Resistance of a human serum-selected human immunodeficiency virus type 1 escape mutant to neutralization by CD4 binding site monoclonal antibodies is conferred by a single amino acid change in gp120.
We have selected an HXB2 variant which can replicate in the presence of a neutralizing human serum. Sequencing of the gp120 region of the env gene from the variant and parental viruses identified a single amino acid substitution in the third conserved region of gp120 at residue 375 (AGT-->AAT, Ser-->Asn; designated 375 S/N). The escape mutant was found to be resistant to neutralization by soluble CD4 (sCD4) and four monoclonal antibodies (MAbs), 39.13g, 1.5e, G13, and 448, binding to epitopes overlapping that of the CD4 binding site (CD4 b.s.). Introduction of the 375 S/N mutation into HXB2 by site-directed mutagenesis confirmed that this mutation is responsible for the neutralization-resistant phenotype. Both sCD4 and three of the CD4 b.s. MAbs (39.13g, 1.5e, and G13) demonstrated reduced binding to the native 375 S/N mutant gp120. The ability to select for an escape variant resistant to multiple independent CD4 b.s. MAbs by a human serum confirms the reports that antibodies to the discontinuous CD4 b.s. are a major component of the group-specific neutralizing activity in human sera.


Tropicamide eyedrops cannot be used for reliable diagnosis of Alzheimer's disease.
To evaluate the mydriatic effect of tropicamide eyedrops as a diagnostic test for Alzheimer's disease. In a double-blind, placebo-controlled study, we assessed pupillary responses in 22 normal control subjects, 23 patients with probable Alzheimer's disease, 4 patients with isolated memory difficulty, and 6 patients with non-Alzheimer's dementia. Three separate studies were performed, the second and third on a subset of the original group. With use of infrared binocular pupillography, after 5 minutes of dark adaptation, we averaged pupil size during a 1-minute interval for baseline determinations. We then instilled 0.01% tropicamide into one eye. In the first two studies, we averaged pupil size for a 1-minute period at 5-minute intervals for 30 minutes, followed by a pupil light reflex test. In the third study, we measured pupil size every 5 minutes for 45 minutes and omitted the light reflex test. No significant difference was noted in pupil dilatation between normal subjects and patients with Alzheimer's disease and between patients with non-Alzheimer's dementias and the Alzheimer's disease group in all three studies. Furthermore, on reperformance of the test in the same patients, more than 50% changed from a group above or below 13% pupil dilatation (a cutoff reported to distinguish Alzheimer's disease from normal control subjects) to the opposite group. Results of this study indicate that pupil measurement after instillation of tropicamide cannot be used as a reliable diagnostic test for Alzheimer's disease. Moreover, test-retest reliability with use of dilute tropicamide eyedrops is questionable.


Monoclonal antibodies directed against gonococcal protein I vary in bactericidal activity.
Monoclonal antibodies (Mab) with specificity for protein I (PI) from Neisseria gonorrhoeae (GC) were examined for bactericidal activity. Mab 4G5 (gamma 3), ID3 (gamma 2a), and 1G6 (gamma 2a) bound to surface-exposed epitopes on PI of GC strain R11 (IA serotype) as assessed by co-agglutination and 125I protein A uptake. Mab 2H1 (gamma 3) that were directed against IB serotype strains and Mab 2E9 (gamma 2a) were negative in co-agglutination and protein A uptake assays and served as controls for some experiments. Only 4G5 and 1D3 were bactericidal for R11 when presensitized organisms were incubated in 10% absorbed, pooled normal human serum (PNHS) or 10% hypogammaglobulinemic serum (H gamma S) despite binding of nearly equivalent numbers of 4G5, 1D3, and 1G6 to R11 during presensitization, as assessed by 125I-protein A uptake. These Mab activated complement to a similar extent on GC R11, leading to deposition of 56.4 X 10(3), 61.9 X 1093), and 47.1 X 10(3) molecules of C3/organism during incubation in 10% C8-deficient serum. Deposition occurred almost exclusively via the classical complement pathway. Measurement of complement component C9 binding to R11 during incubation in H gamma S showed 35,700 molecules of C9/organism with 4G5, 32,600 C9/organism with 1D3, and surprisingly, 29,600 C9/organism with 1G6. Eight thousand four hundred molecules of C9/organism bound to 2E9-coated organisms, 6000 C9/organism to 2H1-coated bacteria, and 3600 C9/organism to nonpresensitized organisms. The C5b-9 complex deposited by 4G5 had a different sedimentation profile by sucrose density gradient analysis from the C5b-9 complex deposited by 1G6, consistent with a different molecular configuration of the bound complex. Mab 1G6 and 1D3, but not 2E9 or 2H1, were able to compete with 125I-4G5 for binding to GC R11. A Mab (2E6) directed against protein III of GC competed weakly with 125I-4G5 for binding to GC R11. Mab 1G6, but not 1D3, blocked 4G5-dependent killing in a dose-related fashion. Both 4G5 and IG6 reacted weakly with native PI of GC R11 by immunoblotting, but neither Mab recognized the 34,800 m.w. fragment of PI generated by trypsin and chymotrypsin treatment of outer membranes. In contrast, 2E9 reacted strongly by immunoblot with both native and cleaved PI of GC R11, suggesting binding to buried determinants of PI. These experiments show that Mab directed against identical or closely associated, surface-exposed epitopes on gonococcal PI differ markedly in bactericidal activity, despite leading to deposition of nearly equivalent numbers of C3 and C9 molecules per organism.


Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy.
Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach. Of 5,382 men in the database who underwent primary radical prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1,352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome. Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05). The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue.


A rat CD4 mutant containing the gp120-binding site mediates human immunodeficiency virus type 1 infection.
CD4 is the primary receptor for the human immunodeficiency virus type 1 (HIV-1). Early mutational studies implicated a number of residues of CD4, centered in the region 41-59, in binding to gp120. However, further mutational analyses, together with studies using inhibitory antibodies or CD4-derived peptides, have suggested that other regions of CD4 are also involved in binding or postbinding events during infection. To resolve these ambiguities, we used rat CD4 mutants in which particular regions were replaced with the corresponding sequence of human CD4. We have previously shown that some of these are able to bind HIV-1 gp120, and here we test their ability to act as functional receptors. We find that the presence of human CD4 residues 33-62 is enough to confer efficient receptor function to rat CD4, and we conclude that it is unlikely that regions of CD4 outside this sequence are involved in specific interactions with HIV-1 during either infection or syncytium formation.


Medicinal Cannabis in Pregnancy - Panacea or Noxious Weed?
The use of medicinal cannabis has been the subject of enabling legislation in Australia since 2016. At present the medical profession has not supported its use for anything but a few indications which include paediatric treatment-resistant epilepsy (especially Dravet's syndrome), pain syndromes associated with multiple sclerosis, Parkinson's disease and chemotherapy-induced nausea. However, in the United States where medicinal cannabis has been legalised in 29 States and Washington DC, nausea is an approved indication in many jurisdictions and this has been followed by widespread use for pregnancy-induced nausea and vomiting. This may prove to be ill advised as serious concerns have been expressed about its safety in pregnancy particularly its proven potential to restrict fetal and postnatal growth as well as to impair childhood cognitive functions such as memory, verbal skills and emotional development. These reported effects on neuropsychiatric behavioural and executive functions may influence future adult productivity and lifetime outcomes. Twenty-one States of the United States approve the use of legal cannabis for nausea and vomiting including its use in pregnancy. This is likely to encourage complacency regarding its fetal risks in pregnancy. In Australia the federal and State legislation restricts use of legal cannabis by placing the pharmaceutical under Sch 8 of the Poisons Act 1971 Tas which requires specific application for each individual patient use. It is to be hoped that this will prevent the excesses of use in pregnancy witnessed in the United States.


Developing a risk-based composite neurologic outcome for a trial of hydroxyurea in young children with sickle cell disease.
Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial. In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the "Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial" (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome. In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well. This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study.


Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases: Multidisciplinary Consensus Document from the COLLISION Trial Group.
The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.


Multicentric performance analysis of HCV quantification assays and its potential relevance for HCV treatment.
An accurate quantification of low viremic HCV RNA plasma samples has gained importance since the approval of direct acting antivirals and since only one single measurement predicts the necessity of a prolonged or shortened therapy. As reported previously, HCV quantification assays such as Abbott RealTime HCV and Roche COBAS AmpliPrep/COBAS TaqMan HCV version 2 (CTM v2) may vary in sensitivity and precision particularly in low-level viremia. Importantly, substantial variations were previously demonstrated between some of these assays compared to the Roche High Pure System/COBAS TaqMan assay (HPS) reference assay, which was used to establish the clinical decision points in clinical studies. In this study, the reproducibility of assay performances across several laboratories was assessed by analysing quantification results generated by six independent laboratories (3× RealTime, 3× CTM v2) in comparison with one HPS reference laboratory. The 4th WHO Standard was diluted to 100, 25 and 10 IU/ml, and aliquots were tested in triplicates in 5 independent runs by each assay in the different laboratories to assess assay precision and detection rates. In a second approach, 2 clinical samples (GT 1a & GT 1b) were diluted to 100 and 25 IU/ml and tested as described above. While the result range for WHO 100 IU/ml replicates across all laboratories was similar in this analysis, the CVs of each laboratory ranged from 19.3 to 25.6 % for RealTime laboratories and were lower than CVs of CTM v2 laboratories with a range of 26.1-47.3 %, respectively, and also in comparison with the CV of the HPS reference laboratory (34.9 %). At WHO standard dilution of 25 IU/ml, 24 replicates were quantified by RealTime compared to 8 replicates with CTM v2. Results of clinical samples again revealed a higher variation of CTM v2 results as compared to RealTime values. (CVs at 100 IU/ml: RealTime: 13.1-21.0 % and CTM v2: 15.0-32.3 %; CVs at 25 IU/ml: RealTime 17.6-34.9 % and CTM v2 28.2-54.9 %). These findings confirm the superior precision of RealTime versus CTM v2 at low-level viremia even across different laboratories including the new clinical decision point at 25 IU/ml. A highly precise monitoring of HCV viral load during therapy will remain crucial for patient management with regard to futility rules, therapy efficacy and SVR.


