A comparison of first trimester blood pressures obtained at the time of first trimester pre-eclampsia screening and those obtained during prenatal care visits.

OBJECTIVE: To determine if enrollment blood pressures in a study on first trimester preeclampsia prediction significantly differed from those obtained during routine prenatal care visits in the first trimester. STUDY DESIGN: Women carrying a singleton gestation were prospectively enrolled in a first trimester study on preeclampsia prediction, and had systolic and diastolic blood pressure (SBP, DBP) measured at the time of enrollment. Blood pressure was also measured with the same technique by clinic nurses during the routine prenatal visits throughout the first trimester of pregnancy (9-14 weeks). The enrollment-BP (E-BP) and average first trimester-BP (aFT-BP) were compared using a paired samples t-test or Wilcoxon test, as appropriate. Smokers and patients on antihypertensive medications were excluded from the analysis. test. RESULTS: 644 women had prenatal care in the primary study center and met study criteria. The mean gestational age at study enrollment was 12.5 weeks. No significant difference was found between E-SBP and aFT-SBP (p = 0.10). Enrollment DBP and mean arterial pressure (MAP) were significantly lower than the aFT- DBP and -MAP (median DPB 67 vs 70 mm Hg and median MAP 83.7 vs 85 mmHg, respectively, p < 0.001). However, the difference was not clinically relevant (3 mmHg for DBP, and 1.3 mmHg for MAP). CONCLUSIONS: Blood pressures obtained in a setting of preeclampsia screening are not higher than those obtained during regular prenatal care in the first trimester. This suggests that the setting in which pre-eclampsia screening is performed is unlikely to be a confounder for blood pressure measurements and the risk assessment.

Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia.

Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 µmol/L in patients with relapsed or refractory (R/R) AML. Five patients were enrolled before the study was halted due to issues with Erwinaze manufacturing supply. All patients received Erwinaze at a dose of 25,000 IU/m2 intravenously three times weekly for 2 weeks. Median trough plasma Gln level at 48 h after initial Erwinaze administration was 27.6 µmol/L, and 80% (lower limit of 1-sided 95% CI 34%) of patients achieved at least one undetectable plasma Gln value (< 12.5 µmol/L), with the fold reduction (FR) in Gln level at 3 days, relative to baseline, being 0.16 (p < 0.001 for rejecting FR = 1). No dose-limiting toxicities were identified. Two patients responded, one achieved partial remission and one achieved hematologic improvement after six doses of Erwinaze monotherapy. These data suggest asparaginase-induced Gln depletion may have an important role in the management of patients with AML, and support more pharmacologic and clinical studies on the mechanistically designed asparaginase combinations in AML.

Relationship between first-trimester serum placental protein-13 and maternal characteristics, placental Doppler studies and pregnancy outcome.

OBJECTIVE: To examine potential correlations between maternal serum placental protein-13 (PP-13) and first trimester maternal and placental factors, and to evaluate the association of this marker with adverse pregnancy outcome. METHODS: Serum samples from prospectively enrolled patients between 11 and 13 weeks and 6 days were analyzed for PP-13 using an ELISA assay. The relationships between maternal serum PP-13 levels and gestational age, maternal age, ethnicity, parity, smoking status, body mass index (BMI), mean arterial blood pressure, uterine and umbilical artery Doppler parameters were examined. The association between first-trimester PP-13 levels and subsequent pre-eclampsia and delivery of a small for gestational age (SGA) neonate was also investigated, after excluding patients who received aspirin. RESULTS: In 908 patients, PP-13 levels ranged from 8.0 to 537.5 pg/mL. A significant negative correlation was identified between PP13 and BMI (Spearman rho -0.20, P<0.0001). Smoking significantly decreased PP-13 (P<0.01). No relationship was identified with the other parameters. In a subgroup of 668 low-risk patients who did not receive aspirin, PP-13 levels were not associated with development of pre-eclampsia, SGA or the combination of them. CONCLUSION: First-trimester PP-13 levels are significantly correlated with BMI and smoking. These correlations appear independent of uterine and umbilical artery resistance. In low risk patients, PP-13 levels fail to predict the risk for pre-eclampsia or SGA.

Second-trimester prediction of delivery of a small-for-gestational-age neonate: integrating sequential Doppler information, fetal biometry, and maternal characteristics.

