminal fragmentation of filamin A, an actin binding cytoskeletal protein in aorta. Conclusion Calpain-2 compensates for loss of calpain-1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation in mice. PMID:23977256

Source of solutes to the coastal sabkha of Abu Dhabi

USGS Publications Warehouse

Wood, W.W.; Sanford, W.E.; Al Habshi, A.R.S.

2002-01-01

An ascending-brine model is proposed to address the observed isotope geochemistry, solute composition, and solute and water fluxes in the coastal sabkha of the Emirate of Abu Dhabi. Mass-balance measurements document that >95% of the solutes are derived from ascending continental brines; minor amounts are derived from rainfall and from groundwater entering from upgradient areas. Nearly 100% of the annual water loss is from evaporation and not lateral discharge. Direct rainfall on the sabkha and subsequent recharge to the underlying aquifer account for ~ 90% of the annual water input to the system; the remaining 10% comes from both lateral and ascending groundwater flow. Thus, the water and solutes in this system are from different sources. Solute concentrations of conservative (i.e., nonreactive) elements in the coastal, sabkha-covered aquifer are consistent with the fluid pore volumes of ascending brine calculated from hydrologic properties. Calcium to sulfate ratios and sulfur isotopes are consistent with this source of solute from the underlying Tertiary formations. Recharging rainwater dissolves halite and other soluble minerals on the surface, causing the solution to become more dense and sink to the bottom of the aquifer where it vertically mixes with less dense ascending brines. Solutes are returned to the surface by capillary forces and recycled or lost from the system by eolian or fluvial processes. Thus, the system becomes vertically mixed, consistent with the presence of tritium throughout the aquifer; but there is essentially no horizontal mixing of seawater with groundwater. The observed seawater solutes in the supratidal zone come from interstitial seawater trapped by the rapid progradation of the sediments into the Arabian Gulf and are not refluxed or laterally mixed. The ascending-brine model contrasts significantly with both the seawater-flooding and evaporative-pumping models previously proposed as a source of solutes to the coastal sabkha of the Emirate of Abu Dhabi. Use of these earlier models leads to incorrect conclusions and raises serious questions about their applicability in the evaluation of sabkhat in the geologic record.

Purinergic and cholinergic neuro-neuronal transmission underlying reflexes activated by mucosal stimulation in the isolated guinea-pig ileum

PubMed Central

Spencer, Nick J; Walsh, Michelle; Smith, Terence K

2000-01-01

We present evidence that adenosine triphosphate (ATP) plays a major role in excitatory neuro-neuronal transmission in ascending and descending reflex pathways to the longitudinal (LM) and circular muscle (CM). A partitioned bath was used for the pharmacological isolation of a segment of guinea-pig ileum (∼6 cm in length), allowing drugs to be selectively applied to an intermediate region between the region where mucosal stimulation was applied and that where mechanical recordings were made. Brush stroking the mucosa (3 strokes) elicited a synchronous contraction of the LM and CM both above (ascending excitation) and below (descending excitation) the site of stimulation. All reflexes were abolished when tetrodotoxin (1 μm) was applied to the intermediate chamber. Hexamethonium (300 μm) added to the intermediate chamber abolished the ascending contraction in 15 % of oral preparations (from 26 preparations, 18 animals) and the descending contraction in 13 % of anal preparations studied (from 53 preparations, 48 animals). In the remaining 85 % of oral preparations, hexamethonium usually attenuated the oral contraction of the LM and CM. However, in the remaining 87 % of anal preparations, hexamethonium had no effect on the anal contraction of the LM and CM. Oral and anal reflexes that were hexamethonium resistant were either abolished or attenuated by the further addition of the P2 purinergic receptor antagonist pyridoxal phosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS, 10 μm) or α,β-methylene ATP (50–100 μm) to the intermediate chamber. 1,1-Dimethyl-4-phenyl-piperazinium iodide (DMPP, 20 μm) or α,β-methylene ATP (50–100 μm) stimulated both ascending and descending excitatory pathways, when applied to the intermediate chamber. In conclusion, ascending and descending neuro-neuronal transmission in excitatory nervous pathways to the LM and CM is complex and clearly involves neurotransmitter(s) other than acetylcholine (ACh). We suggest mucosal stimulation releases ACh and ATP in both ascending and descending excitatory reflex pathways that synapse with excitatory motoneurons to the LM and CM. PMID:10639107

Pharmacokinetics and tolerability of intravenous ibuprofen injection in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose study
.

PubMed

Zhou, Huili; Xu, Wei; Wu, Guolan; Wu, Lihua; Shentu, Jianzhong; Pan, Zhengfei; Hu, Shuai; Liu, Yang

2016-11-01

Recently a formulation of intravenous (IV) ibuprofen was developed in China for management of mild to moderate pain in patients who could not take oral medications or where intravenous administration was preferable. The aim of this study was to evaluate the pharmacokinetic properties and tolerability of single and multiple doses of ibuprofen injection in healthy Chinese volunteers. This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. In the single-dose phase, subjects were randomized to receive a single dose of ibuprofen injection 0.2, 0.4, or 0.8 g administered as a 30-minute IV infusion with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 12.5 hours after drug administration and were analyzed using a validated LC-MS/MS method. In the multiple-dose phase, subjects received 0.4 g ibuprofen every 6 hours for 9 doses. Blood samples were obtained before the 7^th, 8^th, and 9^th administration to determine the C_min at steady state; on the 9^th intravenous administration, blood samples were also collected for 12.5 hours after drug administration. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). A total of 12 healthy male (n = 6) and female (n = 6) Chinese volunteers were enrolled and completed the trial. After IV administration of single dose, the mean (SD) C_max value increased from 35.77 (6.98) to 117.12 (19.78) µg/mL, and the mean (SD) AUC_0-t value increased from 67.63 (10.30) to 230.50 (33.55) µg×h/mL in the range of 0.2-g to 0.8-g dose. The terminal half-life in plasma was ~ 2.0 hours. After IV administration of 9 doses of ibuprofen 400 mg every 6 hours, the mean (SD) C_max was 66.49 (8.49) µg/mL, the AUC_0-t was 135.65 (26.91) µg×h/mL, the t_1/2 was 2.14 (0.34) hours, the Cl/F was 3.34 (0.68) L/h, and the Vz/F was 10.32 (2.69) L, which were comparable with those after single dosing. The accumulation index was 1.17 (0.06), and the fluctuation was 304.0 (57.7) %. Results of the t-tests of C_max and AUC found no significant differences between the male and female groups. No serious AEs were reported, and there were no discontinuations due to AEs. The pharmacokinetics of ibuprofen exhibited dose-related kinetics from the 0.2- to the 0.8-g dose. After multiple doses, the pharmacokinetic parameters of ibuprofen were consistent with those after single doses. There was no accumulation in ibuprofen exposure in healthy Chinese between multiple doses and single dose. At the doses studied, ibuprofen appeared to be well tolerated in these healthy volunteers.
.

Addressing matrix effects in ligand-binding assays through the use of new reagents and technology.

PubMed

Chilewski, Shannon D; Mora, Johanna R; Gleason, Carol; DeSilva, Binodh

2014-04-01

Ligand-binding assays (LBAs) used in the quantification of biotherapeutics for pharmacokinetic determinations rely on interactions between reagents (antibodies or target molecule) and the biotherapeutic. Most LBAs do not employ an analyte extraction procedure and are susceptible to matrix interference. Here, we present a case study on the development of a LBA for the quantification of a PEGylated domain antibody where matrix interference was observed. The assay used to support the single ascending dose study was a plate-based electrochemiluminescent assay with a lower limit of quantification of 80 ng/mL. To meet sensitivity requirements of future studies, new reagents and the Gyrolab™ Workstation were evaluated. Assay sensitivity improved nearly threefold in the final method utilizing new antibody reagents, a buffer containing blockers to human anti-animal antibodies, and the Gyrolab Workstation. Experimental data indicate that all factors changed played a role in overcoming matrix effects.

A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Single Enantiomer (+)-Mefloquine Compared with Racemic Mefloquine in Healthy Persons

PubMed Central

Tansley, Robert; Lotharius, Julie; Priestley, Anthony; Bull, Fiona; Duparc, Stephan; Möhrle, Jörg

2010-01-01

Racemic mefloquine is a highly effective antimalarial whose clinical utility has been compromised by its association with neuropsychiatric and gastrointestinal side effects. It is hypothesized that the cause of the side effects may reside in the (−) enantiomer. We sought to compare the safety, tolerability and pharmacokinetic profile of (+)-mefloquine with racemic mefloquine in a randomized, ascending-dose, double-blind, active and placebo-controlled, parallel cohort study in healthy male and female adult volunteers. Although differing in its manifestations, both study drugs displayed a substantially worse tolerability profile compared with placebo. The systemic clearance was slower for (−)-mefloquine than (+)-mefloquine. Thus, (+)-mefloquine has a different safety and tolerability profile compared with racemic mefloquine but its global safety profile is not superior and replacement of the currently used antimalarial drug with (+)-mefloquine is not warranted. PMID:21118921

[Peculiarities of treatment policy for lower-limb phlebothromboses].

PubMed

Kletskin, A É; Kudykin, M N; Mukhin, A S; Durandin, P Iu

2014-01-01

Quality of treatment for acute venous thrombosis is determined by adequacy of conservative treatment and optimization of the operative procedure. We analysed the outcomes of management of 1,768 patients presenting with various forms of lower-limb phlebothrombosis. Deep veins were affected in 1,158 (65.5%) cases. Of these, thrombosis of crural veins was revealed in 672 (58%) patients, iliofemoral phlebothrombosis in 486 (42%) subjects. A total of 47 (9.7%) patients were operated on for iliofemoral thrombosis with floating thrombus confirmed by ultrasonic angioscanning. Criteria for floatation were determined. A total of 610 (43.5%) patients were diagnosed as having ascending subcutaneous thrombophlebitis of the femur. Of these, a total of 592 (97%) patients were operated on within 1-48 hours following admission. We propose a methodology of comprehensive conservative treatment with the use of Antistax in a double dose and alternating pneumocompression with elevated pressure in the cuffs.

Pressor response to oral tyramine and monoamine oxidase inhibition during treatment with ralfinamide (NW-1029).

