47 research outputs found
Response to 'The drugs we deserve'
No full textDNM Papatsonis, VJ. Flenady, GA. Dekker, B. Carbonne, JF Kin
Risk of developmental dysplasia of the hip in breech presentation: the effect of successful external cephalic version
No full textArticle first published online: 12 NOV 2012Objective: To evaluate the effect of successful external cephalic version on the incidence of developmental dysplasia of the hip (DDH) requiring treatment in singleton breech presentation at term. Design: Observational cohort study. Setting: Three large teaching hospitals in the Netherlands. Population: Women with a singleton breech presentation of 34 weeks of gestation or more, who underwent an external cephalic version attempt. Methods: We made a comparison of the incidence of DDH between children born in breech presentation and children born in cephalic presentation after a successful external cephalic version. Main outcome measure: The incidence of DDH requiring either conservative treatment, with a harness, or surgical treatment. Results: A total of 498 newborns were included in the study, of which 40 (8%) were diagnosed with DDH and 35 required treatment. Multivariate analysis showed that female gender (OR 2.79, 95% CI 1.23–6.35) and successful external cephalic version (OR 0.29, 95% CI 0.09–0.95) were independently associated with DDH. Conclusions: A successful external cephalic version is associated with a lower incidence of DDH, although a high percentage of children born after a successful external cephalic version still appear to have DDH. A larger cohort study is needed to establish the definite nature of this relationship. Until then, we recommend the same screening policy for infants born in cephalic position after a successful external cephalic version as for infants born in breech position.AF Lambeek, M De Hundt, F Vlemmix, BMC Akerboom, JMJ Bais, DNM Papatsonis, BWJ Mol, M Ko
Calcium channel blockers for inhibiting preterm labour
No full textThe definitive version may be found at www.wiley.comBackgroundPreterm birth is a major contributor to perinatal mortality and morbidity and affects approximately six to seven per cent of births in developed countries. Tocolytics are drugs used to suppress uterine contractions. The most widely tested tocolytics are betamimetics. Although they have been shown to delay delivery, betamimetics have not been shown to improve perinatal outcome, and they have a high frequency of unpleasant and even fatal maternal side effects. There is growing interest in calcium channel blockers as a potentially effective and well tolerated form of tocolysis.ObjectivesTo assess the effects on maternal, fetal and neonatal outcomes of calcium channel blockers, administered as a tocolytic agent, to women in preterm labour.Search strategyWe searched the Cochrane Pregnancy and Childbirth Group's specialised register of controlled trials, the Cochrane Controlled Trials Register (February 2002), MEDLINE, EMBASE, and Current Contents. We also contacted recognised experts and cross referenced relevant material.Selection criteriaAll published and unpublished randomised trials in which calcium channel blockers were used for tocolysis for women in labour between 20 and 36 weeks gestation.Data collection and analysisStandard methods of the Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group were used. Evaluation of methodological quality and trial data extraction were undertaken independently by three authors. Additional information was sought to enable assessment of methodology and conduct of intention-to-treat analyses. Meta-analysis was conducted assessing the effects of calcium channel blockers compared with any other tocolytic agent. Results are presented using relative risk for categorical data and weighted mean difference for continuous data.Main resultsEleven randomised controlled trials involving 870 women were included. When compared with any other tocolytic agent (mainly betamimetics), calcium channel blockers reduced the number of women giving birth within 48 hours (relative risk (RR) 0.73; 95% confidence interval (CI) 0.54, 0.98) and within seven days (RR 0.76; 95% CI 0.59, 0.99). Calcium channel blockers also reduced the requirement for women to have treatment ceased for adverse drug reaction (RR 0.15; 95% CI 0.06, 0.43), the frequency of neonatal respiratory distress syndrome (RR 0.64; 95% CI 0.45, 0.91) and neonatal jaundice (RR 0.73; 95% CI 0.57, 0.93).Reviewer's conclusionsWhen tocolysis is indicated for women in preterm labour, calcium channel blockers are preferable to betamimetic agents. Further research should address the effects of different dosage regimens and formulations of nifedipine on maternal and neonatal outcomes.King JF, Flenady VJ, Papatsonis DNM, Dekker GA, Carbonne
