Prepregnancy Weight in Women with Type I Diabetes Mellitus: Effect on Pregnancy Outcomes.

Objective This study aims to evaluate the association between prepregnancy body mass index (BMI) and adverse pregnancy outcomes in women with type 1 diabetes mellitus (DM). Methods This is a secondary analysis of a cohort of 426 pregnancies in women with type 1 DM recruited before 20 weeks gestation. Women were categorized according to prepregnancy BMI: low BMI (< 20 kg/m2), normal BMI (20 to < 25 kg/m2), and high BMI (≥ 25 kg/m2). The outcomes of interest were: spontaneous abortion (delivery < 20 weeks gestation); preeclampsia; emergent delivery for maternal indications (hypertension or placental abruption); and preterm delivery (< 37 weeks gestation). Analyses included proportional hazards and multiple logistic regression models with covariates: age, age at diagnosis of type 1 DM, previous spontaneous abortion, microvascular disease (nephropathy or retinopathy), and glycohemoglobin A1 concentrations. Results Low BMI was associated with preterm delivery. High BMI was associated with emergent delivery for maternal indications. Glycemic control as measured by glycohemoglobin A1 was associated with increased risk of spontaneous abortion, attenuating the association with low prepregnancy weight. Conclusion Prepregnancy BMI is a risk factor to be considered when caring for women with type 1 DM, in particular for preterm delivery (low BMI) and emergent delivery for maternal indications (high BMI).

Height and the risk of gestational diabetes: variations by race/ethnicity.

AIMS: Gestational diabetes is a common pregnancy complication affecting races/ethnicities disproportionally. Adult height, an indicator of both genetic and early-life factors, is inconsistently associated with gestational diabetes risk. We examined the association and whether it varies by races in a nationally representative US cohort. METHODS: Analyses were conducted among 135 861 pregnancies in the Consortium on Safe Labor, 5567 of which were diagnosed with gestational diabetes based on medical records review. Generalized estimating equations were used to estimate odds ratios (95% confidence intervals) of gestational diabetes, controlling for other risk factors including body weight. Additionally, a meta-analysis of 15 761 pregnancies with gestational diabetes and 205 828 without gestational diabetes was conducted to estimate the pooled mean difference in height between those with gestational diabetes and control subjects. RESULTS: Height was inversely associated with gestational diabetes risk across races/ethnicities, with the strongest association among Asians (P for interaction < 0.01). Comparing extreme quartiles (> 168 vs. < 157 cm), adjusted odds ratios (95% confidence intervals) were 0.18 (0.09-0.36) for Asians/Pacific Islanders, 0.33 (0.29-0.38) for non-Hispanic white women, 0.39 (0.31-0.51) for Hispanics and 0.59 (0.47-0.75) for non-Hispanic black women. Meta-analysis found women with gestational diabetes to be significantly shorter than others. CONCLUSIONS: Taller women are at lower risk of developing gestational diabetes, with the magnitude of association varying significantly across races/ethnicities.

Gestational diabetes, pre-pregnancy obesity and pregnancy weight gain in relation to excess fetal growth: variations by race/ethnicity.

AIMS/HYPOTHESIS: The escalating rate of childhood obesity is a public health concern worldwide, with children in certain ethnic groups being disproportionately affected. Our objective was to examine the joint effects of pre-pregnancy adiposity, pregnancy weight gain and gestational diabetes (GDM) in relation to excess fetal growth and to identify susceptible races or ethnic populations. METHODS: The risk for delivery of a large-for-gestational-age (LGA) infant, specific to race and fetal sex, was evaluated in 105,985 pregnancies in the Consortium on Safe Labor from 2002-2008. Generalised estimating equations were used to estimate the risk for delivery of LGA infants. Joint effects were employed to evaluate the interplay of three risk factors. Models were stratified by racial group considering one, two or three factors (i.e. pre-pregnancy adiposity, pregnancy weight gain and GDM, with 0 factors as the reference group). RESULTS: Greater pre-pregnancy adiposity, pregnancy weight gain and GDM were independently associated with increased risk of giving birth to an LGA infant across all races (except GDM among non-Hispanic whites), in both underweight and normal-weight women. Among non-Hispanic white, non-Hispanic black and Hispanic women, the three-factor joint effect was associated with substantially increased odds of LGA (OR [95% CI] 11.27 [8.40, 15.11], 7.09 [4.81, 10.45] and 10.19 [6.84, 15.19], respectively). However, for Asian women the joint effect of all three factors (OR [95% CI] 5.14 [2.11, 12.50]) was approximately the same as any of the two factors. CONCLUSIONS/INTERPRETATION: GDM, pre-pregnancy obesity and excessive pregnancy weight gain were jointly associated with elevated risk of giving birth to an LGA infant and the effects varied by race. This suggests that those involved in public health efforts aimed at preventing LGA deliveries should consider variations in racial groups when devising effective strategies.