PubMed

Di Stefano, Andrea F D; Radicioni, Milko Massimiliano; Rusca, Antonio

2013-05-01

Ralfinamide, an original Na(+) channel blocker developed for the treatment of chronic pain, inhibits monoamineoxidase-B with no apparent effect on monoamineoxidase-A. To evaluate the pressor response to oral tyramine under fasting conditions during treatment with ralfinamide in healthy normotensive subjects. Ten women and 10 men aged 52.9 ± 5.5, sensitive to the oral tyramine pressor effect in the dose range 200-400 mg, received ralfinamide 320 mg daily during 7 days of confinement. Starting on day 5, ascending doses of tyramine 50, 100 and 200 mg were daily administered to subjects, who had responded to 200 mg at screening, and 100, 200 and 400 mg to the 400 mg responders. Vital parameters were monitored. The systolic blood pressure peak (ΔSBP), the time to achieve the peak (Δt) and the area under the pressure curve (over baseline) were calculated. ΔSBP ≥ 30 mmHg were measured for one subject with tyramine 200 mg and for 11 subjects with 400 mg, whilst ΔSBP was <30 mmHg for eight subjects at all the tested doses. ΔSBP, Δt and AUC after co-treatment with ralfinamide and tyramine were not significantly different from those measured after tyramine alone. Ralfinamide did not potentiate the pressor response to single oral doses of tyramine from 50 to 400 mg. These preliminary results give an evidence for the specificity of ralfinamide for MAO-B in comparison with MAO-A, analogously to the observations previously done for safinamide. Dietary tyramine restrictions may not be necessary in neuropathic pain patients receiving ralfinamide as a therapy.

A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV

PubMed Central

Canini, Laetitia; Chatterjee, Anushree; Guedj, Jeremie; Lemenuel-Diot, Annabelle; Brennan, Barbara; Smith, Patrick F; Perelson, Alan S

2014-01-01

Background Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct acting antivirals (DAAs). Methods We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a phase 1 study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naïve and 8 were non-responders to prior PEG-IFN-α/ribavirin treatment. Results In most patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg bid) and 0.99 at the highest dose (200 mg tid). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg bid). The second phase decline showed two different behaviors, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 d−1), whereas the viral decline was slower in the other patients. Conclusions Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir. PMID:25321394

Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI).

PubMed

Dunbar, Geoffrey C; Inglis, Fraser; Kuchibhatla, Ramana; Sharma, Tonmoy; Tomlinson, Mark; Wamsley, James

2007-03-01

Cognitive decline seen in the normal elderly is associated with selective loss of neuronal nicotinic acetylcholine receptors (nAChRs). Nicotine given either by inhalation or transdermally helps cognition, but unacceptable side effects limit its utility. The present study assessed the safety, tolerability and effect on cognition of ispronicline, a highly selective partial agonist at the 4beta2 nAChR, in elderly subjects (n =76) with age associated memory impairment (AAMI). This double-blind, placebo-controlled cross-over study explored ascending oral doses of ispronicline in the range 50-150 mg given as a single morning dose for a period of 3 weeks. Pharmacokinetics (PK) were assessed, as well as cognitive function measured by means of the Cognitive Drug Research (CDR) computerized test battery. Ispronicline had a favourable safety profile and was well tolerated at doses below 150 mg. No effect of clinical importance was seen on biochemistry, haematology, urine analysis, vital signs, electrocardiogram (ECG) or Holter monitoring. The most frequent drug induced adverse event was light-headedness (dizziness). A beneficial effect was seen on cognition across the dose range. This was most marked at 50 mg on factors measuring attention and episodic memory. PK analysis indicated a plasma Cmax range of 5-25/35 ng/ml ispronicline was associated with the most beneficial effect. These early results demonstrate ispronicline was well tolerated and did not display the side effects typical of nicotine. Ispronicline also had a beneficial effect on cognition in subjects with AAMI. This was seen most strongly in a Cmax range that had been predicted from pre-clinical animal studies.

Silexan, an essential oil from flowers of Lavandula angustifolia, is not recognized as benzodiazepine-like in rats trained to discriminate a diazepam cue.

PubMed

Silenieks, Leo B; Koch, Egon; Higgins, Guy A

2013-01-15

Recently, an essential oil of selected quality produced from the flowering tops of Lavandula angustifolia Mill. by steam distillation (Silexan) has been approved in Germany for the treatment of restlessness in case of anxious mood. Based on the observed clinical effects, it has been speculated that lavender oil may exert benzodiazepine-like action including the known dependence and abuse potential of this class of drugs. Although no evidence for such an activity was generated during the long-standing medicinal use of lavender oil, further preclinical investigations were now conducted to evaluate this potential side effect in more detail. Twelve adult, male, Sprague-Dawley rats were trained to discriminate the benzodiazepine drug diazepam (2 mg/kg i.p.) from saline using a two-lever operant procedure. After approximately 40 training sessions the majority of rats learned the discrimination and pre-treatment with ascending doses of diazepam (0.3-2 mg/kg i.p.) produced a dose related generalization to the diazepam cue. In these same animals Silexan was administered to see if animals recognized the drug as "diazepam-like" i.e. generalized to diazepam or "saline-like". Silexan tested at doses 3-30 mg/kg i.p. produced almost exclusively (>90%) saline-like responding. Also there was no effect of Silexan on response rate, i.e. rate of lever pressing, at any dose suggesting that the test article is well tolerated and does not exert a sedating effect. In sum, Silexan has no diazepam-like interoceptive property in adult, male rats. This suggests that Silexan does not share the potential of benzodiazepines to induce the development of tolerance, dependence and addiction. Copyright © 2012 Elsevier GmbH. All rights reserved.

Long-Acting Injectable Naltrexone Induction: A Randomized Trial of Outpatient Opioid Detoxification With Naltrexone Versus Buprenorphine.

PubMed

Sullivan, Maria; Bisaga, Adam; Pavlicova, Martina; Choi, C Jean; Mishlen, Kaitlyn; Carpenter, Kenneth M; Levin, Frances R; Dakwar, Elias; Mariani, John J; Nunes, Edward V

2017-05-01

At present there is no established optimal approach for transitioning opioid-dependent adults to extended-release injection naltrexone (XR-naltrexone) while preventing relapse. The authors conducted a trial examining the efficacy of two methods of outpatient opioid detoxification for induction to XR-naltrexone. Participants were 150 opioid-dependent adults randomly assigned 2:1 to one of two outpatient detoxification regimens, naltrexone-assisted detoxification or buprenorphine-assisted detoxification, followed by an injection of XR-naltrexone. Naltrexone-assisted detoxification lasted 7 days and included a single day of buprenorphine followed by ascending doses of oral naltrexone along with clonidine and other adjunctive medications. Buprenorphine-assisted detoxification included a 7-day buprenorphine taper followed by a week-long delay before administration of XR-naltrexone, consistent with official prescribing information for XR-naltrexone. Participants from both groups received behavioral therapy focused on medication adherence and a second dose of XR-naltrexone. Compared with participants in the buprenorphine-assisted detoxification condition, participants assigned to naltrexone-assisted detoxification were significantly more likely to be successfully inducted to XR-naltrexone (56.1% compared with 32.7%) and to receive the second injection at week 5 (50.0% compared with 26.9%). Both models adjusted for primary type of opioid use, route of opioid administration, and morphine equivalents at baseline. These results demonstrate the safety, efficacy, and tolerability of low-dose naltrexone, in conjunction with single-day buprenorphine dosing and adjunctive nonopioid medications, for initiating adults with opioid dependence to XR-naltrexone. This strategy offers a promising alternative to the high rates of attrition and relapse currently observed with agonist tapers in both inpatient and outpatient settings.

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

Canini, Laetitia; Chatterjee, Anushree; Guedj, Jeremie

Background—Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct acting antivirals (DAAs). Methods—We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a phase 1 study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naïve and 8 were non-responders to prior PEG-IFN-α/ribavirin treatment. Results—In most patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VKmore » model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. We found the antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg bid) and 0.99 at the highest dose (200 mg tid). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg bid). Finally, the second phase decline showed two different behaviors, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 d-1), whereas the viral decline was slower in the other patients. Conclusions—Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.« less

A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV

DOE PAGES

Canini, Laetitia; Chatterjee, Anushree; Guedj, Jeremie; ...

2014-10-16

Background—Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct acting antivirals (DAAs). Methods—We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a phase 1 study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naïve and 8 were non-responders to prior PEG-IFN-α/ribavirin treatment. Results—In most patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VKmore » model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. We found the antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg bid) and 0.99 at the highest dose (200 mg tid). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg bid). Finally, the second phase decline showed two different behaviors, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 d-1), whereas the viral decline was slower in the other patients. Conclusions—Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.« less

Age-dependent effects of initial exposure to nicotine on serotonin neurons.

PubMed

Bang, S J; Commons, K G

2011-04-14

Adolescence is a critical vulnerable period during which exposure to nicotine greatly enhances the possibility to develop drug addiction. Growing evidence suggests that serotonergic (5-HT) neurotransmission may contribute to the initiation and maintenance of addictive behavior. As the dorsal raphe (DR) and median raphe (MnR) nuclei are the primary 5-HT source to the forebrain, the current study tested the hypothesis that there are age-dependent effects of acute nicotine administration on activation of 5-HT neurons within these regions. Both adolescent (Postnatal day 30) and adult (Postnatal day 70) male Sprague-Dawley rats received subcutaneous injection of either saline or nicotine (0.2, 0.4, or 0.8 mg/kg). Subsequently, the number of 5-HT cells that were double-labeled for Fos and tryptophan hydroxylase was counted in seven subregions within the DR and the entire MnR. The results show that acute nicotine injection induces Fos expression in 5-HT neurons in a region-specific manner. In addition, adolescents show broader regional activations at either a lower (0.2 mg/kg) and a higher (0.8 mg/kg) dose of nicotine, displaying a unique U-shape response curve across doses. In contrast, 5-HT cells with activated Fos expression were restricted to fewer regions in adults, and the patterns of expression were more consistent across doses. The results reveal dose-dependent effects of nicotine during adolescence with apparent sensitization at different ends of the dosage spectrum examined compared to adults. These data indicate that initial exposure to nicotine may have unique effects in adolescence on the ascending 5-HT system, with the potential for consequences on the affective-motivational qualities of the drug and the subsequent propensity for repeated use. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Age-Dependent Effects of Initial Exposure to Nicotine on Serotonin Neurons

PubMed Central

Bang, Sun Jung; Commons, Kathryn G.

2011-01-01

Adolescence is a critical vulnerable period during which exposure to nicotine greatly enhances the possibility to develop drug addiction. Growing evidence suggests that serotonergic (5-HT) neurotransmission may contribute to the initiation and maintenance of addictive behavior. As the dorsal raphe (DR) and median raphe (MnR) nuclei are the primary 5-HT source to the forebrain, the current study tested the hypothesis that there are age-dependent effects of acute nicotine administration on activation of 5-HT neurons within these regions. Both adolescent (Postnatal day 30) and adult (Postnatal day 70) male Sprague-Dawley rats received subcutaneous injection of either saline or nicotine (0.2, 0.4, or 0.8 mg/kg). Subsequently, the number of 5-HT cells that were double-labeled for Fos and tryptophan hydroxylase was counted in 7 subregions within the DR and the entire MnR. The results show that acute nicotine injection induces Fos expression in 5-HT neurons in a region-specific manner. In addition, adolescents show broader regional activations at either a lower (0.2 mg/kg) and a higher (0.8 mg/kg) dose of nicotine, displaying a unique U-shape response curve across doses. In contrast, 5-HT cells with activated Fos expression were restricted to fewer regions in adults, and the patterns of expression were more consistent across doses. The results reveal dose-dependent effects of nicotine during adolescence with apparent sensitization at different ends of the dosage spectrum examined compared to adults. These data indicate that initial exposure to nicotine may have unique effects in adolescence on the ascending 5-HT system, with the potential for consequences on the affective-motivational qualities of the drug and the subsequent propensity for repeated use. PMID:21277949

Species-specific effects of neuregulin-1β (cimaglermin alfa) on glucose handling in animal models and humans with heart failure.

