D Holden

St. George's School, Middletown, Rhode Island, United States

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Publications (11)49.45 Total impact

  • Source
    P Schwärzler · J M Bland · D Holden · S Campbell · Y Ville ·
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    ABSTRACT: Female fetuses, on average, weigh less than male fetuses at all gestational ages. The purpose of this study was to compare female and male fetuses in terms of intrauterine ultrasound growth measurements and to develop gestational-age-related charts based on a computerized perinatal database. This was a retrospective study of unselected women in the second and third trimesters of pregnancy, who had a normal scan at 10-14 weeks. Data analysis was performed using measurements obtained from a mixed-race population of 4234 women, who underwent 5198 ultrasound examinations. The scans were performed by four trained sonographers, according to a standardized protocol. Routine measurements included biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL). The main end-points were sex- and race-specific differences in fetal biometry, which were also used to estimate fetal weight. The base-line demographic characteristics and risk factors were comparable in female and male fetuses. Significant differences in fetal BPD, HC, AC and estimated fetal weight, but not FL, were seen between male and female fetuses. Centile charts for each of these variables were constructed for both male and female fetuses. This study suggests that small but consistent sex-related differences in prenatal BPD, HC and AC measurements are established by as early as 15 weeks of gestation. The use of sex-specific nomograms may improve the prenatal assessment of fetal growth as well as the diagnosis of structural abnormalities.
    Ultrasound in Obstetrics and Gynecology 01/2004; 23(1):23-9. DOI:10.1002/uog.966 · 3.85 Impact Factor
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    ABSTRACT: Experimental evidence suggests that estrogens stimulate the production of nitric oxide (NO) by vascular endothelial cells. This effect has been attributed to increased expression and enzymatic activity of both the constitutive and inducible isoforms of NO synthase. In this study, we have investigated whether estrogens regulate the metabolism or release of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase. The concentration of ADMA in the plasma of 15 postmenopausal women was 0.722+/-0.04 micromol/L (mean+/-SEM). Two weeks after subcutaneous implantation with estradiol, there was an increase in plasma estradiol concentration from 0.693+/-0.075 to 0.81+/-87 nmol/L, which was accompanied by a significant fall in plasma ADMA concentration to 0.588+/-0.03 micromol/L (P=0.006). Human and murine endothelial cell lines previously cultured in estrogen-free medium and then exposed to 17beta-estradiol showed a dose-dependent decrease in the release of ADMA. This reached statistical significance at 10-14 mol/L 17beta-estradiol and was accompanied by a corresponding increase in the activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catalyzes the metabolism of ADMA. We have demonstrated that estrogens can alter the catabolism and release of ADMA in vitro and reduce the circulating concentration in vivo. We therefore propose that increased DDAH activity and the subsequent fall in ADMA could contribute to the positive effect of estrogen on NO synthesis.
    Circulation 10/2003; 108(13):1575-80. DOI:10.1161/01.CIR.0000091083.61609.DF · 14.43 Impact Factor
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    E Mavrides · D Holden · J M Bland · A Tekay · B Thilaganathan ·
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    ABSTRACT: To assess the intraobserver repeatability and interobserver reproducibility of transabdominal Doppler ultrasound measurements of ductus venosus blood flow in fetuses between 10 and 14 weeks of gestation. A prospective study with the following end-points: coefficient of variation, intraclass correlation coefficients within and between observers, repeatability coefficient and Cohen's kappa coefficient. Doppler velocimetry indices (maximum peak systolic velocity during ventricular systole, end-diastolic velocity during atrial contraction, peak systolic velocity/end-diastolic velocity ratio and pulsatility index for veins) were successfully measured three times by the same trained observer in 67 fetuses. Of these, in 24 fetuses, the measurements were then repeated by a second trained observer. In addition, both observers classified qualitatively the blood flow as being normal or abnormal with regard to the presence or absence/reversal of flow during atrial contraction. The intraobserver repeatability of the pulsatility index for veins measurements was considered good with a coefficient of variation of 8.9% and an intraclass correlation coefficient value of 0.62. However, inconsistencies occurred in