Self-organized bursts of coherent stimulated Raman scattering and hot electron transport in speckled laser plasma media.

Nonlinear electron trapping physics governs the onset and saturation of stimulated Raman scattering (SRS) in laser beams with many speckles. Hot electrons from intense speckles, produced during SRS daughter electron-plasma-wave bowing and filamentation, seed and enhance the growth of SRS in neighboring speckles by reducing Landau damping. Trapping-induced nonlinearity and speckle interaction through transport of hot electrons and back- and sidescattered SRS waves enable the system of speckles to self-organize and exhibit coherent, sub-ps SRS bursts with more than 100% instantaneous reflectivity, consistent with a SRS transverse coherence width much larger than a speckle width.

Three-dimensional dynamics of breakout afterburner ion acceleration using high-contrast short-pulse laser and nanoscale targets.

Breakout afterburner (BOA) laser-ion acceleration has been demonstrated for the first time in the laboratory. In the BOA, an initially solid-density target undergoes relativistically induced transparency, initiating a period of enhanced ion acceleration. First-ever kinetic simulations of the BOA in three dimensions show that the ion beam forms lobes in the direction orthogonal to laser polarization and propagation. Analytic theory presented for the electron dynamics in the laser ponderomotive field explains how azimuthal symmetry breaks even for a symmetric laser intensity profile; these results are consistent with recent experiments at the Trident laser facility.

Monoenergetic ion beam generation by driving ion solitary waves with circularly polarized laser light.

Experimental data from the Trident Laser facility is presented showing quasimonoenergetic carbon ions from nm-scaled foil targets with an energy spread of as low as ±15% at 35 MeV. These results and high-resolution kinetic simulations show laser acceleration of quasimonoenergetic ion beams by the generation of ion solitons with circularly polarized laser pulses (500 fs, λ=1054 nm). The conversion efficiency into monoenergetic ions is increased by an order of magnitude compared with previous experimental results, representing an important step towards applications such as ion fast ignition.

The use of hypnosis to enhance recall.

The forensic use of hypnosis is increasing. A hypermnesic procedure was used in an experiment that calls this practice into question. Subjects tried for a week to recall 60 previously presented pictures. They were then either hypnotized or not and encouraged to recall even more pictures. Most of the newly recalled material was incorrect, especially for highly hypnotizable subjects in the hypnosis condition. Such errors in recall can have profound implications for forensic investigations.

PCO2 and room air saturation values in premature infants at risk for bronchopulmonary dysplasia.

OBJECTIVE: To determine the capillary partial pressure of carbon dioxide (PCO(2)) and room air transcutaneous hemoglobin saturation (RA SAT) at 36 weeks' postmenstrual age (PMA) in infants born with weight between 501 and 1250 g. STUDY DESIGN: Multicenter, prospective investigation with primary data collection within 72 h of 36 weeks PMA or discharge, whichever first. PCO(2) and RA SAT determinations were done at rest on infants not requiring mechanical ventilation or nasal continuous positive airway pressure (NCPAP). RESULT: A total of 220 infants were enrolled (mean gestational age 27.7 weeks, mean birthweight 951 g). In infants with traditionally defined chronic lung disease (CLD) compared to those without CLD, the mean PCO(2) was significantly higher (54 versus 45 mm Hg) and the median RA SAT significantly lower (<80 versus 97%). In infants with the new classification of bronchopulmonary dysplasia (BPD), there was a significant linear trend toward increasing PCO(2) with increasing severity of BPD (45, 47, 54 and 62 mm Hg in No, Mild, Moderate and Severe BPD). There was a significant linear trend toward decreasing RA SAT with increasing severity of BPD (97, 95 <80, <80% in No, Mild, Moderate and Severe BPD). CONCLUSION: Defining CLD as BPD based upon a RA SAT test is a more discriminate, objective method to categorize lung injury. PCO(2) is an objective measure of lung function that inversely correlates with RA SAT. These determinations done together at 36 weeks PMA may provide more precise and accurate estimates of lung injury that might allow for better understanding of pulmonary therapies and clearer comparison of BPD rates and severities among NICUs.

The sodium/proton exchanger Nhx1p is required for endosomal protein trafficking in the yeast Saccharomyces cerevisiae.

