MoonDB 2.0: an updated database of extreme multifunctional and moonlighting proteins.
MoonDB 2.0 (http://moondb.hb.univ-amu.fr/) is a database of predicted and manually curated extreme multifunctional (EMF) and moonlighting proteins, i.e. proteins that perform multiple unrelated functions. We have previously shown that such proteins can be predicted through the analysis of their molecular interaction subnetworks, their functional annotations and their association to distinct groups of proteins that are involved in unrelated functions. In MoonDB 2.0, we updated the set of human EMF proteins (238 proteins), using the latest functional annotations and protein-protein interaction networks. Furthermore, for the first time, we applied our method to four additional model organisms - mouse, fly, worm and yeast - and identified 54 novel EMF proteins in these species. In addition to novel predictions, this update contains 63 human and yeast proteins that were manually curated from literature, including descriptions of moonlighting functions and associated references. Importantly, MoonDB's interface was fully redesigned and improved, and its entries are now cross-referenced in the UniProt Knowledgebase (UniProtKB). MoonDB will be updated once a year with the novel EMF candidates calculated from the latest available protein interactions and functional annotations.


Functional disruption of alpha4 integrin mobilizes bone marrow-derived endothelial progenitors and augments ischemic neovascularization.
The cell surface receptor alpha4 integrin plays a critical role in the homing, engraftment, and maintenance of hematopoietic progenitor cells (HPCs) in the bone marrow (BM). Down-regulation or functional blockade of alpha4 integrin or its ligand vascular cell adhesion molecule-1 mobilizes long-term HPCs. We investigated the role of alpha4 integrin in the mobilization and homing of BM endothelial progenitor cells (EPCs). EPCs with endothelial colony-forming activity in the BM are exclusively alpha4 integrin-expressing cells. In vivo, a single dose of anti-alpha4 integrin antibody resulted in increased circulating EPC counts for 3 d. In hindlimb ischemia and myocardial infarction, systemically administered anti-alpha4 integrin antibody increased recruitment and incorporation of BM EPCs in newly formed vasculature and improved functional blood flow recovery and tissue preservation. Interestingly, BM EPCs that had been preblocked with anti-alpha4 integrin ex vivo or collected from alpha4 integrin-deficient mice incorporated as well as control cells into the neovasculature in ischemic sites, suggesting that alpha4 integrin may be dispensable or play a redundant role in EPC homing to ischemic tissue. These data indicate that functional disruption of alpha4 integrin may represent a potential angiogenic therapy for ischemic disease by increasing the available circulating supply of EPCs.


The effect of sympathetic innervation on canine muscle and skin blood flow.
Two microsphere techniques were used to measure skin and muscle capillary blood flow, plus blood flow through arteriovenous anastomoses (AVAs), before and after unilateral lumbar sympathectomy in 12 anesthetized dogs. Sympathectomy did not alter capillary flow to tibial muscle, thigh, or lower leg skin, whereas paw skin capillary flow decreased, from 28 to 13 mL/min/100 g. However, total extremity blood flow increased after sympathectomy, because of the rate of AVA flow, which increased from 7 to 30 mL/min. Transient nerve stimulation of the cut distal end of the lumbar sympathetic chain immediately and reversibly decreased the AVA flow rate, from 30 to 10 mL/min. The rate of total hind-limb capillary flow also decreased during nerve stimulation, from 86 to 46 mL/min. The only significant effect of sympathectomy in anesthetized dogs was to redistribute distal hind-limb capillary blood flow to AVAs, which are anatomically located in this region. In contrast to capillaries, AVAs have little intrinsic myogenic tone and are highly dependent on adrenergic innervation.


