Role of aromatic stacking interactions in the modulation of the two-electron reduction potentials of flavin and substrate/product in Megasphaera elsdenii short-chain acyl-coenzyme A dehydrogenase.
The effects of aromatic stacking interactions on the stabilization of reduced flavin adenine dinucleotide (FAD) and substrate/product have been investigated in short-chain acyl-coenzyme A dehydrogenase (SCAD) from Megasphaera elsdenii. Mutations were made at the aromatic residues Phe160 and Tyr366, which flank either face of the noncovalently bound flavin cofactor. The electrochemical properties of the mutants were then measured in the presence and absence of a butyryl-CoA/crotonyl-CoA mixture. Results from these redox studies suggest that the phenylalanine and tyrosine both engage in favorable pi-sigma interactions with the isoalloxazine ring of the flavin to help stabilize formation of the anionic flavin hydroquinone. Disruption of these interactions by replacing either residue with a leucine (F160L and Y366L) causes the midpoint potential for the oxidized/hydroquinone couple (E(ox/hq)) to shift negative by 44-54 mV. The E(ox/hq) value was also found to decrease when aromatic residues containing electron-donating heteroatoms were introduced at the 160 position. Potential shifts of -32 and -43 mV for the F160Y and F160W mutants, respectively, are attributed to increased pi-pi repulsive interactions between the ring systems. This study also provides evidence for thermodynamic regulation of the substrate/product couple in the active site of SCAD. Binding to the wild-type enzyme caused the midpoint potential for the butyryl-CoA/crotonyl-CoA couple (E(BCoA/CCoA)) to shift 14 mV negative, stabilizing the oxidized product. Formation of product was found to be even more favorable in complexes with the F160Y and F160W mutants, suggesting that the electrostatic environment around the flavin plays a role in substrate/product activation.


Reconstructive treatment of posterolateral rotatory instability of the knee: a biomechanical study.
Twelve cadaveric knees were tested to determine effective reconstructive treatment for severe chronic posterolateral rotatory knee instability accompanied by excessive varus and posterior laxity. Posterolateral, varus, and posterior laxity were measured, first with the ligaments intact, then after complete sectioning of the posterior cruciate ligament (PCL) and posterolateral structures, and finally after reconstruction of these structures in different orders. The increases in those laxities were produced following the sectioning of all of the structures and disappeared throughout the flexion range after combined reconstruction of the PCL, lateral collateral ligament (LCL), and popliteus tendon. However, some residual increase in the laxity was always observed if any of the three structures were excluded from reconstruction. Therefore, combined reconstruction of the PCL, LCL, and popliteus tendon is essential and adequate for treating severe chronic posterolateral rotatory instability.


A novel method for source-specific hemoglobin adducts of nitro-polycyclic aromatic hydrocarbons.
Polycyclic aromatic hydrocarbons (PAH) are ubiquitous air pollutants associated with negative impacts on growth, development and behavior in children. Source-specific biological markers of PAH exposure are needed for targeting interventions to protect children. Nitro-derivatives of PAH can act as markers of exposure to diesel exhaust, gasoline exhaust, or general combustion sources. Using a novel HPLC-APCI-MS/MS detection method, we examined four hemoglobin (Hb) adducts of nitro-PAH metabolites and the Hb adduct of a benzo[a]pyrene (BaP) metabolite in 22 umbilical cord blood samples. The samples were collected from a birth cohort with comprehensive data on prenatal PAH exposure, including prenatal personal air monitoring and DNA adducts in maternal and umbilical cord blood. Using non-parametric analyses, heat maps, and principal component analysis (PCA), we analyzed the relationship between the five Hb adducts and previous PAH measurements, with each measurement representing a different duration of exposure. We found that Hb adducts derived from several diesel-related nitro-PAHs (2-nitrofluorene and 1-nitropyrene) were significantly correlated (r = 0.77, p ≤ 0.0001) and grouped together in PCA. Nitro-PAH derived Hb adducts were largely unrelated to previously collected measures of exposure to a number of PAH parent compounds. These measures need to be validated in a larger sample.


GHB free acid: I. Solution formation studies and spectroscopic characterization by 1HNMR and FT-IR.
In forensic evidence, gamma-hydroxybutyric acid (GHB) has frequently been encountered in one of its salt forms (gamma-hydroxybutyrate), but has also been encountered in its free acid form (GHB). Owing to the physical properties, encounters of the free acid have been largely restricted to forensic exhibits comprising aqueous solutions, such as acidic beverages that have been "spiked" or formulated with GHB salts or gamma-butyrolactone (GBL). The analysis of GHB free acid presents particular difficulties including the potential for altering the original proportions of GHB free acid, GHB carboxylate, and GBL in the course of analysis, and discrimination between GHB free acid and carboxylate forms. In this work, the formation of GHB free acid in aqueous solutions (water and/or D2O) was studied as a function of solution pH. Proton nuclear magnetic resonance (1HNMR) and Fourier-transform infrared spectrometry (FT-IR) measurements were obtained on freshly prepared mixtures of NaGHB and HCl stock solutions representing a series of points along the GHB titration curve. Both 1HNMR and FT-IR were shown to track the changing proportions of GHB free acid and carboxylate forms as a function of pH, while simultaneously monitoring for the formation of the lactone (GBL). The results were consistent with acid-base conversion behavior for a carboxylic acid. 1HNMR was shown to provide an ideal means for analysis of aqueous-based GHB/GBL forensic exhibits based on simple dilution of the neat liquid exhibit, without altering the original proportions of GHB free acid, carboxylate, and GBL in the samples.


Primary dexamethasone treatment of multiple myeloma.
Intermittent courses of dexamethasone (DEX) were administered to 112 consecutive, previously untreated patients with multiple myeloma (MM). Using criteria based on a 75% or greater reduction of calculated tumor mass, the overall response rate was 43%. Among comparable patients, response rate were approximately 15% less than those observed previously with vincristine-doxorubicin by continuous infusion with intermittent DEX (VAD) and similar to those with melphalan-prednisone. The projected survival times with VAD or DEX were similar. Results indicated that DEX accounted for most of the plasma cell reduction achieved with VAD. Serious complications occurred in 27% of patients treated with VAD, but in only 4% of those who received DEX. In view of the similar outcome with fewer serious complications, DEX provided a simple, effective, and safe primary treatment for a large fraction of patients with MM. Patients who appear most likely to benefit include those with hypercalcemia or pancytopenia, or who require simultaneous radiotherapy for a pathologic fracture.


The size of an attentional window affects working memory guidance.
We ask whether attentional guidance from working memory (WM) is influenced by the size of an attentional window. Participants adopted either a focused or a diffuse attentional window when responding to a search display. Prior to the search display an initial cue had to be held in memory (Experiment 1A, visual WM; Experiment 1C, verbal WM) or merely identified (Experiment 1B, identification). In all cases, search performance was affected by the re-presentation of the cue in the search display, with the cuing effects (either cost or benefit) being larger when the cue was held in memory than when it was merely identified. Critically, the magnitude of the cuing benefit increased when participants adopted a diffuse attentional window. This held for effects that are based on items held in WM and for effects that are based only on item priming. The results suggest that variations in the size of an attentional window modulate top-down (both WM conditions) as well as bottom-up guidance of attention (identification condition).


Quantitative dynamic nuclear polarization-NMR on blood plasma for assays of drug metabolism.
Analytical platforms for the fast detection, identification and quantification of circulating drugs with a narrow therapeutic range are vital in clinical pharmacology. As a result of low drug concentrations, analytical tools need to provide high sensitivity and specificity. Dynamic nuclear polarization-NMR (DNP-NMR) in the form of the hyperpolarization-dissolution method should afford the sensitivity and spectral resolution for the direct detection and quantification of numerous isotopically labeled circulating drugs and their metabolites in single liquid-state NMR transients. This study explores the capability of quantitative in vitro DNP-NMR to assay drug metabolites in blood plasma. The lower limit of detection for the anti-epileptic drug (13)C-carbamazepine and its pharmacologically active metabolite (13)C-carbamazepine-10,11-epoxide is 0.08 µg/mL in rabbit blood plasma analyzed by single-scan (13)C DNP-NMR. An internal standard is used for the accurate quantification of drug and metabolite. Comparison of quantitative DNP-NMR data with an established analytical method (liquid chromatography-mass spectrometry) yields a Pearson correlation coefficient r of 0.99. Notably, all DNP-NMR determinations were performed without analyte derivatization or sample purification other than plasma protein precipitation. Quantitative DNP-NMR is an emerging methodology which requires little sample preparation and yields quantitative data with high sensitivity for therapeutic drug monitoring.


Comparative study of serum MDA and vitamin C levels in non-smokers, chronic smokers and chronic smokers with acute myocardial infarction in men.
It is a well-known fact that there is increased oxidative stress and decreased serum antioxidant levels in smokers than in non-smokers. In this study, the aim was to compare the serum levels of malondialdehyde (MDA), a lipid peroxidation product and vitamin C, an antioxidant, between non- smokers (Group A) and chronic smokers (Group B) and also between chronic smokers (Group B) and chronic smokers with acute myocardial infarction (AMI) (Group C). Thirty six non-smokers and 36 chronic smokers appropriately matched with AMI patients were selected. Thirty six smokers with AMI were selected from Hanagal Kumareshwara hospital, Bagalkot, Karnataka, India. Fasting blood sample was collected in group A and group B. In AMI patients, blood sample was collected before any intervention. Serum levels of MDA and vitamin C were estimated. Statistical analysis was done by t test using SPSS version 11. The p< 0.05 was considered statistically significant. All the results were expressed as mean ± SD. The MDA and vitamin C were compared between Group A and Group B and also between Group B and Group C. There was a significant rise in MDA (p<0.0001) and significant decrease in vitamin C (p<0.01) in Group B compared to Group A. There was a significant rise in MDA (p<0.0001) and significant decrease in vitamin C (p<0.001) in Group C compared to Group B. The increase in serum MDA level and decrease in vitamin C was found in chronic smokers compared to non-smokers. It was also found that there is increase in serum MDA and decrease in vitamin C in smokers with AMI compared with smokers without AMI, and the reason for this inter-subject variability of MDA and vitamin C levels may be due to gene-environmental factors.