Data-dependent systems profilometry of two-dimensional surfaces.
Fourier-transform profilometry (FTP) and data-dependent systems profilometry (DDSP) are two methods that are available for recovering one-dimensional fine surface profiles from the phase of a single interferogram. FTP has already been extended to two-dimensional surfaces; a similar extension of DDSP is introduced here. Inasmuch as this extension involves autoregressive modeling of the rows or columns of an interferogram, the feasibility of using a common model order is explored. The common order reduces not only the amount of computation but also the errors caused by the heterodyned phase-removal procedure. As autoregression requires masking the first few data values, the length of the mask is determined by means of a Green's function. A comparison shows that DDSP outperforms FTP in roughness measurements in terms of rms and center-line average. The comparison also shows that DDSP is able to recover a detailed surface, whereas FTP outlines only the global features. An interferogram regeneration procedure provides a reference surface for the verification of results.


Electronic and thermal transport study of sinusoidally corrugated nanowires aiming to improve thermoelectric efficiency.
Improvement of thermoelectric efficiency has been very challenging in the solid-state industry due to the interplay among transport coefficients which measure the efficiency. In this work, we modulate the geometry of nanowires to interrupt thermal transport with causing only a minimal impact on electronic transport properties, thereby maximizing the thermoelectric power generation. As it is essential to scrutinize comprehensively both electronic and thermal transport behaviors for nano-scale thermoelectric devices, we investigate the Seebeck coefficient, the electrical conductance, and the thermal conductivity of sinusoidally corrugated silicon nanowires and eventually look into an enhancement of the thermoelectric figure-of-merit [Formula: see text] from the modulated nanowires over typical straight nanowires. A loss in the electronic transport coefficient is calculated with the recursive Green function along with the Landauer formalism, and the thermal transport is simulated with the molecular dynamics. In contrast to a small influence on the thermopower and the electrical conductance of the geometry-modulated nanowires, a large reduction of the thermal conductivity yields an enhancement of the efficiency by 10% to 35% from the typical nanowires. We find that this approach can be easily extended to various structures and materials as we consider the geometrical modulation as a sole source of perturbation to the system.


Study of interactions between Mycobacterium tuberculosis proteins: SigK and anti-SigK.
The development of novel antituberculosis therapeutic molecules is a global health concern. Complex gene expression in Mycobacterium tuberculosis is mediated mainly by various sigma factors. The SigK protein binds to RNA polymerase, facilitating the expression of genes encoding the antigenic proteins mpt70 and mpt83. The anti-SigK protein is a negative regulator of SigK and inhibits the initiation of transcription. This study focuses on the interactions between SigK and the N-terminal domain of anti-SigK. The 3D structures of SigK (187 residues) and the N-terminal domain of anti-SigK (92 residues) are elucidated, using the crystal structures of the A and B chains of sigma E and anti-sigma ChrR of Rhodobacter spheroides (PDB code: 2Q1Z) as templates, respectively. Molecular dynamic simulations were performed for the SigK and anti-SigK proteins to refine their structures. The predicted active sites of SigK and anti-SigK and the results of protein-protein docking studies revealed the residues that are important for binding. The models generated and the binding site residues identified in this work throw new light on the interactions between the sigma K and anti-sigma K proteins, which should further aid the modulation of antigenic protein production in Mycobacterium tuberculosis.


STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity.
Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α (Stat1α/α) or the STAT1β (Stat1β/β ) isoform. NK cells from Stat1α/α mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1β/β mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (Stat1-/- ). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in Stat1β/β mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1β/β mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance.


The Peritoneum: Beyond the Tissue - A Review.
Background: Despite its complexity, the peritoneum is usually underestimated in classical medical texts simply as the surrounding tissue (serous membrane) of the gut. Novel findings on physiology and morphology of the peritoneum and mesothelial cell exist but they are usually focused or limited to Continuous Ambulatory Peritoneal Dialysis research and practice. This review aims to expose, describe and analyze the most recent evidence on the peritoneum's morphology, embryology and physiology. Materials and Methods: A literature review was performed on Pubmed and MEDLINE. With no limit of publication date, original papers and literature reviews about the peritoneum, the peritoneal cavity, peritoneal fluid, and mesothelial cells were included (n = 72). Results: Peritoneum develops in close relationship to the gut from an early period in embryogenesis. Analyzing together the development of the primitive gut and the surrounding mesothelium helps understanding that the peritoneal cavity, the mesenteries and other structures can be considered parts of the peritoneum. However, some authors consider that structures like the mesenteries are different to the peritoneum. The mesothelial cell has a complex ultrastructural organization with intercellular junctions and apical microvilli. This complexity is further proven by the large array of functions like selective fluid and cell transport; physiological protective barrier; immune induction, modulation, and inhibition; tissue repair and scarring; preventing adhesion and tumoral dissemination; cellular migration; and the epithelial-mesenchymal transition capacity. Conclusion: Recent evidence on the anatomy, histology, and physiology of the peritoneum, shows that this structure is more complex than a simple serous membrane. These results call for a new conceptualization of peritoneum, and highlight the need of adequate research for identifying clinical relevance of this knowledge.


Antioxidant activity, total phenolic and total flavonoid contents of whole plant extracts Torilis leptophylla L.
The aim of this study was to screen various solvent extracts of whole plant of Torilis leptophylla to display potent antioxidant activity in vitro and in vivo, total phenolic and flavonoid contents in order to find possible sources for future novel antioxidants in food and pharmaceutical formulations. A detailed study was performed on the antioxidant activity of the methanol extract of whole plant of Torilis leptophylla (TLM) and its derived fractions {n-hexane (TLH), chloroform (TLC) ethyl acetate (TLE) n-butanol (TLB) and residual aqueous fraction (TLA)} by in vitro chemical analyses and carbon tetrachloride (CCl4) induced hepatic injuries (lipid peroxidation and glutathione contents) in male Sprague-Dawley rat. The total yield, total phenolic (TPC) and total flavonoid contents (TFC) of all the fractions were also determined. TLM was also subjected to preliminary phytochemical screening test for various constituents. The total phenolic contents (TPC) (121.9±3.1 mg GAE/g extract) of TLM while total flavonoid contents (TFC) of TLE (60.9 ±2.2 mg RTE/g extract) were found significantly higher as compared to other solvent fractions. Phytochemical screening of TLM revealed the presence of alkaloids, anthraquinones, cardiac glycosides, coumarins, flavonoids, saponins, phlobatannins, tannins and terpenoids. The EC50 values based on the DPPH (41.0±1 μg/ml), ABTS (10.0±0.9 μg/ml) and phosphomolybdate (10.7±2 μg/ml) for TLB, hydroxyl radicals (8.0±1 μg/ml) for TLC, superoxide radicals (57.0±0.3 μg/ml) for TLM and hydrogen peroxide radicals (68.0±2 μg/ml) for TLE were generally lower showing potential antioxidant properties. A significant but marginal positive correlation was found between TPC and EC50 values for DPPH, hydroxyl, phosphomolybdate and ABTS, whereas another weak and positive correlation was determined between TFC and EC50 values for superoxide anion and hydroxyl radicals. Results of in vivo experiment revealed that administration of CCl4 caused a significant increase in lipid peroxidation (TBARS) while decrease in GSH contents of liver. In contrast, TLM (200 mg/kg bw) and silymarin (50 mg/kg bw) co-treatment effectively prevented these alterations and maintained the antioxidant status. Data from present results revealed that Torilis leptophylla act as an antioxidant agent due to its free radical scavenging and cytoprotective activity.


Design and numerical analysis of surface plasmon-enhanced fin Ge-Si light-emitting diode.
Heavily-doped strained germanium (Ge) can emit light efficiently thanks to its pseudo direct band gap characteristic. This makes Ge a good candidate for on-chip monolithic light sources in silicon (Si) photonics systems. We propose fin-shaped Ge-Si heterojunction light-emitting diode (LED) with metal gates, which can enhance light emission by coupling with surface plasmon resonant modes and modulate light emission from the LED. We verify these two aspects through numerical analysis and device simulations. We develop the method to find the optimal device structure and specific device dimensions to maximize the spontaneous emission rate enhancement. Also we find that the LED can be modulated by a gate voltage bias.


