Aplastic anemia in two consecutive pregnancies: obstetric and anesthetic management.

Aplastic anemia is a serious condition occasionally coexisting with pregnancy. This pathological process is associated with significant maternal and neonatal morbidity and mortality. Obstetric and anesthetic management are particularly challenging, and treatment requires knowledge of pathophysiologic mechanisms in order to provide safe care to this group of patients. We describe the successful obstetric management and labor analgesia of a patient with a diagnosis of aplastic anemia in two consecutive pregnancies.

Human milk insulin is related to maternal plasma insulin and BMI: but other components of human milk do not differ by BMI.

BACKGROUND/OBJECTIVES: The impact of maternal BMI and insulin sensitivity on bioactive components of human milk (HM) is not well understood. As the prevalence of obesity and diabetes rises, it is increasingly critical that we understand how maternal BMI and hormones associated with metabolic disease relate to concentrations of bioactive components in HM. SUBJECTS/METHODS: This longitudinal cohort design followed 48 breastfeeding mothers through the first four months of lactation, collecting fasting morning HM samples at 2-weeks and 1, 2, 3 and 4-months, and fasting maternal blood at 2-weeks and 4-months. Insulin, glucose, adipokines leptin and adiponectin, appetite regulating hormone ghrelin, marker of oxidative stress 8OHdG and inflammatory cytokines (IL-6, IL-8, and TNF-a) were measured in HM and maternal plasma. RESULTS: A total of 26 normal weight (NW) (BMI=21.4±2.0 kg/m2) and 22 overweight/obese (OW/Ob) (BMI=30.4±4.2 kg/m2) were followed. Of all HM analytes measured, only insulin and leptin were different between groups - consistently higher in the OW/Ob group (leptin: P<0.001; insulin: P<0.03). HM insulin was 98% higher than maternal plasma insulin at 2-weeks and 32% higher at 4-months (P<0.001). Maternal fasting plasma insulin and HOMA-IR were positively related to HM insulin at 2-weeks (P<0.001, R2⩾0.38, n=31), and 4-months (P⩽0.005, R2⩾0.20, n=38). CONCLUSIONS: The concentrations of insulin in HM are higher than in maternal plasma and are related to maternal BMI and insulin sensitivity. With the exception of leptin, there were minimal other differences observed in HM composition across a wide range in maternal BMI.

Early infant adipose deposition is positively associated with the n-6 to n-3 fatty acid ratio in human milk independent of maternal BMI.

BACKGROUND/OBJECTIVES: Excessive infant weight gain in the first 6-month of life is a powerful predictor of childhood obesity and related health risks. In mice, omega-6 fatty acids (FAs) serve as potent ligands driving adipogenesis during early development. The ratio of omega-6 relative to omega-3 (n-6/n-3) FA in human milk (HM) has increased threefold over the last 30 years, but the impact of this shift on infant adipose development remains undetermined. This study investigated how maternal obesity and maternal dietary FA (as reflected in maternal red blood cells (RBCs) composition) influenced HM n-6 and n-3 FAs, and whether the HM n-6/n-3 ratio was associated with changes in infant adipose deposition between 2 weeks and 4 months postpartum. SUBJECTS/METHODS: Forty-eight infants from normal weight (NW), overweight (OW) and obese (OB) mothers were exclusively or predominantly breastfed over the first 4 months of lactation. Mid-feed HM and maternal RBC were collected at either transitional (2 weeks) or established (4 months) lactation, along with infant body composition assessed using air-displacement plethysmography. The FA composition of HM and maternal RBC was measured quantitatively by lipid mass spectrometry. RESULTS: In transitional and established HM, docosahexaenoic acid (DHA) was lower (P=0.008; 0.005) and the arachidonic acid (AA)/DHA+eicosapentaenoic acid (EPA) ratio was higher (P=0.05; 0.02) in the OB relative to the NW group. Maternal prepregnancy body mass index (BMI) and AA/DHA+EPA ratios in transitional and established HM were moderately correlated (P=0.018; 0.001). Total infant fat mass was increased in the upper AA/DHA+EPA tertile of established HM relative to the lower tertile (P=0.019). The amount of changes in infant fat mass and percentage of body fat were predicted by AA/EPA+DHA ratios in established HM (P=0.038; 0.010). CONCLUSIONS: Perinatal infant exposures to a high AA/EPA+DHA ratio during the first 4 months of life, which is primarily reflective of maternal dietary FA, may significantly contribute to the way infants accumulate adipose.

