Functional characteristics of N8, a new recombinant FVIII.

The aim of this study was to evaluate the in vitro function of the new recombinant factor VIII (FVIII) compound, N8. The specific activity of N8 as measured in a FVIII:C one-stage clot assay was 9300±400 IU mg(-1) based on the analysis of seven individual batches. The ratio between the FVIII:C activity measured in clot and chromogenic assays was 1.00 (95% confidence interval 0.97-1.03). N8 bound to von Willebrand factor with Kd values of 0.2 nm when measured by ELISA and by surface plasmon resonance. FVIIIa cofactor activity was determined from the kinetic parameters of factor IXa-catalysed factor X (FX) activation. The rate of activation of N8 by thrombin as well as Km and kcat for FX activation was in the same range as those observed for Advate®. The rate of activated protein C (APC)-catalysed inactivation was similar for activated N8 and Advate®. N8 improved thrombin generation in a dose-dependent manner and induced similar rates of thrombin generation as Advate® and the plasma-derived FVIII product Haemate®. Using thromboelastography (TEG®), N8 was shown to improve the clot formation and clot stability in whole blood from haemophilia A patients. Comparable potency and efficacy of N8 and Advate® was found based on TEG® parameters. Finally, similar binding profiles to immobilized lipoprotein receptor-related protein (LRP) of N8 and Advate® were observed. The study demonstrated that N8 is fully functional in a variety of assays measuring FVIII activity. No functional differences were found between N8 and comparator compounds.

Fetal abdominal wall defects and mode of delivery: a systematic review.

OBJECTIVE: To determine whether there is sufficient evidence to support cesarean delivery over vaginal delivery in women carrying a fetus with an abdominal wall defect. DATA SOURCES: An OVID MEDLINE search of English language abstracts using medical subject heading terms "gastroschisis," "omphalocele," and "fetal abdominal wall defects" was performed. The generated list of articles was supplemented by a review of their bibliographies and the bibliographies of obstetric texts. STUDY SELECTION: A total of 27 peer-reviewed observational studies were identified, and 15 were included in the meta-analysis. Our primary inclusion criterion was the reporting of neonatal outcomes for infants with abdominal wall defects who delivered vaginally and who delivered by cesarean section. Studies were excluded if they were a case series or if neonatal outcomes could not be ascertained from the data presented in the manuscript. TABULATION, INTEGRATION, AND RESULTS: Standard meta-analytic techniques were applied to assess the question of whether cesarean delivery improves neonatal outcomes in infants with abdominal wall defects. There was no significant relationship between mode of delivery and the rate of primary fascial repair (random effects model: pooled relative risk [RR] 1.22, 95% confidence interval [CI] 0.99, 1.51), neonatal sepsis (random effects model: pooled RR 0.70, 95% CI 0.30, 1.62), or pediatric mortality (random effects model: pooled RR 1.14, 95% CI 0.59, 2.21). Additionally, there was no significant relationship between mode of delivery and time until enteral feeding or length of hospital stay. CONCLUSION: The available data do not provide evidence to support a policy of cesarean delivery for infants with abdominal wall defects.

Amniotic fluid matrix metalloproteinase-8 indicates intra-amniotic infection.

OBJECTIVE: This study was undertaken to determine whether matrix metalloproteinase-8, which is produced by neutrophils, is a useful marker for the detection of intra-amniotic infection. STUDY DESIGN: We performed a case-control study using enzyme-linked immunosorbent assays to detect matrix metalloproteinase-8 in 77 amniotic fluid specimens that were obtained by amniocentesis from women with preterm contractions or preterm labor and intact fetal membranes (n = 66) and from women with preterm premature rupture of membranes (n = 11). RESULTS: Thirty women had culture-proven intra-amniotic infection (cases), 21 of whom had intact membranes. After constructing receiver operating characteristic curves to establish the optimal threshold concentration of matrix metalloproteinase-8 for a positive test result, we detected matrix metalloproteinase-8 in 27 of 30 women with intra-amniotic infection; only 10 of 47 control specimens contained matrix metalloproteinase-8 (P <.001; odds ratio, 33.3; 95% CI, 8.4, 132.7). Matrix metalloproteinase-8 was present in 20 of 21 women with intact membranes and intra-amniotic infection and in only 10 of 45 control subjects (P <.001; odds ratio, 70.0; 95% CI, 8.3, 587.6). Among women with intact membranes, the sensitivity of the assay was 0.95 and the specificity was 0.78. CONCLUSION: Our results indicate that matrix metalloproteinase-8 is highly correlated with intra-amniotic infection and that enzyme-linked immunosorbent assay for matrix metalloproteinase-8 may be a clinically useful test for the diagnosis of intra-amniotic infection in women with preterm contractions and preterm labor.