Central fat mass versus peripheral fat and lean mass: opposite (adverse versus favorable) associations with arterial stiffness? The Amsterdam Growth and Health Longitudinal Study.
Central and peripheral fatness seem to confer opposite (i.e. adverse vs. protective) effects on cardiovascular risk, but how this occurs is not clear. In addition, the role of peripheral lean mass needs to be elucidated. We therefore investigated, in 336 (175 women) 36-yr-old and apparently healthy adults, the relationship between trunk fat, peripheral fat, and peripheral lean mass on the one hand, and estimates of stiffness of three large arteries on the other. Body composition was assessed by dual-energy x-ray absorptiometry. Arterial properties were assessed by ultrasound imaging. We found that 1) trunk fat was positively (i.e. adversely) associated with stiffness of the carotid and femoral arteries, whereas peripheral fat was inversely (i.e. favorably) associated with stiffness of the brachial and the carotido-femoral segment; 2) peripheral lean mass was positively associated with arterial diameter and carotid compliance and inversely associated with stiffness of the carotido-femoral segment; and 3) after adjustment for the other body composition variables, the above-mentioned associations remained, but peripheral fat in addition became, if anything, favorably associated with stiffness of the femoral artery. We conclude that trunk fat is adversely associated with large artery stiffness, whereas some degree of protection is conferred by peripheral fat and lean mass.


Increased sheep lung vascular permeability caused by Escherichia coli endotoxin.
We infused Escherichia coli endotoxin, 0.07-1.33 microgram/kg, intravenously into chronically instrumented unanesthetized sheep and measured pulmonary arterial and left atrial pressures, lung lymph flow, lymph and blood plasma protein concentrations, and arterial blood gases. Endotoxin caused a biphasic reaction: an early phase of pulmonary hypertension and a long late phase of steady state increased pulmonary vascular permeability during which pulmonary arterial and left atrial pressures were not increased significantly and lung lymph flow was 5 times the baseline value. Lymph: plasma total protein concentration ratio during the late phase (0.76 +/- 0.04) was significantly (P less than 0.05) higher than during baseline (0.66 +/- 0.03). The lymph response was reproducible. Lung lymph clearance of endogenous proteins with molecular radii (r) 35.5 to 96 A was increased during the steady state late phase of the reaction, but, as during baseline, clearance decreased as r increased. The endotoxin reaction was similar to the reaction to infusing whole Pseudomonas bacteria, except that endotoxin had less effect on pressures during the steady state response and caused a relatively larger increase in lymph clearance of large proteins. We conclude that E. coli endotoxin in sheep causes a long period of increased lung vascular permeability and may have a greater effect on large solute pathways across microvessels than do Pseudomonas bacteria.


Fabrication and characterisation of drug-loaded electrospun polymeric nanofibers for controlled release in hernia repair.
The chemical distribution and mechanical effects of drug compounds in loaded electrospun scaffolds, a potential material for hernia repair mesh, were characterised and the efficacy of the material was evaluated. Polycaprolactone electrospun fibres were loaded with either the antibacterial agent, irgasan, or the broad-spectrum antibiotic, levofloxacin. The samples were subsequently characterised by rheological studies, scanning electron microscopy (SEM), atomic force microscopy (AFM), contact angle goniometry (CAG), in vitro drug release studies, antibacterial studies and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Increased linear viscoelastic regions observed in the rheometry studies suggest that both irgasan and levofloxacin alter the internal structure of the native polymeric matrix. In vitro drug release studies from the loaded polymeric matrix showed significant differences in release rates for the two drug compounds under investigation. Irgasan showed sustained release, most likely driven by molecular diffusion through the scaffold. Conversely, levofloxacin exhibited a burst release profile indicative of phase separation at the edge of the fibres. Two scaffold types successfully inhibited bacterial growth when tested with strains of E. coli and S. aureus. Electrospinning drug-loaded polyester fibres is an alternative, feasible and effective method for fabricating non-woven fibrous meshes for controlled release in hernia repair.


Mapping of the gene specifying aminoglycoside 3'-phosphotransferase II on the Pseudomonas aeruginosa chromosome.
We examined the aminoglycoside inactivation enzymes in Pseudomonas aeruginosa strains, seven clinical isolates and seven laboratory strains without plasmids. All strains were found to possess the enzyme aminoglycoside 3'-phosphotransferase II [APH(3')-II]. We isolated an APH(3')-II-deficient mutant from a PAO strain by mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine. By plasmid (FP5 or R68.45)-mediated conjugation, we determined the locus of the gene specifying the APH(3')-II between trp-6 and pro-82 on the PAO chromosome and designated this gene aphA. It was concluded that the intrinsic resistance of P. aeruginosa to kanamycins, neomycins, paromomycins, ribostamycin, and butirosins was due to this newly determined gene.


Spectral and kinetic fluorescence properties of native and nonisomerizing retinal in bacteriorhodopsin.
Steady-state and picosecond (ps) fluorescence studies of wild-type bacteriorhodopsin (wt-bR) and of a nonisomerizing analog locked in the all-trans configuration have been performed. Extending earlier work done by femtosecond absorption spectroscopy, we observe a strong similarity between both proteins in both fluorescence spectra and Stokes shift thus confirming the previous result that the fluorescent state I460 of the native bR proteins is in the all-trans configuration. Comparison of the spectra of fluorescence and stimulated emission of the locked pigments indicates the presence of an excited-state absorption situated around 750 nm. Upon increase of the excitation energy, the time-integrated fluorescence shows an interesting weak blue shift, which is identical for both pigments. Finally, we discuss the primary structural processes in retinal and in the protein that lead to the sub-100 fs formation of I460 and in particular to the considerable Stokes shift.


Impact of nursing care in Australian general practice on the quality of care: A pilot of the Patient Enablement and Satisfaction Survey (PESS).
Nursing roles in general practice have undergone significant expansion, but as yet there are few tools to measure the quality of nursing care in general practice. This study piloted the Patient Enablement and Satisfaction Survey (PESS) to evaluate two aspects of quality of care in this setting. Participants were patients attending nurse-led general and chronic-disease clinics in two general practices The survey was posted to 180 consecutive patients attending these clinics over one week (response rate, 28% for general clinic, 40% chronic diseases clinic; n = 57). Scores were calculated for enablement and satisfaction and free text comments were analysed. Comparisons were made between patients who had attended the general clinic for influenza vaccination and for other conditions, and those who attended the chronic diseases clinic. Overall results indicate high levels of satisfaction (M = 68.3/75 SD = 8.1) and moderate enablement (M = 4.7/8 SD = 3.2). Significant differences were observed between satisfaction scores for patients attending the chronic disease clinic and the general clinic for influenza vaccinations alone, and between those attending the general clinic for influenza vaccinations versus treatment of other conditions. Patients attending the chronic disease clinic had higher enablement scores than patients receiving influenza vaccinations at the general clinic. Analysis of free-text comments in the survey supported these findings. All patients reported satisfaction with nursing care. Patients receiving chronic disease management reported high levels of enablement. This pilot indicated that the PESS can distinguish between two aspects of the quality of nursing care that may impact on patient outcomes.


A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells.
Allelic deletions of 10q25-26 and 19q13.3-13.4 are the most common genetic alterations in glial tumors. We have identified a balanced t(10;19) reciprocal translocation in the A172 glioblastoma cell line which involves both critical regions on chromosomes 10 and 19. In addition, loss of an entire copy of chromosome 10 has occurred in this cell line suggesting that the translocation event may provide a highly specific critical inactivating event in a gene responsible for tumorigenesis. Positional cloning of this translocation breakpoint resulted in the identification of a novel chromosome 10 gene, WDR11, which is a member of the WD-repeat gene family. The WDR11 gene is ubiquitously expressed, including normal brain and glial tumors. WDR11 is composed of 29 exons distributed over 58 kilobases and oriented towards the telomere. The translocation resulted in deletion of exon 5 and consequently fusion of intron 4 of WDR11 to the 3' untranslated region of a novel member, ZNF320, of the Krüppel-like zinc finger gene family. Since ZNF320 is oriented toward the centromere of chromosome 19, both genes appeared on the same derivative chromosome der(10). The chimeric transcript encodes the WDR11 polypeptide, which is truncated after the second of six WD-repeats. ZNF320 is also expressed in A172 cells, although it is not clear if the translocation affects the expression of the altered gene because of the presence of another unrearranged gene on chromosome 19. We suggest that, because of its localization in a region frequently showing LOH and the observation of inactivation of this gene in glioblastoma cells, WDR11 is a candidate gene for the frequently proposed tumor suppressor gene in 10q25-26 which is involved in tumorigenesis of glial and other tumors showing frequent alterations in the distal 10q region.