Hybrid optoacoustic tomography and pulse-echo ultrasonography using concave arrays.
Implementation of hybrid imaging using optoacoustic tomography (OAT) and ultrasound (US) brings together the important advantages and complementary features of both methods. However, the fundamentally different physical contrast mechanisms of the two modalities may impose significant difficulties in the optimal tomographic data acquisition and image formation strategies. We investigate the applicability of the commonly applied imaging geometries for acquisition and reconstruction of hybrid optoacoustic tomography and pulse-echo ultrasound (OPUS) images. Optimization of the ultrasound image formation strategy using concave array geometry was implemented using a synthetic aperture method combined with spatial compounding. Experimental validation was performed using a custom-made multiplexer unit executing switching between the two modalities employing the same transducer array. A variety of array probes with different angular coverages were subsequently tested, including arrays for clinical hand-held imaging as well as stationary arrays for tomographic small animal imaging. The results demonstrate that acquisition of OAT data by mere addition of an illumination source to the common US linear array geometry may result in significant limited-view artifacts and overall loss of image quality. On the other hand, unsatisfactory US image quality is achieved with tomographic arrays solely optimized for OAT image acquisition without considering the optimal transmit-receive beamforming parameters. Optimal selection of the array pitch size, tomographic coverage and spatial compounding parameters has achieved here an accurate hybrid imaging performance, which was experimentally showcased in tissuemimicking phantoms, post-mortem mice, and hand-held imaging of a healthy volunteer. The efficient combination of the two modalities in a single imaging device reveals the true power of functional and molecular imaging capacities of OAT in addition to the morphological and functional imaging capabilities of US.


Site specific protein O-glucosylation with bacterial toxins.
Using a MALDI-MS based assay, the kinetic parameters for peptide glucosylation using the C. difficile toxin B glycosyltransferase domain were determined. The minimum consensus sequence for glucosylation was YXXTXFXXY and the optimal peptide found was YAPTVFDAY. Using this sequence, homogenous glucosylated proteins could be readily produced.


A comprehensive evaluation of cattle introgression into US federal bison herds.
Genetic introgression, especially from interspecies hybridization, is a significant threat to species conservation worldwide. In this study, 11 US federal bison populations were comprehensively examined for evidence of both mitochondrial and nuclear domestic cattle (Bos taurus) introgression. Mitochondrial introgression was examined using established polymerase chain reaction methods and confirmed through analysis of D-loop sequences. Nuclear introgression was assessed in 14 chromosomal regions through examination of microsatellite electromorph and sequence differences between bison and domestic cattle. Only one population was identified with domestic cattle mitochondrial DNA introgression. In contrast, evidence of nuclear introgression was found in 7 (63.6%) of the examined populations. Historic accounts of bison transfers among populations were corroborated with evidence of introgressed DNA transmission. While neither nuclear nor mitochondrial domestic cattle introgression was detected in bison from Grand Teton National Park, Sully's Hill National Game Preserve, Wind Cave National Park, or Yellowstone National Park, adequate sample sizes were available only from the last 2 populations to allow for statistical confidence (>90%) in nuclear introgression detection limits. The identification of genetically unique and undisturbed populations is critical to species conservation efforts, and this study serves as a model for the genetic evaluation of interspecies introgression.


Osteoarthritis prevalence and modifiable factors: a population study.
This study's objectives were to investigate the prevalence of self-reported knee and hip osteoarthritis (OA) stratified by age and sex and to examine the association of modifiable factors with knee and hip OA prevalence. The study was conducted using randomly sampled data gathered from four communities in the province of Alberta, Canada. A large adult population sample (N = 4733) of individuals ≥18 years were selected. Health-related information was collected through telephone interviews and community measurement clinics for which a sub-sample (N = 1808) attended. Participants self-reported OA during telephone interviews. Clinic interviews further assessed if the diagnosis was made by a health care professional. Statistical analyses compared prevalence of OA between sexes and across age categories. Associations between modifiable factors for OA and the prevalence of knee and hip OA were assessed using binary logistic regression modelling. Overall prevalence of self-reported OA in the total sample was 14.8 %, where 10.5 % of individuals reported having knee OA and 8.5 % reported having hip OA. Differences in prevalence were found for males and females across age categories for both knee and hip OA. In terms of modifiable factors, being obese (BMI >30 kg/m2) was significantly associated with the prevalence of knee (OR: 4.37; 95 % CI: 2.08,9.20) and hip (OR: 2.52; 95 % CI: 1.17,5.43) OA. Individuals who stand or walk a lot, but do not carry or lift things during their occupational activities were 2.0 times less likely to have hip OA (OR: 0.50; 95 % CI: 0.26,0.96). Individuals who usually lift or carry light loads or have to climb stairs or hills were 2.2 times less likely to have hip OA (OR: 0.45; 95 % CI: 0.21,0.95). The odds of having hip OA were 1.9 times lower in individuals consuming recommended or higher vitamin C intake (OR: 0.52; 95 % CI: 0.29,0.96). Significant differences in prevalence were found for both males and females across age categories. The prevalence of knee and hip OA obtained in this study is comparable to other studies. Females have greater knee OA prevalence and a greater proportion of women have mobility limitations as well as hip and knee pain; it is important to target this sub-group.