Blood-to-brain glucose transport, cerebral glucose metabolism, and cerebral blood flow are not increased after hypoglycemia.

Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (including adrenomedullary epinephrine), symptomatic, and other responses to subsequent hypoglycemia to lower plasma glucose concentrations. This change in threshold is the basis of the clinical syndromes of hypoglycemia unawareness and, in part, defective glucose counterregulation and the unifying concept of hypoglycemia-associated autonomic failure in type 1 diabetes. We tested in healthy young adults the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport, a plausible mechanism of this phenomenon. Eight subjects were studied after euglycemia, and nine were studied after approximately 24 h of interprandial hypoglycemia ( approximately 55 mg/dl, approximately 3.0 mmol/l). The latter were shown to have reduced plasma epinephrine (P = 0.009), neurogenic symptoms (P = 0.009), and other responses to subsequent hypoglycemia. Global bihemispheric blood-to-brain glucose transport and cerebral glucose metabolism were calculated from rate constants derived from blood and brain time-activity curves-the latter determined by positron emission tomography (PET)-after intravenous injection of [1-(11)C]glucose at clamped plasma glucose concentrations of 65 mg/dl (3.6 mmol/l). For these calculations, a model was used that includes a fourth rate constant to account for egress of [(11)C] metabolites. Cerebral blood flow was measured with intravenous [(15)O]water using PET. After euglycemia and after hypoglycemia, rates of blood-to-brain glucose transport (24.6 +/- 2.3 and 22.4 +/- 2.4 micromol. 100 g(-1). min(-1), respectively), cerebral glucose metabolism (16.8 +/- 0.9 and 15.9 +/- 0.9 micromol. 100 g(-1). min(-1), respectively) and cerebral blood flow (56.8 +/- 3.9 and 53.3 +/- 4.4 ml. 100 g(-1). min(-1), respectively) were virtually identical. These data do not support the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport during subsequent hypoglycemia. They do not exclude regional increments in blood-to-brain glucose transport. Alternatively, the fundamental alteration might lie beyond the blood-brain barrier.

Prediction of delivery among women with early preterm labor by means of clinical characteristics alone.

OBJECTIVE: This study was undertaken to assess whether individual clinical factors or combinations thereof could be used to accurately predict the risk of delivery within 1 week of admission among women with preterm labor and minimal cervical dilatation. STUDY DESIGN: We performed a case-control study of patients admitted to our institution with preterm labor and minimal cervical dilatation. A case patient was a patient who sought treatment with uterine contractions between 24 and 34 weeks' gestation with cervical dilatation 70 potential predictors was recorded. Statistical analysis consisted of bivariate and multivariable methods. We also generated a multivariable clinical predictive model with the purpose of detecting a proportion as high as possible of those destined to be delivered within 1 week (high sensitivity). We estimated that we would need 50 case patients and 150 control subjects to detect an odds ratio of 2.5 for risk factors with a prevalence of 20%, an alpha error of.05, a beta error of.20, and a control subject/case patient ratio of 3:1. RESULTS: Three variables were eligible for inclusion in our logistic models according to the bivariate analyses-bleeding on admission, substance abuse, and admission white blood cell count >/=14,000 cells/microL. The simplest and most favorable model included only 2 variables, bleeding and substance abuse, and yielded a sensitivity of 46% and a specificity of 76%. The full 3-variable model had similar test characteristics. For no model were we able to achieve a sensitivity >/=50%. CONCLUSION: The results of this case-control study suggest that combinations of clinical factors do not yield an adequate level of discrimination to be used alone for predicting the likelihood of delivery within 1 week among patients with minimal degrees of cervical dilatation.