Global O-GlcNAc Levels Modulate Transcription of the Adipocyte Secretome during Chronic Insulin Resistance.
Increased flux through the hexosamine biosynthetic pathway and the corresponding increase in intracellular glycosylation of proteins via O-linked β-N-acetylglucosamine (O-GlcNAc) is sufficient to induce insulin resistance (IR) in multiple systems. Previously, our group used shotgun proteomics to identify multiple rodent adipocytokines and secreted proteins whose levels are modulated upon the induction of IR by indirectly and directly modulating O-GlcNAc levels. We have validated the relative levels of several of these factors using immunoblotting. Since adipocytokines levels are regulated primarily at the level of transcription and O-GlcNAc alters the function of many transcription factors, we hypothesized that elevated O-GlcNAc levels on key transcription factors are modulating secreted protein expression. Here, we show that upon the elevation of O-GlcNAc levels and the induction of IR in mature 3T3-F442a adipocytes, the transcript levels of multiple secreted proteins reflect the modulation observed at the protein level. We validate the transcript levels in male mouse models of diabetes. Using inguinal fat pads from the severely IR db/db mouse model and the mildly IR diet-induced mouse model, we have confirmed that the secreted proteins regulated by O-GlcNAc modulation in cell culture are likewise modulated in the whole animal upon a shift to IR. By comparing the promoters of similarly regulated genes, we determine that Sp1 is a common cis-acting element. Furthermore, we show that the LPL and SPARC promoters are enriched for Sp1 and O-GlcNAc modified proteins during insulin resistance in adipocytes. Thus, the O-GlcNAc modification of proteins bound to promoters, including Sp1, is linked to adipocytokine transcription during insulin resistance.


The importance of dynamics in integrative modeling of supramolecular assemblies.
Revealing the atomistic architecture of supramolecular complexes is a fundamental step toward a deeper understanding of cellular functioning. To date, this formidable task is facilitated by an emerging array of integrative modeling approaches that combine experimental data from different sources. One major challenge these methods have to face is the treatment of the dynamic rearrangements of the individual subunits upon assembly. While this flexibility can be sampled at different levels, integrating native dynamic determinants with available experimental inputs can provide an effective way to reveal the molecular recognition mechanisms at the basis of supramolecular assembly.


Market forces and technological substitutes cause fluctuations in the value of bat pest-control services for cotton.
Critics of the market-based, ecosystem services approach to biodiversity conservation worry that volatile market conditions and technological substitutes will diminish the value of ecosystem services and obviate the "economic benefits" arguments for conservation. To explore the effects of market forces and substitutes on service values, we assessed how the value of the pest-control services provided by Mexican free-tailed bats (Tadarida brasiliensis mexicana) to cotton production in the southwestern U.S. has changed over time. We calculated service values each year from 1990 through 2008 by estimating the value of avoided crop damage and the reduced social and private costs of insecticide use in the presence of bats. Over this period, the ecosystem service value declined by 79% ($19.09 million U.S. dollars) due to the introduction and widespread adoption of Bt (Bacillus thuringiensis) cotton transgenically modified to express its own pesticide, falling global cotton prices and the reduction in the number of hectares in the U.S. planted with cotton. Our results demonstrate that fluctuations in market conditions can cause temporal variation in ecosystem service values even when ecosystem function--in this case bat population numbers--is held constant. Evidence is accumulating, however, of the evolution of pest resistance to Bt cotton, suggesting that the value of bat pest-control services may increase again. This gives rise to an economic option value argument for conserving Mexican free-tailed bat populations. We anticipate that these results will spur discussion about the role of ecosystem services in biodiversity conservation in general, and bat conservation in particular.


Methanolic extract of Lupinus termis ameliorates DNA damage in alloxan-induced diabetic mice.
Diet therapy is showing a bright future in the therapy of diabetes mellitus (DM). The seeds of Lupinus termis are used in the Middle East and Africa as food and in folklore medicine. In traditional medicine, the seeds are reputed to be effective for diabetes. The aim of this work was to evaluate the antigenotoxic effect of Lupinus termis methanolic extract (LTE) against DM oxidative stress. The analysis of micronuclei (MN) and chromosomal aberrations are accurate cytogenetic techniques used to show chromosomal damage caused by clastogenic affects. The present study was designed to evaluate: (1) the effects of DM on bone marrow MN frequency and chromosomal aberrations, (2) the effect of oral treatment by gavage of LTE on MN frequency and chromosomal aberrations produced by DM. Frequencies of MN and chromosomal aberrations have been significantly increased in diabetic mice compared with the normal mice (p < 0.05). LTE at a dose 25, 50 and 100 mg/kg b.wt. for 15 days groups treatment in diabetic mice were significantly decreased MN frequency and chromosomal aberrations in a dose dependent manner. Our results suggest that LTE is a suitable agent for preventing DM-induced DNA damage. To the best of our knowledge, this is the first report on LTE having a potential diabetes-associated DNA damage-protecting activity in vivo.


Ultraviolet radiation and free radical damage to skin.
Solar UVB (290-320 nm) and particularly UVA (320-380 nm) radiations have a capacity to generate reactive chemical species, including free radicals, in cells. These intermediates have been shown to be involved in various biological effects in cultured human skin cells (e.g. cell death) and skin (e.g. erythema). Endogenous glutathione is a critical molecule in protection against the cytotoxic effects of both wavelength ranges. Although there is evidence from cellular studies for the involvement of an oxidative component of UVC/UVB radiations in activation of several genes, the doses used are generally extremely cytotoxic and could cause aberrant signalling. Genes activated by sublethal doses of UVA radiations (e.g. haem oxygenase 1 and the CL100 phosphatase) are clearly redox regulated. The strong induction of haem oxygenase 1 in human fibroblasts has been implicated in an adaptive response to oxidative membrane damage that involves increased synthesis of the iron storage protein, ferritin.


Incidentally discovered solid pancreatic masses: imaging and clinical observations.
The purpose of this study was to review the CT findings and clinical outcome in patients with incidentally discovered solid pancreatic masses. Over an 8-year period, from 2001 to 2009, we identified 24 patients with solid pancreatic masses incidentally detected by CT. There were 13 females and 11 males, with a mean age of 67 years. We determined the indication for initial CT, analyzed the CT features, and ascertained the clinical follow-up in all the patients. All of the solid masses were malignant. There were 14 adenocarcinomas and 10 neuroendocrine tumors. The most common indications for the initial CT were surveillance of an extrapancreatic malignancy (n = 10) and evaluation for hematuria (n = 6). On the initial CT, 16 of the patients (67%) had a clearly visible pancreatic mass. In eight patients isoattenuating masses were identified, only recognized by subtle signs including unexplained dilatation of the pancreatic duct (n = 5) or minimal contour deformity or density of the pancreas (n = 3). The mean survival time for the patients with adenocarcinoma was 21.6 months, and 42 months for the patients with neuroendocrine tumors. Although uncommon, incidentally discovered solid pancreatic masses are malignant neoplasms, either ductal adenocarcinomas or neuroendocrine tumors. Unlike incidentally discovered small cystic lesions, solid pancreatic lesions are often biologically aggressive.


Clinical translation of microfluidic sensor devices: focus on calibration and analytical robustness.
We present approaches to facilitate the use of microfluidics outside of the laboratory, in our case within a clinical setting and monitoring from human subjects, where the complexity of microfluidic devices requires high skill and expertise and would otherwise limit translation. Microfluidic devices show great potential for converting complex laboratory protocols into on-chip processes. We demonstrate a flexible microfluidic platform can be coupled to microfluidic biosensors and used in conjunction with clinical microdialysis. The versatility is demonstrated through a series of examples of increasing complexity including analytical processes relevant to a clinical environment such as automatic calibration, standard addition, and more general processes including system optimisation, reagent addition and homogenous enzyme reactions. The precision and control offered by this set-up enables the use of microfluidics by non-experts in clinical settings, increasing uptake and usage in real-world scenarios. We demonstrate how this type of system is helpful in guiding physicians in real-time clinical decision-making.


Gender differences in urinary kallikrein excretion in man: variation throughout the menstrual cycle.
1. Urinary kallikrein excretion was measured in healthy male subjects and in healthy pre- and post-menopausal females. 2. Urinary kallikrein excretion was shown to be constant throughout a 24 h period. Individual male subjects showed little fluctuation in urinary kallikrein excretion; within-subject variance accounted for 1.65% of the total. 3. Female subjects with ovulatory menstrual periods excreted significantly more kallikrein than post-menopausal females and males. 4. Pre-menopausal females showed a much greater within-subject variation in urinary kallikrein excretion and this could be related to the stage of the menstrual cycle, with significantly greater urinary kallikrein excretion in the luteal phase than in the follicular phase. 5. Plasma renin activity and plasma aldosterone concentration also showed a menstrual variation, with concentrations in the luteal phase being significantly higher than those in the follicular phase. 6. The rise in urinary kallikrein excretion in the luteal phase could be abolished by oral administration of the aldosterone antagonist spironolactone. 7. Urinary kallikrein excretion in post-menopausal females was similar to the range found in males, and showed no cyclic changes over a 4 week period. 8. Gender and menstrual status should be taken into account in studies of the physiological role of tissue kallikreins.


Unveiling excited state energy transfer and charge transfer in a host/guest coordination cage.
Host-guest charge transfer (HGCT) plays a key role in applications from solar energy conversion to photocatalysis. Herein, a HGCT system, a pillared Pt(ii) metallacage with encapsulated coronene was synthesized and the ultrafast excited-state dynamics were investigated by combination of femtosecond transient absorption spectroscopy, nanosecond transient emission spectrocopy and quantum chemistry calculations. Two significant ultrafast dynamic processes were unveiled: (i) charge transfer from a singlet local excited (1LE) state associated with the coronene moiety to a 1HGCT state with τ = 9.5 ps; and (ii) triplet-triplet energy transfer from a high 3HGCT state to a 3LE state with τ = 139.5 ps. The resulting long-lived species, the lowest 3LE and 3HGCT states eventually decay to the ground state in microsecond time scales of 5.2 and 43.4 μs respectively. Moreover, a clear mechanism depicting the main excited-state decay pathways connecting the initial photoexcited transients with the resulting species was proposed.