Plasma 3S gamma-1-globulin: identity with erythrocyte carbonic anhydrase B.
The 3S (gamma1), 2S (gamma2), and 0.5S (gamma2) fractions of human plasma are heterogeneous in protein composition. Although each fraction contained a relatively small amount of protein antigenically related to the immunoglobulin light chains, most of the proteins were unrelated to immunogloublin G or its light chains. Of the 3S (gamma1)-globulins the greater part was immunochemically identical to carbonic anhydrase B and had carbonic anhydrase activity. These findings explain earlier reports of an immunochemical similarity between 3S (gamma1)-globulins and immunoglobulin light chains in spite of marked differences in amino acid and peptide composition between the two. Apparently not all plasma gamma-globulins are necessarily immunoglobulins.


Interventions employing mobile technology for overweight and obesity: an early systematic review of randomized controlled trials.
Obesity is a global epidemic with major healthcare implications and costs. Mobile technologies are potential interventions to promote weight loss. An early systematic review of this rapidly growing area of research was conducted. Electronic databases were searched for articles published between January 1998 and October 2011. Data sources included Medline, Embase and the Cochrane Central Register of Controlled Trials. Ongoing research was searched for using clinical trials databases and registers. Out of 174 articles retrieved, 21 met the inclusion criteria of randomized controlled trials (RCTs) on mobile technology interventions facilitating weight loss in overweight and obese adults with any other comparator. A narrative synthesis was undertaken. Seven articles were included and appraised using the Cochrane risk of bias tool: four presented a low risk of bias and three presented a high risk of bias. There is consistent strong evidence across the included multiple high-quality RCTs that weight loss occurs in the short-term because of mobile technology interventions, with moderate evidence for the medium-term. Recommendations for improving the reporting and quality of future trials are made including reporting weight loss in percent to meet clinical standards, and including features such as long-term follow-up, cost-effectiveness and patient acceptability.


Novel drug delivery approaches on antiviral and antiretroviral agents.
Viruses have the property to replicate very fast in host cell. It can attack any part of host cell. Therefore, the clinical efficacy of antiviral drugs and its bioavailability is more important concern taken into account to treat viral infections. The oral and parenteral routes of drug administration have several shortcomings, however, which could lead to the search for formulating better delivery systems. Now, a day's novel drug delivery systems (NDDS) proved to be a better approach to enhance the effectiveness of the antivirals and improve the patient compliance and decrease the adverse effect. The NDDS have reduced the dosing frequency and shorten the duration of treatment, thus, which could lead the treatment more cost-effective. The development of NDDS for antiviral and antiretroviral therapy aims to deliver the drug devoid of toxicity, with high compatibility and biodegradability, targeting the drug to specific sites for viral infection and in some instances it also avoid the first pass metabolism effect. This article aims to discuss the usefulness of novel delivery approaches of antiviral agents such as niosomes, microspheres, microemulsions, nanoparticles that are used in the treatment of various Herpes viruses and in human immunodeficiency virus (HIV) infections.


Spatial Resolution Improvement of EEG Source Reconstruction Using swLORETA.
Electroencephalography (EEG) and magnetic resonance imaging (MRI) are noninvasive neuro-imaging modalities largely used in neurology explorations. MRI is considered as a static modality and could be so important for anatomy by its high spatial resolution. EEG, on the other hand, is an important tool permitting to image temporal dynamic activities of the human brain. Fusion of these two essential modalities would be hence a so emerging research domain targeting to explore brain activities with the MRI static modality. Our present research investigates a sophisticated approach for localization of the cerebral activity that could be involved by the dynamic EEG modality and carefully illustrated within MRI static modality. Such careful cerebral activity localization would be first based on an advanced methodology yielding therefore a singular value decomposition-based lead field weighting to sLORETA method formalism, for solving in fact the inverse problem in the EEG. The conceived method for source localization, carried out on different cases of simulated dipoles experiments, showed satisfactory results. Different cases of simulated dipoles experiments and metrics were used to confirm the reliability of the proposed method. The experimental results confirm that our method presents a flexible and robust tool for EEG source imaging.