Maternal diet quality in pregnancy and neonatal adiposity: the Healthy Start Study.

BACKGROUND/OBJECTIVES: Poor maternal diet in pregnancy can influence fetal growth and development. We tested the hypothesis that poor maternal diet quality during pregnancy would increase neonatal adiposity (percent fat mass (%FM)) at birth by increasing the fat mass (FM) component of neonatal body composition. METHODS: Our analysis was conducted using a prebirth observational cohort of 1079 mother-offspring pairs. Pregnancy diet was assessed via repeated Automated Self-Administered 24-h dietary recalls, from which Healthy Eating Index-2010 (HEI-2010) scores were calculated for each mother. HEI-2010 was dichotomized into scores of ⩽57 and >57, with low scores representing poorer diet quality. Neonatal %FM was assessed within 72 h after birth with air displacement plethysmography. Using univariate and multivariate linear models, we analyzed the relationship between maternal diet quality and neonatal %FM, FM, and fat-free mass (FFM) while adjusting for prepregnancy body mass index (BMI), physical activity, maternal age, smoking, energy intake, preeclampsia, hypertension, infant sex and gestational age. RESULTS: Total HEI-2010 score ranged between 18.2 and 89.5 (mean: 54.2, s.d.: 13.6). An HEI-2010 score of ⩽57 was significantly associated with higher neonatal %FM (ß=0.58, 95% confidence interval (CI) 0.07-1.1, P<0.05) and FM (ß=20.74; 95% CI 1.49-40.0; P<0.05) but no difference in FFM. CONCLUSIONS: Poor diet quality during pregnancy increases neonatal adiposity independent of maternal prepregnancy BMI and total caloric intake. This further implicates maternal diet as a potentially important exposure for fetal adiposity.

Striking differences in estimates of infant adiposity by new and old DXA software, PEAPOD and skin-folds at 2 weeks and 1 year of life.

BACKGROUND: Infant adiposity better predicts childhood obesity/metabolic risk than weight, but technical challenges fuel controversy over the accuracy of adiposity estimates. OBJECTIVE: We prospectively measured adiposity (%fat) in term newborns (NB) at 2 weeks (n = 41) and 1 year (n = 30). METHODS: %fat was measured by dual X-ray absorptiometry (DXA), PEAPOD and skin-folds (SF). DXAs were analyzed using Hologic Apex software 3.2(DXAv1) and a new version 5.5.2(DXAv2). RESULTS: NB %fat by DXAv2 was 55% higher than DXAv1 (14.2% vs. 9.1%), 45% higher than SF (9.8%), and 36% higher than PEAPOD (10.4%). Among NB, Pearson correlations were 0.73-0.89, but agreement (intra-class correlations) poor between DXAv2 and DXAv1 (0.527), SF (0.354) and PEAPOD (0.618). At 1 year, %fat by DXAv2 was 51% higher than DXAv1 (33.6% vs. 22.4%), and twice as high compared with SF (14.6%). Agreement was poor between DXAv2 and DXAv1 (0.204), and SF (0.038). The absolute increase in %fat from 2 weeks to 1 year was 19.7% (DXAv2), 13.6% (DXAv1) and only 4.8% by SF. CONCLUSION: Analysis of the same DXA scans using new software yielded considerably higher adiposity estimates at birth and 1 year compared with the previous version. Using different modalities to assess body composition longitudinally is problematic. Standardization is gravely needed to determine how early life exposures affect childhood obesity/metabolic risk.

Transient subluxation of the femoral head after total hip replacement.

Dislocation is a common and well-studied complication after total hip replacement. However, subluxation, which we define as a clinically recognised episode of incomplete movement of the femoral head outside the acetabulum with spontaneous reduction, has not been studied previously. Out of a total of 2521 hip replacements performed over 12 years by one surgeon, 30 patients experienced subluxations which occurred in 31 arthroplasties. Data were collected prospectively with a minimum follow-up of two years. Subluxation occurred significantly more frequently after revision than after primary hip replacement, and resolved in 19 of 31 cases (61.3%). In six of the 31 hips (19.4%) the patient subsequently dislocated the affected hip, and in six hips (19.4%) intermittent subluxation continued. Four patients had a revision operation for instability, three for recurrent dislocation and one for recurrent subluxation. Clinical and radiological comparisons with a matched group of stable total hips showed no correlation with demographic or radiological parameters. Patients with subluxing hips reported significantly more concern that their hip would dislocate, more often changed their behaviour to prevent instability and had lower postoperative Harris hip scores than patients with stable replacements.

