The short-term effect of atorvastatin on carotid plaque morphology assessed by computer-assisted gray-scale densitometry: a pilot study.
Soft, lipid-containing carotid plaques, which appear echolucent on ultrasound imaging, have been associated with increased risk of ischemic stroke. We sought to investigate the effect of short-term treatment with atorvastatin on the change of carotid plaque echodensity. We treated 40 stroke-free and statin-naive subjects with 80 mg atorvastatin daily for 30 days. Computer assisted gray-scale densitometry (GSD) index was calculated at baseline and 30 days after treatment from the normalized plaque images. A multiple logistic regression was used to assess the effect modification of low-density lipoprotein (LDL) cholesterol on plaque stabilization after adjusting for age, sex, and smoking. The average number of carotid plaques at baseline was 2 (range: 0-5; 27 subjects with carotid plaque) and did not change 30 days following atorvastatin treatment. The mean GSD index significantly increased from 73±16 (range: 1-125) at baseline to 89±15 (range: 1-137) at 30 days after treatment (P<0.05). The adjusted odds ratio for the positive GSD plaque index change (vs. no change or decreased gray-scale median (GSM) index) was 1.71 (95% confidence interval: 1.1-7.6, P<0.01). In conclusion, we observed decreased echolucency (increased echodensity) of carotid artery plaques after short-term treatment with atorvastatin.


CD44 triggering enhances human NK cell cytotoxic functions.
CD44, a major hyaluronate receptor, is involved in a variety of lymphocyte functions including lympho-hemopoiesis, adhesion to high endothelial venules or the extracellular matrix, and T cell activation. Here we investigated the ability of CD44 to affect the cytotoxic functions of human NK cells. Ligation of CD44 by selected mAb (J173 and F10442) resulted in a rapid, dose-response-dependent enhancement of NK cytotoxic activity against a panel of tumor target cells that varied in their sensitivity to NK killing. Neither enhanced killing against NK-resistant target cells nor CD44 mAb-mediated redirected lysis was not observed. CD44 cross-linking also was found to up-regulate CD16-mediated lysis. In an attempt to investigate the early biochemical events that occur after CD44 ligation, we found that optimal cross-linking conditions induce a rapid increase of intracellular free calcium levels, which is abrogated by extracellular Ca2+ chelation. Moreover, enhanced and more sustained Ca2+ rise resulted from CD16 and CD44 coengagement. In contrast, no inositol 1,4,5-trisphosphate generation was found after optimal CD44 cross-linking. These results suggest that although CD44 is not capable of delivering a lytic signal in human NK cells, it coactivates spontaneous or CD16-mediated NK cytotoxicity. The variation in intracellular free calcium may be one of the signals that account for the costimulation of the lytic activity.


Risk for eating disorders modulates startle-responses to body words.
Body image disturbances are core symptoms of eating disorders (EDs). Recent evidence suggests that changes in body image may occur prior to ED onset and are not restricted to in-vivo exposure (e.g. mirror image), but also evident during presentation of abstract cues such as body shape and weight-related words. In the present study startle modulation, heart rate and subjective evaluations were examined during reading of body words and neutral words in 41 student female volunteers screened for risk of EDs. The aim was to determine if responses to body words are attributable to a general negativity bias regardless of ED risk or if activated, ED relevant negative body schemas facilitate priming of defensive responses. Heart rate and word ratings differed between body words and neutral words in the whole female sample, supporting a general processing bias for body weight and shape-related concepts in young women regardless of ED risk. Startle modulation was specifically related to eating disorder symptoms, as was indicated by significant positive correlations with self-reported body dissatisfaction. These results emphasize the relevance of examining body schema representations as a function of ED risk across different levels of responding. Peripheral-physiological measures such as the startle reflex could possibly be used as predictors of females' risk for developing EDs in the future.


Plasma Angiotensin-converting Enzyme Levels in Patients With Keloids and/or Hypertension.
Keloidal scarring is associated with hypertension and its pathogenesis remains poorly understood. The role of angiotensin-converting enzyme (ACE) in both hypertensive and fibrotic conditions suggests ACE may be a common mechanism for the pathogenesis of both hypertension and keloids. This paper aims to investigate the possible underlying role of ACE in keloid pathogenesis. Plasma samples were collected from participants with and without keloids. Enzyme-linked immunosorbent assays were then performed to determine ACE levels in the plasma samples. The plasma ACE levels of patients with and without keloid scarring were compared, while controlling for hypertension. The 78 samples (39 keloid participants, 39 controls) were divided into 4 cohorts of either 18 (hypertensive) or 21 (normotensive) participants. The mean ± standard deviation ACE levels were 77.9 ± 31.2 ng/mL for the hypertensive keloid group (n = 18), 69.2 ± 18.8 ng/mL for the normotensive keloid group (n = 21), 72.7 ± 21.5 ng/mL for the hypertensive control group (n = 18), and 77.6 ± 18.5 ng/mL for the normotensive control group (n = 21). No significant differences in the mean plasma ACE levels were found between any of the 4 groups. Although the data showed no significant correlation between plasma ACE levels, keloids, and hypertension, additional studies may be pursued to determine the possible underlying role of ACE in keloid pathogenesis.


Spatial neglect: new issues and their implications for occupational therapy practice.
Competent clinical practice relies on scientific theory to explain phenomena and to provide the rationale for rehabilitation strategies. Despite research advances and new insights, no unified theory has yet been offered to explain all aspects of the puzzling neglect syndrome. To find clinical relevance for new discoveries, theoretical models have to be integrated into assessment procedures and treatment strategies. The aim of this article is to briefly review recent theories about spatial hemineglect with emphasis on their potential use for practice, assessment strategies, and rehabilitative approaches.


Clinical Outcomes of Tenofovir Versus Zidovudine-based Regimens Among People Living with HIV/AIDS: a Two Years Retrospective Cohort Study.
Tenofovir (TDF) based regimen is one of the first line agents that has been utilized routinely since 2013 in Ethiopia. Unfortunately, there is limited information regarding the Clinical outcomes and associated risk factors in this setting, where patients generally present late, have high rates of TB and other infectious conditions. A two year retrospective cohort study was conducted from February 10/2015 to March 10/2015 at Jimma University Specialized Hospital. A total of 280 records were reviewed by including data from September 3, 2012 to July 31, 2014. Records were selected using a simple random sampling technique. Data was collected on socio-demographic, clinical and drug related variables. Data was analyzed using STATA 13.1. Kaplan-Meier and Cox regression were used to compare survival experience and identify independent predictors. Propensity score matching analysis was conducted to elucidate the average treatment effects of each regimen over opportunistic infections. Of 280 patients, 183(65.36%) were females and 93(33.32%) of females belong to Tenofovir group. Through 24 months analysis, TDF based regimen had a protective effect against death and opportunistic infections (OIs), (AHR=0.79, 95% CI [0.24, 2.62]) and (AHR=0.78, 95%CI [0.43, 1.4] respectively. The average treatment effect of TDF/3TC/EFV was (-71/1000, p=0.026), while it was (+114/1000, p=0.049) for AZT/3TC/EFV. However, TDF/3TC/NVP was associated with statistically insignificant morbidity reduction (-74/1000, p=0.377). Those with body mass-index (BMI) <18.5kg/m2 (AHR=3.21, 95%CI [0.93, 11.97]) had higher hazard of death. Absence of baseline prophylaxis (AHR=8.22, 95% CI [1.7, 39.77]), Cotrimoxazole prophylaxis alone (AHR=6.15, 95% CI [1.47, 26.67]) and BMI<18.5kg/m2 (AHR=2.06, 95% CI [1.14, 3.73]) had higher hazards of OIs. The survival benefit of TDF based regimen was similar to AZT based regimen and therefore can be used as an alternative for HIV/AIDS patients in resource limited setups. However, since this study was not dealt with toxicity of the regimens, we recommend to conduct high quality design on this issue.


Decreased Intrathoracic Impedance Associated With OptiVol Alert Can Diagnose Increased B-Type Natriuretic Peptide - MOMOTARO (Monitoring and Management of OptiVol Alert to Reduce Heart Failure Hospitalization) Study - .
Ambulatory measurement of intrathoracic impedance (ITI) with an implanted device may detect increases in pulmonary fluid retention early, but the clinical utility of this method is not well established. The goal of this study was to test whether conventional ITI-derived parameters can diagnose fluid retention that may cause early stage heart failure (HF). HF patients implanted with high-energy devices with OptiVol (Medtronic) monitoring were enrolled in this study. Patients were monitored remotely. At both baseline and OptiVol alert, patients were assessed on standard examinations, including analysis of serum brain natriuretic peptide (BNP). From April 2010 to August 2011, 195 patients from 12 institutes were enrolled. There were 154 primary OptiVol alert events. BNP level at the alerts was not significantly different from that at baseline. Given that ITI was inversely correlated with log BNP, we added a criterion specifying that the OptiVol alert is triggered only when ITI decreases by ≥4% from baseline. This change improved the diagnostic potential of increase in BNP at OptiVol alert (sensitivity, 75%; specificity, 88%). BNP increase could not be identified based on OptiVol alert. Decrease in ITI ≥4% compared with baseline, in addition to the alert, however, may be a useful marker for the likelihood of HF (Clinical trial info: UMIN000003351).


A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants.
Unlike the soma, which ages during the lifespan of multicellular organisms, the germ line traces an essentially immortal lineage. Genomic instability in somatic cells increases with age, and this decline in somatic maintenance might be regulated to facilitate resource reallocation towards reproduction at the expense of cellular senescence. Here we show that Caenorhabditis elegans mutants with increased longevity exhibit a soma-to-germline transformation of gene expression programs normally limited to the germ line. Decreased insulin-like signalling causes the somatic misexpression of the germline-limited pie-1 and pgl family of genes in intestinal and ectodermal tissues. The forkhead boxO1A (FOXO) transcription factor DAF-16, the major transcriptional effector of insulin-like signalling, regulates pie-1 expression by directly binding to the pie-1 promoter. The somatic tissues of insulin-like mutants are more germline-like and protected from genotoxic stress. Gene inactivation of components of the cytosolic chaperonin complex that induce increased longevity also causes somatic misexpression of PGL-1. These results indicate that the acquisition of germline characteristics by the somatic cells of C. elegans mutants with increased longevity contributes to their increased health and survival.