PubMed

Huang, Zhihong; Sawyer, Douglas B; Troy, Erika L; McEwen, Corissa; Cleator, John H; Murphy, Abigail; Caggiano, Anthony O; Eisen, Andrew; Parry, Tom J

2017-10-01

Neuregulin-1β is a member of the neuregulin family of growth factors and is critically important for normal development and functioning of the heart and brain. A recombinant version of neuregulin-1β, cimaglermin alfa (also known as glial growth factor 2 or GGF2) is being investigated as a possible therapy for heart failure. Previous studies suggest that neuregulin-1β stimulation of skeletal muscle increases glucose uptake and, specifically, sufficient doses of cimaglermin alfa acutely produce hypoglycemia in pigs. Since acute hypoglycemia could be a safety concern, blood glucose changes in the above pig study were further investigated. In addition, basal glucose and glucose disposal were investigated in mice. Finally, as part of standard clinical chemistry profiling in a single ascending-dose human safety study, blood glucose levels were evaluated in patients with heart failure after cimaglermin alfa treatment. A single intravenous injection of cimaglermin alfa at doses of 0.8mg/kg and 2.6mg/kg in mice resulted in a transient reduction of blood glucose concentrations of approximately 20% and 34%, respectively, at 2h after the treatment compared to pre-treatment levels. Similar results were observed in diabetic mice. Treatment with cimaglermin alfa also increased blood glucose disposal following oral challenge in mice. However, no significant alterations in blood glucose concentrations were found in human heart failure patients at 0.5 and 2h after treatment with cimaglermin alfa over an equivalent human dose range, based on body surface area. Taken together, these data indicate strong species differences in blood glucose handling after cimaglermin alfa treatment, and particularly do not indicate that this phenomenon should affect human subjects. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- and Multiple-Dose Study.

PubMed

Agarwal, Suresh K; Hu, Beibei; Chien, David; Wong, Shekman L; Salem, Ahmed Hamed

2016-11-01

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single-dose and multiple-dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax C max and AUC ∞ by 106% (90%CI, 73%-145%) and 78% (90%CI, 50%-111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax C max and AUC ∞ by 42% (90%CI, 31%-52%) and 71% (90%CI, 66%-76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P-glycoprotein (P-gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax C max and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P-gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax. © 2016, The American College of Clinical Pharmacology.

TH-AB-207A-03: Skin Dose to Patients Receiving Multiple CTA and CT Exams of the Head

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

Nawfel, RD; Young, G

Purpose: To measure patient skin dose from CT angiography (CTA) and CT exams of the head, and determine if patients having multiple exams could receive cumulative doses that approach or exceed deterministic thresholds. Methods: This study was HIPAA compliant and conducted with IRB approval. Patient skin doses were measured over a 4 month period using nanoDot OSL dosimeters placed on the head of 52 patients for two CT scanners. On each scanner, 26 patients received CT exams (scanner 1: 10 females, 16 males, mean age 64.2 years; scanner 2: 18 females, 8 males, mean age 61.2 years). CT exam dosemore » metrics, CTDIvol and dose-length product (DLP) were recorded for each exam. Additionally, skin dose was measured on an acrylic skull phantom in each scanner and on a neuro-interventional imaging system using clinical protocols. Measured dose data was used to estimate peak skin dose (PSD) for 4 patients receiving multiple exams including CTA, head CT, and cerebral angiography. Results: For scanner 1, the mean PSD for CTA exams (98.9 ± 5.3 mGy) and for routine head CT exams (39.2 ± 3.7 mGy) agreed reasonably well with the PSD measured on the phantom, 105.4 mGy and 40.0 mGy, respectively. Similarly for scanner 2, the mean PSD for CTA exams (98.8 ± 7.4 mGy) and for routine head CT exams (42.9 ± 9.4 mGy) compared well with phantom measurements, 95.2 mGy and 37.6 mGy, respectively. In addition, the mean PSD was comparable between scanners for corresponding patient exams, CTA and routine head CT respectively. PSD estimates ranged from 1.9 – 4.5 Gy among 4 patients receiving multiple exams. Conclusion: Patients having several exams including both CTA and routine head CT may receive cumulative doses approaching or exceeding the threshold for single dose deterministic effects.« less

Concomitant replacement of the dilated ascending aorta during aortic valve replacement; does it increase the perioperative morbidity and mortality risks?

PubMed

Lim, Ju Y; Jung, Sung H; Kim, Joon B; Kim, Dong K; Chung, Cheol H; Song, Hyun; Lee, Jae W; Choo, Suk J

2013-05-01

Concerns of increased surgical risks with ascending aortic replacement have led surgeons to manage post-stenotic aortic dilatation more conservatively during aortic valve replacement (AVR). The present study aimed to assess the prognostic implications and surgical risks of replacing the dilated aorta during AVR. Between January 1999 and March 2010, 134 patients who received surgery for aortic stenosis and post-stenotic dilatation (aorta size ≥40 mm) were included in the present study. AVR was performed in 92 patients (AVR group) while aortic valve and ascending aorta replacement (AVR + aorta group) were performed in 42 patients. Overall survival was compared between the two groups using Cox proportional hazard model after adjustment with inverse-probability-of-treatment weighting. The mean follow-up duration was 3.5 ± 3 years. There were no significant differences in the operative mortality and morbidity between the two groups. The late cardiac deaths were also not significantly different between the two groups (p = 1.00). In the AVR group, the ascending aortic expansion rate which was 0.18 mm/year over a mean follow-up duration of 2.3 ± 2.2 years by echocardiography showed a positive correlation with time (r = 0.3, p = 0.08). A relatively greater aortic expansion rate was identified as a risk factor for late mortality (p = 0.015, HR 1.08 (CI: 1.02 to 1.15). Concomitant replacement of the dilated ascending aorta during AVR did not increase the immediate postoperative morbidity or mortality risks and tended to exert a long-term beneficial effect on the risk of late mortality. © 2013 Wiley Periodicals, Inc.

A Regional CO2 Observing System Simulation Experiment Using ASCENDS Observations and WRF-STILT Footprints

NASA Technical Reports Server (NTRS)

Wang, James S.; Kawa, S. Randolph; Eluszkiewicz, Janusz; Collatz, G. J.; Mountain, Marikate; Henderson, John; Nehrkorn, Thomas; Aschbrenner, Ryan; Zaccheo, T. Scott

2012-01-01

Knowledge of the spatiotemporal variations in emissions and uptake of CO2 is hampered by sparse measurements. The recent advent of satellite measurements of CO2 concentrations is increasing the density of measurements, and the future mission ASCENDS (Active Sensing of CO2 Emissions over Nights, Days and Seasons) will provide even greater coverage and precision. Lagrangian atmospheric transport models run backward in time can quantify surface influences ("footprints") of diverse measurement platforms and are particularly well suited for inverse estimation of regional surface CO2 fluxes at high resolution based on satellite observations. We utilize the STILT Lagrangian particle dispersion model, driven by WRF meteorological fields at 40-km resolution, in a Bayesian synthesis inversion approach to quantify the ability of ASCENDS column CO2 observations to constrain fluxes at high resolution. This study focuses on land-based biospheric fluxes, whose uncertainties are especially large, in a domain encompassing North America. We present results based on realistic input fields for 2007. Pseudo-observation random errors are estimated from backscatter and optical depth measured by the CALIPSO satellite. We estimate a priori flux uncertainties based on output from the CASA-GFED (v.3) biosphere model and make simple assumptions about spatial and temporal error correlations. WRF-STILT footprints are convolved with candidate vertical weighting functions for ASCENDS. We find that at a horizontal flux resolution of 1 degree x 1 degree, ASCENDS observations are potentially able to reduce average weekly flux uncertainties by 0-8% in July, and 0-0.5% in January (assuming an error of 0.5 ppm at the Railroad Valley reference site). Aggregated to coarser resolutions, e.g. 5 degrees x 5 degrees, the uncertainty reductions are larger and more similar to those estimated in previous satellite data observing system simulation experiments.

[Simultaneous interventions on the ascending portion, arch of the aorta and cardiac valves in patients with Marfan's syndrome].

PubMed

Belov, Iu V; Stepanenko, A B; Gens, A P; Charchian, E R; Savichev, D D

2007-01-01

Simultaneous surgical interventions on the aorta and valvular system of the heart were performed in four patients presenting with aortic dissections and aneurysms conditioned by Marfan's syndrome. The following reconstructive operations were carried out: 1) prosthetic repair of the aortic valve and the ascending portion of the aorta by means of a valve-containing conduit with replantation of the openings of the coronary arteries into the side of the prosthesis according to the Benthall - De Bono technique, annuloplasty of the tricuspid valve according to the De Vega technique, valvuloplasty of the mitral valve by the Alferi technique; 2) grafting of the aortic valve and the ascending portion of the aorta by means of a valve-containing conduit with replantation of the openings of the coronary arteries according to the Kabrol's technique, plasty of the tricuspid valve by the De Vega technique; 3) prosthetic repair of the aortic arch with distal wedge-like excision of the membrane of the dissection and directing the blood flow along the both channels, plasty of the mitral valve, plasty of the aortic valve and the ascending portion of the aorta with a valve-containing conduit, accompanied by replantation of the openings of the coronary arteries into the side of the graft according to the Benthall - De Bono technique; (4) plasty of the mitral valve with a disk graft through the fibrous ring of the aortic valve, prosthetic repair of the aortic valve and the ascending portion of the aorta with a valve-containing conduit, accompanied by replantation of the openings of the coronary arteries into the side according to the Benthall-De Bono technique.

Advanced atherosclerosis is associated with increased medial degeneration in sporadic ascending aortic aneurysms.