Alkali metal cation-pi interactions observed by using a lariat ether model system.

The Na(+) or K(+) cation-pi interaction has been experimentally probed by using synthetic receptors that comprise diaza-18-crown-6 lariat ethers having ethylene sidearms attached to aromatic pi-donors. The side chains are 2-(3-indolyl)ethyl (7), 2-(3-(1-methyl)indolyl)ethyl (8), 2-(3-(5-methoxy)indolyl)ethyl (9), 2-(4-hydroxyphenyl)ethyl (10), 2-phenylethyl (11), 2-pentafluorophenylethyl (12), and 2-(1-naphthyl)ethyl (13). Solid-state structures are reported for six examples of alkali metal complexes in which the cation is pi-coordinated by phenyl, phenol, or indole. Indole-containing crown, 7, adopts a similar conformation when bound by NaI, KI, KSCN, or KPF(6). In each case, the macroring and both arenes coordinate the cation; the counteranion is excluded from the solvation sphere. NMR measurements in acetone-d(6) solution confirm the observed solid-state conformations of unbound 7 and 7.NaI. In 7.Na(+) and 7.K(+), the pyrrolo, rather than benzo, subunit of indole is the pi-donor for the alkali metal cation. Cation-pi complexes were also observed for 10.KI and11.KI. In these cases, the orientation of the cation on the aromatic ring is in accord with the binding site predicted by computational studies. In contrast to the phenyl case (11) the pentafluorophenyl group of 12 failed to coordinate K(+). Solid-state structures are also reported for 7.NaPF(6), 10.NaI, 11.NaI, 13.KI, 13.KPF(6), and 9.NaI, in which cation-pi complexation is not observed. Steric and electrostatic considerations in the pi-complexation of alkali metal cations by these lariat ethers are thought to account for the observed complexation behavior or lack thereof.

Hydrogen-bonded molecular capsules are stable in polar media.

Robust, very large hydrogen-bonded capsules which are even stable in 50:50 water-acetone mixtures have been characterized both in solution and in the solid state.

Non-covalent interactions exert extraordinary influence over conformation and properties of a well-known supramolecular building block.

At low pH, and in the presence of 4,4'-bipyridine, p-sulfonatocalix[4]arene crystallizes in the 1,3-alternate conformation rather than the expected cone conformation and exhibits remarkable stability.

Solid state evidence for pi-complexation of sodium cation by carbon-carbon double bonds.

Solid state evidence shows that neutral double bonds, attached to flexible sidearms of a lariat ether, serve as intramolecular pi-donors for a ring-bound Na+ cation.

Improving synthetic lethal screens by regulating the yeast centromere sequence.

The synthetic lethal screen is a useful method in identifying novel genes functioning in an alternative pathway to the gene of interest. The current synthetic lethal screen protocol in yeast is based on a colony-sectoring assay that allows direct visualization of mutant colonies among a large population by their inability to afford plasmid loss. This method demands an appropriate level of stability of the plasmid carrying the gene of interest. YRp-based plasmids are extremely unstable and complete plasmid loss occurs within a few generations. Consequently, YCp plasmids are the vector of choice for synthetic lethal screens. However, we found that the high-level stability of YCp plasmids resulted in a large number of false positives that must be further characterized. In this study, we attempt to improve the existing synthetic lethal screen protocol by regulating the plasmid stability and copy number. It was found that by placing a yeast centromere sequence under the control of either inducible or constitutive promoters, plasmid stability can be significantly decreased. Hence, altering the conditions under which yeast cells carrying the plasmid PGAL1-CEN4 were cultivated allowed us to develop a method that eliminated virtually 100% of false positives and drastically reduced the time required to carry out a synthetic lethal screen.

Synthetic receptors as models for alkali metal cation-pi binding sites in proteins.