Diversification of DNA-Binding Specificity by Permissive and Specificity-Switching Mutations in the ParB/Noc Protein Family.
Specific interactions between proteins and DNA are essential to many biological processes. Yet, it remains unclear how the diversification in DNA-binding specificity was brought about, and the mutational paths that led to changes in specificity are unknown. Using a pair of evolutionarily related DNA-binding proteins, each with a different DNA preference (ParB [Partitioning Protein B] and Noc [Nucleoid Occlusion Factor], which both play roles in bacterial chromosome maintenance), we show that specificity is encoded by a set of four residues at the protein-DNA interface. Combining X-ray crystallography and deep mutational scanning of the interface, we suggest that permissive mutations must be introduced before specificity-switching mutations to reprogram specificity and that mutational paths to new specificity do not necessarily involve dual-specificity intermediates. Overall, our results provide insight into the possible evolutionary history of ParB and Noc and, in a broader context, might be useful for understanding the evolution of other classes of DNA-binding proteins.


Reversibility of adverse, calcineurin-dependent cardiac remodeling.
Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, in which genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet nothing is known about the effects of calcineurin when its activation commences in adulthood. Furthermore, despite the fact that ventricular hypertrophy is a well-established risk factor for heart failure, the relative pace and progression of these 2 major phenotypic features of heart disease are unknown. Finally, even though therapeutic interventions in adults are designed to slow, arrest, or reverse disease pathogenesis, little is known about the capacity for spontaneous reversibility of calcineurin-dependent pathological remodeling. We set out to address these 3 questions by studying mice engineered to harbor in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element. Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Furthermore, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility. Together, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible.


Epilepsy in kcnj10 morphant zebrafish assessed with a novel method for long-term EEG recordings.
We aimed to develop and validate a reliable method for stable long-term recordings of EEG activity in zebrafish, which is less prone to artifacts than current invasive techniques. EEG activity was recorded with a blunt electrolyte-filled glass pipette placed on the zebrafish head mimicking surface EEG technology in man. In addition, paralysis of agarose-embedded fish using D-tubocurarine excluded movement artifacts associated with epileptic activity. This non-invasive recording technique allowed recordings for up to one hour and produced less artifacts than impaling the zebrafish optic tectum with a patch pipette. Paralyzed fish survived, and normal heartbeat could be monitored for over 1h. Our technique allowed the demonstration of specific epileptic activity in kcnj10a morphant fish (a model for EAST syndrome) closely resembling epileptic activity induced by pentylenetetrazol. This new method documented that seizures in the zebrafish EAST model were ameliorated by pentobarbitone, but not diazepam, validating its usefulness. In conclusion, non-invasive recordings in paralyzed EAST syndrome zebrafish proved stable, reliable and robust, showing qualitatively similar frequency spectra to those obtained from pentylenetetrazol-treated fish. This technique may prove particularly useful in zebrafish epilepsy models that show infrequent or conditional seizure activity.


Porous micropillar structures for retaining low surface tension liquids.
The ability to manipulate fluid interfaces, e.g., to retain liquid behind or within porous structures, can be beneficial in multiple applications, including microfluidics, biochemical analysis, and the thermal management of electronic systems. While there are a variety of strategies for controlling the disposition of liquid water via capillarity, such as the use of chemically modified porous adhesive structures and capillary stop valves or surface geometric features, methods that work well for low surface tension liquids are far more difficult to implement. This study demonstrates the microfabrication of a silicon membrane that can retain exceptionally low surface tension fluorinated liquids against a significant pressure difference across the membrane via an array of porous micropillar structures. The membrane uses capillary forces along the triple phase contact line to maintain stable liquid menisci that yield positive working Laplace pressures. The micropillars have inner diameters and thicknesses of 1.5-3 μm and ∼1 μm, respectively, sustaining Laplace pressures up to 39 kPa for water and 9 kPa for Fluorinert™ (FC-40). A theoretical model for predicting the change in pressure as the liquid advances along the porous micropillar structure is derived based on a free energy analysis of the liquid meniscus with capped spherical geometry. The theoretical prediction was found to overestimate the burst pressure compared with the experimental measurements. To elucidate this deviation, transient numerical simulations based on the Volume of Fluid (VOF) were performed to explore the liquid pressure and evolution of meniscus shape under different flow rates (i.e., Capillary numbers). The results from VOF simulations reveal strong dynamic effects where the anisotropic expansion of liquid along the outer micropillar edge leads to an irregular meniscus shape before the liquid spills along the micropillar edge. These findings suggest that the analytical prediction of burst Laplace pressure obtained under quasi-static condition (i.e., equilibrium thermodynamic analysis under low capillary number) is not applicable to highly dynamic flow conditions, where the liquid meniscus shape deformation by flow perturbation cannot be restored by surface tension force instantaneously. Therefore, the critical burst pressure is dependent on the liquid velocity and viscosity under dynamic flow conditions. A numerical simulation using Surface Evolver also predicts that surface defects along the outer micropillar edge can yield up to 50% lower Laplace pressures than those predicted with ideal feature geometries. The liquid retention strategy developed here can facilitate the routing and phase management of dielectric working fluids for application in heat exchangers. Further improvements in the retention performance can be realized by optimizing the fabrication process to reduce surface defects.


Development of electronic medical record charting for hospital-based transfusion and apheresis medicine services: Early adoption perspectives.
Electronic medical records (EMRs) provide universal access to health care information across multidisciplinary lines. In pathology departments, transfusion and apheresis medicine services (TAMS) involved in direct patient care activities produce data and documentation that typically do not enter the EMR. Taking advantage of our institution's initiative for implementation of a paperless medical record, our TAMS division set out to develop an electronic charting (e-charting) strategy within the EMR. A focus group of our hospital's transfusion committee consisting of transfusion medicine specialists, pathologists, residents, nurses, hemapheresis specialists, and information technologists was constituted and charged with the project. The group met periodically to implement e-charting TAMS workflow and produced electronic documents within the EMR (Cerner Millenium) for various service line functions. The interdisciplinary working group developed and implemented electronic versions of various paper-based clinical documentation used by these services. All electronic notes collectively gather and reside within a unique Transfusion Medicine Folder tab in the EMR, available to staff with access to patient charts. E-charting eliminated illegible handwritten notes, resulted in more consistent clinical documentation among staff, and provided greater realered. However, minor updates and corrections to documents as well as select work re-designs were required for optimal use of e-charting-time review/access of hemotherapy practices. No major impediments to workflow or inefficiencies have been encount by these services. Documentation of pathology subspecialty activities such as TAMS can be successfully incorporated into the EMR. E-charting by staff enhances communication and helps promote standardized documentation of patient care within and across service lines. Well-constructed electronic documents in the EMR may also enhance data mining, quality improvement, and biovigilance monitoring activities.


Full analytical solution of the bloch equation when using a hyperbolic-secant driving function.
The frequency-swept pulse known as the hyperbolic-secant (HS) pulse is popular in NMR for achieving adiabatic spin inversion. The HS pulse has also shown utility for achieving excitation and refocusing in gradient-echo and spin-echo sequences, including new ultrashort echo-time imaging (e.g., Sweep Imaging with Fourier Transform, SWIFT) and B1 mapping techniques. To facilitate the analysis of these techniques, the complete theoretical solution of the Bloch equation, as driven by the HS pulse, was derived for an arbitrary state of initial magnetization. The solution of the Bloch-Riccati equation for transverse and longitudinal magnetization for an arbitrary initial state was derived analytically in terms of HS pulse parameters. The analytical solution was compared with the solutions using both the Runge-Kutta method and the small-tip approximation. The analytical solution was demonstrated on different initial states at different frequency offsets with/without a combination of HS pulses. Evolution of the transverse magnetization was influenced significantly by the choice of HS pulse parameters. The deviation of the magnitude of the transverse magnetization, as obtained by comparing the small-tip approximation to the analytical solution, was < 5% for flip angles < 30 °, but > 10% for the flip angles > 40 °. The derived analytical solution provides insights into the influence of HS pulse parameters on the magnetization evolution. Magn Reson Med 77:1630-1638, 2017. © 2016 International Society for Magnetic Resonance in Medicine.


Reduction of human chorionic gonadotropin beta subunit expression by modified U1 snRNA caused apoptosis in cervical cancer cells.
Secretion of human chorionic gonadotropin, especially its beta subunit by malignant trophoblastic tumors and varieties of tumors of different origin is now well documented; however the role of hCG in tumorogenesis is still unknown. This study documents the molecular presence of human chorionic gonadotropin beta subunit in uterine cervix cancer tissues and investigates a novel technique to reduce hCGbeta levels based on expression of a modified U1 snRNA as a method to study the hormone's role in biology of human cervical cancer cells cultured in vitro. The property of U1 snRNA to block the accumulation of specific RNA transcript when it binds to its donor sequence within the 3' terminal exon was used. The first 10 nucleotides of the human U1 snRNA gene, which normally binds to the 5'ss in pre-mRNA were replaced by a sequence complementary to a 10-nt segment in the terminal exon of the hCGbeta mRNA. Three different 5' end-mutated U1 snRNA expression plasmids were tested, each targeting a different sequence in the hCGbeta mRNA, and we found each one blocked the expression of hCGbeta in HeLa cells, a cervix carcinoma cell line, as shown by immunohistochemistry and qRT-PCR. Reduction of hCGbeta levels resulted in a significantly increased apoptosis rate with almost 90% of cells transfected with modified anti-hCGbeta U1 snRNAs showing morphological changes characteristic of the apoptotic process. These data suggest that human chorionic gonadotropin beta subunit may act as a tumor growth-stimulating factor.