We show that the vacuolar protein sorting gene VPS44 is identical to NHX1, a gene that encodes a sodium/proton exchanger. The Saccharomyces cerevisiae protein Nhx1p shows high homology to mammalian sodium/proton exchangers of the NHE family. Nhx1p is thought to transport sodium ions into the prevacuole compartment in exchange for protons. Pulse-chase experiments show that approximately 35% of the newly synthesized soluble vacuolar protein carboxypeptidase Y is missorted in nhx1 delta cells, and is secreted from the cell. nhx1 delta cells accumulate late Golgi, prevacuole, and lysosome markers in an aberrant structure next to the vacuole, and late Golgi proteins are proteolytically cleaved more rapidly than in wild-type cells. Our results show that efficient transport out of the prevacuolar compartment requires Nhx1p, and that nhx1 delta cells exhibit phenotypes characteristic of the "class E" group of vps mutants. In addition, we show that Nhx1p is required for protein trafficking even in the absence of the vacuolar ATPase. Our analysis of Nhx1p provides the first evidence that a sodium/proton exchange protein is important for correct protein sorting, and that intraorganellar ion balance may be important for endosomal function in yeast.

Cluster of differentiation antigen 4 (CD4) endocytosis and adaptor complex binding require activation of the CD4 endocytosis signal by serine phosphorylation.

Cluster of differentiation antigen 4 (CD4), the T lymphocyte antigen receptor component and human immunodeficiency virus coreceptor, is down-modulated when cells are activated by antigen or phorbol esters. During down-modulation CD4 dissociates from p56(lck), undergoes endocytosis through clathrin-coated pits, and is then sorted in early endosomes to late endocytic organelles where it is degraded. Previous studies have suggested that phosphorylation and a dileucine sequence are required for down-modulation. Using transfected HeLa cells, in which CD4 endocytosis can be studied in the absence of p56(lck), we show that the dileucine sequence in the cytoplasmic domain is essential for clathrin-mediated CD4 endocytosis. However, this sequence is only functional as an endocytosis signal when neighboring serine residues are phosphorylated. Phosphoserine is required for rapid endocytosis because CD4 molecules in which the cytoplasmic domain serine residues are substituted with glutamic acid residues are not internalized efficiently. Using surface plasmon resonance, we show that CD4 peptides containing the dileucine sequence bind weakly to clathrin adaptor protein complexes 2 and 1. The affinity of this interaction is increased 350- to 700-fold when the peptides also contain phosphoserine residues.

The human cytomegalovirus US28 protein is located in endocytic vesicles and undergoes constitutive endocytosis and recycling.

Genes encoding chemokine receptor-like proteins have been found in herpes and poxviruses and implicated in viral pathogenesis. Here we describe the cellular distribution and trafficking of a human cytomegalovirus (HCMV) chemokine receptor encoded by the US28 gene, after transient and stable expression in transfected HeLa and Cos cells. Immunofluorescence staining indicated that this viral protein accumulated intracellularly in vesicular structures in the perinuclear region of the cell and showed overlap with markers for endocytic organelles. By immunogold electron microscopy US28 was seen mostly to localize to multivesicular endosomes. A minor portion of the protein (at most 20%) was also expressed at the cell surface. Antibody-feeding experiments indicated that cell surface US28 undergoes constitutive ligand-independent endocytosis. Biochemical analysis with the use of iodinated ligands showed that US28 was rapidly internalized. The high-affinity ligand of US28, the CX(3)C-chemokine fractalkine, reduced the steady-state levels of US28 at the cell surface, apparently by inhibiting the recycling of internalized receptor. Endocytosis and cycling of HCMV US28 could play a role in the sequestration of host chemokines, thereby modulating antiviral immune responses. In addition, the distribution of US28 mainly on endosomal membranes may allow it to be incorporated into the viral envelope during HCMV assembly.

An examination of the spatial distribution of the tissue fragments created during a single explosive attack.

Throughout the course of a forensic investigation following an explosive attack, the identification and recovery of tissue fragments is of extreme importance. There are few universally accepted methods to achieve this end. This project aims to explore this issue through the examination of the spatial distribution of the tissue fragments resulting from an explosive event. To address this, a two stage pilot study was conducted: first, a series of controlled explosions on porcine carcases was undertaken. Second, the data produced from these explosions were used to chart the spatial distribution of the tissue debris. In the controlled explosions, 3kg military grade explosive was chosen to create the maximum amount of fragmentation; this level of explosive also prevented the complete disappearance of forensic evidence through evaporation. Additionally, the blast created by military grade explosive is highly powerful and would mean that the maximum possible distance was achieved and would therefore allow the recorded distances and pattern spread to be a guideline for forensic recovery of associated with an explosive amount of an unknown size and quality. A total station was employed to record the location of the resulting forensic evidence, with the collected data analysed using R Studio. The observed patterns suggested that the distribution of remains is fairly consistent in trials under similar environmental conditions. This indicates potential for some general guidelines for forensic evidence collection (for example, the distance from the explosion that a search should cover).