The alkali metal cations Na(+) and K(+) have several important physiological roles, including modulating enzyme activity. Recent work has suggested that alkali metal cations may be coordinated by pi systems, such as the aromatic amino acid side chains. The ability of K(+) to interact with an aromatic ring has been assessed by preparing a family of synthetic receptors that incorporate the aromatic side chains of phenylalanine, tyrosine, and tryptophan. These receptors are constructed around a diaza-18-crown-6 scaffold, which serves as the primary binding site for an alkali metal cation. The ability of the aromatic rings to coordinate a cation was determined by crystallizing each of the receptors in the presence of K(+) and by solving the solid state structures. In all cases, complexation of K(+) by the pi system was observed. When possible, the structures of the unbound receptors also were determined for comparison. Further proof that the aromatic ring makes an energetically favorable interaction with the cation was obtained by preparing a receptor in which the arene was perfluorinated. Fluorination of the arene reverses the electrostatics, but the aromaticity is maintained. The fluorinated arene rings do not coordinate the cation in the solid state structure of the K(+) complex. Thus, the results of the predicted electrostatic reversal were confirmed. Finally, the biological implications of the alkali metal cation-pi interaction are addressed.

Unusual folded conformation of nicotinamide adenine dinucleotide bound to flavin reductase P.

The 2.1 A resolution crystal structure of flavin reductase P with the inhibitor nicotinamide adenine dinucleotide (NAD) bound in the active site has been determined. NAD adopts a novel, folded conformation in which the nicotinamide and adenine rings stack in parallel with an inter-ring distance of 3.6 A. The pyrophosphate binds next to the flavin cofactor isoalloxazine, while the stacked nicotinamide/adenine moiety faces away from the flavin. The observed NAD conformation is quite different from the extended conformations observed in other enzyme/NAD(P) structures; however, it resembles the conformation proposed for NAD in solution. The flavin reductase P/NAD structure provides new information about the conformational diversity of NAD, which is important for understanding catalysis. This structure offers the first crystallographic evidence of a folded NAD with ring stacking, and it is the first enzyme structure containing an FMN cofactor interacting with NAD(P). Analysis of the structure suggests a possible dynamic mechanism underlying NADPH substrate specificity and product release that involves unfolding and folding of NADP(H).

Alveolar-arterial oxygen gradient in acute pulmonary embolism in pregnancy.

OBJECTIVE: Our goal was to determine the prevalence of normal alveolar-arterial gradients in pregnant patients with documented pulmonary embolism. STUDY DESIGN: A retrospective chart review was performed on all pregnant women with pulmonary embolism at two large obstetric centers between 1990 and 1995. Alveolar-arterial gradients were calculated from room air arterial blood gas values and compared with values from patients who had been established as normal. RESULTS: Ten of 17 patients with pulmonary embolism identified had alveolar-arterial gradients that were normal. CONCLUSIONS: In our study 58% of pregnant women with documented pulmonary embolism had a normal alveolar-arterial gradient. This markedly differs from the published data in nonpregnant patients, in which the incidence of normal alveolar-arterial gradients in pulmonary embolism has ranged from 1.9% to 20%. This suggests that the alveolar-arterial gradient should not be used to determine the likelihood of pulmonary embolism in pregnant women because this could lead to the withholding of appropriate treatment for this life-threatening condition.

Current concepts of anticoagulant therapy in pregnancy.

The optimal use of anticoagulants during pregnancy will continue to be controversial until appropriate randomized controlled and prospective trials with adequate sample sizes are completed. The relative low frequency of thromboembolic events, the concerns about maternal and fetal safety of both treatment and withholding treatment, and the reservations about prospectively enrolling pregnant women in treatment trials has sadly dissuaded the appropriate study of this life-threatening condition. North American trials that enroll pregnant women to evaluate the efficacy of LMWH are of preeminent importance owing to their superior bioavailability, ease in dosing, longer half-life, and side effect profile. Similarly, trials evaluating the optimal management of women of childbearing age with valvular disease are critical to reduce the considerable maternal and fetal morbidity and mortality associated with these pregnancies. Such definitive studies will need to be multicenter in design and it is hoped that the National Institutes of Health initiative to enroll pregnant women in clinical trials will at last be realized in the near future.