PubMed

Albini, Paul T; Segura, Ana Maria; Liu, Guanghui; Minard, Charles G; Coselli, Joseph S; Milewicz, Dianna M; Shen, Ying H; LeMaire, Scott A

2014-02-01

The pathogenesis of non-familial, sporadic ascending aortic aneurysms (SAAA) is poorly understood, and the relationship between ascending aortic atherosclerosis and medial degeneration is unclear. We evaluated the prevalence and severity of aortic atherosclerosis and its association with medial degeneration in SAAA. Atherosclerosis was characterized in ascending aortic tissues collected from 68 SAAA patients (mean age, 62.9 ± 12.0 years) and 15 controls (mean age, 56.6 ± 11.4 years [P = 0.07]) by using a modified American Heart Association classification system. Upon histologic examination, 97% of SAAA patients and 73% of controls showed atherosclerotic changes. Most SAAA samples had intermediate (types 2 and 3, 35%) or advanced atherosclerosis (types ≥ 4; 40%), whereas most control samples showed minimal atherosclerosis (none or type 1, 80%; P < 0.001 after adjusting for age). In a separate analysis, we examined the total incidence and grade distribution of medial degenerative changes among SAAA samples according to atherosclerosis grade. Advanced atherosclerosis was associated with higher grades of smooth muscle cell depletion (P < 0.001), elastic fiber depletion (P = 0.02), elastic fiber fragmentation (P < 0.001), and mucopolysaccharide accumulation (P = 0.04). Aortic diameter was larger in SAAA patients with advanced atherosclerosis than in patients with minimal (P = 0.04) or intermediate atherosclerosis (P = 0.04). Immunostaining showed marked CD3+ T-cell and CD68+ macrophage infiltration, MMP-2 and MMP-9 production, and cryopyrin expression in the medial layer adjacent to atherosclerotic plaque. SAAA tissues exhibited advanced atherosclerosis that was associated with severe medial degeneration and increased aortic diameter. Our findings suggest a role for atherosclerosis in the progression of sporadic ascending aortic aneurysms. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The complementary role of magnetic resonance imaging, Doppler echocardiography, and computed tomography in the diagnosis of dissecting thoracic aneurysms.

PubMed

Goldman, A P; Kotler, M N; Scanlon, M H; Ostrum, B; Parameswaran, R; Parry, W R

1986-05-01

Non-ECG gated MRI was compared with 2DE and/or CT scans in 10 patients with dissecting aneurysms proven by angiography and/or surgery. Patient ages ranged from 48 to 85 years (mean 69.6). Six had DeBakey type I dissections and four had DeBakey type III dissections. MRI was diagnostic for aortic dissection in nine cases and suggestive in the tenth. 2DE was diagnostic in six out of nine patients, suggestive in two patients, and nondiagnostic in one patient. CT was diagnostic in the three cases in which it was employed. MRI demonstrated a dilated ascending aorta with thickened walls in all type I dissections as well as an intimal flap and slow flow in the false channel in four patients. In the other two patients with type I dissection, MRI detected the intimal flap in the descending aorta but not in the ascending aorta, whereas 2DE revealed the ascending aortic intimal flap in both of these patients and CT showed it in one of them. In the type III dissections, MRI demonstrated a thickened wall and thrombus in the lumen in all four cases, and the intimal flap in three out of the four. 2DE excluded ascending aortic involvement in all three type III dissections. Six other patients with fusiform dilated ascending aortas had no evidence of dissection by MRI, 2DE, and aortography. Thus, non-ECG gated MRI alone or in combination with 2DE and/or CT is useful in the diagnosis of dissecting thoracic aneurysm and in assessing the extent of the dissection. In addition, the differentiation of dissecting aneurysms of the aorta from fusiform dilatation of the aorta is made possible by these noninvasive techniques.

Percutaneous valved stent implantation in the ascending aorta for the treatment of very high-risk aortic regurgitation: an animal study.

PubMed

Zong, Gang-Jun; Jiang, Hai-Bin; Bai, Yuan; Wu, Gang-Yong; Ye, Guang-Ming; Chen, Jing-Kai; Qin, Yong-Wen; Zhao, Xian-xian

2013-12-01

We investigated the effects of percutaneous valved stent implantation in the ascending aorta as an alternative treatment for aortic regurgitation in a canine model. A total of 16 healthy dogs weighing an average of 18.3 ± 2.1 kg were used for the establishment of animal models of chronic aortic regurgitation by percutaneous aortic valve perforation and balloon dilation. At 2 mo after successful model establishment, all experimental animals underwent valved stent implantation in the ascending aorta and then were followed up for 3 mo. Experimental models of chronic aortic regurgitation were successfully established in 10 dogs. Surviving dogs underwent successful valved stent implantation in the ascending aorta and were subsequently followed up for 3 mo. The level of instantaneous aortic regurgitation at 3-mo follow-up was significantly reduced compared with that before valved stent implantation (2.4 ± 0.9 versus 10.6 ± 2.1 mL/s, P < 0.05). The left ventricular ejection fraction was significantly increased (53.8 ± 4.2% versus 37.8 ± 3.7%, P < 0.05), and the left ventricular end-diastolic volume was also significantly reduced (30.3 ± 2.2 versus 40.1 ± 3.6 mL, P < 0.05). No paravalvular leak, stroke, atrioventricular block, or other complications occurred in dogs undergoing valved stent implantation. Percutaneous valved stent implantation in the ascending aorta is feasible, effective, and safe as an alternative treatment for very high-risk aortic regurgitation in a canine model. Copyright © 2013 Elsevier Inc. All rights reserved.

Effect of extended-release dexmethylphenidate and mixed amphetamine salts on sleep: a double-blind, randomized, crossover study in youth with attention-deficit hyperactivity disorder.

PubMed

Santisteban, J A; Stein, M A; Bergmame, L; Gruber, R

2014-09-01

We sought to determine the dose-response effects of extended-release (ER) dexmethylphenidate (d-MPH) and ER mixed amphetamine salts (MAS) on objective measures of sleep. This was an 8-week, double-blind, placebo-controlled, randomized, two period, crossover study of youth with attention-deficit hyperactivity disorder (ADHD) as confirmed by the Kiddie Schedule for Affective Disorders for School-Age Children-Present and Lifetime version (K-SADS-PL). Children aged 10-17 years were recruited from clinical practice, colleague referrals, and flyers. Participants were randomized to initially receive either d-MPH or MAS. During each 4-week drug period, children received three dose levels (10, 20, and 25/30 mg) in ascending order, with placebo substituted for active medication in a randomized fashion during 1 week of the study. After 4 weeks, participants were switched to the alternative medication for another 4 weeks of treatment. The main outcome measure was sleep duration as measured by actigraphy. Children, parents, and researchers were blinded to drug, dose, and placebo status. Sixty-five participants met the inclusion criteria and were enrolled in the study. Of these, 37 participants with sufficient sleep data for analysis were included. Sleep schedule measures showed a significant effect for dose on sleep start time (F(1,36) = 6.284; p < 0.05), with a significantly later sleep start time when children were receiving 20- or 30-mg doses, compared with placebo (p < 0.05). A significant dose effect was found on actual sleep duration (F(1,36) = 8.112; p < 0.05), with significantly shorter actual sleep duration for subjects receiving 30 mg compared with those receiving placebo (p < 0.05). There were no significant differences on sleep duration or sleep schedule between the two stimulant medications. The trial is complete and closed to follow-up. Higher stimulant doses were associated with reduced sleep duration and later sleep start times, regardless of medication class. ClinicalTrials.gov: NCT00393042.

A first-in-human pharmacodynamic and pharmacokinetic study of a fully human anti-glucagon receptor monoclonal antibody in normal healthy volunteers.

PubMed

Kostic, Ana; King, Thomas Alexander; Yang, Feng; Chan, Kuo-Chen; Yancopoulos, George D; Gromada, Jesper; Harp, Joyce B

2018-02-01

Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first-in-human healthy volunteer randomized double-blinded trial. Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose-lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges. REGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose-dependent increases in hepatic aminotransferases. No increase in LDL-C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration-time profiles suggest a 2-compartment disposition and marked nonlinearity, consistent with target-mediated clearance. REGN1193 inhibited the glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose area under the curve for 0 to 90 minutes (AUC 0-90 minutes ) by 80% to 90% on days 3 and 15, while blunting the increase in C-peptide. REGN1193 dose-dependently increased total GLP-1, GLP-2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups. REGN1193, a GCGR-blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on-target effect of glucagon receptor blockade. The underlying mechanism is unknown. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Bayesian dose-response analysis for epidemiological studies with complex uncertainty in dose estimation.

PubMed

Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian E; Simon, Steven L

2016-02-10

Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure. Copyright © 2015 John Wiley & Sons, Ltd.

Pharmacokinetics and tolerability of febuxostat after oral administration in healthy Chinese volunteers: a randomized, open-label, singleand multiple-dose three-way crossover study.

PubMed

Zhou, Huili; Zheng, Yunliang; Wu, Guolan; Hu, Xingjiang; Zhai, You; Iv, Duo; Liu, Jian; Wu, Lihua; Shentu, Jianzhong

2016-02-01

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase indicated for the chronic management of hyperuricemia in patients with gout. The aim of the present study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of febuxostat capsules in healthy Chinese volunteers. This openlabel, single- and multiple-dose three-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of febuxostat 40, 80, or 120 mg in separate trial periods, with a 1-week washout between periods. Those allocated to the 40 mg and 80 mg dose continued into the multiple-dose phase, in which they received 40 mg or 80 mg once daily for 6 consecutive days. During the course of the study, blood samples were collected and the concentrations of febuxostat were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). 12 healthy Chinese volunteers were enrolled and completed 3 treatment periods. After oral administration of single doses of 40, 80, and 120 mg of febuxostat, the mean (SD) Cmax was 2,835.43 (1,136.41), 5,356.75 (1,711.33), and 7,718.21 (2,446.34) ng/mL, respectively; the AUC0-48h was 8,821.10 (3,018.35), 17,854.46 (5,113.28), and 30,832.05 (10,992.20) ng×h/ mL; the AUC0-∞ was 8,990.33 (3,046.14), 18,193.58 (5,160.80), and 31,466.93 (1,1074.74) ng×h/mL; the t1/2 was 5.95 (2.71), 9.41 (7.47), and 12.34 (10.34) hours; the Cl/F was 4.81 (1.18), 4.70 (1.21), and 4.18(1.19) L/h; and the Vz/F was 39.66 (16.69), 62.72 (51.41), and 73.41 (64.84) L. After administration of multiple doses of 40 and 80 mg febuxostat, the mean (SD) Cmax,ss was 2,762.38 (1,331.96) and 5,047.27 (1,456.57) ng/mL; the Cmin,ss was 124.10 (6.32) and 46.93 (15.86) ng/mL; the AUCss,0-τ was 8,525.49 (2,160.64) and 16,757.12 (4,223.17) ng×h /mL; the steadystate plasma concentration (Css) was 355.23 (90.03) and 698.21 (175.97) ng/mL; the t1/2 was 7.68 (3.30) and 11.33 (6.94) hours; the Cl/F was 4.99 (1.30) and 5.05 (1.22) L/h; and the Vz/F was 54.10 (24.10) and 85.51 (65.99) L. No serious AEs were reported, and there were no discontinuations due to AEs. The PK of febuxostat exhibited dose proportional kinetics from 40 to 120 mg dose. After multiple doses, the pharmacokinetic parameters of febuxostat were consistent with those after single doses. There was no accumulation in febuxostat exposure in healthy Chinese between multiple doses and single dose. At the doses studied, febuxostat appeared to be well tolerated in these healthy volunteers.

Patterns in the knee flexion-extension moment profile during stair ascent and descent in patients with total knee arthroplasty.