Chemical consequences of mechanical bonding in catenanes and rotaxanes: isomerism, modification, catalysis and molecular machines for synthesis.
Research on mechanically interlocked molecules has advanced substantially over the last five decades. A large proportion of the published work focusses on the synthesis of these challenging targets, and the subsequent control of the relative position of the covalent sub-components, to generate novel molecular devices and machines. In this Feature Article we instead review some of the less discussed consequences of mechanical bonding for the chemical behaviour of catenanes and rotaxanes, and their application in synthesis, including striking recent examples of molecular machines which carry out complex synthetic tasks.


Evidence of effectiveness of clinical audit in improving histopathology reporting standards of mastectomy specimens.
To assess the effectiveness of clinical audit in improving standards in histopathological reporting of mastectomy specimens. Reports on mastectomy specimens containing tumour issued by non-specialist histopathologists in 1990, 1992, 1994, and 1996 were scored for their information content. There were 10 reports evaluated from each year. Before 1990 no reporting guidelines had been formulated within the department. The audits in 1992 and 1994 were performed after agreed written guidelines (including the establishment of six essential pieces of information), and in 1996 the specimens were reported using a proforma. There was a significant increase in information after the introduction of written guidelines but there was a reduction in information over time. In 1990 none of the 10 reports included all six pieces of mandatory information; in 1992 four of the reports contained all mandatory information; in 1994 only one report contained all mandatory information. The introduction of a proforma for reporting resulted in further significant improvement with all 10 reports in 1996 containing all mandatory information. Successive rounds of audit increases the standard of reporting in histopathology. There is a need for continuing monitoring of standards as these may deteriorate over time. Reporting complex specimens on a proforma has a significant beneficial effect on information content.


CIP4 is a new ArgBP2 interacting protein that modulates the ArgBP2 mediated control of WAVE1 phosphorylation and cancer cell migration.
ArgBP2 is a multi-adapter protein involved in signal transduction associated to the cytoskeleton and was shown to regulate the migration and adhesion of pancreatic cancer cells thereby modulating their tumorigenicity. Here we describe the interaction of ArgBP2 with CIP4, a new associated protein identified by yeast two-hybrid. We found that both proteins modulated their reciprocal tyrosine phosphorylation catalyzed by the non-receptor tyrosine kinase c-Abl. We observed that, like ArgBP2, CIP4 directly interacted with WAVE1 and could enhance its phosphorylation by c-Abl. ArgBP2 and CIP4 acted synergistically to increase WAVE1 tyrosine phosphorylation. Finally, we could show that CIP4 was dispensable for the ArgBP2 induced blockade of cell migration whereas its overexpression was deleterious for this important function of ArgBP2.


Oxytocin modulates the pulsatile secretion of prostaglandin F2alpha in initiated luteolysis in cattle.
Subluteolytic doses of prostaglandin F2alpha analogue (oestrophan) given i.m. and oxytocin (OT) antagonist (CAP) and noradrenaline (NA) infused into the abdominal aorta were used to test the importance of luteal OT in pulsatile secretion of prostaglandin F2alpha (PGF) during luteolysis in heifers (n = 17). In experiment 1, heifers were pre-infused for 30 minutes with saline on either day 17 of the oestrous cycle (group 1; n = 4) or on day 18 of the oestrous cycle (group 2; n = 3), and with CAP (8 mg per animal) on day 17 of the oestrous cycle (group 3; n = 4). Next, heifers were injected with oestrophan (30 microg per animal). Injection of oestrophan in Group 3 increased OT concentrations (P < 0.001) to values similar to those observed during spontaneous luteolysis (50 to 70 pg ml(-1)). PGFM concentrations in this group also increased (P < 0.001), but were lower (P < 0.05) than the values in groups 1 and 2, CAP given prior to oestrophan decreased both PGFM elevation (P < 0.06) and its area under the curve (P < 0.01), compared to the saline pretreated heifers. In experiment 2 NA (4 mg) was infused twice for 30 minutes at five hour intervals to release OT on day 17 of the oestrous cycle (n = 6). However, during hormone analysis it appeared that three of six heifers had elevated PGFM concentrations (group 1) and three others did not (group 2). NA caused the correlated increase of progesterone and OT secretion (r = 0.68; P < 0.05) in both groups but it only influenced PGF secretion in group 1 only (P < 0.05). We postulate that OT can amplify and modulate the course of induced luteolysis as a regulator of the amplitude of pulsatile PGF secretion. PGF analogue stimulates secretion of endogenous PGF from the uterus in cattle and this may be an important component of the luteolytic response to exogenous PGF.


Clinical significance of tumor volume and lymph node involvement assessed by MRI in stage IIB cervical cancer patients treated with concurrent chemoradiation therapy.
The purpose of this study was to evaluate the prognostic significance of tumor volume assessed by pretreatment MRI in stage IIB cervical cancer patients with concurrent chemoradiation therapy. A retrospective chart review was performed on seventy five patients with cervical cancer who were treated with concurrent weekly cisplatin (40 mg/m(2)) and radiotherapy between January 2000 and April 2007. Potential prognostic factors were age, chemotherapy numbers, histology, tumor diameter and volume, lymph node (LN) involvement and pretreatment squamous cell carcinoma antigen (SCC-Ag) levels. The median follow-up time was 55 months (range, 8 to 104 months). The median tumor size and volume (range) were 4.5 cm (2 to 10) and 33.1 mL (4.2 to 392.7), respectively. Pelvic LN enlargement rate was 58.7%. Para-aortic LN enlargement rate was 14.7%. Using multivariate analysis, a tumor volume (>33 mL, p=0.025), pelvic LN enlargement (p=0.044) revealed a significantly unfavorable outcome on overall survival. PFS was influenced by tumor histology (p<0.001), pelvic LN enlargement (p=0.015) and pretreatment SCC-Ag levels (p=0.018). We found that 22 (29.3%) patients had recurrences and 14 (18.7%) patients died of disease. The 5-year overall survival rate was 80.6% (standard error, 4.9%) and 5-year PFS rate was 71.3% (standard error, 5.3%). Tumor volume and pelvic LN involvement showed possibility to predict overall survival in patient with stage IIB cervical cancer. Optimal tumor volume and pelvic LN assessment by pretreatment MRI might be helpful to predict treatment outcome.


Metasurface-Based Abrupt Autofocusing Beam for Biomedical Applications.
Manipulation and precise delivery of optical energies in the regions of interest within specimens require different strategies. Hence, proper control of input beam parameters is a prerequisite. One of the prominent methods is metasurface optics, capable of crafting properties of light at nanoscales. Here, the generation of an abrupt autofocusing (AAF) beam by a nanophotonic metasurface for biomedical applications is demonstrated. Fluorescence guided laser microprofiling of mouse cardiac samples is experimentally investigated, using the AAF beam to deliver optical energy selectively to specific locations. In addition, photocoagulation of ex vivo swine skin tissue is performed and observed through optical coherence tomography. The results show great potentials for integrating metasurface optics to realize miniature laser surgery instruments for wide applications in biomedicine.


Morphology of travel routes and the organization of cities.
The city is a complex system that evolves through its inherent social and economic interactions. Mediating the movements of people and resources, urban street networks offer a spatial footprint of these activities. Of particular interest is the interplay between street structure and its functional usage. Here, we study the shape of 472,040 spatiotemporally optimized travel routes in the 92 most populated cities in the world, finding that their collective morphology exhibits a directional bias influenced by the attractive (or repulsive) forces resulting from congestion, accessibility, and travel demand. To capture this, we develop a simple geometric measure, inness, that maps this force field. In particular, cities with common inness patterns cluster together in groups that are correlated with their putative stage of urban development as measured by a series of socio-economic and infrastructural indicators, suggesting a strong connection between urban development, increasing physical connectivity, and diversity of road hierarchies.


Accurate Multiobjective Design in a Space of Millions of Transition Metal Complexes with Neural-Network-Driven Efficient Global Optimization.
The accelerated discovery of materials for real world applications requires the achievement of multiple design objectives. The multidimensional nature of the search necessitates exploration of multimillion compound libraries over which even density functional theory (DFT) screening is intractable. Machine learning (e.g., artificial neural network, ANN, or Gaussian process, GP) models for this task are limited by training data availability and predictive uncertainty quantification (UQ). We overcome such limitations by using efficient global optimization (EGO) with the multidimensional expected improvement (EI) criterion. EGO balances exploitation of a trained model with acquisition of new DFT data at the Pareto front, the region of chemical space that contains the optimal trade-off between multiple design criteria. We demonstrate this approach for the simultaneous optimization of redox potential and solubility in candidate M(II)/M(III) redox couples for redox flow batteries from a space of 2.8 M transition metal complexes designed for stability in practical redox flow battery (RFB) applications. We show that a multitask ANN with latent-distance-based UQ surpasses the generalization performance of a GP in this space. With this approach, ANN prediction and EI scoring of the full space are achieved in minutes. Starting from ca. 100 representative points, EGO improves both properties by over 3 standard deviations in only five generations. Analysis of lookahead errors confirms rapid ANN model improvement during the EGO process, achieving suitable accuracy for predictive design in the space of transition metal complexes. The ANN-driven EI approach achieves at least 500-fold acceleration over random search, identifying a Pareto-optimal design in around 5 weeks instead of 50 years.


Contraception and ectopic pregnancy risk.
Studies of the association of ectopic pregnancy with contraception have generated a conflicting array of results because of methodologic differences between studies. We estimated the absolute incidence rates of ectopic pregnancy for various contraceptives by multiplying the pregnancy rate by the proportion of pregnancies with ectopic implantation for each method. Our results indicated a more than 500-fold difference in ectopic pregnancy incidence, from a low of 0.005 ectopic pregnancies per 1000 women years of oral contraception or vasectomy to a high of 2.6 per 1000 women years of no contraception. These estimated incidence rates should be useful for clinicians and patients seeking to better understand the risks and benefits of contraceptives.


Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia.
NK-cell leukemia is a clonal expansion of NK cells. The illness can occur in an aggressive or chronic form. We studied cell lines from human and rat NK-cell leukemias (aggressive NK-cell leukemia) as well as samples from patients with chronic NK-cell leukemia to investigate pathogenic mechanisms. Here we report that Mcl-1 was overexpressed in leukemic NK cells and that knockdown of Mcl-1 induced apoptosis in these leukemic cells. In vitro treatment of human and rat NK leukemia cells with FTY720 led to caspase-dependent apoptosis and decreased Mcl-1 expression in a time- and-dose-dependent manner. These biologic effects could be inhibited by blockade of reactive oxygen species generation and the lysosomal degradation pathway. Lipidomic analyses after FTY720 treatment demonstrated elevated levels of sphingosine, which mediated apoptosis of leukemic NK cells in vitro. Importantly, systemic administration of FTY720 induced complete remission in the syngeneic Fischer rat model of NK-cell leukemia. Therapeutic efficacy was associated with decreased expression of Mcl-1 in vivo. These data demonstrate that therapeutic benefit of FTY720 may result from both altered sphingolipid metabolism as well as enhanced degradation of a key component of survival signaling.


Driving performance and susceptibility to simulator sickness: are they related?
We examined whether participants who failed to complete a simulated drive because of simulator sickness (dropouts) differed from those who completed the simulation (completers). Thirteen healthy older adult dropouts (mean age = 74.8 yr) and 12 comparable completers were compared on the following variables: on-road driving performance, the Useful Field of View test, the Attention Network Test, and the Trail Making Test Part A. Results showed that completers scored more demerit points during the on-road drive than did dropouts. In addition, only 1 of 13 comparisons based on participants' cognition was statistically significant. These results suggest that in healthy senior drivers, simulator sickness does not prevent examination of those who need it most (i.e., those with the poorest on-road driving performance) and that cognitive differences are not associated with dropping out because of simulator sickness.


Unsupervised discovery of temporal sequences in high-dimensional datasets, with applications to neuroscience.
Identifying low-dimensional features that describe large-scale neural recordings is a major challenge in neuroscience. Repeated temporal patterns (sequences) are thought to be a salient feature of neural dynamics, but are not succinctly captured by traditional dimensionality reduction techniques. Here, we describe a software toolbox-called seqNMF-with new methods for extracting informative, non-redundant, sequences from high-dimensional neural data, testing the significance of these extracted patterns, and assessing the prevalence of sequential structure in data. We test these methods on simulated data under multiple noise conditions, and on several real neural and behavioral datas. In hippocampal data, seqNMF identifies neural sequences that match those calculated manually by reference to behavioral events. In songbird data, seqNMF discovers neural sequences in untutored birds that lack stereotyped songs. Thus, by identifying temporal structure directly from neural data, seqNMF enables dissection of complex neural circuits without relying on temporal references from stimuli or behavioral outputs.


Internet-delivered cognitive behavioral therapies for late-life depressive symptoms: a systematic review and meta-analysis.
Background: This study aimed to review and synthesize evidence related to the effectiveness of internet-based cognitive behavioral therapy (iCBT) for reducing depressive symptoms in older adults.Method: The authors conducted a systematic review of intervention studies testing iCBT for symptoms of depression in older adults. An initial search of PubMed, PsychINFO, and Web of Science was undertaken, followed by a manual search of reference lists of the relevant articles. The Cochrane Risk of Bias Tool was used to appraise study quality. The mean effect size for included studies was estimated in a random effects model. Meta-regression was used to examine potential moderators of effect sizes.Results: Nine studies met the inclusion criteria, including 1272 participants averaging 66 years of age. The study design included randomized controlled trials (k = 3), controlled trials without randomization (k = 2), uncontrolled trials (k = 2), and naturalistic evaluation (k = 2). Seven studies tested iCBT with some level of therapist involvement and 2 examined self-guided iCBT. Six studies tested interventions specifically adapted for older adults. The mean within-group effect size was 1.27 (95% CI = 1.09, 1.45) and the mean between-group effect size was 1.18 (95% CI = 0.63, 1.73). Participants' age was negatively associated with within-group effect sizes (b = -0.06, p = .016).Conclusions: iCBT is a promising approach for reducing depressive symptoms among older adults with mild to moderate depressive symptoms. However, studies involving older adults in iCBT trials were limited, had considerable heterogeneity, and were of low quality, calling for more studies with rigorous designs to produce a best-practice guideline.


The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses.
Inhibitors of dipeptidylpeptidase IV (DPP-IV) represent a novel class of frequently used anti-diabetic drugs. In addition to its function in metabolic regulation, DPP-IV also plays a role in the immune system. Whether the DPP-IV inhibitors sitagliptin, vildagliptin or saxagliptin impair immune responses is, however, currently unknown. Here, we investigated the effect of these agents on both innate and adaptive immunity. We found that the DPP-IV inhibitors did not affect the innate immune response induced by Toll-like receptor (TLR) ligands, as cytokine secretion and induction of co-stimulatory molecules by human blood mononuclear cells was not impaired. Furthermore, proliferation of T cells and suppressive function of regulatory T cells was preserved. Mice treated with vildagliptin showed normal cytokine production, immune cell activation and lymphocyte trafficking upon TLR activation. Thus, crucial immunological parameters remain unaffected upon treatment with DPP-IV inhibitors, a fact that is reassuring with respect to safety of these drugs.


Use of HRT and the subsequent risk of cancer.
At least 20 million women in developed countries are estimated to be currently using hormone replacement therapy (HRT). Almost 100 epidemiological studies have reported on the relationship between the use of HRT and the risk of cancer of female reproductive organs, namely the breast, uterus or ovary. Cancer at these sites is common and there are a priori reasons why the use of hormonal therapy to 'replace' the endogenous production of ovarian hormones after the menopause might increase the risk of these cancers. The available evidence indicates that the risk of breast cancer or endometrial cancer is increased while women are using HRT, the risk increasing with increasing duration of use. Most of the evidence about these cancers relates to use of HRT preparations containing oestrogens alone. The limited evidence about combination therapy, with oestrogens and progestogens, suggests that, compared to oestrogens alone, the effect on the breast is similar, but the effect on the endometrium is diminished, the diminution in risk being greater the more days each month that progestogens are used. The effect of HRT on breast cancer wears off after use ceases and has disappeared largely, if not wholly, within 5 years, whereas the effects on endometrial cancer take longer to wear off, if at all. The breast and endometrial cancers that are diagnosed in HRT users are less aggressive clinically than cancers in never-users but, as yet, there is little reliable information about the relationship between use of HRT and mortality from these cancers. For other cancer sites, the existing data about the effects of HRT are inconclusive. The longer the period of use of HRT, the greater the excess incidence of cancer of the breast and endometrium is likely to be. Use of HRT for short periods of time should have little effect on the incidence of these cancers. The cumulative excess incidence in 1000 women who used HRT for 10 years, beginning at age 50, is estimated to be six for breast cancer, 42 for endometrial cancer in women with an intact uterus using oestrogen therapy alone and about 20 for endometrial cancer in women with an intact uterus using oestrogen-progestogen combinations. The estimate for combined therapy is based on small numbers and may well vary with the type of preparation used. The overall balance between the excess incidence of these cancers and other effects of HRT needs to be evaluated carefully and will require more reliable data than exist at present.


Cobalt, chromium and nickel affect hydroxyapatite crystal growth in vitro.
Metals are widely used in orthopaedics and recent studies have reported that patients with metal implants have a significant increase of metal levels in serum and synovial fluid. Femoral neck fracture occurred in some patients with metal-on-metal implants for unknown reasons. Recently, bone quality has emerged as an important factor of bone strength and few studies have investigated the effects of metal ions on hydroxyapatite properties. In the present study, we investigated the effects of Co(2+), Cr(3+) and Ni(2+) on hydroxyapatite (HA) growth in vitro, using carboxymethylated poly(2-hydroxyethyl methacrylate) (pHEMA) as a biomaterial for calcification. We have demonstrated that metal ions reduced the quantity of mineral formed at the surface of the polymer and decreased the ratio Ca/P by 1.12-, 1.05- and 1.08-fold for Cr(2+), Cr(3+) and Ni(2+) respectively. Furthermore, the size of calcospherites was significantly increased in the metal-doped HA compared to the controls, indicating a possible effect of metal ions on the crystal lattice. Indeed, the presence of metal ions increased the crystal size as well as the crystallinity of HA and reduce the lattice parameter c of the HA framework. The information obtained from this work suggests that the quality of the mineral around metallic implants could be altered. However, further investigation should be conducted to further elucidate the effects of metal incorporation on bone mineral and the functional consequences.


Obesity and recovery from acute kidney injury (Ob AKI): a prospective cohort feasibility study.
To test the methodology of recruitment, retention and data completeness in a prospective cohort recruited after a hospitalised episode of acute kidney injury (AKI), to inform a future prospective cohort study examining the effect of obesity on AKI outcomes. Feasibility study. Single centre, multi-site UK tertiary hospital. 101 participants (67M; 34F) with a median age of 64 (IQR 53-73) years, with and without obesity, recruited within 3 months of a hospitalised episode of AKI. Feasibility outcomes were recruitment (>15% meeting inclusion criteria recruited), participant retention at 6 and 12 months (≥80%) and completeness of data collection. Exploratory measures included recovery from AKI (regaining >75% of pre-AKI estimated glomerular filtration rate [eGFR]) at 6 months, development or progression of chronic kidney disease (CKD) (kidney function decrease of ≥25% + rise in CKD category) at 12 months, and associations with poorer kidney outcomes. 41% of eligible patients consented to take part, exceeding the target recruitment uptake rate of 15%. Retention was 86% at 6 months and 78% at 12 months; 10 patients died and three commenced dialysis during the study. Data were 90%-100% complete. Median BMI was 27.9 kg/m2 (range 18.1 kg/m2-54.3 kg/m2). 50% of the cohort had stage 3 AKI and 49% had pre-existing CKD. 46% of the cohort met the AKI recovery definition at 6 months. At 12 months, 20/51 patients developed CKD (39%) and CKD progression occurred in 11/49 patients (22%). Post-AKI interleukin-6 and cystatin-C were associated with 12 months decline in eGFR. Feasibility to conduct a long-term observational study addressing AKI outcomes associated with obesity was demonstrated. A fully powered prospective cohort study to examine the relationships between obesity and outcomes of AKI is warranted.