Human Allergen-Specific IgG Subclass Antibodies Measured Using ImmunoCAP Technology.
Knowledge of human IgG subclass antibody responses to various allergens has been hampered by a lack of reliable standardized assays. The aim here was to develop quantitative immunoassays for human IgG1, IgG2, and IgG3 antibodies using ImmunoCAP® technology and to evaluate their application. Enzyme conjugates with isotype-specific monoclonal antibodies and calibrators composed of purified myeloma paraproteins were developed for each assay and used together with other standardized assay reagents for the Phadia® 100 instrument. The calibrators were adjusted to the international reference preparation IRP 67/86. The assays were characterized and used together with other standard ImmunoCAP assays to measure antibodies to various allergens in preliminary studies. The new assays had limits of quantitation of 1.0 (IgG1), 4.6 (IgG2), and 0.04 mgA/L (IgG3), and coefficients of variation of <20%. Only some minor cross-reactivity with IgG2 was observed for the specific IgG1 assay. The specific IgG2 assay showed a bias for the allotype G2m(23) and compensation factors were used to adjust the measured concentrations accordingly. Preliminary studies indicated a strong and stable IgG4 antibody response to β-lactoglobulin in healthy individuals, a high IgG1 and even higher IgG2 antibody response to house dust mite in sensitized and nonsensitized subjects, and a mixed IgG subclass response to venom allergens in allergic patients with increasing IgG4 antibody levels during venom immunotherapy. The new research assays are valuable tools for immunological studies, enabling the characterization of antibody profiles using a standardized approach, and facilitating data interpretation and the comparison of results across studies.


From linked open data to molecular interaction: studying selectivity trends for ligands of the human serotonin and dopamine transporter.
Retrieval of congeneric and consistent SAR data sets for protein targets of interest is still a laborious task to do if no appropriate in-house data set is available. However, combining integrated open data sources (such as the Open PHACTS Discovery Platform) with workflow tools now offers the possibility of querying across multiple domains and tailoring the search to the given research question. Starting from two phylogenetically related protein targets of interest (the human serotonin and dopamine transporters), the whole chemical compound space was explored by implementing a scaffold-based clustering of compounds possessing biological measurements for both targets. In addition, potential hERG blocking liabilities were included. The workflow allowed studying the selectivity trends of scaffold series, identifying potentially harmful compound series, and performing SAR, docking studies and molecular dynamics (MD) simulations for a consistent data set of 56 cathinones. This delivered useful insights into driving determinants for hDAT selectivity over hSERT. With respect to the scaffold-based analyses it should be noted that the cathinone data set could be retrieved only when Murcko scaffold analyses were combined with similarity searches such as a common substructure search.


Metabolic effects of pent-4-enoate in isolated perfused rat heart.
The metabolic effects of the hypoglycaemic agent pent-4-enoate were studied in isolated, beating or potassium-arrested rat hearts. The addition of 0.8mM-pent-4-enoate to the perfusion fluid increased O2 consumption by 76% in the arrested heart and by 14% in the beating heart; the concentration ratio of phosphocreatine/creatine increase concomitantly by 47% and 27% respectively. Perfusion of the heart with pent-4-enoate resulted in a 30-fold increase in the concentration of the pool of tricarboxylic acid-cycle intermediates in the tissue, about 90% of this increase being due to malate. The sum of the concentrations of the myocardial free amino acids remained virtually unchanged during the accumulation of the tricarboxylic acid-cycle intermediates. It was concluded that pent-4-enoate can be effectively metabolized in the myocardium and that its metabolism probably proceeds via propionyl-CoA, since pent-4-enoate reproduces many of the metabolic characteristics of propionate in the cardiac muscle. The accumulation of the tricarboxylic acid-cycle intermediates is probably due to carboxylation of propionyl-CoA. The response pattern of the metabolite concentrations in the cardiac muscle is quite different from that in the liver, in which decrease of the concentrations of the tricarboxylic acid-cycle intermediates has been observed previously [Williamson, Rostand & Peterson (1970) J. Biol. Chem. 245, 3242-3251].