False positive FISH diagnosis of monosomy X in uncultured amniotic fluid cells due to a chromosome Y deletion
No full textThe effect of liposomal size on the targeted delivery of doxorubicin to Integrin alpha v beta 3-expressing tumor endothelial cells
No full textSize of the liposomes (LPs) specially governs its biodistribution. In this study, LPs were developed with controlled sizes, where variation in LP size dictates the ligand receptor interaction, cellular internalization and its distribution within the tumor microenvironment. The therapeutic efficacies of doxorubicin (DOX)-loaded RGD modified small size (similar to 100 nm in diameter, dnm) and large size (similar to 300 dnm) PEGylated LPs (RGD-PEG-LPs) were compared to that of Doxil (a clinically used DOX-loaded PEG-LP, similar to 100 dnm) in DOX resistant OSRC-2 (Renal cell carcinoma, RCC) tumor xenografts. Doxil, which accumulated in tumor tissue via the enhanced permeability and retention (EPR) effect, failed to suppress tumor growth. Small size RGD-PEG-LP, that targets the tumor endothelial cells (TECs) and extravasates to tumor cells, failed to provide anti-tumor effect. Large size RGD-PEG-LP preferentially targets the TECs via minimization of the EPR effect, and significantly reduced the tumor growth, which was exerted through its strong anti-angiogenic activity on the tumor vasculature rather than having a direct effect on DOX resistant RCC. The prepared large size RGD-PEG-LP that targets the TECs via interacting with Integrin alpha v beta 3, is a potentially effective and alternate therapeutic strategy for the treatment of DOX resistant tumor cells by utilizing DOX, in cases where Doxil is ineffective. (C) 2013 Elsevier Ltd. All rights reserved
Sauropod intervertebral separations.
No full text<p>Examples of articulated sauropod cervical columns with condyles deeply inserted into their associated cotyles, leaving intervertebral gaps of only a few centimeters (see arrows). Camarasaurus lentus (DNM 28, A and D) and Barosaurus (CM 11984, B, C, and E). Photographs by the author and J. Michael Parrish.</p
Survey report 1985/86 summer season Division of National Mapping Author - B.Murphy / DNM
No full textProgress Code: completedStatement: See the report for full details.Surveying and Mapping Program<br/>Bunger Hills 1985/1986 Summer Season<br/><br/>Report by B. Murphy, Division of National Mapping, Canberra<br/><br/>AIM<br/>The aim of the surveying and mapping program undertaken by the Division of National Mapping in the Bunger Hills during the 1986 summer field season was three-fold, namely:<br/><br/>1) Aerial Photography<br/>2) Landsat Imagery rectification<br/>3) Glaciology<br/><br/>Flight lines and photo centres representing the aerial photography flown are included in the aerial photography data available for download from the related metadata (see provided URL) and have Dataset_id = 287. The flight lines and photo centres are provided as shapefiles and Dataset_id is an attribute of the shapefiles
Deoxynyboquinones as NQO1-targeted anticancer compounds and deoxynybomycins as potent and selective antibiotics
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Previous issue date: 2015-09-23Embargo set by: Seth Robbins for item 91378
Lift date: 2018-03-02T20:57:40Z
Reason: Author requested closed access (OA after 2yrs) in Vireo ETD systemEmbargo set by: Seth Robbins for item 91378
Lift date: 2018-03-02T21:07:27Z
Reason: Author requested closed access (OA after 2yrs) in Vireo ETD systemLimited Restriction Lifted for Item 91378 on 2018-03-03T10:15:31Z.Cancer and antibiotic-resistant bacterial infections are currently two of the major health concerns facing the United States. Novel therapeutics capable of specifically targeting either cancer or resistant bacteria are greatly needed. Described herein are three separate efforts to address these needs.
Described in Chapter 2 is the development of a targeted anticancer agent deoxynyboquinone (DNQ) which is specifically activated by the enzyme NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 is a 2-electron reductase that is known to be overexpressed in many solid tumors. Development of an anticancer quinone that is bioactivated by NQO1 has long been a goal of cancer therapy. Previously, several putative NQO1 substrates have been developed including mitomycin C, RH1, streptonigrin, and β-Lapachone (β-Lap). Recently the Hergenrother laboratory discovered the small molecule DNQ which has potent anticancer activity. Due to its quinone moiety and the fact that it causes reactive oxygen species (ROS) dependent cell death, we hypothesized that its activity was due to activation by NQO1.