OBJECTIVE: The aim of this study was to investigate the predictive accuracy of second-trimester ultrasound parameters, maternal characteristics, and sequential Doppler changes between first and second trimesters for the prediction of small-for-gestational-age (SGA) infants (birth weight < 10th percentile). METHODS: We conducted a prospective study of singleton pregnancies enrolled in the first trimester with subsequent second-trimester follow-up. Maternal characteristics, uterine artery (UtA) pulsatility index (PI), fetal biometry, and umbilical artery (UA)-PI were ascertained. UtA and UA-PI change from first to second trimester was calculated (ΔUtA-PI and ΔUA-PI). These parameters were tested for their ability to predict delivery of an SGA infant. RESULTS: Among 1982 women, 172 delivered an SGA neonate. African-American ethnicity, nulliparity, tobacco use, and low abdominal circumference (AC) z-score were independent predictors of SGA. No difference was found in the magnitude of ΔUtA-PI and ΔUA-PI between SGA and no-SGA. Receiver-operating characteristics curve analysis yielded an area under the curve of 0.700 for AC z-score. The combination of low AC and bilateral notching had high specificity (99%) but low sensitivity (7%) for SGA prediction. CONCLUSIONS: A small second-trimester fetal AC is a specific marker for SGA when found with bilateral UtA notching. Only a small proportion is predicted by the factors studied, suggesting a small contributory role or later evolution of SGA.

First-trimester prediction of small-for-gestational age neonates incorporating fetal Doppler parameters and maternal characteristics.

OBJECTIVE: First-trimester screening for subsequent delivery of a small-for-gestational-age (SGA) infant typically focuses on maternal risk factors and uterine artery (UtA) Doppler. Our aim is to test if incorporation of fetal umbilical artery (UA) and ductus venosus (DV) Doppler improves SGA prediction. STUDY DESIGN: Prospective screening study of singletons at 11-14 weeks. Maternal characteristics, serum concentrations of pregnancy-associated plasma protein-A (PAPP-A) and free ß-human chorionic gonadotropin are ascertained and UtA Doppler, UA, and DV Doppler studies are performed. These parameters are tested for their ability to predict subsequent delivery of a SGA infant. RESULTS: Among 2267 enrolled women, 191 (8.4%) deliver an SGA infant. At univariate analysis women with SGA neonates are younger, more frequently African-American (AA), nulliparous, more likely to smoke, have lower PAPP-A and free ß-human chorionic gonadotropin levels. They have a higher incidence of UtA Doppler bilateral notching, higher mean UtA Doppler-pulsatility index z-scores (P < .001) and UA pulsatility index z-scores (P = .03), but no significant difference in DV-pulsatility index z-scores or in the incidence of abnormal qualitative UA and DV patterns. Multivariate logistic regression analysis identifies nulliparity and AA ethnicity (P < .001), PAPP-A multiple of the median and bilateral notching (P < .05) as determinants of SGA infant. Predictive sensitivity was low; receiver operating characteristic curve analysis yields areas under the curve of 0.592 (95% confidence interval, 0.548-0.635) for the combination of UtA Doppler and UA pulsatility index z-scores. CONCLUSION: Delivery of a SGA infant is most frequent in nulliparous women of AA ethnicity. Despite the statistical association with UtA Doppler first-trimester SGA prediction is poor and not improved by the incorporation of fetal Doppler.

Implementation of pharmacogenetics: the University of Maryland Personalized Anti-platelet Pharmacogenetics Program.

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine.

First trimester maternal characteristics, Doppler parameters and serum analytes after preeclampsia.

OBJECTIVE: To evaluate the impact of prior preeclampsia on first trimester assessment in subsequent pregnancy. METHODS: A total of 1283 parous patients were prospectively enrolled at 9-14 weeks of gestation. Maternal biophysical characteristics, ultrasound parameters and placental analytes were compared between women with and without prior preeclampsia. RESULTS: There is no association between prior preeclampsia and the first trimester ultrasound parameters or placental analytes studied. The effects of prior preeclampsia in subsequent pregnancy are exaggerated by increasing parity and are predominantly blood pressure-related, independent of other cardiovascular risk factors. CONCLUSION: There is a potential role for lifestyle modification and stricter pregnancy blood pressure control in patients with prior preeclampsia.

Development and characterization of a mouse with profound biotinidase deficiency: a biotin-responsive neurocutaneous disorder.

Biotinidase deficiency is the primary enzymatic defect in biotin-responsive, late-onset multiple carboxylase deficiency. Untreated children with profound biotinidase deficiency usually exhibit neurological symptoms including lethargy, hypotonia, seizures, developmental delay, sensorineural hearing loss and optic atrophy; and cutaneous symptoms including skin rash, conjunctivitis and alopecia. Although the clinical features of the disorder markedly improve or are prevented with biotin supplementation, some symptoms, once they occur, such as developmental delay, hearing loss and optic atrophy, are usually irreversible. To prevent development of symptoms, the disorder is screened for in the newborn period in essentially all states and in many countries. In order to better understand many aspects of the pathophysiology of the disorder, we have developed a transgenic biotinidase-deficient mouse. The mouse has a null mutation that results in no detectable serum biotinidase activity or cross-reacting material to antibody prepared against biotinidase. When fed a biotin-deficient diet these mice develop neurological and cutaneous symptoms, carboxylase deficiency, mild hyperammonemia, and exhibit increased urinary excretion of 3-hydroxyisovaleric acid and biotin and biotin metabolites. The clinical features are reversed with biotin supplementation. This biotinidase-deficient animal can be used to study systematically many aspects of the disorder and the role of biotinidase, biotin and biocytin in normal and in enzyme-deficient states.