Bioaccumulation and debromination of BDE-209 in Japanese medaka (Oryzias Latipes) when continuously exposed to environmental relevant concentrations.
BDE-209 is the most commonly used commercial polybrominated diphenyl ether, and is of particular concern due to its accumulation and debromination to more toxic congeners in aquatic organisms. In this study, Japanese medaka were continuously exposed to BDE-209 with the exposure concentrations ranging from 1 to 1000 ng/L for 15, 30 and 60 days in a flowing-through exposure device. The results showed that BDE-209 could be accumulated in fish muscle at environmental relevant concentrations and its concentration in the muscle increased with the increase of exposure time and reached to a steady state. Toxicokinetic data showed that the dose-dependent half-life of BDE-209 in the muscle of medaka ranged from 16.5 to 19.4 days. Low brominated congeners could be detected, where tri- to hexa-BDEs were predominant congeners with up to 46% to 93% of total PBDEs and lower brominated BDEs may have slower elimination rates. Concentration level of BDE-155 ranged from several ng/g wet weight (ww) to a maximum of 178 ng/g ww. BDE-154 and BDE-153 as intermediates in fish under continuous exposure were negligible. By comparing with previous work, fish may have a different bioaccumulation capacity and metabolic pattern from other species, either because of species difference or the manner of exposures.


The Unsolved Puzzle of c-Rel in B Cell Lymphoma.
Aberrant constitutive activation of Rel/NF-κB transcription factors is a hallmark of numerous cancers. Of the five Rel family members, c-Rel has the strongest direct links to tumorigenesis. c-Rel is the only member that can malignantly transform lymphoid cells in vitro. Furthermore, c-Rel is implicated in human B cell lymphoma through the frequent occurrence of REL gene locus gains and amplifications. In normal physiology, high c-Rel expression predominates in the hematopoietic lineage and a diverse range of stimuli can trigger enhanced expression and activation of c-Rel. Both expression and activation of c-Rel are tightly regulated on multiple levels, indicating the necessity to keep its functions under control. In this review we meta-analyze and integrate studies reporting gene locus aberrations to provide an overview on the frequency of REL gains in human B cell lymphoma subtypes, namely follicular lymphoma, diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, and classical Hodgkin lymphoma. We also summarize current knowledge on c-Rel expression and protein localization in these human B cell lymphomas and discuss the co-amplification of BCL11A with REL. In addition, we highlight and illustrate key pathways of c-Rel activation and regulation with a specific focus on B cell biology.


Increases in serum concentrations of follicle-stimulating hormone (FSH) during thyrotrophin-releasing hormone (TRH) infusions in normal men.
Increases in serum FSH values to approximately 50% above basal concentrations were found during TRH infusions of 2.0 microgram/min into normal men (n = 10). These increases could not be explained by cross-reactivity of thyrotrophin (TSH) in the FSH assay. No significant change was found in serum concentrations of FSH during saline infusions (n = 4) nor in LH concentrations during either TRH or saline infusions. Many previous studies using single injections of TRH have failed to demonstrate changes in serum FSH concentrations. It is possible that prolonged infusions of TRH, as used in this study, are more likely to lead to non-specificity of the effects of this tripeptide on pituitary hormone secretion.


Poly(propylene glycol) and urethane dimethacrylates improve conversion of dental composites and reveal complexity of cytocompatibility testing.
To determine the effects of various monomers on conversion and cytocompatibility of dental composites and to improve these properties without detrimentally affecting mechanical properties, depth of cure and shrinkage. Composites containing urethane dimethacrylate (UDMA) or bisphenol A glycidyl methacrylate (Bis-GMA) with poly(propylene glycol) dimethacrylate (PPGDMA) or triethylene glycol dimethacrylate (TEGDMA) were characterized using the following techniques: conversion (FTIR at 1 and 4mm depths), depth of cure (BS EN ISO 4049:2009 and FTIR), shrinkage (BS EN ISO 17304:2013 and FTIR), strength and modulus (biaxial flexural test) and water sorption. Cytocompatibility of composites and their liquid phase components was assessed using three assays (resazurin, WST-8 and MTS). UDMA significantly improved conversion, BFS and depth of cure compared to Bis-GMA, without increasing shrinkage. UDMA was cytotoxic at lower concentrations than Bis-GMA, but extracts of Bis-GMA-containing composites were less cytocompatible than of those containing UDMA. PPGDMA improved conversion and depth of cure compared to TEGDMA, without detrimentally affecting shrinkage. TEGDMA was shown by all assays to be highly toxic. Resazurin, but not WST-8 and MTS, suggested that PPGDMA exhibited improved cytocompatibility compared to TEGDMA. The use of UDMA and PPGDMA results in composites with excellent conversion, depth of cure and mechanical properties, without increasing shrinkage. Composites containing UDMA appear to be slightly more cytocompatible than those containing Bis-GMA. These monomers may therefore improve the material properties of dental restorations, particularly bulk fill materials. The effect of diluent monomer on cytocompatibility requires further investigation.


Copy number variation alters local and global mutational tolerance.
Copy number variants (CNVs), duplications and deletions of genomic sequences, contribute to evolutionary adaptation but can also confer deleterious effects and cause disease. Whereas the effects of amplifying individual genes or whole chromosomes (i.e., aneuploidy) have been studied extensively, much less is known about the genetic and functional effects of CNVs of differing sizes and structures. Here, we investigated Saccharomyces cerevisiae (yeast) strains that acquired adaptive CNVs of variable structures and copy numbers following experimental evolution in glutamine-limited chemostats. Although beneficial in the selective environment, CNVs result in decreased fitness compared with the euploid ancestor in rich media. We used transposon mutagenesis to investigate mutational tolerance and genome-wide genetic interactions in CNV strains. We find that CNVs increase mutational target size, confer increased mutational tolerance in amplified essential genes, and result in novel genetic interactions with unlinked genes. We validated a novel genetic interaction between different CNVs and BMH1 that was common to multiple strains. We also analyzed global gene expression and found that transcriptional dosage compensation does not affect most genes amplified by CNVs, although gene-specific transcriptional dosage compensation does occur for ∼12% of amplified genes. Furthermore, we find that CNV strains do not show previously described transcriptional signatures of aneuploidy. Our study reveals the extent to which local and global mutational tolerance is modified by CNVs with implications for genome evolution and CNV-associated diseases, such as cancer.


Structure of a synaptic gammadelta resolvase tetramer covalently linked to two cleaved DNAs.
The structure of a synaptic intermediate of the site-specific recombinase gammadelta resolvase covalently linked through Ser10 to two cleaved duplex DNAs has been determined at 3.4 angstrom resolution. This resolvase, activated for recombination by mutations, forms a tetramer whose structure is substantially changed from that of a presynaptic complex between dimeric resolvase and the cleavage site DNA. Because the two cleaved DNA duplexes that are to be recombined lie on opposite sides of the core tetramer, large movements of both protein and DNA are required to achieve strand exchange. The two dimers linked to the DNAs that are to be recombined are held together by a flat interface. This may allow a 180 degrees rotation of one dimer relative to the other in order to reposition the DNA duplexes for strand exchange.


Impact of human immunodeficiency virus on medical and surgical residents.
BACKGROUND--Previous surveys of resident physicians on human immunodeficiency virus (HIV) matters have tended to focus on urban programs serving a patient population with an expected high prevalence of HIV infection. The objective of this study was to survey a community hospital residency program in a nonurban area with a perceived low HIV patient seroprevalence. METHODS--A 32-question survey was completed on an anonymous basis by the entire 74 member multidisciplinary resident physician group at a two-campus university-affiliated hospital program in southeastern Pennsylvania in May 1991. RESULTS--Residents perceived their patient population's HIV seroprevalence rate to be low although they believed their personal risk of occupational exposure to blood-borne infection was moderate to high. House staff most often complied with universal precautions for fear of acquiring a blood-borne illness and most often did not comply because of time constraints. Not perceiving the exposure as a health risk was the primary reason for nonreporting of exposures. Occupational exposure rates were alarmingly high, with suturing using a curved needle being the most common exposure method. Most residents were unfamiliar with HIV legislation. A majority of the house staff wanted improved HIV patient management training and life and disability insurance against occupationally acquired HIV. Many other important issues were addressed in this survey. CONCLUSION--Residents even in low seroprevalence environments do fear occupationally acquired HIV. A great need exists for improved training in universal precautions, acquired immunodeficiency syndrome legislation, and HIV patient management as well as for insurance against occupationally acquired HIV.


Importance of engaging obstetrician/gynecologists in cardiovascular disease prevention.
To review recent evidence regarding traditional and sex-specific factors identified among women during their reproductive years and their importance in lifetime risk for cardiovascular disease (CVD). Longitudinal studies demonstrated a woman's burden of risk during her reproductive years is associated with future risk of CVD. Similarly, women with a healthy lifestyle are relatively protected and have the lowest lifetime risk. Some primary prevention strategies, when implemented during this age window, were cost-effective. The link between pregnancy outcome and future CVD risk is now better understood, and evidence now relates pregnancy-associated hypertension and diabetes, as well as a preterm delivery or a low birth weight delivery, to excess risk. Gaps in preventive healthcare for women in this age group included low rates of treatment initiation for hypertension and failure to follow guidelines for diabetes surveillance among women with a history of gestational diabetes. Knowledge gaps for standard CVD prevention, as well as the link between pregnancy complications and future CVD risk, were identified among both primary care providers and obstetrician/gynecologists. Traditional and sex-specific risk factors for CVD present during women's reproductive years. Engaging the obstetrician/gynecologist provides a strategy to enhance prevention.