PubMed

McClelland, Jodie A; Feller, Julian A; Menz, Hylton B; Webster, Kate E

2014-06-03

The aim of this study was to investigate the prevalence of abnormal knee biomechanical patterns in 40 patients with a modern TKA prosthesis, compared to 40 matched control participants when ascending and descending stairs. Fewer patients were able to ascend (65%) or descend stairs (53%) unassisted than controls (83%). Of the participants who could ascend and descend, cluster analysis classified most patients (up to 77%) as demonstrating a similar knee moment pattern as all controls. A small subgroup of patients who completed the tasks did so with distinctly abnormal biomechanics compared to other patients and controls. These findings suggest that recovery of normal stair climbing is possible. However, rehabilitation might be more effective if it were tailored to account for these differences between patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

Geodesic Distance Algorithm for Extracting the Ascending Aorta from 3D CT Images

PubMed Central

Jang, Yeonggul; Jung, Ho Yub; Hong, Youngtaek; Cho, Iksung; Shim, Hackjoon; Chang, Hyuk-Jae

2016-01-01

This paper presents a method for the automatic 3D segmentation of the ascending aorta from coronary computed tomography angiography (CCTA). The segmentation is performed in three steps. First, the initial seed points are selected by minimizing a newly proposed energy function across the Hough circles. Second, the ascending aorta is segmented by geodesic distance transformation. Third, the seed points are effectively transferred through the next axial slice by a novel transfer function. Experiments are performed using a database composed of 10 patients' CCTA images. For the experiment, the ground truths are annotated manually on the axial image slices by a medical expert. A comparative evaluation with state-of-the-art commercial aorta segmentation algorithms shows that our approach is computationally more efficient and accurate under the DSC (Dice Similarity Coefficient) measurements. PMID:26904151

Group B Streptococcus Induces Neutrophil Recruitment to Gestational Tissues and Elaboration of Extracellular Traps and Nutritional Immunity

PubMed Central

Kothary, Vishesh; Doster, Ryan S.; Rogers, Lisa M.; Kirk, Leslie A.; Boyd, Kelli L.; Romano-Keeler, Joann; Haley, Kathryn P.; Manning, Shannon D.; Aronoff, David M.; Gaddy, Jennifer A.

2017-01-01

Streptococcus agalactiae, or Group B Streptococcus (GBS), is a gram-positive bacterial pathogen associated with infection during pregnancy and is a major cause of morbidity and mortality in neonates. Infection of the extraplacental membranes surrounding the developing fetus, a condition known as chorioamnionitis, is characterized histopathologically by profound infiltration of polymorphonuclear cells (PMNs, neutrophils) and greatly increases the risk for preterm labor, stillbirth, or neonatal GBS infection. The advent of animal models of chorioamnionitis provides a powerful tool to study host-pathogen relationships in vivo and ex vivo. The purpose of this study was to evaluate the innate immune response elicited by GBS and evaluate how antimicrobial strategies elaborated by these innate immune cells affect bacteria. Our work using a mouse model of GBS ascending vaginal infection during pregnancy reveals that clinically isolated GBS has the capacity to invade reproductive tissues and elicit host immune responses including infiltration of PMNs within the choriodecidua and placenta during infection, mirroring the human condition. Upon interacting with GBS, murine neutrophils elaborate DNA-containing extracellular traps, which immobilize GBS and are studded with antimicrobial molecules including lactoferrin. Exposure of GBS to holo- or apo-forms of lactoferrin reveals that the iron-sequestration activity of lactoferrin represses GBS growth and viability in a dose-dependent manner. Together, these data indicate that the mouse model of ascending infection is a useful tool to recapitulate human models of GBS infection during pregnancy. Furthermore, this work reveals that neutrophil extracellular traps ensnare GBS and repress bacterial growth via deposition of antimicrobial molecules, which drive nutritional immunity via metal sequestration strategies. PMID:28217556

Molecular evidence for a role for K+-Cl− cotransporters in the kidney

PubMed Central

Melo, Zesergio; Cruz-Rangel, Silvia; Bautista, Rocio; Vázquez, Norma; Castañeda-Bueno, María; Mount, David B.; Pasantes-Morales, Herminia; Mercado, Adriana

2013-01-01

K+-Cl− cotransporter (KCC) isoforms 3 (KCC3) and 4 (KCC4) are expressed at the basolateral membrane of proximal convoluted tubule cells, and KCC4 is present in the basolateral membrane of the thick ascending loop of Henle's limb and α-intercalated cells of the collecting duct. Little is known, however, about the physiological roles of these transporters in the kidney. We evaluated KCC3 and KCC4 mRNA and protein expression levels and intrarenal distribution in male Wistar rats or C57 mice under five experimental conditions: hyperglycemia after a single dose of streptozotocin, a low-salt diet, metabolic acidosis induced by ammonium chloride in drinking water, and low- or high-K+ diets. Both KCC3 mRNA and protein expression were increased during hyperglycemia in the renal cortex and at the basolateral membrane of proximal tubule cells but not with a low-salt diet or acidosis. In contrast, KCC4 protein expression was increased by a low-sodium diet in the whole kidney and by metabolic acidosis in the renal outer medulla, specifically at the basolateral membrane of α-intercalated cells. The increased protein expression of KCC4 by a low-salt diet was also observed in WNK4 knockout mice, suggesting that upregulation of KCC4 in these circumstances is not WNK4 dependent. No change in KCC3 or KCC4 protein expression was observed under low- or high-K+ diets. Our data are consistent with a role for KCC3 in the proximal tubule glucose reabsorption mechanism and for KCC4 in salt reabsorption of the thick ascending loop of Henle's loop and acid secretion of the collecting duct. PMID:24089410

Electromyographic Comparison of Squats Using Constant or Variable Resistance.

PubMed

Andersen, Vidar; Steiro Fimland, Marius; Knutson Kolnes, Maria; Jensen, Susanne; Laume, Martine; Hole Saeterbakken, Atle

2016-12-01

Andersen, V, Fimland, MS, Kolnes, MK, Jensen, S, Laume, M and Saeterbakken, AH. Electromyographic comparison of squats using constant or variable resistance. J Strength Cond Res 30(12): 3456-3463, 2016-The aim of the study was to compare the electromyographic (EMG) activity of vastus lateralis, vastus medialis, rectus femoris, and biceps femoris when performing the squat with constant resistance or variable resistance with 2 or 4 elastic bands, respectively, contributing with a mean of 39 and 73% of the total loads. Nineteen resistance-trained women performed 6 repetition maximum using 3 different experimental conditions: free weights (FW), free weights + 2 elastic bands (FW + 2EB), and free weights + 4 elastic bands (FW + 4EB). During analyses, each repetition was divided into 6 phases: upper (more extended knee), middle, and lower phase of the descending and ascending movements. Increased activation in the upper parts of the movement was observed for both variable resistance conditions compared with constant resistance (9-51%, p < 0.001-0.050). Further, a dose-response effect of variable resistance was observed in the upper ascending movement, with 4 elastic bands increasing muscle activation more than 2 elastic bands (7-28%, p = 0.003-0.007). For the whole movement, a 12% higher activation of the biceps femoris was observed for FW + 4EB compared with FW (p = 0.005). There were no differences between the other conditions in any of the muscles (p = 0.077-1.000). In conclusion, performing the squat using free weights in combination with elastic bands seems to be preferable compared with free weights alone and more so with a high contribution from variable resistance to the total load.

A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the "Metabolites in Safety Testing" Regulatory Guidance.

PubMed

Schadt, Simone; Bister, Bojan; Chowdhury, Swapan K; Funk, Christoph; Hop, Cornelis E C A; Humphreys, W Griffith; Igarashi, Fumihiko; James, Alexander D; Kagan, Mark; Khojasteh, S Cyrus; Nedderman, Angus N R; Prakash, Chandra; Runge, Frank; Scheible, Holger; Spracklin, Douglas K; Swart, Piet; Tse, Susanna; Yuan, Josh; Obach, R Scott

2018-06-01

Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated, which has led to more frequent determination of human metabolite profiles from multiple ascending-dose clinical studies. Generating a comprehensive and quantitative profile of human metabolites has become a more urgent task. Together with technological advances, these events have led to a general shift of focus toward earlier human metabolism studies using high-resolution mass spectrometry and to a reduction in animal radiolabel absorption/distribution/metabolism/excretion studies. The changes induced by the MIST guidance are highlighted by six case studies included herein, reflecting different stages of implementation of the MIST guidance within the pharmaceutical industry. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-cyclam-RAFT-c(-RGDfK-)4.

PubMed

Jin, Zhao-Hui; Furukawa, Takako; Degardin, Mélissa; Sugyo, Aya; Tsuji, Atsushi B; Yamasaki, Tomoteru; Kawamura, Kazunori; Fujibayashi, Yasuhisa; Zhang, Ming-Rong; Boturyn, Didier; Dumy, Pascal; Saga, Tsuneo

2016-09-01

The transmembrane cell adhesion receptor αVβ3 integrin (αVβ3) has been identified as an important molecular target for cancer imaging and therapy. We have developed a tetrameric cyclic RGD (Arg-Gly-Asp) peptide-based radiotracer (64)Cu-cyclam-RAFT-c(-RGDfK-)4, which successfully captured αVβ3-positive tumors and angiogenesis by PET. Here, we subsequently evaluated its therapeutic potential and side effects using an established αVβ3-positive tumor mouse model. Mice with subcutaneous U87MG glioblastoma xenografts received single administrations of 37 and 74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 (37 MBq/nmol), peptide control, or vehicle solution and underwent tumor growth evaluation. Side effects were assessed in tumor-bearing and tumor-free mice in terms of body weight, routine hematology, and hepatorenal functions. Biodistribution of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 with ascending peptide doses (0.25-10 nmol) and with the therapeutic dose of 2 nmol were determined at 3 hours and at various time points (2 minutes-24 hours) postinjection, respectively, based on which radiation-absorbed doses were estimated. The results revealed that (64)Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently slowed down the tumor growth. The mean tumor doses were 1.28 and 1.81 Gy from 37 and 74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4, respectively. Peptide dose study showed that the tumor uptake of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently decreased at doses ≥1 nmol, indicating a saturation of αVβ3 with the administered therapeutic doses (1 and 2 nmol). Combined analysis of the data from tumor-bearing and tumor-free mice revealed no significant toxicity caused by 37-74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 Our study demonstrates the therapeutic efficacy and safety of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 for αVβ3-targeted radionuclide therapy. (64)Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising theranostic drug for cancer imaging and therapy. Mol Cancer Ther; 15(9); 2076-85. ©2016 AACR. ©2016 American Association for Cancer Research.

In vitro biotransformation rates in fish liver S9: effect of dosing techniques.