Clinical diagnosis and computer analysis of headache symptoms.
The headache histories obtained from clinical interviews of 600 patients were analysed by computer to see whether patients could be separated systematically into clinical categories and to see whether sets of symptoms commonly reported together differed in distribution among the categories. The computer classification procedure assigned 537 patients to the same category as their clinical diagnosis, the majority of discrepancies between clinical and computer classifications involving common migraine, tension-vascular and tension headache. Cluster headache emerged as a clearly-definable syndrome, and neurological symptoms during headache were most prevalent in the classical migraine group. However, the classical migraine, common migraine, tension-vascular and tension headache categories differed in terms of the number, rather than the nature, of common migraine features. Whether the two extremes of this migraine-tension headache spectrum are different disorders can be determined only by studies of their pathophysiology.


Copper binding and redox chemistry of the Aβ16 peptide and its variants: insights into determinants of copper-dependent reactivity.
The metal-binding sites of Aβ peptides are dictated primarily by the coordination preferences of the metal ion. Consequently, Cu(i) is typically bound with two His ligands in a linear mode while Cu(ii) forms a pseudo-square planar stereochemistry with the N-terminal amine nitrogen acting as an anchoring ligand. Several distinct combinations of other groups can act as co-ligands for Cu(ii). A population of multiple binding modes is possible with the equilibrium position shifting sensitively with solution pH and the nature of the residues in the N-terminal region. This work examined the Cu(ii) chemistry of the Aβ16 peptide and several variants that targeted these binding modes. The results are consistent with: (i) at pH < 7.8, the square planar site in CuII-Aβ16 consists primarily of a bidentate ligand provided by the carboxylate sidechain of Asp1 and the N-terminal amine supported by the imidazole sidechains of two His residues (designated here as component IA); it is in equilibrium with a less stable component IB in which the carboxylate ligand is substituted by the Asp1-Ala2 carbonyl oxygen. (ii) Both IA and IB convert to a common component II (apparent transition pKa ∼7.8 for IA and ∼6.5 for IB, respectively) featuring a tridentate ligand consisting of the N-terminal amine, the Asp1-Ala2 amide and the Ala2-Pro3 carbonyl; this stereochemistry is stabilized by two five-membered chelate rings. (iii) Component IA is stabilized for variant Aβ16-D1H, components I (both IA and IB) are imposed on Aβ16-A2P while the less stable IB is enforced on Aβ16-D1A (which is converted to component II at pH ∼6.5); (iv) components IA and IB share two His ligands with Cu(i) and are more reactive in redox catalysis than component II that features a highly covalent and less reactive amide N- ligand. The redox activity of IA is further enhanced for peptides with a His1 N-terminus that may act as a ligand for either Cu(i) or Cu(ii) with lower re-organization energy required for redox-shuttling. This study provided insights into the determinants that regulate the reactivity of Cu-Aβ complexes.


Template-assisted vapour-liquid-solid growth of InP nanowires on (001) InP and Si substrates.
We report on the synthesis of vertical InP nanowire arrays on (001) InP and Si substrates using template-assisted vapour-liquid-solid growth. A thick silicon oxide layer was first deposited on the substrates. The samples were then patterned by electron beam lithography and deep dry etching through the oxide layer down to the substrate surface. Gold seed particles were subsequently deposited in the holes of the pattern by the use of pulse electrodeposition. The subsequent growth of nanowires by the vapour-liquid-solid method was guided towards the [001] direction by the patterned oxide template, and displayed a high growth yield with respect to the array of holes in the template. In order to confirm the versatility and robustness of the process, we have also demonstrated guided growth of InP nanowire p-n junctions and InP/InAs/InP nanowire heterostructures on (001) InP substrates. Our results show a promising route to monolithically integrate III-V nanowire heterostructure devices with commercially viable (001) silicon platforms.


Regulation and expression of IL-32 in chronic rhinosinusitis.
Activated T lymphocytes and their interaction with resident tissue cells, particularly epithelium, play important roles in inflammatory processes in chronic rhinosinusitis (CRS). IL-32 is a recently described cytokine, which is expressed in a variety of tissue cells and involved in the pathogenesis of several chronic inflammatory diseases. Human sinus epithelial cells were isolated from biopsies and stimulated with different cytokines, which play a role in the pathogenesis of CRS. IL-32 mRNA expression was analyzed using real-time-PCR, IL-32 protein was determined by Western blot and flow cytometry as well as immunofluorescent staining in primary sinus epithelial cells and nasal biopsies from patients with CRS and healthy controls. IL-32 mRNA was upregulated by TNF-α and IFN-γ in primary sinus epithelial cells, whereas IL-1 β, IL-4, IL-13, and IL-17 did not influence IL-32 expression. IL-32 mRNA expression was significantly higher in human primary sinonasal epithelial cells (HSECs) cocultured with Th1 cells compared with HSECs cocultured with Th0 or Th2 cells. IL-32 mRNA expression was significantly higher in biopsies from sinus epithelial tissue of CRS patients with nasal polyps compared with healthy subjects (P = 0.01). IL-32 was detected in biopsies from patients with CRS, whereas it was scarcely present in control tissues. The induction of IL-32 by TNF-α, IFN-γ and Th1 cells as well as its increased expression in sinus tissues from CRS patients with nasal polyps demonstrated a potential role for IL-32 in the pathogenesis of CRS.


A circuit for coding interaural time differences in the chick brainstem.
Third-order auditory neurons in the avian nucleus laminaris (NL) are the first to receive binaural input. In the chick, NL consists of a monolayer of neurons with polarized dendritic arbors oriented dorsally and ventrally. Afferents from second-order neurons in the ipsilateral nucleus magnocellularis (NM) innervate the dorsal dendrites of NL neurons, distributing processes of approximately equal length to NL neurons along an isofrequency band (roughly caudomedial to rostrolateral). Afferents from the contralateral NM innervate the ventral dendrites of NL neurons, distributing collateral branches sequentially as they proceed from caudomedial to rostrolateral along the isofrequency band of neurons. This innervation pattern could be the basis of a "delay line" circuit, as postulated in models of neural networks mediating sound localization. We examined this circuit by analyzing evoked field potentials using a brain slice preparation containing both NL and NM. The results were consistent with the previous anatomical findings. When the ipsilateral auditory nerve or ipsilateral NM was stimulated, there was no consistent variation in the latency of postsynaptic field potentials across the medial-to-lateral extent of NL. In contrast, when the contralateral NM or NM axons in the crossed dorsal cochlear tract were stimulated, a linear increase in the latency of postsynaptic potentials was observed from medial to lateral positions in NL. When stimulation amplitudes for both the ipsilateral and contralateral inputs were adjusted so as to produce little or no postsynaptic field potential, simultaneous bilateral stimulation evoked a pronounced response. Thus, NL neurons can act as "coincidence detectors." The amplitude of the postsynaptic response was dependent on the relative timing of stimulation of the two inputs. The optimal time difference changed systematically across the medial-to-lateral extent of NL. This system of delay lines and coincidence detectors could provide a mechanism for converting interaural time differences into a "place map" within NL.


First-contact care with a medical vs chiropractic provider after consultation with a swiss telemedicine provider: comparison of outcomes, patient satisfaction, and health care costs in spinal, hip, and shoulder pain patients.
The purpose of this study was to identify differences in outcomes, patient satisfaction, and related health care costs in spinal, hip, and shoulder pain patients who initiated care with medical doctors (MDs) vs those who initiated care with doctors of chiropractic (DCs) in Switzerland. A retrospective double cohort design was used. A self-administered questionnaire was completed by first-contact care spinal, hip, and shoulder pain patients who, 4 months previously, contacted a Swiss telemedicine provider regarding advice about their complaint. Related health care costs were determined in a subsample of patients by reviewing the claims database of a Swiss insurance provider. The study sample included 403 patients who had seen MDs and 316 patients who had seen DCs as initial health care providers for their complaint. Differences in patient sociodemographic characteristics were found in terms of age, pain location, and mode of onset. Patients initially consulting MDs had significantly less reduction in their numerical pain rating score (difference of 0.32) and were significantly less likely to be satisfied with the care received (odds ratio = 1.79) and the outcome of care (odds ratio = 1.52). No significant differences were found for Patient's Global Impression of Change ratings. Mean costs per patient over 4 months were significantly lower in patients initially consulting DCs (difference of CHF 368; US $368). Spinal, hip, and shoulder pain patients had clinically similar pain relief, greater satisfaction levels, and lower overall cost if they initiated care with DCs, when compared with those who initiated care with MDs.