Characterization of small HSPs from Anemonia viridis reveals insights into molecular evolution of alpha crystallin genes among cnidarians.
Gene family encoding small Heat-Shock Proteins (sHSPs containing α-crystallin domain) are found both in prokaryotic and eukaryotic organisms; however, there is limited knowledge of their evolution. In this study, two small HSP genes termed AvHSP28.6 and AvHSP27, both organized in one intron and two exons, were characterised in the Mediterranean snakelocks anemone Anemonia viridis. The release of the genome sequence of Hydra magnipapillata and Nematostella vectensis enabled a comprehensive study of the molecular evolution of α-crystallin gene family among cnidarians. Most of the H. magnipapillata sHSP genes share the same gene organization described for AvHSP28.6 and AvHSP27, differing from the sHSP genes of N. vectensis which mainly show an intronless architecture. The different genomic organization of sHSPs, the phylogenetic analyses based on protein sequences, and the relationships among Cnidarians, suggest that the A.viridis sHSPs represent the common ancestor from which H. magnipapillata genes directly evolved through segmental genome duplication. Additionally retroposition events may be considered responsible for the divergence of sHSP genes of N. vectensis from A. viridis. Analyses of transcriptional expression profile showed that AvHSP28.6 was constitutively expressed among different tissues from both ectodermal and endodermal layers of the adult sea anemones, under normal physiological conditions and also under different stress condition. Specifically, we profiled the transcriptional activation of AvHSP28.6 after challenges with different abiotic/biotic stresses showing induction by extreme temperatures, heavy metals exposure and immune stimulation. Conversely, no AvHSP27 transcript was detected in such dissected tissues, in adult whole body cDNA library or under stress conditions. Hence, the involvement of AvHSP28.6 gene in the sea anemone defensome is strongly suggested.


Thumb injuries in intercollegiate men's lacrosse.
Men's intercollegiate lacrosse is played at a fast pace and with significant force. Glove protection is required. However, the thumb is at risk because of contact with opponents' sticks, the ball, other players, and the ground or artificial surface. To characterize patterns of hand injuries in men's intercollegiate lacrosse and to compare them with those in similar intercollegiate stick-handling sports that require gloves. Descriptive epidemiology study. The National Collegiate Athletic Association (NCAA) Injury Surveillance System was utilized to evaluate thumb injuries in intercollegiate stick-handling sports (men's lacrosse, women's lacrosse, and men's ice hockey) during 16 intercollegiate seasons. Injuries were defined as events requiring an athlete to seek medical treatment and miss competition. Data were collected for injuries to the thumb, phalanges, and hand. Descriptive statistics were performed to calculate rates of injury per 1000 athlete-exposures and the relative exposure of the thumb with respect to total hand injuries. chi(2) testing with the Yates correction for continuity was performed to determine differences in proportions of injury among the 3 sports studied. During 16 intercollegiate seasons, there were 692 thumb, finger, and hand injuries in 3 038 255 athlete-exposures. Total thumb injuries were significantly higher in men's lacrosse, accounting for 59.4% of total hand injuries, when compared with women's lacrosse (42%) and men's ice hockey (35.8%) (P <.001). Thumb fractures and contusions were each also found to be significantly more prevalent (P <.001) when compared with women's lacrosse and men's ice hockey. Men's intercollegiate lacrosse requires the use of gloves; nonetheless, injury rates of the thumb are significantly elevated in this sport compared with other gloved, stick-handling sports. Recommendations include the development of gloves with improved thumb protection.


Estimation of the possible economic effects of a sequential testing strategy with NT-proBNP before echocardiography in primary care.
The object of the study was to estimate the possible economic effects of a sequential testing strategy with NT-proBNP from a primary care payer perspective. The study data were collected from primary care physicians in the County of Uppland from 2005 through 2012. Two different cut-off levels were used for negative NT-proBNP in the rule-out test: 300 and 400 pg/mL. The cost-effectiveness of the testing strategy was estimated through the short-term cost avoidance and reduction in demand for echocardiographies. The female patients were slightly older than the males. Based on the data from 2012, the estimated costs for NT-proBNP tests and echocardiographies per county were reduced by EUR 300000/100000 inhabitants with the 300 pg/mL cut-off and EUR 350000/100000 inhabitants with the 400 pg/mL. The use of NT-proBNP as a rule-out test in a sequential testing strategy reduced the cost for diagnostic work-up of primary care patients with suspected heart failure.


Structure of recombinant human carboxylesterase 1 isolated from whole cabbage looper larvae.
The use of whole insect larvae as a source of recombinant proteins offers a more cost-effective method of producing large quantities of human proteins than conventional cell-culture approaches. Human carboxylesterase 1 has been produced in and isolated from whole Trichoplusia ni larvae. The recombinant protein was crystallized and its structure was solved to 2.2 resolution. The results indicate that the larvae-produced enzyme is essentially identical to that isolated from cultured Sf21 cells, supporting the use of this expression system to produce recombinant enzymes for crystallization studies.


Bottom-up gaze shifts and fixations learning by imitation.
The ability to follow the gaze of conspecifics is a critical component in the development of social behaviors, and many efforts have been directed to studying the earliest age at which it begins to develop in infants. Developmental and neurophysiological studies suggest that imitative learning takes place once gaze-following abilities are fully established and joint attention can support the shared behavior required by imitation. Accordingly, gaze-following acquisition should be precursory to most machine learning tasks, and imitation learning can be seen as the earliest modality for acquiring meaningful gaze shifts and for understanding the structural substrate of fixations. Indeed, if some early attentional process, based on a suitable combination of gaze shifts and fixations, could be learned by the robot, then several demonstration learning tasks would be dramatically simplified. In this paper, we describe a methodology for learning gaze shifts based on imitation of gaze following with a gaze machine, which we purposefully introduced to make the robot gaze imitation conspicuous. The machine allows the robot to share and imitate gaze shifts and fixations of a caregiver through a mutual vergence. This process is then suitably generalized by learning both the scene salient features toward which the gaze is directed and the way saccadic programming is attained. Salient features are modeled by a family of Gaussian mixtures. These together with learned transitions are generalized via hidden Markov models to account for humanlike gaze shifts allowing to discriminate salient locations.


Assembly and analysis of a qingke reference genome demonstrate its close genetic relation to modern cultivated barley.
Qingke, the local name of hulless barley in the Tibetan Plateau, is a staple food for Tibetans. The availability of its reference genome sequences could be useful for studies on breeding and molecular evolution. Taking advantage of the third-generation sequencer (PacBio), we de novo assembled a 4.84-Gb genome sequence of qingke, cv. Zangqing320 and anchored a 4.59-Gb sequence to seven chromosomes. Of the 46,787 annotated 'high-confidence' genes, 31 564 were validated by RNA-sequencing data of 39 wild and cultivated barley genotypes with wide genetic diversity, and the results were also confirmed by nonredundant protein database from NCBI. As some gaps in the reference genome of Morex were covered in the reference genome of Zangqing320 by PacBio reads, we believe that the Zangqing320 genome provides the useful supplements for the Morex genome. Using the qingke genome as a reference, we conducted a genome comparison, revealing a close genetic relationship between a hulled barley (cv. Morex) and a hulless barley (cv. Zangqing320), which is strongly supported by the low-diversity regions in the two genomes. Considering the origin of Morex from its breeding pedigree, we then demonstrated a close genomic relationship between modern cultivated barley and qingke. Given this genomic relationship and the large genetic diversity between qingke and modern cultivated barley, we propose that qingke could provide elite genes for barley improvement.


Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study).
Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke. The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults ≥65 years of age. For this study, we excluded participants diagnosed with stroke or AF before baseline. Exposures were several markers of atrial cardiopathy: baseline P-wave terminal force in ECG lead V1, left atrial dimension on echocardiogram, and N terminal pro B type natriuretic peptide (NT-proBNP), as well as incident AF. Incident AF was ascertained from 12-lead electrocardiograms at annual study visits for the first decade after study enrollment and from inpatient and outpatient Medicare data throughout follow-up. The primary outcome was incident ischemic stroke. We used Cox proportional hazards models that included all 4 atrial cardiopathy markers along with adjustment for demographic characteristics and established vascular risk factors. Among 3723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 participants (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When all atrial cardiopathy markers were combined in 1 Cox model, we found significant associations with stroke for P-wave terminal force in ECG lead V1 (hazard ratio per 1000 μV*ms 1.04; 95% confidence interval, 1.001-1.08), log-transformed NT-proBNP (hazard ratio per doubling of NT-proBNP, 1.09; 95% confidence interval, 1.03-1.16), and incident AF (hazard ratio, 2.04; 95% confidence interval, 1.67-2.48) but not left atrial dimension (hazard ratio per cm, 0.96; 95% confidence interval, 0.84-1.10). In addition to clinically apparent AF, other evidence of abnormal atrial substrate is associated with subsequent ischemic stroke. This finding is consistent with the hypothesis that thromboembolism from the left atrium may occur in the setting of several different manifestations of atrial disease.


Neonatal bacterial meningitis and dexamethasone adjunctive usage in Nigeria.
Neonatal bacterial meningitis is devastating, with attendant high mortality and neurological sequelae. We, therefore, aimed to delineate its current incidence, etiologic, clinical, laboratory spectra, and the effect of steroid therapy on the outcome. Babies admitted from 1992 to 1995 in the Special Care Baby Unit of the University of Maiduguri Teaching Hospital, Maduguri, Nigeria, with bacterial meningitis were studied prospectively. Neonatal bacterial meningitis was confirmed if the cerebrospinal fluid (CSF) microbiological, chemical, immunological and clinical criteria were satisfied. Detailed neurological follow-up was made. Sixty-nine cases of neonatal bacterial meningitis were encountered, (25 were early-onset, and 44 late-onset); the incidence was 6.5/1000 live births. 22 Positive CSF cultures were grown in early-onset meningitis, and 28 in late-onset disease. Low birth weight showed higher risk of bacterial meningitis and it was significantly more likely in the preterm. X2 = 24.19, p = 0.000001). Gram-negative pathogens were more isolated (28/50, 56%); Escherichia coli (11) being the commonest, while of the Gram-positive pathogens Staphylococcus aureus was most predominant overall (13/50). Concomitant blood culture was positive in 39/50 (78%), inclusive of all 22 "definite" early-onset disease. The CSF WBC was minimally raised (25-30 x 10(6)/L) in 11 (22%) of "definite" neonatal bacterial meningitis. Detection of unusual pathogens was noteworthy: N. meningitidis (2) and H. influenzae (2), contributing 0.6 and 2.2 per 1000 live births and admissions, respectively. Overall mortality was 24.6%. Of the forty survivors, 9 (22.5%) had neurological sequelae: sensorineural hearing deficit (3), hydrocephalus (2), subdural effusion (2), hemiparesis (1), afebrile (recurrent) seizure (1), and there was reduced developmental quotients at 24 months follow-up in 33. Dexamethasone therapy decreased mortality significantly; p = 0.0004. The new information highlighted by this research includes the lack of Group B Streptococcus isolation, the finding of S. pneumoniae, N. meningitidis, H. influenzae and S. aureus as significant pathogens, usefulness of blood cultures in the detection of neonatal bacterial meningitis, increasing resistance of Gram-positive neonatal pathogens to cloxacillin, low CSF WBC, and the finding that the adjunctive use of dexamethasone significantly decreases case fatality and neurological sequelae.