Described herein is a set of assays that was developed to determine the NQO1-dependence of anticancer compounds. Of the putative NQO1 substrates, only β-Lap and DNQ were found to be selectively activated by NQO1. Due to its excellent potency and pharmacokinetic profile, DNQ was explored further. Mechanistic evaluation of DNQ revealed that after reduction by NQO1, DNQ undergoes reduction-oxidation cycling which concurrently results in the formation of ROS. ROS causes extensive DNA damage that then activates poly(ADP-ribose) polymerase-1 dependent cell death. DNQ was found to be efficacious a murine model of lung cancer. Utilizing a modified version of the DNQ synthesis previously developed by the Hergenrother laboratory, derivatives were synthesized and evaluated. Several were found that have potent activity against a panel of breast and lung cancers along with improved solubility and toxicity profiles compared to DNQ. These derivatives are currently under investigation for in vivo activity.
Described in Chapter 3 is the development of deoxynybomycin (DNM) as an antibiotic with potent activity against fluoroquinolone-resistant (FQR) bacteria. DNM is a natural product that has been shown previously to have antibiotic activity. Recently DNM was found to have potent activity against FQR Methicillin-resistant S. aureus (MRSA). This activity is due to the ability of DNM to inhibit the mutant DNA gyrase (specifically S84L gyrA) responsible for FQR. At the start of the studies described here, two main challenges to the further development of DNM existed: 1) Difficulty in attaining significant quantities of pure DNM for biological evaluation and 2) The poor solubility of DNM. The first issue was addressed by the development of a synthesis of DNM. A single reaction from a late stage intermediate of the DNQ synthesis allowed for the generation of DNM. The modular nature of the synthesis also allowed for the synthesis of a variety of derivatives some of which showed similar potency against FQR MRSA and greatly improved solubility.
DNM and its derivative DNM-2 were tested against a variety of bacterial species to determine the activity profile for this class of compounds. The best activity was observed for FQR MRSA with S84L mutant of DNA gyrase and FQR VRE with S84I mutation. Less potent activity was observed for bacteria that commonly have other mutations such as S84F or S84Y. In vitro inhibition assays suggest that DNM is less potent against DNA gyrase with these mutations, but further studies need to be performed to confirm this. Additionally, DNM is inactive against Gram-negative bacteria likely due to its inability to traverse the outer membrane. Further studies to identify compounds active against Gram-negative bacteria are ongoing. Resistance to DNM was found to occur via regeneration of the WT DNA gyrase, thus re-sensitizing bacteria to FQs. This resistance cycling suggests that bacteria which develop resistance to DNM would be treatable.
After determining that DNM and DNM-2 have good potency against FQR MRSA, studies evaluating their in vivo activity were performed. Initial pharmacokinetic analysis revealed that oral administration of DNM is not a useful administration route likely due to its poor solubility. However, DNM-2 has excellent oral absorption with area under the curve values which predict good in vivo efficacy. DNM-2 was used in further studies. Toxicity studies revealed no significant effects of DNM-2 on mice when treated at 50 mg/kg for ten consecutive days. Excitingly, DNM-2 was the first compound in the deoxynybomycin class to show in vivo activity, saving mice with FQR MRSA sepsis.
Described in Chapter 4 is the analysis of the anticancer compound ersindole, an actiniophyllic acid analogue synthesized by the Martin laboratory. The anticancer activity of ersindole was discovered by the Hergenrother laboratory via a high throughput screen for compounds which induce breast cancer cell death. One of the most striking features of ersindole-induced cancer cell death is the shape of the dose response curve. Specifically, it has a very steep Hill slope and high Emax. These attributes reflect consistent and efficient induction of cancer cell death and suggest that ersindole is a very promising anticancer drug. Analysis of multiple cell lines and timepoints reveal that the steep Hill slope and high Emax of the ersindole dose response curve are general attributes of the compound. Previous mechanistic studies with ersindole suggested that it induced cancer cell death via induction of endoplasmic reticulum stress. This was further confirmed here via Western blot analysis and siRNA knockdown studies. Future efforts should focus on determining the molecular target of ersindole.