Leptin attenuates the anti-estrogen effect of tamoxifen in breast cancer.
Leptin is a circulating peptide hormone, encoded by the obesity (ob) gene, acting as a regulator of food intake via hypothalamic-mediated effects. Recent studies have shown that leptin and leptin receptor (ObR) are involved in the carcinogenesis and development of breast cancer. In addition, functional cross talk between leptin and estrogen signaling has been registered. Here, we investigated the relation of leptin and ObR expression with survival in women with breast cancer treated with the anti-estrogen tamoxifen, and whether leptin can interfere with the estrogen receptor alpha (ERα) and the effect of tamoxifen in breast cancer cells. The protein expression of leptin and ObR(b) in 114 breast cancer samples was evaluated by immunohistochemistry, quantified by Immunoreactivity Score (IRS) and correlated to survival and other clinicopathological features. The expression of ObR(b) in ERα positive MCF-7 breast cancer cells was examined by immunofluorescence and western blot. Leptin effect on cell proliferation was determined by MTT assay. The interference of leptin with tamoxifen on ERα degradation was studied by western blot and immunofluorescence. Effects of leptin on the transcriptional activity of ERα were explored using luciferase reporter assays. Positive staining (Immunoreactivity Score, IRS≥1) of leptin and ObR isoform ObRb in breast cancer tissues were seen in 79.8% and 85.1% of patients respectively. In overall and in tamoxifen-treated breast cancer patients, leptin expression (IRS≥1) correlated with poor prognosis, (log-rank test, P=0.016, overall; P=0.031, tamoxifen-treated). Overexpressed ObRb was found by western blotting andimmunofluorescence in MCF-7 as well as in MDA-MB-231, T47D, and MDA-MB-435 cell lines. Tamoxifen (1000μM) significantly inhibited the proliferation of MCF-7 cells, degraded ERα and reduced ERα-dependent transcription from estrogen response element-containing promoter. On the contrary, simultaneous treatment with leptin (100ng/ml) significantly attenuated these effects, similar to the effects of estradiol. Leptin correlated significantly with poor prognosis in overall and tamoxifen-treated breast cancer patients. Leptin interferes with the action of tamoxifen in MCF-7 cells, at least partly, through inducing increased nuclear expression of ERα. Thus, leptin may contribute to tamoxifen resistance and consequently, leptin suppression could be a novel way of circumventing resistance to anti-estrogen treatment.


Remission in psoriatic arthritis: is it possible and how can it be predicted?
Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFalpha) therapy and to examine possible predictors of response. Analysis of a prospective patient cohort attending a biologic clinic, between November 2004 and March 2008, was performed prior to commencing therapy and at regular intervals. Baseline clinical characteristics including demographics, previous disease-modifying antirheumatic drug (DMARD) response, tender and swollen joint counts, early morning stiffness, pain visual analogue score, patient global assessment, C reactive protein (CRP) and health assessment questionnaire (HAQ) were collected. A total of 473 patients (152 PsA; 321 rheumatoid arthritis (RA)) were analyzed. At 12 months remission, defined according to the disease activity score using 28 joint count and CRP (DAS28-CRP), was achieved in 58% of PsA patients compared to 44% of RA patients, significant improvement in outcome measures were noted in both groups (P<0.05). Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission. Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients (P<0.001). DAS28 remission is possible in PsA patients at one year following anti-TNF therapy, at higher rates than in RA patients and is predicted by baseline HAQ.


A prospective follow-up study on psychological effects in workers exposed to low levels of lead.
A prospective follow-up study on new lead workers who began work at a storage battery factory was carried out between 1975 and 1981. Psychological performances (eg, intelligence, memory, visuomotor functions, vigilance, and personality) were assessed before the commencement of exposure and after one, two, and four years of work. Of an initial number of 89 workers, 24 were available for the one-year, 16 for the two-year, and 11 for the four-year reexamination. The time-weighted average blood lead values ranged between 0.68 and 2.17 mumol/l (14 and 45 micrograms/100 ml, respectively). A reference group, nonexposed workers in a cable manufacturing plant and an electrical power plant, was similarly followed. Initially the average psychological performances were similar among the lead workers and the referents. For some of the psychological tests learning effect, which was clearly evident among the referents during the follow-up, was almost absent among the lead workers. The lead worker's visual intelligence and visuomotor functions in particular were impaired significantly after the first two years of follow-up. When the lead workers were divided into two groups according to the median time-weighted average of the blood lead values (1.30 mumol/l), the Block Design and the Santa Ana coordination tests were those which best separated the subgroups. Although the impairment of the lead workers' performance was rather slight and the dispersion in the psychological changes was wide, it was evident that some higher nervous functions were affected by lead levels above about 1.45 mumol/l.


Growth stanzas in an Epinephelidae-Lutjanidae complex: considerations to length-weight relationships.
Growth stanzas or abrupt changes in growth rates are present throughout the life span of fish. Identifying growth stanzas will help to adequately described growth taking into account that fishes are indeterminate growers. In this study, we used length-weight (L-W) relationships to analyze the growth stanzas in the Grouper-Snapper complex of Southern Gulf of Mexico. For this, the type of sexuality, sex and different sexual maturity phase were considered in the analyses of three species of gonochoric Snappers (Lutjanidae) and six species of protogynous hermaphrodite Groupers (Epinephelidae). Welch ANOVA tests were carried out to deter- mine the existence of differences in length and weight between juveniles and adults per sex. According to the observed differences, L-W relationship parameters (a and b), standard error (SE b) and coefficients of determination (R2) were calculated for all species separately by sex and sexual maturity phase. Snappers' juvenile-females b-value ranged from 2.44-2.77, juvenile-males from 2.16-2.94, adult-females from 2.63-2.80 and adult-males from 2.63-2.98. Groupers' b-value ranged for juvenile-females 2.66-3.20, adult-females from 2.73-3.31 and for adult-males 2.93-3.29. For each relationship b-value was 1-tested (-Student) to explore differences from the allometric coefficient (b=3), which indicated changes in body form. Hypothesis test, for regression slopes (b) between Snappers' juvenile-females vs. adult-females and juvenile-males vs. adult-males and Groupers' juvenile-females vs. adult-females and adult-females vs. adult-males, indicated different growth stanzas related to gonadal development for Snappers, and to gonadal development and sex change in Groupers. The identification of growth stanzas is crucial to avoid an overestimation or misleading growth rate which is used in fisheries management to establish some target reference points, such as maximum sustainable yield or yield-per-recruit.


Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications.
Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features. In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined. We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.


Action-specific disruption of perceptual confidence.
Theoretical models of perception assume that confidence is related to the quality or strength of sensory processing. Counter to this intuitive view, we showed in the present research that the motor system also contributes to judgments of perceptual confidence. In two experiments, we used transcranial magnetic stimulation (TMS) to manipulate response-specific representations in the premotor cortex, selectively disrupting postresponse confidence in visual discrimination judgments. Specifically, stimulation of the motor representation associated with the unchosen response reduced confidence in correct responses, thereby reducing metacognitive capacity without changing visual discrimination performance. Effects of TMS on confidence were observed when stimulation was applied both before and after the response occurred, which suggests that confidence depends on late-stage metacognitive processes. These results place constraints on models of perceptual confidence and metacognition by revealing that action-specific information in the premotor cortex contributes to perceptual confidence.


Use of Fe/Al drinking water treatment residuals as amendments for enhancing the retention capacity of glyphosate in agricultural soils.
Fe/Al drinking water treatment residuals (WTRs), ubiquitous and non-hazardous by-products of drinking water purification, are cost-effective adsorbents for glyphosate. Given that repeated glyphosate applications could significantly decrease glyphosate retention by soils and that the adsorbed glyphosate is potentially mobile, high sorption capacity and stability of glyphosate in agricultural soils are needed to prevent pollution of water by glyphosate. Therefore, we investigated the feasibility of reusing Fe/Al WTR as a soil amendment to enhance the retention capacity of glyphosate in two agricultural soils. The results of batch experiments showed that the Fe/Al WTR amendment significantly enhanced the glyphosate sorption capacity of both soils (p<0.001). Up to 30% of the previously adsorbed glyphosate desorbed from the non-amended soils, and the Fe/Al WTR amendment effectively decreased the proportion of glyphosate desorbed. Fractionation analyses further demonstrated that glyphosate adsorbed to non-amended soils was primarily retained in the readily labile fraction (NaHCO3-glyphosate). The WTR amendment significantly increased the relative proportion of the moderately labile fraction (HCl-glyphosate) and concomitantly reduced that of the NaHCO3-glyphosate, hence reducing the potential for the release of soil-adsorbed glyphosate into the aqueous phase. Furthermore, Fe/Al WTR amendment minimized the inhibitory effect of increasing solution pH on glyphosate sorption by soils and mitigated the effects of increasing solution ionic strength. The present results indicate that Fe/Al WTR is suitable for use as a soil amendment to prevent glyphosate pollution of aquatic ecosystems by enhancing the glyphosate retention capacity in soils.