Stretchable gas barrier achieved with partially hydrogen-bonded multilayer nanocoating.
Super gas barrier nanocoatings are recently demonstrated by combining polyelectrolytes and clay nanoplatelets with layer-by-layer deposition. These nanobrick wall thin films match or exceed the gas barrier of SiOx and metallized films, but they are relatively stiff and lose barrier with significant stretching (≥ 10% strain). In an effort to impart stretchability, hydrogen-bonding polyglycidol (PGD) layers are added to an electrostatically bonded thin film assembly of polyethylenimine (PEI) and montmorillonite (MMT) clay. The oxygen transmission rate of a 125-nm thick PEI-MMT film increases more than 40x after being stretched 10%, while PGD-PEI-MMT trilayers of the same thickness maintain its gas barrier. This stretchable trilayer system has an OTR three times lower than the PEI-MMT bilayer system after stretching. This report marks the first stretchable high gas barrier thin film, which is potentially useful for applications that require pressurized elastomers.


Protein purification using magnetic adsorbent particles.
The application of functionalised magnetic adsorbent particles in combination with magnetic separation techniques has received considerable attention in recent years. The magnetically responsive nature of such adsorbent particles permits their selective manipulation and separation in the presence of other suspended solids. Thus, it becomes possible to magnetically separate selected target species directly out of crude biological process liquors (e.g. fermentation broths, cell disruptates, plasma, milk, whey and plant extracts) simply by binding them on magnetic adsorbents before application of a magnetic field. By using magnetic separation in this way, the several stages of sample pretreatment (especially centrifugation, filtration and membrane separation) that are normally necessary to condition an extract before its application on packed bed chromatography columns, may be eliminated. Magnetic separations are fast, gentle, scaleable, easily automated, can achieve separations that would be impossible or impractical to achieve by other techniques, and have demonstrated credibility in a wide range of disciplines, including minerals processing, wastewater treatment, molecular biology, cell sorting and clinical diagnostics. However, despite the highly attractive qualities of magnetic methods on a process scale, with the exception of wastewater treatment, few attempts to scale up magnetic operations in biotechnology have been reported thus far. The purpose of this review is to summarise the current state of development of protein separation using magnetic adsorbent particles and identify the obstacles that must be overcome if protein purification with magnetic adsorbent particles is to find its way into industrial practice.


Impact of short-course preoperative radiotherapy for rectal cancer on patients' quality of life: data from the Medical Research Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 randomized clinical trial.
The Medical Research Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 (MRC CR07/NCIC CTG C016) trial showed that, in patients with operable rectal cancer, short-course preoperative radiotherapy (PRE) reduced the rate of local recurrence compared with surgery followed by selective postoperative chemoradiotherapy for patients with a positive circumferential resection margin. However, the advantages of giving PRE to all patients needs to be balanced against any negative impact on patients' quality of life. All 1,350 patients were asked to complete the Medical Outcomes Study Short-Form 36-item (MOS SF-36) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Colorectal 38-item (EORTC QLQ-CR38) questionnaires. A priori hypotheses related to the impact of treatment on sexual, bowel, and physical function and general health. Male sexual dysfunction was significantly increased following surgery (P < .001), although there was no difference between treatment arms. However, a treatment difference had emerged at 6 months (PRE patients reporting significantly greater dysfunction; P = .004), which persisted out to at least 2 years (an insufficient number of female patients completed the sexual dysfunction questions to draw firm conclusions). Both treatment groups reported similar levels of decreased physical function at 3 months, but thereafter it returned to baseline levels. There was no evidence of any major changes between treatments or time points in terms of general health or bowel function, but exploratory analysis indicated a significant (P = .006 at 2 years) increase in the level of fecal incontinence with PRE. These results from a large randomized trial using validated patient-completed questionnaires show that, for males, the main adverse effect was sexual dysfunction, and the main cause of this was surgery, but that PRE also affected sexual and some aspects of bowel functioning.