The microRNA-302b-inhibited insulin-like growth factor-binding protein 2 signaling pathway induces glioma cell apoptosis by targeting nuclear factor IA.
MicroRNAs are small noncoding RNAs that post-transcriptionally control the expression of genes involved in glioblastoma multiforme (GBM) development. Although miR-302b functions as a tumor suppressor, its role in GBM is still unclear. Therefore, this study comprehensively explored the roles of miR-302b-mediated gene networks in GBM cell death. We found that miR-302b levels were significantly higher in primary astrocytes than in GBM cell lines. miR-302b overexpression dose dependently reduced U87-MG cell viability and induced apoptosis through caspase-3 activation and poly(ADP ribose) polymerase degradation. A transcriptome microarray revealed 150 downregulated genes and 380 upregulated genes in miR-302b-overexpressing cells. Nuclear factor IA (NFIA), higher levels of which were significantly related to poor survival, was identified as a direct target gene of miR-302b and was involved in miR-302b-induced glioma cell death. Higher NFIA levels were observed in GBM cell lines and human tumor sections compared with astrocytes and non-tumor tissues, respectively. NFIA knockdown significantly enhanced apoptosis. We found high levels of insulin-like growth factor-binding protein 2 (IGFBP2), another miR-302b-downregulated gene, in patients with poor survival. We verified that NFIA binds to the IGFBP2 promoter and transcriptionally enhances IGFBP2 expression levels. We identified that NFIA-mediated IGFBP2 signaling pathways are involved in miR-302b-induced glioma cell death. The identification of a regulatory loop whereby miR-302b inhibits NFIA, leading to a decrease in expression of IGFBP-2, may provide novel directions for developing therapies to target glioblastoma tumorigenesis.


Down-regulation of the intrarenal renin-angiotensin system in the aging rat.
Progressive deterioration of renal function occurs during normal aging. Previous studies on the aging kidney have demonstrated glomerular hemodynamic changes, specifically, glomerular capillary hypertension, as maladaptations that lead to proteinuria and glomerular sclerosis over time. Aging rats treated with angiotensin-converting enzyme inhibition have relatively less proteinuria and sclerosis, suggesting that age-related changes in renal function may be associated with alterations in the intrarenal renin-angiotensin system, which thus may play a major role in the pathogenesis of these maladaptations. To investigate this possibility, renal and systemic renin-angiotensin systems were examined at an early phase of the aging process (3 months) and at a later phase (12 months) in male Sprague-Dawley rats. Although plasma renin and serum angiotensin-converting enzyme concentrations did not differ significantly, the intrarenal system showed down-regulation of renin mRNA and angiotensin-converting enzyme levels with aging, whereas angiotensinogen levels remained stable. The decrease in renin mRNA appeared to precede the fall in plasma renin concentration in the aging process. Additional studies in 15-month-old rats confirmed that, by this time, both basal and stimulated renal renin release rates were impaired in older rats. Thus, both decreased renin synthesis and impaired renin release underlie the fall in plasma renin with normal aging. This decrease may act to lower intrarenal baseline levels of angiotensin II, an adaptation of likely importance in the modulation of intrarenal vascular tone and tubular function in the aging kidney.


Moving from ideas to action - developing health financing systems towards universal coverage in Africa.
Accelerating progress towards universal coverage in African countries calls for concrete actions that reinforce social health protection through establishment of sustainable health financing mechanisms. In order to explore possible pathways for moving past the existing obstacles, panel discussions were organized on health financing bringing together Ministers of health and Ministers of finance with the objective of creating a discussion space where the different perspectives on key issues and needed actions could meet. This article presents a synthesis of panel discussions focusing on the identified challenges and the possible solutions. The overview of this paper is based on the objectives and proceedings of the panel discussions and relies on the observation and study of the interaction between the panelists and on the discourse used. The discussion highlighted that a large proportion of the African population has no access to needed health services with significant reliance on direct out of pocket payments. There are multiple obstacles in making prepayment and pooling mechanisms operational. The relatively strong political commitment to health has not always translated into more public spending for health. Donor investment in health in low income countries still falls below commitments. There is need to explore innovative domestic revenue collection mechanisms. Although inadequate funding for health is a fundamental problem, inefficient use of resources is of great concern. There is need to generate robust evidence focusing on issues of importance to ministry of finance. The current unsatisfactory state of health financing was mainly attributed to lack of clear vision; evidence based plans and costed strategies. Based on the analysis of discussion made, there are points of convergence and divergence in the discourse and positions of the two ministries. The current blockage points holding back budget allocations for health can be solved with a more evidence based approach and dialogue based on a clear vision and costed strategic plan articulated by the ministry of health. Improving health in Africa is a driver for long-term economic growth and development and this is the reason why the ministries of health and finance will need to find common ground on how to create policy coherence and how to articulate their respective objectives.


Generation of correlated spike trains.
Neuronal spike trains display correlations at diverse timescales throughout the nervous system. The functional significance of these correlations is largely unknown, and computational investigations can help us understand their role. In order to generate correlated spike trains with given statistics, several case-specific methods have been described in the litterature. This letter presents two general methods to generate sets of spike trains with given firing rates and pairwise correlation functions, along with efficient simulation algorithms.


High speed optical quantum random number generation.
We present a fully integrated, ready-for-use quantum random number generator (QRNG) whose stochastic model is based on the randomness of detecting single photons in attenuated light. We show that often annoying deadtime effects associated with photomultiplier tubes (PMT) can be utilized to avoid postprocessing for bias or correlations. The random numbers directly delivered to a PC, generated at a rate of up to 50 Mbit/s, clearly pass all tests relevant for (physical) random number generators.


Effects of 6-h exposure to low relative humidity and low air pressure on body fluid loss and blood viscosity.
The purpose of this study was to investigate the effects of 6-h exposure to low relative humidity (RH) and low air pressure in a simulated air cabin environment on body fluid loss (BFL) and blood viscosity. Fourteen young healthy male subjects were exposed to four conditions, which combined RH (10% RH or 60% RH) and air pressure (NP: sea level or LP: equivalent to an altitude of 2000 m). Subjects remained seated on a chair in the chamber for 6 h. Their diet and water intake were restricted before and during the experiment. Insensible water loss (IWL) in LP10% condition was significantly greater than in NP60% condition; thus, combined 10%RH and LP conditions promoted a greater amount of IWL. The BFL under the LP condition was significantly greater than that under the NP condition. Blood viscosity significantly increased under LP conditions. Increases in red blood cell counts (RBCs) and BFL likely contributed to the increased blood viscosity. These findings suggest that hypobaric-induced hypoxia, similar to the conditions in the air cabin environment, may cause increased blood viscosity and that the combined low humidity and hypobaric hypoxia conditions increase IWL.


Revealing evolutionary constraints on proteins through sequence analysis.
Statistical analysis of alignments of large numbers of protein sequences has revealed "sectors" of collectively coevolving amino acids in several protein families. Here, we show that selection acting on any functional property of a protein, represented by an additive trait, can give rise to such a sector. As an illustration of a selected trait, we consider the elastic energy of an important conformational change within an elastic network model, and we show that selection acting on this energy leads to correlations among residues. For this concrete example and more generally, we demonstrate that the main signature of functional sectors lies in the small-eigenvalue modes of the covariance matrix of the selected sequences. However, secondary signatures of these functional sectors also exist in the extensively-studied large-eigenvalue modes. Our simple, general model leads us to propose a principled method to identify functional sectors, along with the magnitudes of mutational effects, from sequence data. We further demonstrate the robustness of these functional sectors to various forms of selection, and the robustness of our approach to the identification of multiple selected traits.


Multi-class protein fold classification using a new ensemble machine learning approach.
Protein structure classification represents an important process in understanding the associations between sequence and structure as well as possible functional and evolutionary relationships. Recent structural genomics initiatives and other high-throughput experiments have populated the biological databases at a rapid pace. The amount of structural data has made traditional methods such as manual inspection of the protein structure become impossible. Machine learning has been widely applied to bioinformatics and has gained a lot of success in this research area. This work proposes a novel ensemble machine learning method that improves the coverage of the classifiers under the multi-class imbalanced sample sets by integrating knowledge induced from different base classifiers, and we illustrate this idea in classifying multi-class SCOP protein fold data. We have compared our approach with PART and show that our method improves the sensitivity of the classifier in protein fold classification. Furthermore, we have extended this method to learning over multiple data types, preserving the independence of their corresponding data sources, and show that our new approach performs at least as well as the traditional technique over a single joined data source. These experimental results are encouraging, and can be applied to other bioinformatics problems similarly characterised by multi-class imbalanced data sets held in multiple data sources.