Left ventricular remodeling after acute myocardial infarction: the influence of viability and revascularization - an echocardiographic substudy of the VIAMI-trial.
Viability seems to be important in preventing ventricular remodeling after acute myocardial infarction (AMI). We investigated the influence of viability, as demonstrated with low-dose dobutamine echocardiography, and the role of early revascularization on the process of left ventricular (LV) remodeling after AMI. We retrospectively investigated 224 patients who were initially included in the viability-guided angioplasty after acute myocardial infarction-trial (VIAMI-trial). Patients in the VIAMI-trial did not undergo a primary or rescue percutaneous coronary intervention and were stable in the early in-hospital phase. Patients underwent viability testing within 72 hours after AMI. Patients with viability were randomized to an invasive strategy or an ischemia-guided strategy. Follow-up echocardiography was performed at a mean of 205 days. In this echocardiographic substudy, patients were divided into three new groups: group 1, viable and revascularized before follow-up echocardiogram; group 2, viable, but medically treated; and group 3, non-viable patients. Group 1 showed preservation of LV volume indices. The ejection fraction (EF) increased significantly from 54.0% to 57.5% (P = 0.047). Group 2 showed a significant increase in LV volume indices with no improvement in EF (53.3% versus 53.0%, P = 0.86). Group 3 showed a significant increase in LV volume indices, with a decrease in EF from 53.5% to 49.1% (P = 0.043). Multivariate logistic regression analysis indicated the number of viable segments and revascularization during follow-up as independent predictors for EF improvement, especially in patients with lower EF at baseline. Viability early after AMI is associated with improvement in LV function after revascularization. When viable myocardium is not revascularized, the LV tends to remodel with increased LV volumes, without improvement of EF. Absence of viability results in ventricular dilatation and deterioration of EF, irrespective of revascularization status. NCT00149591 (assigned: 6 September 2005).


The Veterans Metrics Initiative study of US veterans' experiences during their transition from military service.
Efforts to promote the health and well-being of military veterans have been criticised for being inadequately informed of veterans' most pressing needs as they separate from military service, as well as the programmes that are most likely to meet these needs. The current article summarises limitations of the current literature and introduces The Veterans Metrics Initiative (TVMI) study, a longitudinal assessment of US veterans' well-being and programme use in the first three years after they separate from military service. Veterans were assessed within 3 months of military separation and will complete five additional assessments at 6-month intervals during the subsequent period. The TVMI study cohort consists of a national sample of 9566 newly separated US veterans that were recruited in the fall of 2016. The TVMI sample includes representation from all branches of service, men and women, and officers and enlisted personnel. Although representative of the larger population on many characteristics, differential response rates were observed for some subgroups, necessitating the development of non-response bias weights. Comparisons between unweighed and weighted results suggest that the weighting procedure adequately adjusts for observed differences. Analyses are under way to examine veterans' well-being and programme use in the period following separation after military service, as well as factors associated with poor outcomes. We have also begun to decompose programmes into their core components to facilitate examination of how these components relate to well-being. Once our third data collection is complete, we will examine factors related to different patterns of readjustment over time.


α-cell electrophysiology and the regulation of glucagon secretion.
Glucagon is the principal glucose-elevating hormone that forms the first-line defence against hypoglycaemia. Along with insulin, glucagon also plays a key role in maintaining systemic glucose homeostasis. The cells that secrete glucagon, pancreatic α-cells, are electrically excitable cells and use electrical activity to couple its hormone secretion to changes in ambient glucose levels. Exactly how glucose regulates α-cells has been a topic of debate for decades but it is clear that electrical signals generated by the cells play an important role in glucagon secretory response. Decades of studies have already revealed the key players involved in the generation of these electrical signals and possible mechanisms controlling them to tune glucagon release. This has offered the opportunity to fully understand the enigmatic α-cell physiology. In this review, we describe the current knowledge on cellular electrophysiology and factors regulating excitability, glucose sensing, and glucagon secretion. We also discuss α-cell pathophysiology and the perspective of addressing glucagon secretory defects in diabetes for developing better diabetes treatment, which bears the hope of eliminating hypoglycaemia as a clinical problem in diabetes care.


Pre-treatment with allopurinol or uricase attenuates barrier dysfunction but not inflammation during murine ventilator-induced lung injury.
Uric acid released from injured tissue is considered a major endogenous danger signal and local instillation of uric acid crystals induces acute lung inflammation via activation of the NLRP3 inflammasome. Ventilator-induced lung injury (VILI) is mediated by the NLRP3 inflammasome and increased uric acid levels in lung lavage fluid are reported. We studied levels in human lung injury and the contribution of uric acid in experimental VILI. Uric acid levels in lung lavage fluid of patients with acute lung injury (ALI) were determined. In a different cohort of cardiac surgery patients, uric acid levels were correlated with pulmonary leakage index. In a mouse model of VILI the effect of allopurinol (inhibits uric acid synthesis) and uricase (degrades uric acid) pre-treatment on neutrophil influx, up-regulation of adhesion molecules, pulmonary and systemic cytokine levels, lung pathology, and regulation of receptors involved in the recognition of uric acid was studied. In addition, total protein and immunoglobulin M in lung lavage fluid and pulmonary wet/dry ratios were measured as markers of alveolar barrier dysfunction. Uric acid levels increased in ALI patients. In cardiac surgery patients, elevated levels correlated significantly with the pulmonary leakage index. Allopurinol or uricase treatment did not reduce ventilator-induced inflammation, IκB-α degradation, or up-regulation of NLRP3, Toll-like receptor 2, and Toll-like receptor 4 gene expression in mice. Alveolar barrier dysfunction was attenuated which was most pronounced in mice pre-treated with allopurinol: both treatment strategies reduced wet/dry ratio, allopurinol also lowered total protein and immunoglobulin M levels. Local uric acid levels increase in patients with ALI. In mice, allopurinol and uricase attenuate ventilator-induced alveolar barrier dysfunction.


Comparison between cardiac output values measured by thermodilution and partial carbon dioxide rebreathing in patients with acute lung injury.
Thermodilution, which is considered to be a standard technique for measuring the cardiac output in critically ill patients, is not free from relevant risks. There is a need to find alternative, noninvasive, automatic, simple and accurate methods for monitoring cardiac output at the bedside. To compare cardiac output measurements by thermodilution and partial carbon dioxide rebreathing in patients with acute lung injury at two levels of severity (lung injury score, LIS: below 2.5, group A; and above 2.5, group B). Comparative, prospective and controlled study. Intensive Care Units of two university hospitals. Cardiac output was measured by thermodilution and partial carbon dioxide rebreathing. Twenty patients with acute lung failure (PaO2/FiO2 < 300) who were under mechanical ventilation and from whom 294 measurements were taken: 164 measurements in group A (n = 11) and 130 in group B (n = 9), ranging from 14 to 15 determinations per patient. There was a poor positive correlation between the methods studied for the patients from groups A (r = 0.52, p < 0.001) and B (r = 0.47, p < 0.001). The application of the Bland-Altman test made it possible to expose the lack of agreement between the methods (group A: -0.9 +/- 2.71 l/min; 95% CI = -1.14 to -0.48; and group B: -1.75 +/- 2.05 l/min; 95% CI = -2.11 to -1.4). The comparison of the results (Student t and Mann-Whitney tests) within each group and between the groups showed significant difference (p = 0.000, p < 0.05). Errors in estimating CaCO2 (arterial CO2 content) from ETCO2 (end-tidal CO2) and situations of hyperdynamic circulation associated with dead space and/or increased shunt possibly explain our results. Under the conditions of this study, the results obtained allow us to conclude that, in patients with acute lung injury, the cardiac output determined by partial rebreathing of CO2 differs from the measurements obtained by thermodilution. This difference becomes greater, the more critical the lung injury is.


Intensity Matters: High-intensity Interval Exercise Enhances Motor Cortex Plasticity More Than Moderate Exercise.
A single bout of cardiovascular exercise can enhance plasticity in human cortex; however, the intensity required for optimal enhancement is debated. We investigated the effect of exercise intensity on motor cortex synaptic plasticity, using transcranial magnetic stimulation. Twenty healthy adults (Mage = 35.10 ± 13.25 years) completed three sessions. Measures of cortico-motor excitability (CME) and inhibition were obtained before and after a 20-min bout of either high-intensity interval exercise, moderate-intensity continuous exercise, or rest, and again after intermittent theta burst stimulation (iTBS). Results showed that high-intensity interval exercise enhanced iTBS plasticity more than rest, evidenced by increased CME and intracortical facilitation, and reduced intracortical inhibition. In comparison, the effect of moderate-intensity exercise was intermediate between high-intensity exercise and rest. Importantly, analysis of each participant's plasticity response profile indicated that high-intensity exercise increased the likelihood of a facilitatory response to iTBS. We also established that the brain-derived neurotrophic factor Val66Met polymorphism attenuated plasticity responses following high-intensity exercise. These findings suggest that high-intensity interval exercise should be considered not only when planning exercise interventions designed to enhance neuroplasticity, but also to maximize the therapeutic potential of non-invasive brain stimulation. Additionally, genetic profiling may enhance efficacy of exercise interventions for brain health.