Association of coffee drinking with all-cause mortality: a systematic review and meta-analysis.
We aimed to use the meta-analysis method to assess the relationship between coffee drinking and all-cause mortality. Categorical and dose-response meta-analyses were conducted using random-effects models. We systematically searched and identified eligible literature in the PubMed and Scopus databases. Seventeen studies including 1 054 571 participants and 131 212 death events from all causes were included in the present study. Seventeen studies were included and evaluated in the meta-analysis. A U-shaped dose-response relationship was found between coffee consumption and all-cause mortality (P for non-linearity <0.001). Compared with non/occasional coffee drinkers, the relative risks for all-cause mortality were 0.89 (95 % CI 0.85, 0.93) for 1-<3 cups/d, 0.87 (95 % CI 0.83, 0.91) for 3-<5 cups/d and 0.90 (95 % CI 0.87, 0.94) for ≥5 cups/d, and the relationship was more marked in females than in males. The present meta-analysis of prospective cohort studies indicated that light to moderate coffee intake is associated with a reduced risk of death from all causes, particularly in women.


Using mathematical modelling to estimate the impact of periodic presumptive treatment on the transmission of sexually transmitted infections and HIV among female sex workers.
In settings with poor sexually transmitted infection (STI) control in high-risk groups, periodic presumptive treatment (PPT) can quickly reduce the prevalence of genital ulcers, Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT). However, few studies have assessed the impact on HIV. Mathematical modelling is used to quantify the likely HIV impact of different PPT interventions. A mathematical model was developed to project the impact of PPT on STI/HIV transmission amongst a homogeneous population of female sex workers (FSWs) and their clients. Using data from Johannesburg, the impact of PPT interventions with different coverages and PPT frequencies was estimated. A sensitivity analysis explored how the projections were affected by different model parameters or if the intervention was undertaken elsewhere. Substantial decreases in NG/CT prevalence are achieved among FSWs receiving PPT. Although less impact is achieved among all FSWs, large decreases in NG/CT prevalence (>50%) are possible with >30% coverage and supplying PPT every month. Higher PPT frequencies achieve little additional impact, whereas improving coverage increases impact until NG/CT becomes negligible. The impact on HIV incidence is smaller, longer to achieve, and depends heavily on the assumed NG/CT cofactors, whether they are additive, the assumed STI/HIV transmission probabilities and STI durations. Greater HIV impact can be achieved in settings with lower sexual activity (except at high coverage), less STI treatment or high prevalences of Haemophilus ducreyi. Despite the model's assumption of homogeneous risk behaviour probably resulting in optimistic projections, and uncertainty in STI cofactors and transmission probabilities, projections suggest PPT interventions with sufficient coverage (> or = 40%) and follow-up (> or = 2 years) could noticeably decrease the HIV incidence (>20%) among FSW populations with inadequate STI treatment.


Singlet-to-triplet interconversion using hyperfine as well as ferromagnetic fringe fields.
Until recently the important role that spin-physics ('spintronics') plays in organic light-emitting devices and photovoltaic cells was not sufficiently recognized. This attitude has begun to change. We review our recent work that shows that spatially rapidly varying local magnetic fields that may be present in the organic layer dramatically affect electronic transport properties and electroluminescence efficiency. Competition between spin-dynamics due to these spatially varying fields and an applied, spatially homogeneous magnetic field leads to large magnetoresistance, even at room temperature where the thermodynamic influences of the resulting nuclear and electronic Zeeman splittings are negligible. Spatially rapidly varying local magnetic fields are naturally present in many organic materials in the form of nuclear hyperfine fields, but we will also review a second method of controlling the electrical conductivity/electroluminescence, using the spatially varying magnetic fringe fields of a magnetically unsaturated ferromagnet. Fringe-field magnetoresistance has a magnitude of several per cent and is hysteretic and anisotropic. This new method of control is sensitive to even remanent magnetic states, leading to different conductivity/electroluminescence values in the absence of an applied field. We briefly review a model based on fringe-field-induced polaron-pair spin-dynamics that successfully describes several key features of the experimental fringe-field magnetoresistance and magnetoelectroluminescence.


Left ventricular function in early primary hypertension. Functional consequences of cardiovascular structural changes.
An increase in left ventricular (LV) wall thickness will lead to decreased LV distensibility during both LV passive filling and left atrial contraction. Reduced LV distensibility will change the filling pattern of the left ventricle, and a proportionally smaller part of the stroke volume will be delivered during the passive filling of the preceding diastole and a larger part during late diastole by a more powerful left atrial contraction. With a more pronounced increase in LV wall thickness a reduced distensibility of venous capacitance vessels (functional or structural) will probably help to preserve LV pump function by influencing LV filling and use of the Frank-Starling mechanism. LV wall stress (peak and end-systolic) is high and LV intrinsic contractility is normal or supernormal in early primary hypertension, as judged from the relationship between end-systolic wall stress and different indices of LV function (fractional shortening, mean velocity of circumferential fiber shortening, ejection fraction). Great differences in peak systolic wall stress may be recorded among groups with comparable values for LV end-systolic wall stress, which may be explained by very different degrees of cardiovascular structural changes, with higher values for peak systolic wall stress seen in hypertension caused by high output than those values seen in hypertension caused by high total peripheral resistance. Signs of supernormal LV systolic function are common in high output hypertension, which is also at least partly due to an increase in LV end-diastolic volume and use of the Frank-Starling mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)


Actigraphy assessment of motor activity and sleep in patients with alcohol withdrawal syndrome and the effects of intranasal oxytocin.
The alcohol withdrawal syndrome increases autonomic activation and stress in patients during detoxification, leading to alterations in motor activity and sleep irregularities. Intranasal oxytocin has been proposed as a possible treatment of acute alcohol withdrawal. The aim of the present study was to explore whether actigraphy could be used as a tool to register symptoms during alcohol detoxification, whether oxytocin affected actigraphy variables related to motor activity and sleep compared to placebo during detoxification, and whether actigraphy-recorded motor function during detoxification was different from that in healthy controls. This study was a part of a randomized, double blind, placebo-controlled trial in which 40 patients with alcohol use disorder admitted for acute detoxification were included. Of these, 20 received insufflations with intranasal oxytocin and 20 received placebo. Outcomes were actigraphy-recorded motor activity during 5-hour sequences following the insufflations and a full 24-hour period, as well as actigraphy-recorded sleep. Results were related to clinical variables of alcohol intake and withdrawal, including self-reported sleep. Finally, the actigraphy results were compared to those in a group of 34 healthy individuals. There were no significant differences between the oxytocin group and the placebo group for any of actigraphy variables registered. Neither were there any correlations between actigraphy-recorded motor function and clinical symptoms of alcohol withdrawal, but there was a significant association between self-reported and actigraphy-recorded sleep. Compared to healthy controls, motor activity during alcohol withdrawal was lower in the evenings and showed increased variability. Intranasal oxytocin did not affect actigraphy-recorded motor activity nor sleep in patients with acute alcohol withdrawal. There were no findings indicating that actigraphy can be used to evaluate the degree of withdrawal symptoms during detoxification. However, patients undergoing acute alcohol withdrawal had a motor activity pattern different from than in healthy controls.


Highly specific and sensitive detection of Burkholderia pseudomallei genomic DNA by CRISPR-Cas12a.
Detection of Burkholderia pseudomallei, a causative bacterium for melioidosis, remains a challenging undertaking due to long assay time, laboratory requirements, and the lack of specificity and sensitivity of many current assays. In this study, we are presenting a novel method that circumvents those issues by utilizing CRISPR-Cas12a coupled with isothermal amplification to identify B. pseudomallei DNA from clinical isolates. Through in silico search for conserved CRISPR-Cas12a target sites, we engineered the CRISPR-Cas12a to contain a highly specific spacer to B. pseudomallei, named crBP34. The crBP34-based detection assay can detect as few as 40 copies of B. pseudomallei genomic DNA while discriminating against other tested common pathogens. When coupled with a lateral flow dipstick, the assay readout can be simply performed without the loss of sensitivity and does not require expensive equipment. This crBP34-based detection assay provides high sensitivity, specificity and simple detection method for B. pseudomallei DNA. Direct use of this assay on clinical samples may require further optimization as these samples are complexed with high level of human DNA.


Hypocholesterolemic Effects of Expeller-Pressed and Solvent-Extracted Fruit Seed Oils and Defatted Pomegranate Seed Meals.
Consumptions of fruit seed oils and meals could potentially improve cardiovascular health by reducing plasma total cholesterol and low-density lipoprotein (LDL). The study objective was to compare the effectiveness of expeller-pressed and solvent-extracted grape, tomato, pomegranate seed oils, and defatted pomegranate meals in lowering plasma and hepatic cholesterol using hamster models. Hamsters were fed with fruit seed oils (FSO), defatted pomegranate seed meals (PDM), or control diets. After a 3-week feeding period, plasma total triglycerides of treatment diets were significantly lower. FSO also reduced total, very-low-density lipoprotein- (VLDL), and LDL-cholesterols, while PDM only lowered VLDL-cholesterols. Decreases in low-density and high-density lipoproteins (LDL/HDL) ratios were also observed in most treatments. In liver, triglycerides, total, and free cholesterol levels did not vary between control and treatments. There were no significant differences in lipid modulating properties between solvent-extracted and expeller-pressed oils. In conclusion, partial replacements of saturated fat in high-fat diets with tomato, pomegranate, and grape seed oils could effectively reduce plasma triglyceride levels and improve HDL/LDL ratios.