First-trimester angiopoietin-2: relationships with maternal and placental characteristics.

Angiopoietin-2 (Ang-2), synthesized by endothelial cells, is a marker of placental vascular remodeling. Ang-2 is expressed in the first trimester, and levels may therefore correlate to other parameters of placental vascular development. The aim of this study was to evaluate the relationships between Ang-2 and other maternal/placental factors in the first trimester. This was a prospective observational study of women presenting for first-trimester screening at 11 + 0 to 13 + 6 weeks. Consenting women underwent an ultrasound, physical examination, and blood draw. Maternal serum Ang-2 levels were determined using enzyme-linked immunosorbent assay. Results were evaluated with relation to maternal age, parity, race, body mass index (BMI), mean arterial pressure (MAP), smoking/caffeine use, and parameters of placental blood flow resistance. In 111 consecutive patients, serum Ang-2 ranged from 0.6 to 10.9 ng/mL. Ang-2 levels were unrelated to maternal age, race, parity, smoking, and caffeine intake. Significant negative correlations were observed with BMI (Pearson's R = -0.325; P < 0.0001) and MAP (Pearson's R = -0.287; P = 0.002). Ang-2 levels did not correlate with gestational age (Spearman's rho, 0.064; P = 0.5058), but a significant positive correlation with the crown-rump length was observed (Spearman's rho, 0.261; P = 0.006). Neither uterine artery notching nor umbilical artery Doppler parameters correlated with Ang-2 levels. We concluded that Ang-2 as a marker of placental angiogenesis has significant relationships with maternal risk factors associated with abnormal placental development.

Serum pentraxin-3 levels at 11 to 14 weeks' gestation: association with maternal and placental characteristics.

OBJECTIVE: Pentraxin (PTX)-3 is an inflammatory molecule that may be increased in the first trimester in pregnancies with subsequent preeclampsia. We measured first-trimester serum PTX-3 and correlated levels with maternal/placental factors related to placental development. STUDY DESIGN: Prospectively enrolled women had ultrasound, physical examination, and blood draw at 11-14 weeks. PTX-3 determined by enzyme-linked immunosorbent assay was related to maternal age, parity, race, body mass index (BMI), mean arterial blood pressure (MAP), smoking/caffeine, and uterine/umbilical artery Doppler pulsatility index (PI). RESULTS: In 111 patients PTX-3 levels ranged from 0.2-13.8 ng/mL. Spearman correlation between PTX-3 and gestational age (rho = 0.096), maternal age (rho = -0.049), BMI (rho = -0.07), MAP (rho = -0.085), mean uterine artery PI (rho = 0.150), and umbilical artery PI (rho = -0.021) was nonsignificant (all P > .05). Similarly, PTX-3 distribution was unaffected by smoking/caffeine use, BMI >30, MAP >100 mm Hg, or uterine artery notching (P > .05 for all). CONCLUSION: First-trimester PTX-3 is unrelated to maternal characteristics and placental Doppler.

U.S. genetics nurses in advanced practice.

PURPOSE: To describe characteristics and professional roles of genetics nurses in advanced practice. DESIGN: A cross-sectional descriptive survey administered in 2004 as one component of a comprehensive study of genetic services and the health workforce. The sample was 211 U.S. members of the International Society of Nurses in Genetics. METHODS: The survey included demographic characteristics, education, credentials, professional roles, and attitudes about genetic healthcare issues. FINDINGS: The majority of respondents had master's degrees and many had earned doctorates in nursing (20%) or other fields (12%). Thirty-one percent were certified as nurse practitioners; 57% provided direct patient care, with the largest percentage working in genetics (26%) or oncology (22%) settings. Over one-third were educators and 19% conducted genome-related research. CONCLUSIONS: Genetics nurses in advanced practice in the US focus on both genomic discoveries and clinical health care through the application of genomic knowledge into health care, research, and nursing education.

Biotinidase deficiency: novel mutations and their biochemical and clinical correlates.

Biotinidase deficiency is a defect in the recycling of the vitamin biotin. Biotin supplementation can markedly improve the neurological and cutaneous symptoms of affected children and prevent symptoms in children identified by newborn screening or treated since birth. We have determined thirteen novel mutations in children with the disorder. Two nonsense mutations, eight single missense mutations, three allelic double missense mutations, and two are polymorphisms were identified in the biotinidase gene (BTD). One of the missense mutations, c.734G>A (p. C245Y), is the first to be reported that alters the cysteine in the putative location crucial for ester formation and binding of the biotinyl-moiety in the active site of the enzyme. These mutations add to the growing list of mutations that are helping to delineate structure/function relationships of the enzyme.