maximum peak systolic velocity, end-diastolic velocity and systolic/diastolic ratio measurements, which had coefficients of variation of 19%, 28.5%, and 25.4%, respectively. The corresponding intraclass correlation coefficient values were 0.70, 0.69 and 0.60. Interobserver reproducibility of these indices was unsatisfactory, the coefficient of variation varying between 11.5% and 47.2% and the intraclass correlation coefficient between 0.18 and 0.44. Agreement between the repeated observations with regard to interpretation of normal or abnormal blood flow varied from moderate (interobserver) to very good (intraobserver). There was considerable variability in all Doppler indices except for the intraobserver repeatability of the pulsatility index for veins measurement. This makes the implementation of the semiquantitative Doppler indices in a screening setting difficult. On the contrary, qualitative classification of the flow velocity waveforms seemed to be a reproducible method.
    Ultrasound in Obstetrics and Gynecology 05/2001; 17(4):306-10. DOI:10.1046/j.1469-0705.2001.00386.x · 3.85 Impact Factor
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    E. Mavrides · D. Holden · B. Hollis · A. Tekay · B. Thilaganathan ·
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    ABSTRACT: Background The aim of this study is to assess the intra-observer and inter-observer variability of transabdominal Doppler velocity measurements of ductus venosus (DV) blood flow in fetuses at 10–14 weeks.Method Doppler indices in the DV of first trimester fetuses were repeated three times by the same trained observer in 67 pregnancies and by a second trained observer in 24 pregnancies. In addition, both observers documented the presence of normal/abnormal blood flow during atrial contraction.FindingsIntra-observer reproducibility of measurements of peak systolic velocity, end-diastolic velocity and systolic to diastolic ratio were poor. Intra-observer pulsatility index (PI) repeatability was adequate (CC 0.60, CV 8.9%). Inter-observer agreement for all the Doppler measurements was unsatisfactory (CC 0.18–0.44; CV 11.5% to 47.2%).Conclusion There is significant variability in all Doppler indices, except for the intra-observer repeatability of PI. Determination of normal/abnormal atrial flow is a repeatable measurement.
    Ultrasound in Obstetrics and Gynecology 09/2000; 16(s1):48 - 49. DOI:10.1046/j.1469-0705.2000.00015-1-57.x · 3.85 Impact Factor
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    ABSTRACT: NG,NG-dimethylarginine is an endogenous inhibitor of nitric oxide synthesis produced by endothelial cells and found in the plasma and urine of normal adults. We have examined the ability of NG, NG-dimethylarginine, produced by endothelial cells (SGHEC-7), to regulate the production of nitric oxide by lipopolysaccharide-stimulated mouse macrophage cells (J774.2). Stimulation of SGHEC-7 or J774.2 cells with lipopolysaccharide had no effect on their release of NG,NG-dimethylarginine into the culture supernatant. Stimulation of J774.2 cells with lipopolysaccharide for 24 h significantly stimulated nitric oxide production by J774.2 but not SGHEC-7 cells. When lipopolysaccharide-stimulated J774.2 cells were co-cultured with endothelial cells for 24 h, there was a significant inhibition of nitrite accumulation. The inhibition observed was dependent on the endothelial cell number (12 +/- 5% [mean +/- SEM] following incubation with 0.6 x 105 cells, up to 47 +/- 8% with 4.8 x 105 cells). The inhibitory effect of endothelial cells was prevented by incubation with increasing concentrations of L-arginine; the IC50 was 2.9 +/- 0.6 mM arginine. Western blot analysis indicated that the expression of inducible nitric oxide synthase was not inhibited by co-culture with SGHEC-7 cells. The results presented here demonstrate that NG,NG-dimethylarginine synthesized by endothelial cells may inhibit nitric oxide synthase in adjacent cells and play a role in the regulation of nitric oxide synthesis by macrophages.
    Acta Physiologica Scandinavica 11/1999; 167(2):145-50. DOI:10.1046/j.1365-201x.1999.00587.x · 2.55 Impact Factor
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    Judith E Cartwright · Desmond P Holden · Guy St J Whitley ·