PubMed

Lee, Yung-Shan; Lee, Danny H Y; Delafoulhouze, Maximilien; Otton, S Victoria; Moore, Margo M; Kennedy, Chris J; Gobas, Frank A P C

2014-08-01

In vitro biotransformation assays are currently being explored to improve estimates of bioconcentration factors of potentially bioaccumulative organic chemicals in fish. The present study compares thin-film and solvent-delivery dosing techniques as well as single versus multiple chemical dosing for measuring biotransformation rates of selected polycyclic aromatic hydrocarbons in rainbow trout (Oncorhynchus mykiss) liver S9. The findings show that biotransformation rates of very hydrophobic substances can be accurately measured in thin-film sorbent-dosing assays from concentration-time profiles in the incubation medium but not from those in the sorbent phase because of low chemical film-to-incubation-medium mass-transfer rates at the incubation temperature of 13.5 °C required for trout liver assays. Biotransformation rates determined by thin-film dosing were greater than those determined by solvent-delivery dosing for chrysene (octanol-water partition coefficient [KOW ] =10(5.60) ) and benzo[a]pyrene (KOW  =10(6.04) ), whereas there were no statistical differences in pyrene (KOW  =10(5.18) ) biotransformation rates between the 2 methods. In sorbent delivery-based assays, simultaneous multiple-chemical dosing produced biotransformation rates that were not statistically different from those measured in single-chemical dosing experiments for pyrene and benzo[a]pyrene but not for chrysene. In solvent-delivery experiments, multiple-chemical dosing produced biotransformation rates that were much smaller than those in single-chemical dosing experiments for all test chemicals. While thin-film sorbent-phase and solvent delivery-based dosing methods are both suitable methods for measuring biotransformation rates of substances of intermediate hydrophobicity, thin-film sorbent-phase dosing may be more suitable for superhydrophobic chemicals. © 2014 SETAC.

Dose-Dependent Negative Effects of Prior Multiple Vaccinations against Influenza A and Influenza B among School Children: A Study of Kamigoto Island in Japan during the 2011/12, 2012/13 and 2013/14 Influenza Seasons.

PubMed

Saito, Nobuo; Komori, Kazuhiro; Suzuki, Motoi; Kishikawa, Takayuki; Yasaka, Takahiro; Ariyoshi, Koya

2018-03-08

We investigated the negative effects of prior multiple vaccinations on influenza vaccine effectiveness (VE) and analysed the association of VE with prior vaccine doses. Patients aged 9-18 years presenting with influenza-like illness at a community hospital on a Japanese remote island during the 2011/12, 2012/13 and 2013/14 seasons were tested for influenza using a rapid diagnostic test (RDT). A test-negative case-control study design was used to estimate the VEs of trivalent inactivated influenza vaccine (TIV). Histories of vaccination and medically-attended influenza (MA-flu) A and B during three previous seasons were collected from registry systems. VE was calculated using multi-level mixed-effects logistic regression models adjusted for the history of RDT-confirmed MA-flu. During three influenza seasons, 1668 influenza-like illness episodes were analysed, including 421 and 358 episodes of MA-fluA and MA-fluB, respectively. The adjusted VE yielded significant dose-dependent attenuations by prior vaccinations against both MA-fluA [0 doses during previous three seasons: 96% (95% CI: 69%-100%), 1 dose: 48% (-7% to 74%), 2 doses: 52% (11%-74%), 3 doses: 21% (-25% to 51%); P for trend <0.05] and MA-fluB [0 doses: 66% (-5% to 89%), 1 dose: 48% (-14% to 76%), 2 doses: 34% (-33% to 67%), 3 doses: -7% (-83% to 37%); P for trend <0.05]. After excluding episodes of MA-flu during prior three seasons, similar trends were observed. Repeated previous vaccinations over multiple seasons had significant dose-dependent negative impacts on VE against both MA-fluA and MA-fluB. Further studies to confirm this finding are necessary.

Bilateral anomalous origins of the posterior meningeal artery from the ascending pharyngeal arteries.

PubMed

Hsu, C Y; Sheu, J J; Huang, K M; Li, Y W

2001-06-01

We present a rare case of angiographically confirmed dural arteriovenous fistula supplied mainly by the posterior meningeal artery with bilateral anomalous origins from the bilateral ascending pharyngeal arteries. The bilaterality of the origins of the posterior meningeal artery is important in the angiographic diagnosis and management of a dural vascular malformation in the posterior fossa or the posterior part of the falx cerebri.

Endovascular closure of ascending aortic pseudoaneurysm with a type II Amplatzer vascular plug.

PubMed

De Boo, Diederick W; Mott, Nigel; Kavnoudias, Helen; Walton, Antony; Lyon, Stuart M

2014-05-01

A 71-year-old man initially presented with an asymptomatic, incidentally detected ascending aortic pseudoaneurysm 25 years following aortic root repair with mechanical aortic valve replacement. This pseudoaneurysm was previously treated with coil embolization but due to coil impaction it reopened 8 years later. Endovascular closure of the pseudoaneurysm was achieved with the off-label use of a type II Amplatzer vascular plug.

Using the Inflection Points and Rates of Growth and Decay to Predict Levels of Solar Activity

NASA Technical Reports Server (NTRS)

Wilson, Robert M.; Hathaway, David H.

2008-01-01

The ascending and descending inflection points and rates of growth and decay at specific times during the sunspot cycle are examined as predictors for future activity. On average, the ascending inflection point occurs about 1-2 yr after sunspot minimum amplitude (Rm) and the descending inflection point occurs about 6-7 yr after Rm. The ascending inflection point and the inferred slope (including the 12-mo moving average (12-mma) of (Delta)R (the month-to-month change in the smoothed monthly mean sunspot number (R)) at the ascending inflection point provide strong indications as to the expected size of the ongoing cycle s sunspot maximum amplitude (RM), while the descending inflection point appears to provide an indication as to the expected length of the ongoing cycle. The value of the 12-mma of (Delta)R at elapsed time T = 27 mo past the epoch of RM (E(RM)) seems to provide a strong indication as to the expected size of Rm for the following cycle. The expected Rm for cycle 24 is 7.6 +/- 4.4 (the 90-percent prediction interval), occurring before September 2008. Evidence is also presented for secular rises in selected cycle-related parameters and for preferential grouping of sunspot cycles by amplitude and/or period.

Effective connectivity of ascending and descending frontal-thalamic pathways during sustained attention: Complex brain network interactions in adolescence

PubMed Central

Jagtap, Pranav; Diwadkar, Vaibhav A.

2016-01-01

Frontal-thalamic interactions are crucial for bottom-up gating and top-down control, yet have not been well studied from brain network perspectives. We applied network modeling of fMRI signals (Dynamic Causal Modeling; DCM) to investigate frontal-thalamic interactions during an attention task with parametrically varying levels of demand. fMRI was collected while subjects participated in a sustained continuous performance task with low and high attention demands. 162 competing model architectures were employed in DCM to evaluate hypotheses on bilateral frontal-thalamic connections and their modulation by attention demand, selected at a second level using Bayesian Model Selection. The model architecture evinced significant contextual modulation by attention of ascending (thalamus → dPFC) and descending (dPFC → thalamus) pathways. However, modulation of these pathways was asymmetric: While positive modulation of the ascending pathway was comparable across attention demand, modulation of the descending pathway was significantly greater when attention demands were increased. Increased modulation of the (dPFC → thalamus) pathway in response to increased attention demand constitutes novel evidence of attention-related gain in the connectivity of the descending attention pathway. By comparison demand-independent modulation of the ascending (thalamus → dPFC) pathway suggests unbiased thalamic inputs to the cortex in the context of the paradigm. PMID:27145923

Volcanic conduit failure as a trigger to magma fragmentation

NASA Astrophysics Data System (ADS)

Lavallée, Y.; Benson, P. M.; Heap, M. J.; Flaws, A.; Hess, K.-U.; Dingwell, D. B.

2012-01-01

In the assessment of volcanic risk, it is often assumed that magma ascending at a slow rate will erupt effusively, whereas magma ascending at fast rate will lead to an explosive eruption. Mechanistically viewed, this assessment is supported by the notion that the viscoelastic nature of magma (i.e., the ability of magma to relax at an applied strain rate), linked via the gradient of flow pressure (related to discharge rate), controls the eruption style. In such an analysis, the physical interactions between the magma and the conduit wall are commonly, to a first order, neglected. Yet, during ascent, magma must force its way through the volcanic edifice/structure, whose presence and form may greatly affect the stress field through which the magma is trying to ascend. Here, we demonstrate that fracturing of the conduit wall via flow pressure releases an elastic shock resulting in fracturing of the viscous magma itself. We find that magma fragmentation occurred at strain rates seven orders of magnitude slower than theoretically anticipated from the applied axial strain rate. Our conclusion, that the discharge rate cannot provide a reliable indication of ascending magma rheology without knowledge of conduit wall stability, has important ramifications for volcanic hazard assessment. New numerical simulations are now needed in order to integrate magma/conduit interaction into eruption models.

On the Ability of Space-Based Passive and Active Remote Sensing Observations of CO2 to Detect Flux Perturbations to the Carbon Cycle

NASA Astrophysics Data System (ADS)

Crowell, Sean M. R.; Randolph Kawa, S.; Browell, Edward V.; Hammerling, Dorit M.; Moore, Berrien; Schaefer, Kevin; Doney, Scott C.

2018-01-01

Space-borne observations of CO2 are vital to gaining understanding of the carbon cycle in regions of the world that are difficult to measure directly, such as the tropical terrestrial biosphere, the high northern and southern latitudes, and in developing nations such as China. Measurements from passive instruments such as GOSAT and OCO-2, however, are constrained by solar zenith angle limitations as well as sensitivity to the presence of clouds and aerosols. Active measurements such as those in development for the Active Sensing of CO2 Emissions over Nights, Days and Seasons (ASCENDS) mission show strong potential for making measurements in the high-latitude winter and in cloudy regions. In this work we examine the enhanced flux constraint provided by the improved coverage from an active measurement such as ASCENDS. The simulation studies presented here show that with sufficient precision, ASCENDS will detect permafrost thaw and fossil fuel emissions shifts at annual and seasonal time scales, even in the presence of transport errors, representativeness errors, and biogenic flux errors. While OCO-2 can detect some of these perturbations at the annual scale, the seasonal sampling provided by ASCENDS provides the stronger constraint.

Effective radiation exposure evaluation during a one year follow-up of urolithiasis patients after extracorporeal shock wave lithotripsy.

PubMed

Kaynar, Mehmet; Tekinarslan, Erdem; Keskin, Suat; Buldu, İbrahim; Sönmez, Mehmet Giray; Karatag, Tuna; Istanbulluoglu, Mustafa Okan

2015-01-01

To determine and evaluate the effective radiation exposure during a one year follow-up of urolithiasis patients following the SWL (extracorporeal shock wave lithotripsy) treatment. Total Effective Radiation Exposure (ERE) doses for each of the 129 patients: 44 kidney stone patients, 41 ureter stone patients, and 44 multiple stone location patients were calculated by adding up the radiation doses of each ionizing radiation session including images (IVU, KUB, CT) throughout a one year follow-up period following the SWL. Total mean ERE values for the kidney stone group was calculated as 15, 91 mSv (5.10-27.60), for the ureter group as 13.32 mSv (5.10-24.70), and in the multiple stone location group as 27.02 mSv (9.41-54.85). There was no statistically significant differences between the kidney and ureter groups in terms of the ERE dose values (p = 0.221) (p >0.05). In the comparison of the kidney and ureter stone groups with the multiple stone location group; however, there was a statistically significant difference (p = 0.000) (p <0.05). ERE doses should be a factor to be considered right at the initiation of any diagnostic and/or therapeutic procedure. Especially in the case of multiple stone locations, due to the high exposure to ionized radiation, different imaging modalities with low dose and/or totally without a dose should be employed in the diagnosis, treatment, and follow-up bearing the aim to optimize diagnosis while minimizing the radiation dose as much as possible.