Unfortunately, ersindole was found to induce hemolysis of red blood cells. A set of derivatives was investigated in an effort to find compounds that do not lyse red blood cells. Ersindole-9 was found to be nearly as potent as ersindole against a panel of cancer cell lines and to have a similarly shaped dose-response curve. Gratifyingly, ersindole-9 does not induce significant hemolysis. For this reason, ersindole-9 was studied in a murine model of breast cancer where it was found to have good efficacy. Evaluation of a second set of derivatives was then performed in order to find additional derivatives that are potent and do not induce hemolysis. Several leads were discovered. Further analysis of these compounds is needed to determine the best compound for future evaluation.Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2017-12-01The student, Elizabeth Parkinson, accepted the attached license on 2015-09-20 at 20:17.The student, Elizabeth Parkinson, submitted this Dissertation for approval on 2015-09-20 at 20:30.This Dissertation was approved for publication on 2015-09-23 at 10:50.DSpace SAF Submission Ingestion Package generated from Vireo submission #8694 on 2016-03-02 at 14:12:1
Oxytocin Antagonists for the Management of Preterm Birth: A Review
No full textPreterm birth, the leading cause of neonatal morbidity and mortality, is estimated at incidence of 12.7percent of all births, which has not decreased over the last four decades despite intensive antenatal care programs aimed at high-risk groups, the widespread use of tocolytics, and a series of other preventive and therapeutic interventions. Oxytocin antagonists, namely atosiban, represent an appealing choice that seems to be effective with apparently fewer side effects than the traditional tocolytics. This article reviews the available literature on the pharmacokinetics, mode of administration, and clinical utility of oxytocin antagonists for acute and maintenance tocolysis with special emphasis on its safety profile. © 2011 by Thieme Medical Publishers, Inc.Afschar P, 2004, BJOG-INT J OBSTET GY, V111, P316, DOI 10.1111-j.1471-0528.2004.00095.x; Akerlund M, 1999, BRIT J OBSTET GYNAEC, V106, P1047, DOI 10.1111-j.1471-0528.1999.tb08112.x; AKERLUND M, 1985, ACTA OBSTET GYN SCAN, V64, P499; Al-Omari WR, 2006, EUR J OBSTET GYN R B, V128, P129, DOI 10.1016-j.ejogrb.2005.12.010; Coomarasamy A, 2003, BJOG-INT J OBSTET GY, V110, P1045, DOI 10.1111-j.1471-0528.2003.03071.x; COPPER RL, 1993, AM J OBSTET GYNECOL, V168, P78; de Heus R, 2008, EUR J OBSTET GYN R B, V139, P139, DOI 10.1016-j.ejogrb.2008.01.001; eMC, TRACT 7 5 MG ML CONC; eMC, TRACT 7 5 MG ML SOL; Engstrom T, 1999, BIOL REPROD, V60, P322, DOI 10.1095-biolreprod60.2.322; Food and Drug Administration, 1998, 20797 NDA FOOD DRUG; Food and Drug Administration, 1998, 20797 NDA FOOD DRUG; Cabrol D, 2001, EUR J OBSTET GYN R B, V98, P177; FUCHS AR, 1984, AM J OBSTET GYNECOL, V150, P734; FUCHS AR, 1982, SCIENCE, V215, P1396, DOI 10.1126-science.6278592; GOODWIN TM, 1994, AM J OBSTET GYNECOL, V170, P474; Goodwin TM, 1996, AM