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    ABSTRACT: 1. The expression of hepatocyte growth factor (HGF) is essential for normal placental development although its function is unknown. In this study we examined the effect of HGF on trophoblast cell motility and invasion of fibrin gels and investigated the possible role of nitric oxide (NO) in this process. 2. The human extravillous trophoblast cell line SGHPL-4 express both the constitutive and inducible isoforms of nitric oxide synthase (NOS). 3. HGF significantly stimulates cell motility in monolayer culture, the invasion of fibrin gels and the production of guanosine 3':5'-cyclic monophosphate (cyclic GMP). 4. Invasion, motility and cyclic GMP production were inhibited by Ng-monomethyl-L-arginine (L-NMMA). 5. Cell motility was also significantly inhibited by the inducible NOS specific inhibitor 1400 W. 6. Neither 8 Br-cyclic GMP nor the NO donor spermine-NO had any significant effect on basal trophoblast cell motility. 7. The data presented in this study demonstrate a direct effect of trophoblast-derived NO synthesis on trophoblast cell function and support the idea that HGF is involved in the regulation of trophoblast invasion through mechanisms that involve the production of NO. However neither exogenous NO nor activation of cyclic GMP-dependent pathways alone are sufficient to stimulate trophoblast cell motility.
    British Journal of Pharmacology 10/1999; 128(1):181-9. DOI:10.1038/sj.bjp.0702757 · 4.84 Impact Factor
  • D P Holden · P Schwarzler · R De Tayrac · M V Senat · Y Ville ·
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    ABSTRACT: To investigate the effect of anhydramnios on the lung development of 1 twin in the presence of a normal amniotic fluid volume in its diamniotic co-twin. Three sets of diamniotic twins, discordant for complete urinary tract obstruction and anhydramnios, were followed prospectively with regular ultrasound scans and after delivery. All 3 twins with complete urinary tract obstruction and anhydramnios died within 2 days after birth, with confirmed severe pulmonary hypoplasia. In every case the twin with a normal amount of surrounding amniotic fluid had a normal postnatal outcome. The observation that a normal amniotic fluid volume in one sac does not protect the anhydramniotic twin from pulmonary hypoplasia has important implications for the aetiology of the condition and for the possibility of therapeutic septostomy. These results are discussed in relation to previous human and animal studies.
    Fetal Diagnosis and Therapy 09/1999; 14(5):296-300. DOI:10.1159/000020943 · 2.94 Impact Factor
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    P Schwärzler · M V Senat · D Holden · J P Bernard · T Masroor · Y Ville ·
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    ABSTRACT: To date, there have been no studies on the optimal timing of second-trimester ultrasound screening for fetal abnormalities. The purpose of this study was to investigate whether, of three gestational ages (18, 20 and 22 weeks), any one was associated with a significant advantage in terms of identification of abnormalities or need for further ultrasound assessment. Prospective, randomized study of second-trimester unselected pregnant women, who had had an ultrasound examination with normal results at 10-14 weeks. A total of 1206 women were randomized into three mutually exclusive groups relating to their second-trimester appointment for a screening ultrasound examination for fetal abnormalities in the second trimester of pregnancy: Group 1 at 18-18 + 6 weeks, Group 2 at 20-20 + 6 weeks and Group 3 at 22-22 + 6 weeks. The anomaly scans were carried out according to a standardized protocol. The fetuses were examined for structural and developmental abnormalities. Uterine artery Doppler measurements, including waveform recordings, were performed in all cases. The main end-points were the need for rescanning of all or part of the fetal anatomy, fetal outcome, placental localization, and incidence of notches in the uterine artery waveform. The baseline demographic characteristics and risk factors in the three groups were similar and gestational age-related fetal measurements were comparable. There were significantly higher percentages of completed scans in Group 2 (90%) and Group 3 (88%) than in Group 1 (76%; p < 0.001), but no significant difference between those scanned at 20 and at 22 weeks. This was associated with a higher incidence of non-cephalic presentation in Group 1 (46%) than in the other two groups (36%, p < 0.001). Significant differences in completing the assessment of the thorax, heart, spine and skeleton were also observed. There was no significant difference in maternal body habitus, fetal movements or the occurrence of uterine fibroids between the study groups. The incidences of low-lying placenta and of abnormal uterine artery Doppler screening were also higher at 18 weeks than at 20 and 22 weeks (p < 0.001 for both variables), with no difference seen between Groups 2 and 3. The numbers of fetal anomalies detected in the three groups were three, two and two, respectively; these did not differ significantly between the groups. This study suggests that, in an unselected pregnant population, second-trimester ultrasound screening is easier to perform and less likely to require an additional scan at 20-22 weeks than at 18 weeks.
    Ultrasound in Obstetrics and Gynecology 09/1999; 14(2):92-7. DOI:10.1046/j.1469-0705.1999.14020092.x · 3.85 Impact Factor