Health and economic burden of respiratory syncytial virus (RSV) disease and the cost-effectiveness of potential interventions against RSV among children under 5 years in 72 Gavi-eligible countries.
Respiratory syncytial virus (RSV) frequently causes acute lower respiratory infection in children under 5, representing a high burden in Gavi-eligible countries (mostly low-income and lower-middle-income). Since multiple RSV interventions, including vaccines and monoclonal antibody (mAb) candidates, are under development, we aim to evaluate the key drivers of the cost-effectiveness of maternal vaccination and infant mAb for 72 Gavi countries. A static Multi-Country Model Application for RSV Cost-Effectiveness poLicy (MCMARCEL) was developed to follow RSV-related events monthly from birth until 5 years of age. MCMARCEL was parameterised using country- and age-specific demographic, epidemiological, and cost data. The interventions' level and duration of effectiveness were guided by the World Health Organization's preferred product characteristics and other literature. Maternal vaccination and mAb were assumed to require single-dose administration at prices assumed to align with other Gavi-subsidised technologies. The effectiveness and the prices of the interventions were simultaneously varied in extensive scenario analyses. Disability-adjusted life years (DALYs) were the primary health outcomes for cost-effectiveness, integrated with probabilistic sensitivity analyses and Expected Value of Partially Perfect Information analysis. The RSV-associated disease burden among children in these 72 countries is estimated at an average of 20.8 million cases, 1.8 million hospital admissions, 40 thousand deaths, 1.2 million discounted DALYs, and US$611 million discounted direct costs. Strategy 'mAb' is more effective due to its assumed longer duration of protection versus maternal vaccination, but it was also assumed to be more expensive. Given all parameterised uncertainty, the optimal strategy of choice tends to change for increasing willingness to pay (WTP) values per DALY averted from the current situation to maternal vaccination (at WTP > US$1000) to mAB (at WTP > US$3500). The age-specific proportions of cases that are hospitalised and/or die cause most of the uncertainty in the choice of optimal strategy. Results are broadly similar across countries. Both the maternal and mAb strategies need to be competitively priced to be judged as relatively cost-effective. Information on the level and duration of protection is crucial, but also more and better disease burden evidence-especially on RSV-attributable hospitalisation and death rates-is needed to support policy choices when novel RSV products become available.


Determination of absorption and scattering coefficients for nonhomogeneous media. 1: theory.
Equations are derived to determine the diffuse reflectance and transmittance of inhomogeneous materials. The equations are valid for collimated incident radiation for any angle of incidence. The effects of boundary reflectance and anisotropic scattering are included. The equations are derived from the equation of radiative transport, using the Schuster-Schwartzchild approximation. They are sufficiently simple to be used for spectroscopic determination of the absorption and scattering coefficients. Numerical comparison with more exact solutions of the equation of radiative transfer show very good agreement for all cases except for reflectance in the highly anisotropic case, where agreement is only fair.


Distinct modes of molecular regulation of CCL3 induced calcium flux in monocytic cells.
The chemokine receptor CCR5 has been shown to be targeted to cholesterol- and sphingolipid-rich membrane microdomains. Here we elucidate the effects of membrane fluidity on CCR5 signalling and expression using the monocytic THP-1 cells. MCD treatment of THP-1 cells, which removes nearly all cholesterol from the plasma membrane, leads to an increase in the signalling properties of CCR5. In contrast, the prevention of cholesterol production with lovastatin and simvastatin decreases the release of intracellular calcium and also decreases receptor cell surface expression. The loss of response in lovastatin treated cells can be rescued by MCD addition, which shows that the cholesterol content in the membrane is only one factor in determining the amount of receptor response. We show that CCR5 signalling is dependent on thapsigargin-sensitive Ca2+ stores and on activation of ryanodine receptors as well as InsP3 receptors or store-operated channels. Cholesterol depletion with MCD changes the thapsigargin sensitivity in THP-1 cells and also alters receptor-G-protein coupling towards pertussis toxin (PTX) independent G-proteins. Cholesterol removal by MCD in THP-1 cells has far reaching consequences for receptor activation and signalling and emphasises the need for a clearer understanding of how membrane fluidity affects receptor signalling events.


Utility and effectiveness of a remote telepresence robotic system in nursing education in a simulated care environment.
There is a growing shortage of nursing graduates and faculty to prepare students for careers in nursing. One way to ameliorate this paradigm is to integrate technology such as a remote presence robot (RPR) in both clinical and educational settings. The InTouch Health (Santa Barbara, CA) RP-7, an RPR, was deployed in a simulated, multigenerational home where nursing students and faculty interact in a variety of activities. Seventy students and five faculty members were instructed by a remotely located instructor who controlled the RP-7 from a distant site. Students and faculty, using questionnaires, provided feedback on the didactic interaction. Of the 70 student participants, 56 (80%) responded, and faculty and clinical staff were 100% compliant, resulting in 69 total respondents. Using Krippendorf's themes of (1) usefulness, (2) acceptability, and (3) impact, the data indicated the following. The majority of the students (89%) had no previous experience with the RPR, but the majority (75%) felt that the RPR was a good faculty extender. The students were initially evenly split on first exposure in (a) a positive experience, (b) a negative experience, or (c) a mixed experience. Although there were some technical challenges in operations, these were not deemed significant; nevertheless, they must be addressed. The results of this study support the use of RPRs as faculty extenders to facilitate course quality assurance when the lead faculty is not on site. Both faculty and students perceive this type of technology as a potential faculty extender, but both faculty and students need preparation for the experience.


Omeprazole once or twice daily with clarithromycin and metronidazole for Helicobacter pylori.
Triple therapy for one week with omeprazole, clarithromycin and metronidazole (OCM) is accepted worldwide as a first line therapy for Helicobacter pylori eradication. It is unclear whether omeprazole needs to be given once or twice daily. To assess the efficacy and safety of these regimens in a single-centre, Canadian practice. Histologically proven H pylori-positive patients were treated for seven days with clarithromycin 250 mg bid and metronidazole 500 mg bid, and randomly allocated to omeprazole 20 mg either once or twice daily in this open, cohort study. Endoscopy with histology (two antrum and two body biopsies, Giemsa stain) was done four weeks or longer after the pills were completed to assess H pylori eradication. Whether omeprazole was given once or twice daily, eradication was high and the same in both arms. All-patients-treated eradication was 85% (39 of 46 in the omeprazole once daily group and 41 of 48 in the omeprazole twice daily group) and intent-to-treat eradication was 80% (39 of 49 in the omeprazole once daily group and 41 of 51 in the omeprazole twice daily group). Side effects were frequently seen, suffered by 65% to 69% of patients treated. However, these were mild and compliance was high, with 94% of patients taking all of their pills. Mild side effects included loose stools, taste disturbance, nausea, headache and upper or lower gastrointestinal gas. Only one patient (1%) from the omeprazole once daily arm stopped taking metronidazole due to excessive perspiring. In this community practice, OCM triple therapy was effective whether omeprazole was given once or twice daily. For those with financial constraint, omeprazole 20 mg once daily can be considered. The regimens were well tolerated without serious adverse events.


The Peritoneal Surface Proteome in a Model of Chronic Peritoneal Dialysis Reveals Mechanisms of Membrane Damage and Preservation.
Peritoneal dialysis (PD) fluids are cytotoxic to the peritoneum. Recent studies have shown that alanyl-glutamine (AlaGln) modulates the cellular stress response, improves mesothelial cell survival, reduces submesothelial thickening in experimental models of PD, and in clinical studies improves PD effluent cell stress and immune responses. However, the mechanisms of AlaGln-mediated membrane protection are not yet fully understood. Here, we explore those mechanisms through application of a novel proteomics approach in a clinically relevant in vivo model in rats. Experimental PD was performed for 5 weeks using conventional single-chamber bag (SCB) or neutral dual-chamber bag (DCB), PD fluid (PDF), with or without AlaGln supplementation, via a surgically implanted catheter. Rats subjected to a single dwell without catheter implantation served as controls. The peritoneal surface proteome was directly harvested by detergent extraction and subjected to proteomic analysis by two-dimensional difference gel electrophoresis (2D-DiGE) with protein identification by mass spectrometry. An integrated bioinformatic approach was applied to identify proteins significantly affected by the treatments despite biological variation and interfering high abundance proteins. From 505 of 744 common spots on 59 gels, 222 unique proteins were identified. Using UniProt database information, proteins were assigned either as high abundance plasma proteins, or as cellular proteins. Statistical analysis employed an adapted workflow from RNA-sequencing, the trimmed mean of M-values (TMM) for normalization, and a mixed model for computational identification of significantly differentially abundant proteins. The most prominently enriched pathways after 5 weeks chronic treatment with SCB or DCB, PDFs belonged to clusters reflecting tissue damage and cell differentiation by cytoskeletal reorganization, immune responses, altered metabolism, and oxidative stress and redox homeostasis. Although the AlaGln effect was not as prominent, associated enriched pathways showed mostly regression to control or patterns opposite that of the PDF effect. Our study describes the novel peritoneal surface proteome through combined proteomic and bioinformatic analyses, and assesses changes elicited by chronic experimental PD. The biological processes so identified promise to link molecular mechanisms of membrane damage and protection in the in vivo rat model to pathomechanisms and cytoprotective effects observed in vitro and in clinical PD.


Rate of antigen entry into the circulation in experimental versus naturally occurring immune complex glomerulonephritis.
This study tested the hypothesis that the rate of antigen entry into the circulation in systemic lupus erythematosus (SLE), a naturally occurring immune complex glomerulonephritis (IC-GN), is slow compared with that of traditional experimental models of IC-GN, in which the antigen is delivered rapidly as a daily iv bolus. This hypothesis was tested by comparing rates of decline of the third component of complement (C3) and of circulating neutrophils (PMN) in SLE patients with active disease with those of cynomolgus monkeys (CYN) undergoing induction of experimental IC-GN by means of a daily bolus infusion of antigen. It has previously been shown that, as antigen enters the circulation and forms circulating IC, C3 levels and circulating PMN decline acutely. Thus, acute changes in these parameters can be surrogates for the rate of antigen entry into the circulation. In the CYN undergoing induction of IC-GN (N = 11), infusion of the antigen (bovine gamma-globulin) over 10 min resulted in acute declines in C3 levels (25 +/- 6.6%; P = 0.0018 and PMN counts (59 +/- 9%; P < 0.0002). In addition, the CYN experienced the onset of acute respiratory distress and hypotension. By contrast, in patients with active SLE (N = 9), C3 and white blood cell counts measured at 24-h intervals did not change significantly, and episodes of acute hypotension or respiratory distress were not observed. In the CYN, the onset of visible vasculitic lesions in the omentum were also documented within minutes of the infusion of bovine gamma-globulin. The rapidity of onset of these vascular lesions suggests that the tempo at which lesions develop in experimental models of IC disease is faster than that of naturally occurring IC diseases. It was concluded that, in naturally occurring IC diseases, antigen probably enters the circulation slowly over prolonged periods of time, rather than as large boluses over short periods of time, as in traditional experimental models of IC-GN. Thus, models of IC-GN involving a daily bolus infusion of antigen may not be clinically relevant, particularly when IC clearing mechanisms are tested, because the efficiency of these mechanisms may be markedly influenced by the rate at which IC form in the circulation.