Prevalence of chronic kidney disease using estimated glomerular filtration rate among diabetes patients attending a tertiary clinic in Botswana.
Diabetes mellitus (DM) is one of the most common contributors of chronic kidney disease (CKD). The epidemiology of CKD, a concern among patients with DM, has not been studied in Botswana. Consequently, the objective of this study was to estimate its prevalence among these patients in Botswana to provide future guidance to both government personnel and physicians. Observational cross-sectional study in a leading clinic in Botswana. Demographic and clinical data were obtained from patients through interviews and from their notes using a standard questionnaire. The study was conducted from July to October 2015. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet for Renal Disease equation. CKD was defined as an eGFR < 60 ml/min/1.73 m2. Multivariable logistic regression analyses were performed to assess the associations between CKD and potential factors. The mean age and duration of DM among study participants were 54.67 years (range 21-92 years) and 5.0 years, respectively. Over half, i.e. 213/370 (57.6%) and 232/370 (62.7%), had an average blood pressure greater than 140/90 mmHg and poor glycemic control (HbA1c > 7%), respectively. 31/370 patients (8.4%) had CKD. However, only 18/370 (4.9%) had a diagnosis of CKD documented in their charts. Age, level of education, and duration of diabetes were independently associated with CKD. The prevalence of CKD by estimated eGFR was low compared to most previous studies. However, half of patients with CKD are not documented resulting in the potential for prescription errors and drug toxicity. A substantial number of our patients had uncontrolled hypertension and poor glycemic control. Older age, low level of education and longer duration of DM were associated with CKD. There is a need to carry out prospective studies to determine the association and role of glycemic and blood pressure control in CKD causation among patients with DM in Botswana.


[The profile of antimicrobial utilization in a private hospital].
The antimicrobials are one of the groups of the most prescribed drugs in hospitals and which cause a great concern for the suitability of their use. The profile of the antimicrobials utilized in a private hospital in the countryside of Rio Grande do Sul State was described and the quantity of each antimicrobial consumed was analyzed. All the prescriptions of patients who utilized antimicrobials while they were hospitalized in the period from March to June 2006 were analyzed. The antimicrobial consumption was expressed in Defined Daily Dose (DDD) in 100 day-beds. The antimicrobial utilization analysis were done generally speaking and divided by age groups and by medical clinics. During the studying period the antimicrobial use prevalence was of 52.4 % (IC 95 % 49.2 - 55.7). The cephalosporins were the most utilized (43.4 %), followed by the penicillins (16.3 %), fluoroquinolones (13.0 %) and aminoglycosides (9.7 %). The high consumption of antimicrobials during the studying period is the result of the absence of a policy for controlling the drugs prescribed in hospital and the lack of protocols of antimicrobial use. In order to exist a control of antimicrobial consumption the hospitals must assume a surveillance policy on the prescriptions of this drug group.


CGRP receptor antagonism and migraine.
Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. alphaCGRP is prominently localized in primary spinal afferent C and ADelta fibers of sensory ganglia, and betaCGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. CGRP is released from trigeminal nerves in migraine. Trigeminal nerve activation results in antidromic release of CGRP to cause non-endothelium-mediated vasodilatation. At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.


Swing-leg trajectory of running guinea fowl suggests task-level priority of force regulation rather than disturbance rejection.
To achieve robust and stable legged locomotion in uneven terrain, animals must effectively coordinate limb swing and stance phases, which involve distinct yet coupled dynamics. Recent theoretical studies have highlighted the critical influence of swing-leg trajectory on stability, disturbance rejection, leg loading and economy of walking and running. Yet, simulations suggest that not all these factors can be simultaneously optimized. A potential trade-off arises between the optimal swing-leg trajectory for disturbance rejection (to maintain steady gait) versus regulation of leg loading (for injury avoidance and economy). Here we investigate how running guinea fowl manage this potential trade-off by comparing experimental data to predictions of hypothesis-based simulations of running over a terrain drop perturbation. We use a simple model to predict swing-leg trajectory and running dynamics. In simulations, we generate optimized swing-leg trajectories based upon specific hypotheses for task-level control priorities. We optimized swing trajectories to achieve i) constant peak force, ii) constant axial impulse, or iii) perfect disturbance rejection (steady gait) in the stance following a terrain drop. We compare simulation predictions to experimental data on guinea fowl running over a visible step down. Swing and stance dynamics of running guinea fowl closely match simulations optimized to regulate leg loading (priorities i and ii), and do not match the simulations optimized for disturbance rejection (priority iii). The simulations reinforce previous findings that swing-leg trajectory targeting disturbance rejection demands large increases in stance leg force following a terrain drop. Guinea fowl negotiate a downward step using unsteady dynamics with forward acceleration, and recover to steady gait in subsequent steps. Our results suggest that guinea fowl use swing-leg trajectory consistent with priority for load regulation, and not for steadiness of gait. Swing-leg trajectory optimized for load regulation may facilitate economy and injury avoidance in uneven terrain.


Move it or lose it? The ecological ethics of relocating species under climate change.
Managed relocation (also known as assisted colonization, assisted migration) is one of the more controversial proposals to emerge in the ecological community in recent years. A conservation strategy involving the translocation of species to novel ecosystems in anticipation of range shifts forced by climate change, managed relocation (MR) has divided many ecologists and conservationists, mostly because of concerns about the potential invasion risk of the relocated species in their new environments. While this is indeed an important consideration in any evaluation of MR, moving species across the landscape in response to predicted climate shifts also raises a number of larger and important ethical and policy challenges that need to be addressed. These include evaluating the implications of a more aggressive approach to species conservation, assessing MR as a broader ecological policy and philosophy that departs from longstanding scientific and management goals focused on preserving ecological integrity, and considering MR within a more comprehensive ethical and policy response to climate change. Given the complexity and novelty of many of the issues at stake in the MR debate, a more dynamic and pragmatic approach to ethical analysis and debate is needed to help ecologists, conservationists, and environmental decision makers come to grips with MR and the emerging ethical challenges of ecological policy and management under global environmental change.


Atomic/molecular layer deposition of Cu-organic thin films.
The gas-phase atomic/molecular layer deposition (ALD/MLD) technique is strongly emerging as a viable approach to fabricate new exciting inorganic-organic hybrid thin-film materials. However, much less effort has been made to develop new precursors specifically intended for ALD/MLD; this applies to both the organic and inorganic precursors, and in the latter case in particular to transition metal precursors. Here we introduce copper bisdimethylaminopropoxide (Cu(dmap)2) as a promising transition metal precursor for ALD/MLD to be combined with a variety of organic precursors with different backbones and functional groups, i.e. hydroquinone (HQ), terephthalic acid (TPA), 4,4'-oxydianiline (ODA), p-phenylenediamine (PPDA) and 1,4-benzenedithiol (BDT). Hybrid Cu-organic thin films were obtained from all five organic precursors with appreciably high growth rates ranging from 1.0 to 2.6 Å per cycle. However, the Cu(dmap)2 + HQ process was found to yield hybrid Cu-organic films only at temperatures below 120 °C, while at higher temperatures metallic Cu films were obtained. The films were characterized by XRR, GIXRD, FTIR, Raman, XPS and UV-Vis spectroscopy.


The effects of neighborhood density and street connectivity on walking behavior: the Twin Cities walking study.
A growing body of health and policy research suggests residential neighborhood density and street connectivity affect walking and total physical activity, both of which are important risk factors for obesity and related chronic diseases. The authors report results from their methodologically novel Twin Cities Walking Study; a multilevel study which examined the relationship between built environments, walking behavior and total physical activity. In order to maximize neighborhood-level variation while maintaining the exchangeability of resident-subjects, investigators sampled 716 adult persons nested in 36 randomly selected neighborhoods across four strata defined on density and street-connectivity - a matched sampling design. Outcome measures include two types of self-reported walking (from surveys and diaries) and so-called objective 7-day accelerometry measures. While crude differences are evident across all outcomes, adjusted effects show increased odds of travel walking in higher-density areas and increased odds of leisure walking in low-connectivity areas, but neither density nor street connectivity are meaningfully related to overall mean miles walked per day or increased total physical activity. Contrary to prior research, the authors conclude that the effects of density and block size on total walking and physical activity are modest to non-existent, if not contrapositive to hypotheses. Divergent findings are attributed to this study's sampling design, which tends to mitigate residual confounding by socioeconomic status.


Improving the measurement performance for a self-mixing interferometry-based displacement sensing system.
Approaches that are, to our knowledge, novel, are proposed in this paper to improve the accuracy performance of self-mixing interferometry (SMI) for displacement measurement. First, the characteristics associated with signals observed in SMI systems are studied, based on which a new procedure is proposed for achieving accurate estimation of the laser phase. The studies also revealed the reasons for the inherent errors associated with the existing SMI-based techniques for displacement measurement. Then, this paper presents a new method for estimating the optical feedback level factor (denoted by C) in real time. Combining the new algorithms for estimating the laser phase and updating C value, the paper finally presents a novel technique for displacement measurement with improved accuracy performance in contrast to existing techniques. The proposed technique is verified by both simulation and experimental data.


Age- and sex-dependent distribution of persistent organochlorine pollutants in urban foxes.
The colonization of urban and suburban habitats by red foxes (Vulpes vulpes) provides a novel sentinel species to monitor the spread of anthropogenic pollutants in densely populated human settlements. Here, red foxes were collected in the municipal territory of Zürich, Switzerland, and their perirenal adipose tissue was examined for persistent organochlorine residues. This pilot study revealed an unexpected pattern of contamination by polychlorinated biphenyls (PCBs), with significantly higher levels of the predominant congeners PCB-138, PCB-153, and PCB-180 in juvenile foxes relative to adult animals. Further data analysis demonstrated that the observed difference was attributable to an age-dependent reduction of PCB concentrations in females, whereas male foxes retained approximately the same PCB burden throughout their life span. A similar sex-related bias between population members has been observed, primarily in marine mammals. Interestingly, the reduction of organochlorine contents with progressive age is reminiscent of human studies, where an extensive maternal transfer of xenobiotics to the offspring has been shown to result in increased exposure levels of infants relative to adults. To our knowledge, this is the first example of an urban wildlife species that faithfully reflects the dynamic distribution of toxic contaminants in the corresponding human population. Suburban and urban foxes occupy habitats in close proximity to humans, depend on anthropogenic food supplies, are relatively long-lived and readily available for sampling, can be easily aged and sexed, have a limited home range, and, therefore, meet several important requirements to serve as a surrogate species for the assessment of toxic health hazards.