Albumin associated with purified pig lymphocyte plasma membrane.
Plasma-membrane preparations purified from pig lymphocytes contained a major polypeptide component of mol.wt. about 68 000. This component was identified as pig albumin by the following comparisons with authentic pig serum albumin: (a) co-migration when analysed by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis under reducing and non-reducing conditions; (b) identical isoelectric points; (c) similar "fingerprints" of arginine-containing tryptic peptides; (d) reactivity with anti-(pig albumin) serum. The albumin was bound tightly to the plasma membrane. Biosynthetic labelling of pig lymphocytes under a variety of conditions failed to provide evidence that albumin was synthesized by lymphocytes, suggesting that the plasma-membrane-associated albumin was of extraneous origin. Radiolabelled pig serum albumin, however, failed to bind to the plasma-membrane fraction when added before cell disruption. Although lymphocyte plasma membrane preparations from other species possessed a polypeptide of about 68 000 mol.wt., this was judged not to be albumin on the basis of electrophoretic mobility under non-reducing conditions; also, no polypeptide was precipitated by anti-albumin sera. It is concluded that pig lymphocyte plasma-membrane preparations possess albumin which, although firmly attached, was probably of extraneous origin. This association appeared not to be common to lymphocytes from other species.


Differential effects of HIF2α antagonist and HIF2α silencing in renal cancer and sensitivity to repurposed drugs.
In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385. PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity. this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.


Kinome-wide functional screen identifies role of PLK1 in hormone-independent, ER-positive breast cancer.
Estrogen receptor (ER) α-positive breast cancers initially respond to antiestrogens but eventually become estrogen independent and recur. ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit hormone-independent ER transcriptional activity and growth. A kinome-wide siRNA screen using a library targeting 720 kinases identified Polo-like kinase 1 (PLK1) as one of the top genes whose downregulation resulted in inhibition of estrogen-independent ER transcriptional activity and growth of LTED cells. High PLK1 mRNA and protein correlated with a high Ki-67 score in primary ER(+) breast cancers after treatment with the aromatase inhibitor letrozole. RNAi-mediated knockdown of PLK1 inhibited ER expression, estrogen-independent growth, and ER transcription in MCF7 and HCC1428 LTED cells. Pharmacologic inhibition of PLK1 with volasertib, a small-molecule ATP-competitive PLK1 inhibitor, decreased LTED cell growth, ER transcriptional activity, and ER expression. Volasertib in combination with the ER antagonist, fulvestrant, decreased MCF7 xenograft growth in ovariectomized mice more potently than each drug alone. JUNB, a component of the AP-1 complex, was expressed 16-fold higher in MCF7/LTED compared with parental MCF7 cells. Furthermore, JUNB and BCL2L1 (which encodes antiapoptotic BCL-xL) mRNA levels were markedly reduced upon volasertib treatment in MCF7/LTED cells, while they were increased in parental MCF7 cells. Finally, JUNB knockdown decreased ER expression and transcriptional activity in MCF7/LTED cells, suggesting that PLK1 drives ER expression and estrogen-independent growth via JUNB. These data support a critical role of PLK1 in acquired hormone-independent growth of ER(+) human breast cancer and is therefore a promising target in tumors that have escaped estrogen deprivation therapy.


Changes in air quality and second-hand smoke exposure in hospitality sector businesses after introduction of the English Smoke-free legislation.
To monitor and disseminate the short-term effects of the English Smoke-free legislation on air quality and employee exposure in businesses of the hospitality industry. Indoor particle concentrations and salivary cotinine levels were measured in businesses in the hospitality sector and non-smoking employees one month before and after the implementation of the legislation. Results were immediately released to the media to announce the improvements in air quality and employee exposure to the wider public. Measurements were collected in 49 businesses and from 75 non-smoking individuals. Indoor PM(2.5) concentrations decreased by 95% from 217 microg/m(3) at baseline to 11 microg/m(3) at follow-up (P < 0.001). Salivary cotinine in employees was reduced by 75%, from 3.6 ng/ml at baseline to 0.9 ng/ml at follow-up (P < 0.001). The findings were presented to the public through press releases and interviews and were cited in over 20 media articles. The project demonstrates the positive effects of the English Smoke-free legislation on air quality and second-hand smoke exposure in the hospitality industry sector. We believe that quick and positive feedback to the public on the effects of smoking restrictions is essential when introducing public health legislation such as the Smoke-free legislation.