Complications of biliary-enteric anastomoses.

INTRODUCTION Biliary-enteric anastomoses are performed for a range of indications and may result in early and late complications. The aim of this study was to assess the risk factors and management of anastomotic leak and stricture following biliary-enteric anastomosis. METHODS A retrospective analysis of the medical records of patients who underwent biliary-enteric anastomoses in a tertiary referral centre between 2000 and 2010 was performed. RESULTS Four hundred and sixty-two biliary-enteric anastomoses were performed. Of these, 347 (75%) were performed for malignant disease. Roux-en-Y hepaticojejunostomy or choledocho-jejunostomy were performed in 440 (95%) patients. Perioperative 30-day mortality was 6.5% (n=30). Seventeen patients had early bile leaks (3.7%) and 17 had late strictures (3.7%) at a median of 12 months. On univariable logistic regression analysis, younger age was a significant risk factor for biliary anastomotic leak. However, on multivariable analysis only biliary reconstruction following biliary injury (odds ratio [OR]=6.84; p=0.002) and anastomosis above the biliary confluence (OR=4.62; p=0.03) were significant. Younger age and biliary reconstruction following injury appeared to be significant risk factors for biliary strictures but multivariable analysis showed that only younger age was significant. CONCLUSIONS Biliary-enteric anastomoses have a low incidence of early and late complications. Biliary reconstruction following injury and a high anastomosis (above the confluence) are significant risk factors for anastomotic leak. Younger patients are significantly more likely to develop an anastomotic stricture over the longer term.

Characterization of a selective and potent antagonist of human P2X(7) receptors, AZ11645373.

BACKGROUND AND PURPOSE: The ATP-gated P2X(7) receptor has been shown to play a role in several inflammatory processes, making it an attractive target for anti-inflammatory drug discovery. We have recently identified a novel set of cyclic imide compounds that inhibited P2X(7) receptor-mediated dye uptake in human macrophage THP-1 cells. In this study the actions and selectivity of one of these compounds, AZ11645373, were characterized. EXPERIMENTAL APPROACH: We measured membrane currents, calcium influx, and YOPRO-1 uptake from HEK cells expressing individual P2X receptors, and YOPRO1 uptake and interleukin-1beta release from THP-1 cells in response to ATP and the ATP analogue benzoylbenzoyl ATP (BzATP). KEY RESULTS: AZ11645373 up to 10 microM, had no agonist or antagonist actions on membrane currents due to P2X receptor activation at human P2X(1), rat P2X(2), human P2X(3), rat P2X(2/3), human P2X(4), or human P2X(5) receptors expressed in HEK cells. AZ11645373 inhibited human P2X(7) receptor responses in HEK cells in a non-surmountable manner with K (B) values ranging from 5 - 20 nM, with mean values not significantly different between assays. K (B) values were not altered by removing extracellular calcium and magnesium. ATP-evoked IL-1beta release from lipopolysaccharide-activated THP-1 cells was inhibited by AZ11645373, IC(50) = 90 nM. AZ11645373 was > 500-fold less effective at inhibiting rat P2X(7) receptor-mediated currents with less than 50% inhibition occurring at 10 microM. CONCLUSIONS AND IMPLICATIONS: AZ11645373 is a highly selective and potent antagonist at human but not rat P2X(7) receptors and will have much practical value in studies of human cells.

Endogenous monocyte chemoattractant protein-1 recruits monocytes in the zymosan peritonitis model.

The role of monocyte chemoattractant protein-1 (MCP-1) in the recruitment of blood-derived monocytes in a model of zymosan peritoneal inflammation was investigated. After zymosan injection (1 mg) a rapid influx of polymorphonuclear leukocytes (PMN) and monocytes into the peritoneal cavity associated with mouse MCP-1 (JE) gene activation and protein secretion in the exudates occurred. MCP-1 production (maximal at 4 h) preceded the accumulation of monocytes (F4/80-positive cells, maximally recovered between 16 and 24 h). Treatment of mice with a single injection of anti-mouse MCP-1 antibody inhibited 16-h monocyte accumulation by approximately 40%, however, a significant decrease in the number of PMN was also measured. Finally, intraperitoneal injection of murine recombinant MCP-1 (1 microg) produced a selective accumulation of monocytes (F4/80-positive cells) into the peritoneal cavity. In conclusion, we show the novel existence of a strict relationship between MCP-1 production and leukocyte accumulation in this model of acute inflammation.