Metrics for environmental compensation: A comparative analysis of Swedish municipalities.
Environmental compensation (EC) aims at addressing environmental losses due to development projects and involves a need to compare development losses with compensation gains using relevant metrics. A conceptual procedure for computing no net loss is formulated and used as a point of departure for a comparative analysis of metrics used by five Swedish municipalities as a part of their EC implementation in the spatial planning context of detailed development plans. While Swedish law does not require EC in this context, these municipalities have still decided to introduce EC requirements for development projects that occur on municipality-owned land and to promote voluntary EC among private actors in development projects on private land. There is substantial variation across the municipalities studied with respect to both metrics and attributes subject to measurement, but there are also similarities: The attributes considered when assessing the need for EC in conjunction with development are not only about nature per se, but also about recreational opportunities and other types ecosystem services; semi-quantitative metrics such as scores are common while quantitative or monetary metrics are rare; and metrics are rarely applied to assess compensatory gains, focusing instead on losses from development. Streamlining across municipalities might be warranted for increasing predictability and transparency for developers and citizens, but it also introduces considerable challenges such as a need for developing consistent guidelines for semi-quantitative metrics, and to handle substitutability issues if metrics are not only applied on individual attributes but also on groups of attributes. The broad scope of attributes used by the municipalities is in line with an international tendency to broaden EC to include not only biodiversity aspects but also ecosystem services. Moreover, the EC systems applied by the municipalities are of particular importance for highlighting the crucial role of environmental management for maintaining and enhancing biodiversity and ecosystem services not only in areas having formal protection status but also in the everyday landscape. The municipalities' experience and strengths and weaknesses associated with their EC systems are therefore relevant also in an international perspective.


The Adam Williams initiative: collaborating with community resources to improve care for traumatic brain injury.
The Brain Trauma Foundation has developed treatment guidelines for the care of patients with acute traumatic brain injury. However, a method to provide broad acceptance and application of these guidelines has not been published. To describe methods for the development, funding, and continued educational efforts of the Adam Williams Initiative; the experiences from the first 10 years may serve as a template for hospitals and nurses that seek to engage in long-term quality improvement collaborations with foundations and/or industry. In 2004, the nonprofit Adam Williams Initiative was established with the goal of providing education and resources that would encourage hospitals across the United States to incorporate the Brain Trauma Foundation's guidelines into practice. Between 2004 and 2014, 37 hospitals have been funded by the Adam Williams Initiative and have had staff members participate in an immersion experience at Mission Hospital (Mission Viejo, California) during which team members received both didactic and hands-on education in the care of traumatic brain injury. Carefully cultivated relationships and relentless teamwork have contributed to successful implementation of the Brain Trauma Foundation's guidelines in US hospitals.


A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase.
Retinal hyperpermeability and subsequent macular edema is a cardinal feature of early diabetic retinopathy (DR). Here, we investigated the role of bioactive lipid metabolites, in particular 12/15-lipoxygenase (LOX)-derived metabolites, in this process. LC/MS lipidomic screen of human retinal endothelial cells (HRECs) demonstrated that 15-HETE was the only significantly increased metabolite (2.4 ± 0.4-fold, P = 0.0004) by high glucose (30 mM) treatment. In the presence of arachidonic acid, additional eicosanoids generated by 12/15-LOX, including 12- and 11-HETEs, were significantly increased. Fluorescein angiography and retinal albumin leakage showed a significant decrease in retinal hyperpermeability in streptozotocin-induced diabetic mice lacking 12/15-LOX compared with diabetic WT mice. Our previous studies demonstrated the potential role of NADPH oxidase in mediating the permeability effect of 12- and 15-HETEs, therefore we tested the impact of intraocular injection of 12-HETE in mice lacking the catalytic subunit of NADPH oxidase (NOX2). The permeability effect of 12-HETE was significantly reduced in NOX2(-/-) mice compared with the WT mice. In vitro experiments also showed that 15-HETE induced HREC migration and tube formation in a NOX-dependent manner. Taken together our data suggest that 12/15-LOX is implicated in DR via a NOX-dependent mechanism.


The association between maternal postnatal depressive symptoms and offspring sleep problems in adolescence.
Sleep problems are associated with increased risk of physical and mental illness. Identifying risk factors is an important method of reducing public health impact. We examined the association between maternal postnatal depression (PND) and offspring adolescent sleep problems. The sample was derived from Avon Longitudinal Study of Parents and Children (ALSPAC) participants. A sample with complete data across all variables was used, with four outcome variables. A sensitivity analysis imputing for missing data was conducted (n = 9633). PND was associated with increased risk of sleep problems in offspring at ages 16 and 18 years. The most robust effects were sleep problems at 18 years [adjusted odds ratio (OR) for a 1 s.d. increase in PND, 1.26, 95% confidence interval (CI) 1.15-1.39, p < 0.001] and waking more often (adjusted OR 1.14, 95% CI 1.05-1.25, p = 0.003). This remained after controlling for confounding variables including antenatal depression and early sleep problems in infancy. PND is associated with adolescent offspring sleep problems. Maternal interventions should consider the child's increased risk. Early sleep screening and interventions could be introduced within this group.


The effect of public health-oriented drug law reform on HIV incidence in people who inject drugs in Tijuana, Mexico: an epidemic modelling study.
As countries embark on public health-oriented drug law reform, health impact evaluations are needed. In 2012, Mexico mandated the narcomenudeo reform, which depenalised the possession of small amounts of drugs and instituted drug treatment instead of incarceration. We investigated the past and future effect of this drug law reform on HIV incidence in people who inject drugs in Tijuana, Mexico. In this epidemic modelling study, we used data from the El Cuete IV cohort study to develop a deterministic model of injecting and sexual HIV transmission in people who inject drugs in Tijuana between 2012 and 2030. The population was stratified by sex, incarceration status, syringe confiscation by the police, HIV stage, and exposure to drug treatment or rehabilitation (either opioid agonist treatment or compulsory drug abstinence programmes). We modelled the effect of these exposures on HIV risk in people who inject drugs, estimating the effect of observed and potential future reform enforcement levels. In 2011, prior to the narcomenudeo reform, 547 (75%) of 733 people who inject drugs in the El Cuete cohort reported having ever been incarcerated, on average five times since starting injecting. Modelling estimated the limited reform implementation averted 2% (95% CI 0·2-3·0) of new HIV infections in people who inject drugs between 2012 and 2017. If implementation reduced incarceration in people who inject drugs by 80% from 2018 onward, 9% (95% CI 4-16) of new HIV infections between 2018 and 2030 could be averted, with 21% (10-33) averted if people who inject drugs were referred to opioid agonist treatment instead of being incarcerated. Referral to compulsory drug abstinence programmes instead of prison could have a lower or potentially negative impact with -2% (95% CI -23 to 9) infections averted. Mexican drug law reform has had a negligible effect on the HIV epidemic among people who inject drugs in Tijuana. However, appropriate implementation could markedly reduce HIV incidence if linked to opioid agonist treatment. Unfortunately, compulsory drug abstinence programmes are the main type of drug rehabilitation available and their expansion could potentially increase HIV transmission. National Institute on Drug Abuse, UC San Diego Center for AIDS Research.


Long-term follow-up after callosotomy--a prospective, population based, observational study.
Analyze the long-term outcome of callosotomies with regard to seizure types and frequencies and antiepileptic drug treatment. This longitudinal observational study is based on data from the prospective Swedish National Epilepsy Surgery Register. Thirty-one patients had undergone callosotomy in Sweden 1995-2007 and had been followed for 2 and 5 or 10 years after surgery. Data on their seizure types and frequencies, associated impairments, and use of antiepileptic drugs have been analyzed. The median total number of seizures per patient and month was reduced from 195 before surgery to 110 two years after surgery and 90 at the long-term follow-up (5 or 10 years). The corresponding figures for drop attacks (tonic or atonic) were 190 before surgery, 100 2 years after surgery, and 20 at the long-term follow-up. Ten (56%) of the 18 patients with drop attacks were free from drop attacks at long-term follow-up. Three of the remaining eight patients had a reduction of >75%. At long-term follow-up, four were off medication. Only one of the 31 patients had no neurologic impairment. The present population-based, prospective observational study shows that the corpus callosotomy reduces seizure frequency effectively and sustainably over the years. Most improvement was seen in drop attacks. The improvement in seizure frequency over time shown in this study suggests that callosotomy should be considered at an early age in children with intractable epilepsy and traumatizing drop attacks.


A survey of Internet utilization among patients with cancer.
Recently published articles have established that a substantial number of cancer patients utilize the Internet to gather information about their respective diagnoses. The challenges for medical providers include understanding the prevalence and characteristics of patients using the Internet, reasons for Internet use, and the effectiveness of currently available websites in providing useful health-related information to patients. Adults with cancer were asked to complete a self-administered, anonymous, 21-item questionnaire upon registration at the Alvin J. Siteman Cancer Center at the Washington University School of Medicine. There were 500 respondents (mean age 58 years (range 18-90), 83% Caucasian and 15% African-American). Three hundred ninety-eight participants (80%) reported access to the Internet, and 315 (63%) reported searching for information about cancer on the Internet. Patients accessing the Internet for cancer information were younger than those who did not (median age 56 vs. 63 years; p < 0.001). Internet usage for cancer information also differed by race (p < 0.0001) and education (p < 0.0001). Among patients who searched the Internet for cancer information, 13.3% of patients had their decisions towards treatments affected or changed, and 11.4% of patients had their choice in physicians affected or changed because of Internet use; 23.5% of patients sought information on clinical trials, and 9.5% of patients were influenced or changed their decision regarding clinical trial enrollment due to Internet information. Approximately two thirds of patients with cancer used the Internet to obtain information about their disease. Factors affecting Internet use for cancer information included age, race, and education. Clinical decisions can be affected by Internet use.