[Outpatient Parenteral Antimicrobial Therapy (OPAT) with Elastomeric Pumps in Collaboration with Home-visit Nursing Services in Japan: Experience of the First 10 Patients].
In 2014, we reported the first trial based on outpatient parenteral antimicrobial therapy (OPAT) with continuous infusions in Japan. Following this, we found many patients who were eligible for OPAT but could not undertake it owing to difficulties in accessing the clinic daily. To overcome this problem, we created a model in collaboration with visiting nursing stations and started providing OPAT with the services. We report herein on a summary of the investigation of the first 10 patients treated under this model. We collected data pertaining to diseases, organisms, antimicrobials, treatment duration, bed days saved, outcome, readmission rate, and cost reductions associated with these patients. The most commonly targeted disease was osteomyelitis, followed by infective endocarditis. The condition of nine of the patients was complicated by bacteremia. The most commonly targeted organism was Staphylococcus aureus. Cefazolin was the most frequently prescribed antimicrobial, followed by Penicillin G. The median duration for OPAT was 12 days (range: 5-23 days). The total number of bed days saved was 129. All patients completed the planned OPAT. Eight patients were cured and two showed improvement. Only one patient was readmitted within a month after the completion of therapy. The estimated medical cost reduction was 496,540 yen, which is approximately 4,200 US dollars. Collaboration with visiting nursing stations provided OPAT to the patients who had difficulties in accessing the clinic daily. Our study shows that OPAT administered by continuous infusion in collaboration with home-visit nursing services would be a safe and feasible practice for efficient bed utilization and medical cost saving.


Comparison of indirect assessments of association as predictors of marijuana use among at-risk adolescents.
In this study, the authors compared indirect measures that attempt to quantify the level of marijuana associations among adolescents. They also evaluated whether these various methods overlap or tap different aspects of associative processes that may act in concert to influence marijuana use. Automatic drug-relevant associations were assessed in 121 at-risk youth in continuation high schools in California with the use of a word association index and computer-based, reaction time measures (i.e., Implicit Association Test [IAT] and Extrinsic Affective Simon Task [EAST]). Measures of working memory capacity, sensation seeking, and explicit cognitions also were included in analyses as potential confounders. The word association index and the marijuana IAT excited D measure were significant predictors of marijuana use. The word association index accounted for more variance in marijuana use than did the IAT or EAST measures. Further, confirmatory factor analytic models of the indirect measures of marijuana use revealed a significant moderate correlation between the EAST Excitement and Word Association factors but no significant correlations between the Word Association and IAT factors. These findings suggest that there is some convergence among the different indirect measures, but these assessments also appear to tap different aspects of associative processes. The types of indirect measures evaluated in this work provide information about spontaneous cognitions related to substance use, capturing influences on behavior that are not evaluated with traditional explicit assessments of behavior. Findings from this work add to a growing body of research that implicates the importance of implicit associative processes in risk and health behaviors.


Paediatric mastocytosis: a systematic review of 1747 cases.
Paediatric mastocytosis was previously considered to be a benign and spontaneously regressing disease. However, this evolution is impossible to predict. To clarify the characteristics and course of paediatric mastocytosis, we performed a literature review of 1747 cases published between 1950 and April 2014. Lesions occurred before the age of 2 years in 90% of cases, and presented as urticaria pigmentosa (75% of cases), mastocytoma (20%) or diffuse cutaneous mastocytosis (5%). The male-to-female ratio was 1·4. KIT D816V mutation was detected in 34% of 215 tested patients. Clinical regression (complete or partial) occurred in 67% of cases and stabilization in 27%. However, the outcome was fatal in 2·9% of patients.


The monoamine regulon including syntheses of arylsulfatase and monoamine oxidase in bacteria.
Bacterial cells respond to monoamine compounds, such as tyramine, dopamine, octopamine, or norepinephrine, and induce the syntheses of tyramine oxidase encoded by tynA and monoamine oxidase encoded by maoA. These monoamine compounds also derepress the synthesis of atsA-specified arylsulfatase that is repressed by sulfur compounds. These complex mechanisms of regulons regulated by monoamine and sulfur compounds has been analyzed by cloning and characterization of genes that are involved in the repression and derepression of the synthesis of arylsulfatase. The atsA gene forms an operon with the atsB gene, which encodes an activator of the expression of atsA. The negative regulator gene for arylsulfatase was found to code for dihydrofolate reductase (folA). The maoA gene forms an operon with the maoC gene, which has similarity to a dehydrogenase involved in the tyramine metabolism. The moaF gene encoding a 30-kDa protein, which is induced by tyramine, also forms an operon with the moaE gene. Finally, the moaR gene, which is induced by monoamine, was found to play a central role in the positive regulation of the expression of the monoamine regulon (moa) including the atsBA, maoCA, moaEF, and tyn operons. The moaR expression is subject to autogenous regulation and to cAMP-CRP control. The MoaR protein has a helix-turn-helix motif in its C terminus. Thus, the MoaR protein probably regulates the operons by binding to the regulatory region of the moa regulon.


Diagnosis of insulinoma using the ratios of serum concentrations of insulin and C-peptide to glucose during a 5-hour oral glucose tolerance test.
The 72-hour fast test is the current standard for the diagnosis of insulinoma. However, to conduct this test patients require hospitalization due to the chance of severe hypoglycemic episodes. Thus, it is costly and stressful for the patient. An out-patient test would serve the patient better and be more economical. Our aim was to evaluate the value of insulin to glucose and C-peptide to glucose ratios during a prolonged 5-hour oral glucose tolerance test (5-hour OGTT) in qualitative diagnosis of insulinoma, and to identify the optimal threshold for clinical screening. Initially, 15 subjects with pathological insulinoma and 12 control subjects with reactive hypoglycemia were enrolled in the study. A further 75 subjects with symptoms of hypoglycemia as a chief complaint at their initial clinic visit were subsequently screened. Serum insulin, C- peptide levels and blood glucose were quantified after a 5-hour OGTT in all participants and the ratios of serum concentrations of insulin and C-peptide to glucose were calculated. Subjects with insulinoma had significantly different insulin-to-glucose and C-peptide-to-glucose ratios from reactive hypoglycemia at the times of fasting, 4-hour post glucose load and 5-hour post glucose load. Higher specificity (73.08%) and sensitivity (82.67%) were achieved with the combined insulin-to-glucose ratio at the 5-hour post load and the C-peptide-to-glucose ratio at fasting. In combination, ratios of insulin and C-peptide release relative to blood glucose levels, measured during a 5-hour OGTT, may have important clinical value in the diagnosis of insulinoma.


Near ultra-violet to mid-visible band gap tuning of mixed cation RbxCs1-xPbX3 (X = Cl or Br) perovskite nanoparticles.
One of the most attractive features of perovskite materials is their chemical flexibility. Due to innovative chemical compositions of perovskites, their optical and structural properties, and functionalities have become more advanced, enabling better solar performance in photovoltaics, as well as robustness and excellent properties in the nanoscale for optoelectronics. The quest for novel perovskite compositions in the nano-scale is significantly important. This paper reports on a mixed-cation system of RbxCs1-xPbX3 (where X = Cl or Br) nanoparticles. The absorption of the nanoparticles is tunable in the near ultra-violet and visible regions between ∼395-525 nm for RbxCs1-xPbX3 (x = 0 to x = 0.8 and X = Cl or Br). The photoluminescence quantum yields (PLQY) of the mixed Rb+/Cs+ nanoparticle systems are comparable to the PLQY of CsPbX3 nanoparticles. Interestingly an attempt to synthesize Cl- and Br-based nanoparticles with high Rb+ content was successful, although possessing low tolerance factors. We conclude that these mixed Rb+/Cs+ nanoparticles are more adjustable to structural distortions caused by cation substitutions than their bulk counterparts, which opens a way towards the development of more advanced mixed-ion perovskite compositions in the nano-scale.


Evidence That Event Boundaries Are Access Points for Memory Retrieval.
When recalling memories, we often scan information-rich continuous episodes, for example, to find our keys. How does our brain access and search through those memories? We suggest that high-level structure, marked by event boundaries, guides us through this process: In our computational model, memory scanning is sped up by skipping ahead to the next event boundary upon reaching a decision threshold. In adult Mechanical Turk workers from the United States, we used a movie (normed for event boundaries; Study 1, N = 203) to prompt memory scanning of movie segments for answers (Study 2, N = 298) and mental simulation (Study 3, N = 100) of these segments. Confirming model predictions, we found that memory-scanning times varied as a function of the number of event boundaries within a segment and the distance of the search target to the previous boundary (the key diagnostic parameter). Mental simulation times were also described by a skipping process with a higher skipping threshold than memory scanning. These findings identify event boundaries as access points to memory.


Relationship between organizational climate and empowerment of nurses in Menoufiya hospitals, Egypt.
One factor influencing the outcome of care may be the nursing staffs experience of organizational work climate. We compared organizational climate and nurse's empowerment in specialty units at 2 hospitals in Egypt. Data were collected from 164 diploma school staff nurses using 2 tools: the situational outlook questionnaire to assess organizational climate and the psychological empowerment in the workplace questionnaire. There was no statistically significant difference in the level of organizational climate between the 2 hospitals, which the majority of nurses classified as moderate. Most nurses reported a moderate level of empowerment in both hospitals and there was a statistically significant positive correlation between organizational climate and nurse's empowerment.