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    ABSTRACT: This study of patients with first trimester miscarriage evaluates whether conservative management is a feasible strategy and assesses the value of colour Doppler ultrasonography for patient selection. After confirmation of the diagnosis by transvaginal sonography all patients were offered the choice of immediate dilatation and curettage or conservative management. The presence of a gestational sac, the occurrence of spontaneous complete miscarriage within 28 days, detectable pulsatile blood flow within the placenta in the presumed region of the intervillous space and post-treatment complications were the main end-points. Out of a total of 108 women recruited, 23 (21.3%) elected to undergo immediate dilatation and curettage and 85 (78.7%) chose conservative management. The treatment groups were similar in age, gestational age, gestational sac diameter, serum concentrations of human chorionic gonadotrophin (HCG) and progesterone, and proportion of patients who had post-treatment complications (12-13%). Of patients in the conservative management group, 71 out of 85 (84%) had a spontaneous, complete abortion, while 37 out of 46 cases (80%) with detectable presumed intervillous pulsatile blood flow had a complete, spontaneous abortion within 1 week; this occurred in 23% of cases with no detectable flow. This suggests that conservative management is a successful approach for many patients with first trimester miscarriage; colour Doppler ultrasonography can be used to select the most suitable patients for this strategy, and thus reduce the need for hospital admission and surgery.
    Human Reproduction 06/1999; 14(5):1341-5. DOI:10.1093/humrep/14.5.1341 · 4.57 Impact Factor
  • Desmond P. Holden · Sara A. Fickling · Guy St.J. Whitley · Stephen S. Nussey ·
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    ABSTRACT: We investigated the change in the plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, in early-, mid-, and late-gestation normotensive pregnancies and in gestational age-matched preeclamptic pregnancies and compared the observed changes with changes in blood pressure. Blood pressure and peripheral plasma asymmetric dimethylarginine concentrations were measured in 20 nonpregnant and 145 pregnant women (33 first-trimester, 50 second-trimester, and 44 third-trimester normotensive pregnancies and 18 third-trimester pregnancies complicated by preeclampsia). In 23 normotensive pregnancies serial plasma asymmetric dimethylarginine concentrations were measured. Statistical analysis was by analysis of variance and linear regression. The blood pressures recorded throughout normal pregnancy were significantly lower than in nonpregnant subjects (p < 0.0001). The mean systolic, diastolic, and average blood pressures were significantly higher in the second-trimester groups than in the first-trimester groups, whereas in the third trimester average and diastolic blood pressures were significantly higher than in the second trimester. The mean (+/-SD) systolic and diastolic blood pressures in third-trimester preeclamptic patients was 157.7 +/- 11.2 and 110.9 +/- 8.5 mm Hg. The mean plasma asymmetric dimethylarginine concentration in nonpregnant women was 0.82 +/- 0.31 micromol/L (significantly higher than in normotensive pregnancy, p < 0.0001). The plasma asymmetric dimethylarginine concentration was also significantly higher in second-trimester than in first-trimester normotensive groups (respectively, 0.52 +/- 0.20 micromol/L and 0.40 +/- 0.15 micromol/L, p = 0.001) and was higher in third-trimester normotensive pregnancy 0.56 +/- 0.23 micromol/L than it was in the second trimester. The asymmetric dimethylarginine concentration in third-trimester preeclamptic patients was 1.17 +/- 0.42 micromol/L (p < 0.0001 vs normotensive third-trimester subjects). It is well recognized that blood pressure falls in early normal pregnancy and rises again toward term. These studies show that the early fall in blood pressure is accompanied by a significant fall in the plasma asymmetric dimethylarginine concentration. Later in pregnancy circulating concentrations increase and, when pregnancy is complicated by preeclampsia, concentrations are higher than in the nonpregnant state. Our data support a role for both asymmetric dimethylarginine and nitric oxide in the changes in blood pressure seen in both normal and preeclamptic pregnancy.
    American Journal of Obstetrics and Gynecology 04/1998; 178(3):551-6. DOI:10.1016/S0002-9378(98)70437-5 · 4.70 Impact Factor
  • D P Holden · Stephen Nussey ·

    International Anesthesiology Clinics 02/1997; 35(4):143-57. DOI:10.1097/00004311-199703540-00010

Publication Stats

502 Citations
49.45 Total Impact Points


  • 1999
    • St. George's School
      • Department of Biochemistry
      Middletown, Rhode Island, United States
    • The Fetal Medicine Foundation
      Londinium, England, United Kingdom
  • 1997-1998
    • St George's, University of London
      Londinium, England, United Kingdom