Predicting delivery within 48 hours in women treated with parenteral tocolysis.

OBJECTIVE: To develop a prediction rule using clinical admission characteristics for women treated with parenteral tocolysis for preterm labor who are at highest risk of delivery within 48 hours. METHODS: We performed a case-control study of patients treated with magnesium sulfate for idiopathic preterm labor. A case was defined as a patient who received magnesium sulfate tocolysis and delivered within 48 hours of admission. We selected a 48-hour delay to delivery as a clinically relevant endpoint for the maximization of steroid benefit. Controls were patients who received magnesium sulfate tocolysis and remained undelivered 48 hours after admission. Cases and controls were identified by merging a pharmacy billing database with International Classification of Disease codes for premature labor. Medical records were reviewed and risk factor information was obtained. We focused on risk factors within the first hour of admission, because our goal was to identify patients at high risk of delivery early in their hospital course. Backward stepwise logistic regression was used to develop explanatory and predictive models. The focus of the predictive model was to maximize the test's sensitivity and negative predictive value. RESULTS: We identified 50 cases and 150 controls. The following six variables were included in the initial multivariable models based on bivariate analyses: white blood cell count at least 14.0 (1000/microL), cervical dilation at least 2 cm, bleeding, substance abuse, parity, and previous abortion. A two-variable model containing cervical dilation and bleeding had an overall accuracy of 73%, sensitivity of 62%, and specificity of 76%, and it was as sensitive and specific as more complex models. CONCLUSION: Cervical dilation of at least 2 cm and bleeding on admission had an overall accuracy of 73% in predicting the likelihood of delivery within 48 hours in women receiving magnesium sulfate.

Symptomatic anti-parkinsonian effects of monoamine oxidase-B inhibition: comparison of selegiline and lazabemide.

Selegiline (deprenyl) and lazabemide (Ro 19-6327) are inhibitors of monoamine oxidase-B but differ in several other pharmacological properties. We compared 4-week monotherapy trials of each to assess their actions against signs and disabilities of Parkinson's disease (PD). In a group of 20 mildly affected Parkinson patients treated with each drug, there were no statistically significant changes from the pretreatment baseline. There were no differences between the drugs. This work confirms that the symptomatic effects of selegiline against Parkinsonism are small and are likely due to its inhibition of monoamine oxidase-B.

End-tidal carbon dioxide in critically ill patients during changes in mechanical ventilation.

Values of end-tidal CO2 (PETCO2) approximate PaCO2 in spontaneous breathing normal subjects and in stable patients receiving mechanical ventilatory support (MVS). Because marked inequality of ventilation/perfusion ratios in critically ill patients might affect this correlation, we assessed changes of PETCO2 in predicting changes in PaCO2 (delta PaCO2) and changes in minute ventilation (delta Ve) in this patient population. Twenty consecutive intubated patients 38 to 89 yr of age (mean, 70 yr) with respiratory failure while receiving MVS with indwelling arterial lines were studied. Settings on the mechanical ventilator were varied for frequency and tidal volume, and after a minimum of 5 to 10 min equilibration, PaCO2 and PETCO2 were measured. Vt and Ve were recorded from the digital indicator of the pneumotachygraph within the mechanical ventilator and corrected for compression volume in the respirator circuit. A total of 116 simultaneous measurements were performed. PETCO2 correlated well with PaCO2 (r = 0.78, p less than 0.001). The 95% confidence interval for the mean difference in PaCO2-PETCO2 was 4.0 +/- 0.97 mm Hg. However, delta PETCO2 (measured from baseline) did not correlate as well with delta PaCO2 (r = 0.58, p = less than 0.001). In four patients, the trend in their PETCO2 during changes in mechanical ventilation were in the opposite direction from the trend in their PaCO2. Thus, many critically ill patients, who cannto be preidentified, have an inconstant PaCO2-PETCO2 gradient with changes of ventilation. Utilization of PETCO2 as a noninvasive monitoring substitute for trends in PaCO2 in critically ill patients may be misleading despite establishing an initial PaCO2-PETCO2 relationship.