J PERINAT, V13, P143, DOI 10.1055-s-2007-994312; GOODWIN TM, 1995, AM J OBSTET GYNECOL, V173, P913; Goodwin TM, 1996, OBSTET GYNECOL, V88, P331, DOI 10.1016-0029-7844(96)00200-1; Hamilton B. E., 2009, NATL VITAL STAT REP, V57, P1; Helmer H, 2003, BJOG-INT J OBSTET GY, V110, P113, DOI 10.1016-S1470-0328(03)00056-9; Husslein P, 2006, BJOG-INT J OBSTET GY, V113, P105, DOI 10.1111-j.1471-0528.2006.01134.x; Husslein P, 2003, INT J CLIN PRACT, V57, P121; Kashanian M, 2005, INT J GYNECOL OBSTET, V91, P10, DOI 10.1016-j.ijgo.2005.06.005; Kim A, 2006, BJOG-INT J OBSTET GY, V113, P113, DOI 10.1111-j.1471-0528.2006.01135.x; LUNDIN S, 1993, CLIN ENDOCRINOL, V39, P369, DOI 10.1111-j.1365-2265.1993.tb02379.x; Lurie S, 2004, J PERINAT MED, V32, P137; MORRISON JC, 1990, OBSTET GYNECOL, V76, pS5; Moutquin JM, 2000, AM J OBSTET GYNECOL, V182, P1191, DOI 10.1067-mob.2000.104950; Norwitz ER, 2004, AM J OBSTET GYNECOL, V191, P1491, DOI 10.1016-j.ajog.2004.06.043; Papatsonis D, 2009, COCHRANE DB SYST REV, DOI 10.1002-14651858.CD005938.pub2; Papatsonis D, 2005, COCHRANE DB SYST REV, DOI DOI 10.1002-14651858.CD004452.PUB2; Papatsonis DNM, 1997, OBSTET GYNECOL, V90, P230, DOI 10.1016-S0029-7844(97)00182-8; Papatsonis DNM, 2000, OBSTET GYNECOL, V95, P477, DOI 10.1016-S0029-7844(99)00596-7; Perry K, 1998, 46 ACOG ANN M MAY 9; Pierzynski P, 2004, J SOC GYNECOL INVEST, V11, P384, DOI 10.1016-j.jsgi.2004.02.008; Rasmussen BB, 2005, BJOG-INT J OBSTET GY, V112, P1492, DOI 10.1111-j.1471-0528.2005.00735.x; Reinheimer Torsten M, 2007, BMC Pregnancy Childbirth, V7 Suppl 1, pS15, DOI 10.1186-1471-2393-7-S1-S15; Reinheimer TM, 2005, J CLIN ENDOCR METAB, V90, P2275, DOI 10.1210-jc.2004-2120; Richter Oliver N., 2005, Archives of Gynecology and Obstetrics, V272, P26, DOI 10.1007-s00404-004-0652-8; ROMERO R, 1989, AM J OBSTET GYNECOL, V161, P817; Romero R, 2000, AM J OBSTET GYNECOL, V182, P1173, DOI 10.1067-mob.2000.95834; Steinwall M, 2004, ACTA OBSTET GYN SCAN, V83, P12, DOI 10.1111-j.1600-0412.2004.00320.x; Steinwall M, 2005, GYNECOL ENDOCRINOL, V20, P104, DOI 10.1080-09513590400021144; The European Atosiban Study Group, 2001, ACTA OBSTET GYNECOL, V80, P413; The worldwide Atosiban versus andbeta;-agonists Study Group, 2001, BJOG, V108, P133; Thornton JG, 2005, BJOG-INT J OBSTET GY, V112, P118, DOI 10.1111-j.1471-0528.2005.00599.x; Thornton JG, 2006, BJOG-INT J OBSTET GY, V113, P93, DOI 10.1111-j.1471-0528.2003.01131.x; Thornton S, OXYTOCIN RECEPTOR AN; Thornton S, 2009, AM J OBSTET GYNECOL, V200, P627; Thornton S, 2009, AM J OBSTET GYNECOL, V200, DOI 10.1016-j.ajog.2009.01.015; Treschan TA, 2006, ANESTHESIOLOGY, V105, P639; Treschan TA, 2006, ANESTHESIOLOGY, V105, P599, DOI 10.1097-00000542-200609000-00026; Tsatsaris V, 2004, DRUGS, V64, P375, DOI 10.2165-00003495-200464040-00003; UKMi, NEW MED MARK; VALENZUELA GJ, 1995, AM J OBSTET GYNECOL, V172, P1304, DOI 10.1016-0002-9378(95)91497-8; Valenzuela GJ, 2000, AM J OBSTET GYNECOL, V182, P1184, DOI 10.1067-mob.2000.105816; Wilson RJ, 2001, BRIT J OBSTET GYNAEC, V108, P960, DOI 10.1111-j.1471-0528.2001.00226.x43