Diagnostic imaging of benign and malignant neck masses in children-a pictorial review.
Neck masses are frequently encountered in pediatric medicine, and can present a diagnostic dilemma for the clinicians involved. There are several means by which neck masses in children can be subdivided, for example by age at presentation, anatomical location including compartments and fascia of the neck, their classical appearance when imaged, or by etiology. When imaging children the clinicians must be mindful of radiation exposure and as such ultrasound (US) is often attempted first. Cross sectional imaging can be helpful for problem solving with CT being particularly useful for assessing the patient in more acute scenarios, for example when there is airway compromise. Nuclear medicine scintigraphy has a role in specific circumstances and can aid in staging in the presence of malignancy. If required, additional acquisition by means of magnetic resonance imaging (MRI) and computed tomography (CT) can be considered. This pictorial review describe the diagnostic imaging of (I) congenital and Developmental Pathologies, including thyroglossal duct cyst, branchial cleft cyst, cystic hygroma, dermoid cyst, thymic cyst and ectopic thymus; (II) neoplastic lesions, including hemangiomas and vascular malformations, pilomatrixoma, neurofibroma, neuroblastoma, rhabdomyosarcoma, papillary thyroid cancer, lymphoma & leukemia; (III) neck masses of Infective causes, including lymphadenitis, retropharyngeal and peritonsilar abscess, salivary gland inflammation; and (IV) other miscellaneous lesions, including ranula, sternocleidomastoid fibromatosis coli, and goiter. Neck masses are common in the pediatric population with a broad and varied differential; malignant etiologies are less frequently encountered when compared with adults but an awareness of its potential is important when reviewing imaging.


Transmission of the frequency components of the vibrational signal of the glassy-winged sharpshooter, Homalodisca vitripennis, within and between grapevines.
The agricultural pest, Homalodisca vitripennis, relies on vibrational communication through plants for species identification, location, and courtship. Their vibrational signal exhibits a dominant frequency between 80 and 120 Hz, with higher frequency, lower intensity harmonics occurring approximately every 100 Hz. However, previous research revealed that not all harmonics are recorded in every signal. Therefore, how the female H. vitripennis vibrational signal changes as it travels through the plant was investigated. Results confirmed that transmission was a bending wave, with decreased signal intensity for increasing distance from the source; moreover, at distances of 50 cm, higher frequencies traveled faster than lower frequencies, suggesting that dispersion of H. vitripennis signal components may enable signaling partners to encode distance. Finally, H. vitripennis generates no detectable airborne signal (pressure wave), yet their low vibrational frequency components are detectable in neighboring plants as a result of leaf-to-air-to-leaf propagation. For instance, with isolated key female signal frequencies, 100 Hz was detected at a 10 cm gap between leaves, whereas 600 Hz was detectable only with a 0.1 cm gap. Together, these results highlight the complexity of vibration propagation in plants and suggest the possibility of the animals using the harmonic content to determine distance to the signaling H. vitripennis source.


SU-E-T-634: Convex Direct Aperture Optimization for Sliding Window IMRT.
To introduce a convex Direct Aperture Optimization (DAO) technique for sliding window IMRT. This method combines the accuracy of aperture-based dose calculations, which include leaf end effect, scatter, and leakage, with the convexity, and hence efficient solvability, of classic two phase IMRT optimization (fluence map optimization followed by sliding window leaf sequencing). Artificial pencil beam profiles used in fluence map optimization are replaced with sigmoid-like profiles representing the dose "blocked" by a leaf while at some incremental position, per MU. More precisely, the profiles represent the dose from photons blocked minus that from photons leaked through or scattered by the leaf. These profiles can be computed by any clinically validated IMRT dose engine, and the scatter component for an individual leaf can be accurately included to the extent that it is independent of positions of other leaves. Variables of the resulting convex optimization are the MUs delivered while each leaf is at each incremental position. All constraints necessary to ensure a deliverable sliding window solution, such as those preventing leaf collision, are linear. Thus, provided the dose objective functions are convex, the entire IMRT optimization is convex, and therefore can be efficiently solved to provable optimality. Our derivations prove that DAO is convex for sliding window IMRT, and we demonstrate the technique on a clinical prostate case. By moving from the standard idealized fluence beamlet approach to a'fluence blocked by a leaf at position x' approach, we fully convexify the sliding window IMRT optimization problem, and thus avoid the dose degradation observed in two-step IMRT optimization and the non-convexity of the traditionally posed DAO problem.


Climate change and fire effects on a prairie-woodland ecotone: projecting species range shifts with a dynamic global vegetation model.
Large shifts in species ranges have been predicted under future climate scenarios based primarily on niche-based species distribution models. However, the mechanisms that would cause such shifts are uncertain. Natural and anthropogenic fires have shaped the distributions of many plant species, but their effects have seldom been included in future projections of species ranges. Here, we examine how the combination of climate and fire influence historical and future distributions of the ponderosa pine-prairie ecotone at the edge of the Black Hills in South Dakota, USA, as simulated by MC1, a dynamic global vegetation model that includes the effects of fire, climate, and atmospheric CO2 concentration on vegetation dynamics. For this purpose, we parameterized MC1 for ponderosa pine in the Black Hills, designating the revised model as MC1-WCNP. Results show that fire frequency, as affected by humidity and temperature, is central to the simulation of historical prairies in the warmer lowlands versus woodlands in the cooler, moister highlands. Based on three downscaled general circulation model climate projections for the 21st century, we simulate greater frequencies of natural fire throughout the area due to substantial warming and, for two of the climate projections, lower relative humidity. However, established ponderosa pine forests are relatively fire resistant, and areas that were initially wooded remained so over the 21st century for most of our future climate x fire management scenarios. This result contrasts with projections for ponderosa pine based on climatic niches, which suggest that its suitable habitat in the Black Hills will be greatly diminished by the middle of the 21st century. We hypothesize that the differences between the future predictions from these two approaches are due in part to the inclusion of fire effects in MC1, and we highlight the importance of accounting for fire as managed by humans in assessing both historical species distributions and future climate change effects.


In situ analysis of lung antigen-presenting cells during murine pulmonary infection with virulent Mycobacterium tuberculosis.
Scarce information exists about the role of lung antigen-presenting cells (APCs) in vivo during pulmonary tuberculosis. As APCs activate cellular immunity, following intratracheal inoculation with virulent Mycobacterium tuberculosis, we assessed in situ lung APC recruitment, distribution, granuloma involvement, morphology and mycobacterial burden by using MHC-CII, CD14, scavenger receptor class A (SRA), the murine dendritic cell (DC)-restricted marker CD11c and Ziehl-Neelsen staining. CD11c(+) DC and CD14(+) cell recruitment into lungs appeared by day 14, continuing until day 60. MHC-CII(+) cells increased since day 7, persisting until day 60. Thus, virulent mycobacteria delays (14-21 days) lung APC recruitment compared to model antigens and nonvirulent bacilli (24-48 h). Regarding granuloma constitution, highly bacillary CD14(+) and SRA(+) cells were centrally located. MHC-CII(+) cells were more peripheral, with less mycobacteria. CD11c(+) cells were heterogeneously distributed within granulomas, with scarce bacilli. When labelling lung suspensions for MHC-CII and classifying cells as macrophages or DC, then staining for Ziehl-Neelsen, a remarkable segregation was found regarding bacillary burden. Most macrophage-like cells contained numerous bacilli, while DC had no or scarce mycobacteria. This implies differential APC contributions in situ during pulmonary tuberculosis regarding mycobacterial uptake, granuloma involvement and perhaps bacillary growth.


Roles of N-Vacancies over Porous g-C3N4 Microtubes during Photocatalytic NO x Removal.
The development of catalysts that effectively activate target pollutants and promote their complete conversion is an admirable objective in the environmental photocatalysis field. In this work, graphitic carbon nitride (g-C3N4) microtubes with tunable N-vacancy concentrations were controllably fabricated using an in situ soft-chemical method. The morphological evolution of g-C3N4, from the bulk to the porous tubular architecture, is discussed in detail with the aid of time-resolved hydrothermal experiments. We found that the NO removal ratio and apparent reaction rate constant of the g-C3N4 microtubes were 1.8 and 2.6 times higher than those of pristine g-C3N4, respectively. By combining detailed experimental characterization and density functional theory calculations, the effects of N-vacancies in the g-C3N4 microtubes on O2 and NO adsorption activation, electron capture, and electronic structure were systematically investigated. These results demonstrate that surface N-vacancies act as specific sites for the adsorption activation of reactants and photoinduced electron capture, while enhancing the light-absorbing capability of g-C3N4. Moreover, the porous wall structures of the as-prepared g-C3N4 microtubes facilitate the diffusion of reactants, and their tubular architectures favor the oriented transfer of charge carriers. The intermediates formed during photocatalytic NO removal processes were identified by in situ diffuse reflectance infrared Fourier transform spectroscopy, and different reaction pathways over pristine and N-deficient g-C3N4 are proposed. This study provides a feasible strategy for air pollution control over g-C3N4 by introducing N-vacancy and porous tubular architecture simultaneously.


Evaluating quality of care in the new health care environment.
Today's health care environment explicitly emphasizes quality monitoring and improvement systems. To better understand the new concepts of quality, the quality systems currently used and under development at the Doheny Eye Institute, Los Angeles, Calif, and The Wilmer Ophthalmological Institute, Baltimore, Md, were reviewed and the underlying principles and pertinent examples extracted. In the future, quality monitoring will require measurement of rates of conformance with indicators of each of the three components of quality of care, ie, structures, processes, and outcomes. As such, significant changes in the philosophy of quality monitoring and development of newer and more advanced measures and indicators will be needed to meet the challenges of quality review in the new health care environment.


Electric-field-induced phase transitions in co-doped Pb(Zr1-xTix)O3 at the morphotropic phase boundary.
The strain- and polarization-electric field behavior was characterized at room temperature for Pb0.98Ba0.01(Zr1-x Ti x )0.98Nb0.02O3, 0.40 ⩽ x ⩽ 0.60. The investigated compositions were located in the vicinity of the morphotropic phase boundary, giving insight into the influence of crystal structure on the hysteretic ferroelectric behavior. The remanent strain of particular compositions is shown to be larger than theoretically allowed by ferroelectric switching alone, indicating the presence of additional remanent strain mechanisms. A phenomenological free energy analysis was used to simulate the effect of an applied electric field on the initial equilibrium phase. It is shown that electric-field-induced phase transitions in polycrystalline ferroelectrics can account for the experimental observations. The experimental and simulation results are contrasted to neutron diffraction measurements performed on representative compositions in the virgin and remanent states.