Infant cardiac CT angiography with 64-slice and 256-slice CT: comparison of radiation dose and image quality using a pediatric phantom.
The aims of this study were to investigate the image quality and radiation exposure of pediatric protocols for cardiac CT angiography (CTA) in infants under one year of age. Cardiac CTA examinations were performed using an anthropomorphic phantom representing a 1-year-old child scanned with non-electrocardiogram-gated (NG), retrospectively electrocardiogram-gated helical (RGH) and prospectively electrocardiogram-gated axial (PGA) techniques in 64-slice and 256-slice CT scanners. The thermoluminescent dosimeters (TLD) were used for direct organ dose measurement, while dose-length product and effective mAs were also used to estimate the patient dose. For image quality, noise and signal-to-noise-ratio (SNR) were assessed based on regions-of-interest drawn on the reconstructed CT images, and were compared with the proposed cardiac image quantum index (CIQI). Estimated dose results were in accordant to the measured doses. The NG scan showed the best image quality in terms of noise and SNR. The PGA scan had better image quality than the RGH scan with 83.70% dose reduction. Noise and SNR were also corresponded to the proposed CIQI. The PGA scan protocol was a good choice in balancing radiation exposure and image quality for infant cardiac CTA. We also suggested that the effective mAs and the CIQI were suitable in assessing the tradeoffs between radiation dose and image quality for cardiac CTA in infants. These results are useful for future implementation of dose reduction strategies in pediatric cardiac CTA protocols.


Reasons why current speech-enhancement algorithms do not improve speech intelligibility and suggested solutions.
Existing speech enhancement algorithms can improve speech quality but not speech intelligibility, and the reasons for that are unclear. In the present paper, we present a theoretical framework that can be used to analyze potential factors that can influence the intelligibility of processed speech. More specifically, this framework focuses on the fine-grain analysis of the distortions introduced by speech enhancement algorithms. It is hypothesized that if these distortions are properly controlled, then large gains in intelligibility can be achieved. To test this hypothesis, intelligibility tests are conducted with human listeners in which we present processed speech with controlled speech distortions. The aim of these tests is to assess the perceptual effect of the various distortions that can be introduced by speech enhancement algorithms on speech intelligibility. Results with three different enhancement algorithms indicated that certain distortions are more detrimental to speech intelligibility degradation than others. When these distortions were properly controlled, however, large gains in intelligibility were obtained by human listeners, even by spectral-subtractive algorithms which are known to degrade speech quality and intelligibility.


Mutagenic studies on histidine 98 of methylglyoxal synthase: effects on mechanism and conformational change.
Two detailed mechanisms [Marks et al. (2001) Biochemistry 40, 6805] have been proposed to explain the activity of methylglyoxal synthase (MGS), a homohexameric allosterically regulated enzyme that catalyzes the elimination of phosphate from DHAP to form enol pyruvaldehyde. This enol then tautomerizes to methylglyoxal in solution. In one of these mechanisms His 98 plays an obligate role in the transfer of a proton from the O(3) oxygen of DHAP to the O2 oxygen. To test this hypothesized mechanism, the variants H98N and H98Q were expressed and purified. Relative to the wild-type enzyme, the H98N variant shows a 50-fold decrease in k(cat) with all other kinetic parameters (i.e., K(m), K(PGA), etc.) being nearly the same. By contrast, the apparent catalytic rate for the H98Q variant is 250-fold lower than that of the wild-type enzyme. Inorganic phosphate acts as a competitive inhibitor (with a K(i) of 15 microM) rather than as an allosteric-type inhibitor as it does in the wild-type enzyme, and the competitive inhibitor phosphoglyolate (PGA) acts as an activator of this variant. These facts are explained by a shift in the conformational equilibrium toward an "inactive" state. When activation by PGA is accounted for, the catalytic rate for the "active" state of H98Q is estimated to be only 6-fold less than that of the wild-type enzyme, and thus His 98 is not essential for catalysis. Primary deuterium isotope effect data were measured for the wild-type enzyme and the two variants. At pH 7.0, the (D)V isotope effect (1.5) and the absence of a (D)(V/K) isotope effect for the wild-type enzyme suggest that the rate for the isotopically sensitive step is partially rate limiting but greater than the rate of substrate dissociation. Both the (D)V (2.0) and (D)(V/K) (3.4) isotope effects were more pronounced in the H98N variant, while the H98Q variant displayed an unusual inverse (D)V (0.8) isotope effect and a normal (D)(V/K) (1.5) isotope effect. The X-ray crystal structures of PGA bound to the H98Q and H98N variants were both determined to a resolution of 2.2 A. These mutations had little effect on the overall structure. However, the pattern of hydrogen bonding in the active site suggests an explanation as to how in the wild-type and H98N mutated enzymes the "inactive to active" equilibrium lies toward the active state, while with the H98Q mutated enzyme the equilibrium lies toward the inactive state. Thus, the role of His 98 appears to be more as a regulator of the enzyme's conformation rather than as a critical contributor to the catalytic mechanism.


Suppressive effect of antibody on processing of T cell epitopes.
Immunoglobulins drive efficient antigen capture by antigen presenting cells for processing and presentation on class II MHC-molecules. High affinity antibody/antigen interactions are stable at endosomal/lysosomal pH thus altering the substrate for antigen processing. We show that this can result in strong suppression of presentation of some T cell epitopes. This effect was observed when the antibody specificity was a B cell surface Ig, or formed part of an immune complex. In the latter case the presence of the suppressing antibody boosts presentation of other T cell epitopes through enhanced uptake into Fc receptor bearing cells. The influence of bound antibodies on the outcome of antigen processing may influence with T cell epitopes dominate T cell responses and may change the focus of the response with time.


Polyomavirus middle T-antigen NPTY mutants.
A polyomavirus middle T-antigen (MTAg) mutant containing a substitution of Leu for Pro at amino acid 248 has previously been described as completely transformation defective (B. J. Druker, L. Ling, B. Cohen, T. M. Roberts, and B. S. Schaffhausen, J. Virol. 64:4454-4461, 1990). This mutant had no alterations in associated proteins or associated kinase activities compared with wild-type MTAg. Pro-248 lies in a tetrameric sequence, NPTY, which is reminiscent of the so-called NPXY sequence in the low-density-lipoprotein receptor. In the low-density-lipoprotein receptor, mutations in the NPXY motif but not in the surrounding amino acids abolish receptor function, apparently by decreasing receptor internalization (W. Chen, J. L. Goldstein, and M. S. Brown, J. Biol. Chem. 265:3116-3123, 1990). To determine whether this sequence represents a functional motif in MTAg as well, a series of single amino acid substitutions was constructed in this region of MTAg. All of the mutations of N, P, T, or Y, including the relatively conservative substitution of Ser for Thr at amino acid 249, resulted in a transformation-defective MTAg, whereas mutations outside of this sequence allowed mutants to retain near-wild-type transformation capabilities. Transformation-defective mutants with mutations in the NPTY region behaved similarly to the mutant with the original Pro-248-to-Leu-248 mutation when assayed for associated proteins and activities in vitro; that is, they retained a full complement of wild-type activities and associated proteins. Further, insertion of the tetrameric sequence NPTY downstream of the mutated motif restored transforming abilities to these mutants. Thus, the tetrameric sequence NPTY in MTAg appears to represent a well-defined functional motif of MTAg.


Grouping plant species by shared native range, and not by native status, predicts response to an exotic herbivore.
Differences among exotic species can be as large as differences between native and exotic species. Typically, however, only the distinction between native and exotic is made when predicting responses in a community. In this paper, I examine the response of plant species to experimental disturbance and exclusion of invasive European rabbits (Oryctolagus cuniculus) in a grassland community with exotic plants originating from five continents. I explore group responses based on native status, shared native range with rabbits, having a congener from the native range of rabbits, life-history (e.g., annual), and life-form (e.g., grass). Individual species responses to rabbits were idiosyncratic, but group responses were predicted by continent of origin, not native status. Native status did predict response to disturbance with almost uniform responses within groups. Exotic species, regardless of origin, were positively affected by disturbance. Native species, in contrast, were negatively affected by disturbance. These results suggest that grouping plant species by native status is valid for questions of disturbance, but when analyzing outcomes of interactions, factors other than native status, such as shared evolutionary history, should be considered.