Therapeutic Horseback Riding Outcomes of Parent-Identified Goals for Children with Autism Spectrum Disorder: An ABA′ Multiple Case Design Examining Dosing and Generalization to the Home and Community

PubMed Central

Baird, Joanne M.; Kim, Young Joo; Rajora, Kuwar B.; D’Silva, Delma; Podolinsky, Lin; Mazefsky, Carla; Minshew, Nancy

2014-01-01

We examined whether different doses of therapeutic riding influenced parent-nominated target behaviors of children with autism spectrum disorder (ASD) (a) during the session (b) at home, and (c) in the community. We used a single subject multiple Baseline, multiple case design, with dosing of 1, 3, and 5 times/week. Three boys with ASD, 6–8 years of age participated, and counts of target behaviors were collected in each setting and phase of the study. Compared to Baseline, 70 % of the target behaviors were better during Intervention and improvement was retained in 63 % of the behaviors during Withdrawal. Increased doses of therapeutic riding were significant for magnitude of change, and the effect of the therapeutic riding sessions generalized to home and community. PMID:24091469

Pharmacokinetics of multiple doses of transdermal flunixin meglumine in adult Holstein dairy cows.

PubMed

Kleinhenz, M D; Gorden, P J; Smith, J S; Schleining, J A; Kleinhenz, K E; Wulf, L L; Sidhu, P K; Rea, D; Coetzee, J F

2018-06-01

A transdermal formulation of the nonsteroidal anti-inflammatory drug, flunixin meglumine, has been approved in the United States and Canada for single-dose administration. Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33 mg/kg every 24 hr for three total treatments. Plasma flunixin concentrations were determined using high-pressure liquid chromatography with mass spectroscopy (HPLC-MS). Pharmacokinetic analysis was completed on each individual animal with noncompartmental methods using computer software. The time to maximum drug concentration (Tmax) was 2.81 hr, and the maximum drug concentration was 1.08 μg/ml. The mean terminal half-life (T½) was determined to be 5.20 hr. Clearance per fraction absorbed (Cl/F) was calculated to be 0.294 L/hr kg -1 , and volume of distribution of fraction (Vz/F) absorbed was 2.20 L/kg. The mean accumulation factor was 1.10 after three doses. This indicates changes in dosing may not be required when giving multiple doses of flunixin transdermal. Further work is required to investigate the clinical efficacy of transdermal flunixin after multiple daily doses. © 2018 John Wiley & Sons Ltd.

Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers.

PubMed

Chien, S C; Wong, F A; Fowler, C L; Callery-D'Amico, S V; Williams, R R; Nayak, R; Chow, A T

1998-04-01

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0-24) following a single 750-mg dose were 7.1 microg/ml and 71.3 microg x h/ml, respectively, compared to 8.6 microg/ml and 90.7 microg x h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0-24 values were 8.9 microg/ml and 95.4 microg x h/ml, respectively; corresponding values at steady state were 11.8 microg/ml and 118 microg x h/ml. These Cmax and AUC0-24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CL[R]) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CL(R) following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.

Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers

PubMed Central

Chien, Shu-Chean; Wong, Frank A.; Fowler, Cynthia L.; Callery-D’Amico, Susan V.; Williams, R. Rex; Nayak, Ramchandra; Chow, Andrew T.

1998-01-01

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These Cmax and AUC0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CLR) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CLR following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache. PMID:9559801

Impact of Fellowship Training Level on Colonoscopy Quality and Efficiency Metrics.

PubMed

Bitar, Hussein; Zia, Hassaan; Bashir, Muhammad; Parava, Pratyusha; Hanafi, Muhammad; Tierney, William; Madhoun, Mohammad

2018-04-18

Previous studies have described variable effects of fellow involvement on the adenoma detection rate (ADR), but few have stratified this effect by level of training. We aimed to evaluate the "fellow effect" on multiple procedural metrics including a newly defined adenoma management efficiency index, which may have a role in documenting colonoscopy proficiency for trainees. We also describe the impact of level of training on moderate sedation use. We performed a retrospective review of 2024 patients (mean age 60.9 ± 10. 94% males) who underwent outpatient colonoscopy between June 2012 and December 2014 at our Veterans Affairs Medical Center. Colonoscopies were divided into 5 groups. The first 2 groups were first year fellows in the first 6 months and last 6 months of the training year. Second and third year fellows and attending only procedures accounted for one group each. We collected data on doses of sedatives used, frequency of adjunctive agent use, procedural times as well as location, size and histology of polyps. We defined the adenoma management efficiency index as average time required per adenoma resected during withdrawal. 1675 colonoscopies involved a fellow. 349 were performed by the attending alone. There was no difference in ADR between fellows according to level of training (P=0.8), or between fellows compared with attending-only procedures (P=0.67). Procedural times decreased consistently during training, and declined further for attending only procedures. This translated into improvement in the adenoma management efficiency index (fellow groups by ascending level of training 23.5 minutes vs 18.3 minutes vs 13.7 minutes vs 13.4 minutes vs attending group 11.7 minutes; P<0.001). There was no difference in the average doses of midazolam and fentanyl used among fellow groups (P=0.16 and P=0.1, respectively). Compared with attending-only procedures, fellow involvement was associated with higher doses of fentanyl and midazolam and more frequent use of diphenhydramine and glucagon (P<0.0001; P=0.0002; P<0.0001; and P=0.01, respectively). ADR was similar at different stages of fellowship training and comparable with the attending group. Efficiency of detecting and resecting polyps improved throughout training without reaching attending level. Fellow involvement led to greater use of moderate sedation, which may relate to a longer procedure duration and an evolving experience in endoscopic technique. Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Radiotherapy in the treatment of multiple myeloma.

PubMed

Bosch, A; Frias, Z

1988-12-01

Fifty-nine patients with multiple myeloma referred for treatment of painful bony lesions received irradiation to 95 local areas, and 16 of the 59 were irradiated using hemibody techniques. Pain relief was obtained in practically all of the irradiated regions. Most local areas were treated to doses of 3000 cGy in 10 to 15 fractions. Patients with generalized pain due to multiple site involvement were treated with single dose hemibody irradiation, to doses of 600 cGy to the upper hemibody, and of 800 cGy to the lower hemibody. This treatment was well tolerated and side effects minimal. Median survival from diagnosis was 30 months and the survival at 1, 3, and 5 years was 80%, 42%, and 12% respectively. Key articles on radiation therapy of multiple myeloma are reviewed and discussed. Since all patients eventually relapse after chemotherapy, the role of radiotherapy using present techniques should be fully evaluated and considered as an alternative in the primary treatment of multiple myeloma.

Impact of Efavirenz on Intestinal Metabolism and Transport: Insights From an Interaction Study With Ezetimibe in Healthy Volunteers

PubMed Central

Oswald, S; zu Schwabedissen, HE Meyer; Nassif, A; Modess, C; Desta, Z; Ogburn, ET; Mostertz, J; Keiser, M; Jia, J; Hubeny, A; Ulrich, A; Runge, D; Marinova, M; Lütjohann, D; Kroemer, HK; Siegmund, W

2013-01-01

Hypercholesterolemia frequently occurs in patients treated with efavirenz who cannot be treated adequately with statins because of drug interactions. These patients may benefit from cholesterol-lowering therapy with ezetimibe. This study determined the influence of single-dose and multiple-dose efavirenz (400 mg/day for 9 days) on the pharmacokinetics and sterol-lowering of ezetimibe (10 mg) in 12 healthy subjects. In addition, the influence of efavirenz on genome-wide intestinal expression and in vitro function of ABCB1, ABCC2, UGT1A1, and OATP1B1 was studied. Efavirenz (multiple dose) had no influence on the pharmacokinetics and lipid-lowering functions of ezetimibe. Intestinal expression of enzymes and transporters (e.g., ABCB1, ABCC2, and UGT1A1) was not affected by chronic efavirenz. Efavirenz (single dose) slightly increased ezetimibe absorption and markedly decreased exposure to ezetimibe-glucuronide (single dose and multiple dose), which may be explained by inhibition of UGT1A1 and ABCB1 (in vitro data). Ezetimibe had no effect on the disposition of efavirenz. Consequently, ezetimibe may be a safe and efficient therapeutic option in patients with HIV infection. PMID:22297387

Placebo-controlled pilot trial of mecamylamine for treatment of autism spectrum disorders.

PubMed

Arnold, L Eugene; Aman, Michael G; Hollway, Jill; Hurt, Elizabeth; Bates, Bethany; Li, Xiaobai; Farmer, Cristan; Anand, Rene; Thompson, Susan; Ramadan, Yaser; Williams, Craig

2012-06-01

To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient α4β2 nAChRs, excess α7 nAChRs) in brains of patients with autism. Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n=8) or mecamylamine (n=12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive. Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ≥0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense. Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific α4β2 nAChR agonist, such as varenicline.