Violence permeating daily life: a qualitative study investigating perspectives on violence among women in Karachi, Pakistan.
This study explored how married women perceive situations which create family conflicts and lead to different forms of violence in urban Pakistan. In addition, it examines perceptions of consequences of violence, their adverse health effects, and how women resist violence within marital life. Five focus group discussions were conducted with 28 women in Karachi. Purposive sampling, aiming for variety in age, employment status, education, and socioeconomic status, was employed. The focus group discussions were conducted in Urdu and translated into English. Manifest and latent content analysis were applied. One major theme emerged during the analysis, ie, family violence through the eyes of females. This theme was subdivided into three main categories. The first category, ie, situations provoking violence and their manifestations, elaborates on circumstances that provoke violence and situations that sustain violence. The second category, ie, actions and reactions to exposure to violence, describes consequences of ongoing violence within the family, including those that result in suicidal thoughts and actions. The final category, ie, resisting violence, describes how violence is avoided through women's awareness and actions. The current study highlights how female victims of abuse are trapped in a society where violence from a partner and family members is viewed as acceptable, where divorce is unavailable to the majority, and where societal support of women is limited. There is an urgent need to raise the subject of violence against women and tackle this human rights problem at all levels of society by targeting the individual, family, community, and societal levels concurrently.


Osmoregulation and excretion.
The article discusses advances in osmoregulation and excretion with emphasis on how multicellular animals in different osmotic environments regulate their milieu intérieur. Mechanisms of energy transformations in animal osmoregulation are dealt with in biophysical terms with respect to water and ion exchange across biological membranes and coupling of ion and water fluxes across epithelia. The discussion of functions is based on a comparative approach analyzing mechanisms that have evolved in different taxonomic groups at biochemical, cellular and tissue levels and their integration in maintaining whole body water and ion homeostasis. The focus is on recent studies of adaptations and newly discovered mechanisms of acclimatization during transitions of animals between different osmotic environments. Special attention is paid to hypotheses about the diversity of cellular organization of osmoregulatory and excretory organs such as glomerular kidneys, antennal glands, Malpighian tubules and insect gut, gills, integument and intestine, with accounts on experimental approaches and methods applied in the studies. It is demonstrated how knowledge in these areas of comparative physiology has expanded considerably during the last two decades, bridging seminal classical works with studies based on new approaches at all levels of anatomical and functional organization. A number of as yet partially unanswered questions are emphasized, some of which are about how water and solute exchange mechanisms at lower levels are integrated for regulating whole body extracellular water volume and ion homeostasis of animals in their natural habitats. © 2014 American Physiological Society.


Absence of relationship between MTTP haplotypes and longevity.
Polymorphisms for the microsomal triglyceride transfer protein (MTTP) gene have been associated with longevity and with lower risk for cardiovascular mortality. However, the association of MTTP with longevity has been contested in a large German collection of nonagenarians and centenarians. We made a detailed characterization of MTTP haplotype carrier status in a cohort of 1398 old men and women (mean age 78 years) and a population-based cohort (n = 777) of younger controls (mean age 40 years) in Oxford, England. There were no significant differences in haplotypes for MTTP gene between the younger and older age groups. This study, which adopted a more detailed genetic analysis of the MTTP gene in a large case-control study of older people provides reliable evidence against any significant association of the MTTP gene with longevity.