Pharmacovigilance from social media: mining adverse drug reaction mentions using sequence labeling with word embedding cluster features.
Social media is becoming increasingly popular as a platform for sharing personal health-related information. This information can be utilized for public health monitoring tasks, particularly for pharmacovigilance, via the use of natural language processing (NLP) techniques. However, the language in social media is highly informal, and user-expressed medical concepts are often nontechnical, descriptive, and challenging to extract. There has been limited progress in addressing these challenges, and thus far, advanced machine learning-based NLP techniques have been underutilized. Our objective is to design a machine learning-based approach to extract mentions of adverse drug reactions (ADRs) from highly informal text in social media. We introduce ADRMine, a machine learning-based concept extraction system that uses conditional random fields (CRFs). ADRMine utilizes a variety of features, including a novel feature for modeling words' semantic similarities. The similarities are modeled by clustering words based on unsupervised, pretrained word representation vectors (embeddings) generated from unlabeled user posts in social media using a deep learning technique. ADRMine outperforms several strong baseline systems in the ADR extraction task by achieving an F-measure of 0.82. Feature analysis demonstrates that the proposed word cluster features significantly improve extraction performance. It is possible to extract complex medical concepts, with relatively high performance, from informal, user-generated content. Our approach is particularly scalable, suitable for social media mining, as it relies on large volumes of unlabeled data, thus diminishing the need for large, annotated training data sets.


Abnormal neurites containing C-terminally truncated alpha-synuclein are present in Alzheimer's disease without conventional Lewy body pathology.
The pathological hallmark of Parkinson's disease and diffuse Lewy body disease (DLBD) is the aggregation of α-synuclein (α-syn) in the form of Lewy bodies and Lewy neurites. Patients with both Alzheimer's disease (AD) and cortical Lewy pathology represent the Lewy body variant of AD (LBV) and constitute 25% of AD cases. C-terminally truncated forms of α-syn enhance the aggregation of α-syn in vitro. To investigate the presence of C-terminally truncated α-syn in DLBD, AD, and LBV, we generated and validated polyclonal antibodies to truncated α-syn ending at residues 110 (α-syn110) and 119 (α-syn119), two products of 20S proteosome-mediated endoproteolytic cleavage. Double immunofluorescence staining of the cingulate cortex showed that α-syn110 and α-syn140 (full-length) aggregates were not colocalized in LBV. All aggregates containing α-syn140 also contained α-syn119; however, some aggregates contained α-syn119 without α-syn140, suggesting that α-syn119 may stimulate aggregate formation. Immunohistochemistry and image analysis of tissue microarrays of the cingulate cortex from patients with DLBD (n = 27), LBV (n = 27), and AD (n = 19) and age-matched controls (n = 15) revealed that AD is also characterized by frequent abnormal neurites containing α-syn119. Notably, these neurites did not contain α-syn ending at residues 110 or 122-140. The presence of abnormal neurites containing α-syn119 in AD without conventional Lewy pathology suggests that AD and Lewy body disease may be more closely related than previously thought.


Feasibility of acute physiology and chronic health evaluation (APACHE) II and III score-based screening in patients receiving allogeneic hematopoietic stem-cell transplantation.
Patients who require management in the intensive care unit (ICU) for complications after allogeneic hematopoietic stem-cell transplantation (HSCT) generally have a poor outcome. We retrospectively studied whether the risk-prediction stratification systems commonly used for patients admitted to the ICU, that is, the Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE III systems, could be useful for identifying patients who should receive intensive care earlier. We reviewed the medical records of 210 patients who underwent allogeneic HSCT and found that 18 (8.6%) had been admitted to the ICU for acute respiratory failure (n=9), acute renal failure (n=7), and septic shock (n=2). The median APACHE II and III scores were, respectively, 16 (10-27) and 55 (22-87) at the onset of complications and 26 (15-43) and 101 (65-157) upon admission to the ICU. Thus, both the APACHE II and APACHE III scores at ICU admission were higher than those at the onset of complications (P <0.0001). Seventeen patients (94%) subsequently died, with a median ICU stay of 7.5 days (1-51 days), as a result of multiorgan failure (n=14), respiratory failure (n=2), and septic shock (n=1). The APACHE II and III scores of the sole surviving patient were, respectively, 21 and 71 at the onset and 24 and 86 upon transfer to the ICU. Thus, the APACHE scores in this study were lower than those reported for other surgical or medical patients treated in the ICU, despite their uniform poor prognosis. Although nine patients had developed grade III to IV acute graft-versus-host disease, which is the most common cause of morbidity and mortality after allogeneic HSCT, this was not fully evaluated in the current scoring systems. Application of these systems to HSCT will require adequate modification, with particular attention to organ dysfunction secondary to graft-versus-host disease.


Contracture Severity at Hospital Discharge in Children: A Burn Model System Database Study.
Contractures can complicate burn recovery. There are limited studies examining the prevalence of contractures following burns in pediatrics. This study investigates contracture outcomes by location, injury, severity, length of stay, and developmental stage. Data were obtained from the Burn Model System between 1994 and 2003. All patients younger than the age of 18 with at least one joint contracture at hospital discharge were included. Sixteen areas of impaired movement from the shoulder, elbow, wrist, hand, hip, knee, and ankle joints were examined. Analysis of variance was used to assess the association between contracture severity, burn size, and length of stay. Age groupings were evaluated for developmental patterns. A P value of less than .05 was considered statistically significant. Data from 225 patients yielded 1597 contractures (758 in the hand) with a mean of 7.1 contractures (median 4) per patient. Mean contracture severity ranged from 17% (elbow extension) to 41% (ankle plantarflexion) loss of movement. Statistically significant associations were found between active range of motion loss and burn size, length of stay, and age groupings. The data illustrate quantitative assessment of burn contractures in pediatric patients at discharge in a multicenter database. Size of injury correlates with range of motion loss for many joint motions, reflecting the anticipated morbidity of contracture for pediatric burn survivors. These results serve as a potential reference for range of motion outcomes in the pediatric burn population, which could serve as a comparison for local practices, quality improvement measures, and future research.


Pre-registration house officers' comments on working in the NHS: a qualitative study of the views of UK medical graduates of 1999.
The authors aimed to report the views of pre-registration house officers (PRHOs) on their experience of working in the UK National Health Service (NHS). All doctors who qualified from UK medical schools in 1999 were surveyed towards the end of their pre-registration year. Structured questions concerning career choices and experiences were accompanied by a form inviting free-text comment. Comments were transcribed and coded by topic. Those related to working conditions were selected for analysis. Respondents commented that aspects of the PRHO year had been enjoyable but were critical of working conditions. For instance: heavy workloads caused working hours to regularly contravene contractual limits, out-of-hours pay did not accurately reflect responsibilities, out-of-hours facilities were sometimes poor. A few respondents' experiences had deterred them from continuing their NHS hospital training. Most PRHOs had enjoyed the year despite poor working conditions; for a few, their educational experience was marred.


Gateway to the Golgi: molecular mechanisms of nucleotide sugar transporters.
The Golgi apparatus plays a central role in the secretory pathway as a hub for posttranslational modification, protein sorting and quality control. To date, there is little structural or biochemical information concerning the function of transporters that reside within this organelle. The SLC35 family of nucleotide sugar transporters link the synthesis of activated sugar molecules and sulfate in the cytoplasm, with the luminal transferases that catalyse their attachment to proteins and lipids during glycosylation and sulfation. A recent crystal structure of the GDP-mannose transporter has revealed key sequence motifs that direct ligand recognition and transport. Further biochemical studies unexpectedly found a requirement for short chain lipids in activating the transporter, suggesting a possible route for transport regulation within the Golgi.


The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins.
Small heat-shock proteins (sHsps), such as αB-crystallin, are one of the major classes of molecular chaperone proteins. In vivo, under conditions of cellular stress, sHsps are the principal defence proteins that prevent large-scale protein aggregation. Progress in determining the structure of sHsps has been significant recently, particularly in relation to the conserved, central and β-sheet structured α-crystallin domain (ACD). However, an understanding of the structure and functional roles of the N- and C-terminal flanking regions has proved elusive mainly because of their unstructured and dynamic nature. In this paper, we propose functional roles for both flanking regions, based around three properties: (i) they act in a localised crowding manner to regulate interactions with target proteins during chaperone action, (ii) they protect the ACD from deleterious amyloid fibril formation and (iii) the flexibility of these regions, particularly at the extreme C-terminus in mammalian sHsps, provides solubility for sHsps under chaperone and non-chaperone conditions. In the eye lens, these properties are highly relevant as the crystallin proteins, in particular the two sHsps αA- and αB-crystallin, are present at very high concentrations.


Ligand-exchange assisted formation of Au/TiO2 Schottky contact for visible-light photocatalysis.
Plasmonic noble metal nanoparticles have emerged as a promising material in sensitizing wide-bandgap semiconductors for visible-light photocatalysis. Conventional methods in constructing such heterocatalysts suffer from either poor control over the size of the metal nanoparticles or inefficient charge transfer through the metal/semiconductor interface, which limit their photocatalytic activity. To solve this problem, in this work we construct Au/TiO2 photocatalysts by depositing presynthesized colloidal Au nanoparticles with well-controlled sizes to TiO2 nanocrystals and then removing capping ligands on the Au surface through a delicately designed ligand-exchange method, which leads to close Au/TiO2 Schottky contact after a mild annealing process. Benefiting from this unique synthesis strategy, the obtained photocatalysts show superior activity to conventionally prepared photocatalysts in dye decomposition and water-reduction hydrogen production under visible-light illumination. This study not only opens up new opportunities in designing photoactive materials with high stability and enhanced performance for solar energy conversion but also provides a potential solution for the well-recognized challenge in cleaning capping ligands from the surface of colloidal catalyst nanoparticles.