Evaluation of volumetric modulated arc therapy for cranial radiosurgery using multiple noncoplanar arcs

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

Audet, Chantal; Poffenbarger, Brett A.; Chang, Pauling

2011-11-15

Purpose: To evaluate a commercial volumetric modulated arc therapy (VMAT), using multiple noncoplanar arcs, for linac-based cranial radiosurgery, as well as evaluate the combined accuracy of the VMAT dose calculations and delivery. Methods: Twelve patients with cranial lesions of variable size (0.1-29 cc) and two multiple metastases patients were planned (Eclipse RapidArc AAA algorithm, v8.6.15) using VMAT (1-6 noncoplanar arcs), dynamic conformal arc (DCA, {approx}4 arcs), and IMRT (nine static fields). All plans were evaluated according to a conformity index (CI), healthy brain tissue doses and volumes, and the dose to organs at risk. A 2D dose distribution was measuredmore » (Varian Novalis Tx, HD120 MLC, 1000 MU/min, 6 MV beam) for the {approx}4 arc VMAT treatment plans using calibrated film dosimetry. Results: The CI (0-1 best) average for all plans was best for {approx}4 noncoplanar arc VMAT at 0.86 compared with {approx}0.78 for IMRT and a single arc VMAT and 0.68 for DCA. The volumes of healthy brain receiving 50% of the prescribed target coverage dose or more (V{sub 50%}) were lowest for the four arc VMAT [RA(4)] and DCA plans. The average ratio of the V{sub 50%} for the other plans to the RA(4) V{sub 50%} were 1.9 for a single noncoplanar arc VMAT [RA(1nc)], 1.4 for single full coplanar arc VMAT [RA(1f)] and 1.3 for IMRT. The V{sub 50%} improved significantly for single isocenter multiple metastases plan when two noncoplanar VMAT arcs were added to a full single coplanar one. The maximum dose to 5 cc of the outer 1 cm rim of healthy brain which one may want to keep below nonconsequential doses of 300-400 cGy, was 2-3 times greater for IMRT, RA(1nc) and RA(1f) plans compared with the multiple noncoplanar arc DCA and RA(4) techniques. Organs at risk near (0-4 mm) to targets were best spared by (i) single noncoplanar arcs when the targets are lateral to the organ at risk and (ii) by skewed nonvertical planes of IMRT fields when the targets are not lateral to the organ at risk. The highest dose gradient observed between an organ at risk and a target at the edge of a VMAT arc plane or plane of IMRT fields was 17%/mm. The average absolute percent difference between the measured and calculated central axis dose for all the VMAT plans was 3.6 {+-} 2.2%. The measured perpendicular profile widths and shifts were on average within 0.5 mm of planned values. The average total MUs for VMAT plans was double the DCA average and similar to the IMRT average. Conclusions: For the aforementioned planning and delivery system and cranial lesions greater than 7 mm in diameter, multiple noncoplanar arc VMAT consistently provides accurate and high quality cranial radiosurgery dose distributions with low doses to healthy brain tissue and high dose conformity to the target. These qualities may make multiple noncoplanar arc VMAT suitable for a greater range of prescription doses or larger and more irregular lesions. For smaller and/or rounder lesions there are other clinically acceptable treatment techniques that may involve fewer couch angles or arcs and reduce treatment times.« less

Estimating the lifetime risk of cancer associated with multiple CT scans.

PubMed

Ivanov, V K; Kashcheev, V V; Chekin, S Yu; Menyaylo, A N; Pryakhin, E A; Tsyb, A F; Mettler, F A

2014-12-01

Multiple CT scans are often done on the same patient resulting in an increased risk of cancer. Prior publications have estimated risks on a population basis and often using an effective dose. Simply adding up the risks from single scans does not correctly account for the survival function. A methodology for estimating personal radiation risks attributed to multiple CT imaging using organ doses is presented in this article. The estimated magnitude of the attributable risk fraction for the possible development of radiation-induced cancer indicates the necessity for strong clinical justification when ordering multiple CT scans.

Influence of caffeine and/or coffee consumption on the initiation and promotion phases of 7,12-dimethylbenz(a)anthracene-induced rat mammary gland tumorigenesis.

PubMed

Welsch, C W; DeHoog, J V; O'Connor, D H

1988-04-15

The effect of caffeine and/or coffee consumption (via the drinking water) during the initiation phase and promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a commercial laboratory animal chow was examined. In the initiation studies, DMBA was administered once at 53-55 days of age; caffeine (100-860 mg/liter of drinking water) and/or coffee (moderate or high dose, sole source of drinking water) treatments were for 32 consecutive days, commencing 29 days prior to DMBA treatment and terminating 3 days after DMBA treatment. In the promotion studies, DMBA was administered once at 54-55 days of age; caffeine and/or coffee treatments were daily from 57-58 days of age to termination of experiments (12-21 weeks after carcinogen treatment). In the initiation studies, either moderate (100-400 mg) or high (860 mg) dose levels of caffeine or moderate to high dose levels of caffeinated coffee significantly (P less than 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat). Consumption of high or moderate dose levels of decaffeinated coffee did not significantly alter mammary carcinoma multiplicity. The addition of caffeine to the moderate dose level of decaffeinated coffee resulted in a significant (P less than 0.05) reduction in mammary carcinoma multiplicity. In the promotion studies, prolonged consumption of moderated dose levels of caffeine or moderate or high dose levels of caffeinated coffee or decaffeinated coffee did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, however, a significant (p less than 0.05) stimulatory effect of caffeine on mammary carcinoma multiplicity was observed; an effect that was temperate and transitory. In both the initiation and promotion studies caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency period of mammary tumor appearance. These results provide evidence that caffeine and/or caffeinated coffee consumption can significantly influence mammary carcinoma multiplicity in female rats treated with DMBA, an effect that is dependent upon the dose level, duration, and time-span of caffeine administration.

Antiphase boundaries on low-energy-ion bombarded Ge(001)

NASA Astrophysics Data System (ADS)

Zandvliet, H. J. W.; de Groot, E.

1997-01-01

Surface vacancy and adatom clusters have been created on Ge(001) by bombarding the surface with 800 eV argon ions at various substrate temperatures ranging from room temperature to 600 K. The vacancies preferentially annihilate at the ends rather than at the sides of the dimer rows, resulting in monolayer deep vacancy islands which are elongated in a direction of the dimer rows of the upper terrace. As vacancy islands nucleate and expand, the dimer rows in neighbouring vacancy islands need not, in general, align with each other. An antiphase boundary will develop if two growing vacancy islands meet, but their internal dimer rows are not in the same registry. In contrast to Si(001), where only one type of antiphase boundary is found, we have found three different types of antiphase boundaries on Ge(001). Higher dose (> several monolayers) room temperature ion bombardment followed by annealing at temperatures in the range 400-500 K results in a surface which contains a high density of valleys. In addition to the preference for the annihilation of dimer vacancies at descending versus ascending steps we also suggest that the development of antiphase boundaries drives the roughening of this surface. Finally, several atomic rearrangement events, which might be induced by the tunneling process, are observed after low-dose ion bombardment at room temperature.

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

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

Muth, H.; Legerlotz, C.

1962-10-01

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

Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial.

PubMed

Campbell, Craig; McMillan, Hugh J; Mah, Jean K; Tarnopolsky, Mark; Selby, Kathryn; McClure, Ty; Wilson, Dawn M; Sherman, Matthew L; Escolar, Diana; Attie, Kenneth M

2017-04-01

ACE-031 is a fusion protein of activin receptor type IIB and IgG1-Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo-controlled, ascending-dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. ACE-031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6-minute walk test (6MWT) distance in the ACE-031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass. ACE-031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non-muscle-related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55: 458-464, 2017. © 2016 Wiley Periodicals, Inc.

Pharmacodynamic Effects of Single and Multiple Doses of Empagliflozin in Patients With Type 2 Diabetes.

PubMed

Heise, Tim; Jordan, Jens; Wanner, Christoph; Heer, Martina; Macha, Sreeraj; Mattheus, Michaela; Lund, Søren S; Woerle, Hans J; Broedl, Uli C

2016-10-01

Our aim was to investigate the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on urinary and serum glucose and electrolytes, urinary volume, osmolality, and the renin-angiotensin system in patients with type 2 diabetes. In an open-label study, 22 patients receiving metformin (median age 56 years; range 40-65 years) received empagliflozin 25 mg once daily for 5 days. Food, fluid, and sodium intake were standardized for 3 days before and during treatment. Twenty patients completed treatment. After single and multiple doses of empagliflozin, mean (SE) changes from baseline in 24-hour urinary glucose excretion were 463.3 (57.3) mmol/d and 599.5 (60.0) mmol/d, respectively (83.5 [10.3] g/d and 108.0 [10.8] g/d, respectively) (both P < 0.001), and in fasting serum glucose concentration were -1.8 (0.4) mmol/L and -1.1 (0.3) mmol/L, respectively (both P < 0.001). After a single dose, mean (SE) change from baseline in urine sodium excretion was 45.3 (9.6) mmol/d (P < 0.001), and in urine volume was 341.0 (140.5) g/d (P = 0.025), but there were no changes compared with baseline in either parameter after multiple doses. There were no changes in plasma renin or serum aldosterone with single or multiple doses of empagliflozin. There was a nonsignificant reduction in weight after a single dose of empagliflozin and a mean (SE) change of -1.4 (0.5) kg after multiple doses (P = 0.020). Empagliflozin 25 mg increased urinary glucose excretion and decreased serum glucose and weight with transient natriuresis and increases in urine volume, without significant changes in the renin-angiotensin system. Clinicaltrials.gov Identifier: NCT01276288. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole sodium injections after single and multiple intravenous doses in healthy Chinese subjects.

PubMed

Jiao, Hui-Wen; Sun, Lu-Ning; Li, Yue-Qi; Yu, Lei; Zhang, Hong-Wen; Wang, Mei-Feng; Yu, Li-Yuan; Yuan, Zi-Qing-Yun; Xie, Li-Jun; Chen, Juan; Meng, Ling; Zhang, Xue-Hui; Wang, Yong-Qing

2018-03-01

The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole (PPZ) sodium injections following single and multiple intravenous doses in healthy Chinese subjects. The dosage groups were set as followed: 20 mg of single and multiple intravenous administration of S-(-)-PPZ, 40 mg of single and multiple intravenous administration of S-(-)-PPZ or pantoprazole, and 80 mg of single dosage group of S-(-)-PPZ. Subjects were sampled for pharmacokinetic analysis and were monitored for 24-h intragastric pH prior to and 48-h intragastric pH after administration for the pharmacodynamic study. The pharmacokinetic and pharmacodynamic parameters were compared between S-(-)-PPZ and PPZ. Safety was evaluated on the basis of adverse events, vital signs, laboratory tests, and physical examination. All adverse events were mild and of limited duration. Maximum plasma concentration and area under the concentration-time curve for S-(-)-PPZ were dose proportional over the range of 20-80 mg following a single intravenous administration. Elimination rate constant and half-life observed statistical difference from a single dose to multiple doses in 40 mg of S-(-)-PPZ groups. After administration of a single dose, the mean 24-h intragastric pH value was observed higher in 80-mg group than in 40- and 20-mg groups. Slightly increase of intragastric pH was found after a single dose of 40 mg S-(-)-PPZ than 40 mg PPZ; however, the differences were not statistically significant. Twice daily of 40 mg S-(-)-PPZ sodium injections is effective in achieving satisfying acid inhibition. Compared with plasma R-(+)-PPZ levels, most subjects presented more potent and prolonged suppression of gastric acid of S-(-)-PPZ, while a few subjects showed faster metabolic rate of S-(-)-PPZ in vivo.

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study

PubMed Central

2014-01-01

Background The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Methods Adults (n = 198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n = 101) or matching placebo lozenges (n = 97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Results Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P <0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P <0.01). There were no serious adverse events. Conclusions Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. Trial registration This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010. PMID:24988909

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease

PubMed Central

Jia, Jing-ying; Zhao, Qian-hua; Liu, Yun; Gui, Yu-zhou; Liu, Gang-yi; Zhu, Da-yuan; Yu, Chen; Hong, Zhen

2013-01-01

Aim: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. Methods: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0–72 h and AUC0–∞ were calculated. Tolerance assessments were conducted throughout the study. Results: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76–0.82 h; the AUC0–72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. Conclusion: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers. PMID:23624756