A comparison of reintervention rates after endovascular aneurysm repair between the Vascular Quality Initiative registry, Medicare claims, and chart review.
The accurate measurement of reintervention after endovascular aneurysm repair (EVAR) is critical during postoperative surveillance. The purpose of this study was to compare reintervention rates after EVAR from three different data sources: the Vascular Quality Initiative (VQI) alone, VQI linked to Medicare claims (VQI-Medicare), and a "gold standard" of clinical chart review supplemented with telephone interviews. We reviewed the medical records of 729 patients who underwent EVAR at our institution between 2003 and 2013. We excluded patients without follow-up reported to the VQI (n = 68 [9%]) or without Medicare claims information (n = 114 [16%]). All patients in the final analytic cohort (n = 547) had follow-up information available from all three data sources (VQI alone, VQI linked to Medicare, and chart review). We then compared reintervention rates between the three data sources. Our primary end points were the agreement between the three data sources and the Kaplan-Meier estimated rate of reintervention at 1 year, 2 years, and 3 years after EVAR. For gold standard assessment, we supplemented chart review with telephone interview as necessary to assess reintervention. VQI data alone identified 12 reintervention events in the first year after EVAR. Chart review confirmed all 12 events and identified 18 additional events not captured by the VQI. VQI-Medicare data successfully identified all 30 of these events within the first year. VQI-Medicare also documented four reinterventions in this time period that did not occur on the basis of patient interview (4/547 [0.7%]). The agreement between chart review and VQI-Medicare data at 1 year was excellent (κ = 0.93). At 3 years, there were 81 (18%) reinterventions detected by VQI-Medicare and 70 (16%) detected by chart review for a sensitivity of 92%, specificity of 96%, and κ of 0.80. Kaplan-Meier survival analysis demonstrated similar reintervention rates after 3 years between VQI-Medicare and chart review (log-rank, P = .59). Chart review after EVAR demonstrated a 6% 1-year and 16% 3-year reintervention rate, and almost all (92%) of these events were accurately captured using VQI-Medicare data. Linking VQI data with Medicare claims allows an accurate assessment of reintervention rates after EVAR without labor-intensive physician chart review.


Genetic correlations among canine hip dysplasia radiographic traits in a cohort of Australian German Shepherd Dogs, and implications for the design of a more effective genetic control program.
Canine hip dysplasia (CHD) is a common musculoskeletal disease in pedigree dog populations. It can cause severe pain and dysfunction which may require extensive medication and/or surgical treatment and often ultimately requires humane euthanasia. CHD has been found to be moderately heritable and, given its impact on welfare, should be considered an imperative breeding priority. The British Veterinary Association/Kennel Club scoring method is one of several measures used to assess the genetic propensity of potential breeding stock for dysplastic changes to the hips based on radiographic examination. It is a complex measure composed of nine ordinal traits, intended to evaluate both early and late dysplastic changes. It would be highly desirable if estimated breeding values (EBVs) for these nine traits were consolidated into a simpler, EBV-based, selection index more easily usable by breeders. A multivariate analysis on the phenotype scores from an Australian cohort of 13,124 German Shepherd Dogs (GSDs) returned genetic correlations between 0.48-0.97 for the nine traits which fell into two trait groups, Group 1 reflecting early changes ("laxity") and Group 2 reflecting late changes ("osteoarthritis"). Principal components analysis of the ordinal EBVs suggested the same pattern, with strong differentiation between "laxity" and "osteoarthritis" traits in the second component. Taking account of all results, we recommend interim use of two selection indexes: the first being the average of ordinal EBVs for "laxity" traits and the second being the average of ordinal EBVs for "osteoarthritis" traits. The correlation between these two selection indexes (0.771-0.774) is sufficiently less than unity enabling the selection of dogs with different genetic propensity for laxity and for osteoarthritic CHD changes in GSDs; this may also be applicable in other breeds. Dogs with low propensity for severe osteoarthritic change in the presence of laxity may be of interest both in molecular research and breeding programs.


Long noncoding RNAs in cell biology.
Whole genome transcriptomic analyses have identified large numbers of dynamically expressed long non-protein-coding RNAs (lncRNAs) in mammals and other animals whose functions are, as yet, largely unknown. Here we summarize the growing evidence that lncRNAs, like mRNAs, can be trafficked to and function in a wide variety of subcellular locations. Investigation of the subcellular distribution of lncRNAs has the potential to greatly expand our knowledge not only of the function of lncRNAs but also of cell biology by identifying previously unknown subcellular structures and novel constituents of known cellular organelles.


SU-E-T-123: Understanding the Meaning of IMRT QA Passing Rates with a 2D Diode Array.
A lower than ideal tolerance limit is used in intensity-modulated radiation therapy quality assurance (IMRT QA) with a 2D diode array due to passing rate fluctuations. The objective is to identify patterns in the passing rates to predict sources of uncertainty that can affect treatment delivery, for example, the need to re-calibrate the multileaf collimator when the passing rates start to decrease. Five complex clinical prostate IMRT plans were evaluated with a 2D diode array. The QA for each plan was repeated five times during one and a half month period. One of the plans was randomly selected and repeated the same day five consecutive times. The planar doses calculated by the treatment planning system were compared to the measurements of the 2D diode array. The individual passing rates per beam per plan were compared. The average passing rate for each plan ranged from 94% to 97%. While the average percent difference of this ranged between -7.67% to 17.61%. Additionally, the minimum and maximum standard deviation among all beams was 0.13% and 9.63% respectively. We also compared the standard deviation of a plan QA repeated during different days versus a plan QA repeated during the same day. For the former the highest standard deviation was 6.05 % while for the later 0.21%. We noticed that the largest discrepancy between the passing rates was for angles at around 155° and 205°. These results show some inconsistency in the IMRT QA passing rates from one day to the next. Moreover, lower passing rates for a specific angle like the ones shown here can represent possible mechanical or tuning problems with the linear accelerator at these specific locations. Early identification of these sources of uncertainty can greatly improve the precision of the treatment delivery.


Safety evaluation of the food enzyme α-amylase from the genetically modified Bacillus licheniformis strain NZYM-BC.
The food enzyme α-amylase (4-α-d-glucan glucanhydrolase; EC 126.96.36.199) is produced with the genetically modified Bacillus licheniformis strain NZYM-BC by Novozymes A/S. The genetic modifications do not give rise to safety concerns. The production strain was shown to qualify for the qualified presumption of safety (QPS) status. The food enzyme was free from viable cells of the production organism and its DNA. It is intended to be used in six food manufacturing processes, namely starch processing for the production of glucose syrups and other starch hydrolysates, distilled alcohol production, brewing processes, cereal-based processes, refined and unrefined sugar production and fruit and vegetable processing for juice production. Since the residual amounts of total organic solids (TOS) are removed by distillation and by the purification steps applied during the production of glucose syrups, dietary exposure was not calculated for these two food manufacturing processes. For the remaining four processes, the dietary exposure to the food enzyme-TOS was estimated to be up to 0.05 mg TOS/kg body weight per day in European populations. Genotoxicity tests did not raise safety concern. The similarity of the amino acid sequence of the food enzyme to those of known allergens was searched and one match was found. The Panel considered that, under the intended conditions of use, the risk of allergic sensitisation and elicitation reactions by dietary exposure cannot be excluded, but the likelihood was considered to be low. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.


On an acute case of Chagas disease in a region under vector control in the state of São Paulo, Brazil.
No vector transmitted cases of Chagas disease had been notified in the state of São Paulo since the 1970s. However, in March, 2006, the death of a six-year-old boy from the municipality of Itaporanga was notified to the Center for Epidemiological Survey of the São Paulo State Health Secretariat: an autochthonous case of acute Chagas disease. The postmortem histopathological examination performed in the Hospital das Clínicas of the Botucatu School of Medicine confirmed the diagnosis. Reference to hospital records, consultation with the health professionals involved in the case and interviews with members of the patient's family supplied the basis for this study. We investigated parasite route of transmission, probable local reservoirs and vectors. No further human cases of acute Chagas disease were diagnosed. No locally captured vectors or reservoirs were found infected with Trypanosoma cruzi. Alternative transmission hypotheses - such as the possible ingestion of foods contaminated with vector excreta - are discussed, as well as the need to keep previously endemic regions and infested houses under close surveillance. Clinicians should give due attention to such signs as uni- or bilateral palpebral edema, cardiac failure, myocarditis, pericarditis, anasarca and atypical signs of nephrotic syndrome or nephritis and consider the diagnostic hypothesis of Chagas disease.


Sertraline-induced pseudocholinesterase enzyme deficiency.
A 47-year-old Turkish male was scheduled for laparoscopic cholecystectomy under general anesthesia. The patient had 2 operations 28 and 19 years ago under general anesthesia. It was learned that the patient was administered succinylcholine during both of these previous operations and that he did not have a history of prolonged recovery or postoperative apnea. The patient had been using sertraline for 3 years before the operation. Pseudocholinesterase is a drug-metabolizing enzyme responsible for hydrolysis of the muscle-relaxant drugs mivacurium and succinylcholine. Deficiency of this enzyme from any cause can lead to prolonged apnea and paralysis following administration of mivacurium and succinylcholine. The diagnosis of pseudocholinesterase enzyme deficiency can be made after careful clinic supervision and peripheral nerve stimulator monitoring. A decrease in the activity of pseudocholinesterase enzyme and a decline in the block effect over time will help verify the diagnosis. Our patient's plasma cholinesterase was found to have low activity. Instead of pharmacological interventions that may further complicate the situation in such cases, the preferred course of action should be to wait until the block effect declines with the help of sedation and mechanical ventilation. In our case, the prolonged block deteriorated in the course of time before any complications developed.


New insights into the pharmacodynamic and pharmacokinetic properties of statins.
The beneficial effects of statins are assumed to result from their ability to reduce cholesterol biosynthesis. However, because mevalonic acid is the precursor not only of cholesterol, but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase may result in pleiotropic effects. It has been shown that several statins decrease smooth muscle cell migration and proliferation and that sera from fluvastatin-treated patients interfere with its proliferation. Cholesterol accumulation in macrophages can be inhibited by different statins, while both fluvastatin and simvastatin inhibit secretion of metalloproteinases by human monocyte-derived macrophages. The antiatherosclerotic effects of statins may be achieved by modifying hypercholesterolemia and the arterial wall environment as well. Although statins rarely have severe adverse effects, interactions with other drugs deserve attention. Simvastatin, lovastatin, cerivastatin, and atorvastatin are biotransformed in the liver primarily by cytochrome P450-3A4, and are susceptible to drug interactions when co-administered with potential inhibitors of this enzyme. Indeed, pharmacokinetic interactions (e.g., increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of simvastatin or lovastatin and cyclosporine A, mibefradil, or nefazodone. In contrast, fluvastatin (mainly metabolized by cytochrome P450-2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, a 5- to 23-fold increase in pravastatin bioavailability has been reported in the presence of cyclosporine A. In summary, statins may have direct effects on the arterial wall, which may contribute to their antiatherosclerotic actions. Furthermore, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.