Continuous measurements of cytoplasmic ATP in single cardiomyocytes during simulation of the "oxygen paradox".

OBJECTIVE: It is now possible to monitor cytoplasmic ATP in single cardiomyocytes and it has recently been shown that cardiomyocytes exposed for several minutes to metabolic inhibitors undergo an abrupt rigor mediated shortening which coincides with a sudden fall in cytoplasmic ATP, from approximately 150 mumol.litre-1 to a few micromolar or less. The objective of this work was to monitor cytoplasmic ATP during simulated reoxygenation of a poisoned cardiomyocyte. METHODS: Firefly luciferase was injected into a single cell and the light signal generated when luciferin was superfused was monitored. Calibration of the signal is complicated by a transient enhancement of the signal (possibly the result of complex luciferase kinetics), and by uncertainties about cytoplasmic pH. RESULTS: The data indicate that millimolar levels of cytoplasmic ATP are restored within 1-2 min of cyanide removal. CONCLUSIONS: Cytoplasmic free calcium is known to rise after poisoned cells undergo shortening, so it is conceivable that the restoration of cytoplasmic ATP in a cell in which free calcium is at micromolar levels may provide a plausible cellular mechanism for the "oxygen paradox". Reoxygenation induces large amplitude, but slow, oscillations in free calcium which, together with the millimolar levels of ATP indicated here, could provide the stimuli for generating the uncoordinated mechanical forces that are prevalent in the oxygen paradox.

Probing minimal independent folding units in dihydrofolate reductase by molecular dissection.

Molecular dissection was employed to identify minimal independent folding units in dihydrofolate reductase (DHFR) from Escherichia coli. Eight overlapping fragments of DHFR, spanning the entire sequence and ranging in size from 36 to 123 amino acids, were constructed by chemical cleavage. These fragments were designed to examine the effect of tethering multiple elements of secondary structure on folding and to test if the secondary structural domains represent autonomous folding units. CD and fluorescence spectroscopy demonstrated that six fragments containing up to a total of seven alpha-helices or beta-strands and, in three cases, the adenine binding domain (residues 37-86), are largely disordered. A stoichiometric mixture of the two fragments comprising the large discontinuous domain, 1-36 and 87-159, also showed no evidence for folding beyond that observed for the isolated fragments. A fragment containing residues 1-107 appears to have secondary and tertiary structure; however, spontaneous self-association made it impossible to determine if this structure solely reflects the behavior of the monomeric form. In contrast, a monomeric fragment spanning residues 37-159 possesses significant secondary and tertiary structure. The urea-induced unfolding of fragment 37-159 in the presence of 0.5 M ammonium sulfate was found to be a well-defined, two-state process. The observation that fragment 37-159 can adopt a stable native fold with unique, aromatic side-chain packing is quite striking because residues 1-36 form an integral part of the structural core of the full-length protein.

CD4: a co-receptor in the immune response and HIV infection.

CD4 is a transmembrane glycoprotein of the immunoglobulin superfamily, expressed on developing thymocytes, major histocompatibility class II (class II MHC) restricted mature T lymphocytes and, in humans, on cells of the macrophage/monocyte lineage. On lymphoid cells, CD4 plays a critical role during thymocyte ontogeny and in the function of mature T cells. CD4 binds to non-polymorphic regions of class II MHC acting as a co-receptor for the T-cell antigen receptor (TCR). It increases avidity between thymocytes and antigen-presenting cells and contributes directly to signal transduction through association with the Src-like protein tyrosine kinase p56lck. Its precise role on monocytes and macrophages is unclear. CD4 is also a co-receptor for the human and simian immunodeficiency viruses (HIV-1, HIV-2 and SIV). Clinically, CD4 antibodies may be used to achieve immunological tolerance to grafts and transplants.

Selective hypnotic amnesia: is it a successful attempt to forget or an unsuccessful attempt to remember?

Subjects in 2 experiments (ns = 72 and 50) learned a 16-item, 4-category word list and were then administered hypnotic suggestions to be amnesic for all the words in 1 of the categories. Even when selective amnesia was completely successful, subjects in both experiments revealed a high level of recall for words not targeted for amnesia; moreover, these words were recalled in a highly organized, category-by-category fashion. Evidently, attention to relevant retrieval (i.e., organizational) cues does not oblige recall of words targeted for amnesia. Forgetting in the presence of such powerful mnemonic cues seems to characterize hypnotic amnesia and some spontaneous forms of forgetting as well. We argue that mnemonic lapses of this kind represent a failed attempt to remember rather than a successful attempt to forget.