Psoriasin is aberrantly expressed in human breast cancer and is related to clinical outcomes.
Psoriasin (S100A7) is a member of the S100 gene family that is involved in psoriasis, which can be induced in cultured squamous epithelial cells. Previously, this molecule has been shown to be over-expressed in human ductal carcinoma in situ and invasive breast cancers. This current study examine the levels of expression of this molecule in a group of human breast tumours, with particular emphasis on the relationship with the clinical outcomes using quantitative PCR and the distribution in tumours using immunohistochemistry. Psoriasin is primarily expressed in breast cancer cells, and at very low level in normal breast epithelial cells. Quantitative analysis of psoriasin mRNA has shown that breast tumour tissues exhibited a significantly high level of psoriasin compared with normal tissues (p=0.0026). The levels do not correlate with nodal status of breast tumours, however levels in grade 2 and grade 3 tumours were significantly higher compared with that in grade 1 tumours (p=0.07 and p=0.0015, vs grade 1 respectively). Lobular carcinoma also had higher levels of psoriasin compared with ductal tumours. The most interesting observation is that levels of psoriasin were significantly higher in patients who developed metastatic disease and in patients who died of breast cancer (p=0.02 and p<0.001, vs disease-free, respectively). It is concluded that aberrant expression of psoriasin is commonly seen in human breast cancer and that excessively high levels are correlated with the clinical outcomes.


Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis.
Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblastoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-β pathway in various tumor models. Cytokine TGF-β can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model.


Use of bone scan during initial prostate cancer workup, downstream procedures, and associated Medicare costs.
For patients with a high likelihood of having metastatic disease (high-risk prostate cancer), bone scan is the standard, guideline-recommended test to look for bony metastasis. We quantified the use of bone scans and downstream procedures, along with associated costs, in patients with high-risk prostate cancer, and their use in low- and intermediate-risk patients for whom these tests are not recommended. Patients in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database diagnosed with prostate cancer from 2004 to 2007 were included. Prostate specific antigen (PSA), Gleason score, and clinical T stage were used to define D'Amico risk categories. We report use of bone scans from the date of diagnosis to the earlier of treatment or 6 months. In patients who underwent bone scans, we report use of bone-specific x-ray, computed tomography (CT), and magnetic resonance imaging (MRI) scans, and bone biopsy within 3 months after bone scan. Costs were estimated using 2012 Medicare reimbursement rates. In all, 31% and 48% of patients with apparent low- and intermediate-risk prostate cancer underwent a bone scan; of these patients, 21% underwent subsequent x-rays, 7% CT, and 3% MRI scans. Bone biopsies were uncommon. Overall, <1% of low- and intermediate-risk patients were found to have metastatic disease. The annual estimated Medicare cost for bone scans and downstream procedures was $11,300,000 for low- and intermediate-risk patients. For patients with apparent high-risk disease, only 62% received a bone scan, of whom 14% were found to have metastasis. There is overuse of bone scans in patients with low- and intermediate-risk prostate cancers, which is unlikely to yield clinically actionable information and results in a potential Medicare waste. However, there is underuse of bone scans in high-risk patients for whom metastasis is likely.


Timing of discharge follow-up for acute pulmonary embolism: retrospective cohort study.
Historically, emergency department (ED) patients with pulmonary embolism (PE) have been admitted for several days of inpatient care. Growing evidence suggests that selected ED patients with PE can be safely discharged home after a short length of stay. However, the optimal timing of follow up is unknown. We hypothesized that higher-risk patients with short length of stay (<24 hours from ED registration) would more commonly receive expedited follow up (≤3 days). This retrospective cohort study included adults treated for acute PE in six community EDs. We ascertained the PE Severity Index risk class (for 30-day mortality), facility length of stay, the first follow-up clinician encounter, unscheduled return ED visits ≤3 days, 5-day PE-related readmissions, and 30-day all-cause mortality. Stratifying by risk class, we used multivariable analysis to examine age- and sex-adjusted associations between length of stay and expedited follow up. The mean age of our 175 patients was 63.2 (±16.8) years. Overall, 93.1% (n=163) of our cohort received follow up within one week of discharge. Fifty-six patients (32.0%) were sent home within 24 hours and 100 (57.1%) received expedited follow up, often by telephone (67/100). The short and longer length-of-stay groups were comparable in age and sex, but differed in rates of low-risk status (63% vs 37%; p<0.01) and expedited follow up (70% vs 51%; p=0.03). After adjustment, we found that short length of stay was independently associated with expedited follow up in higher-risk patients (adjusted odds ratio [aOR] 3.5; 95% CI [1.0-11.8]; p=0.04), but not in low-risk patients (aOR 2.2; 95% CI [0.8-5.7]; p=0.11). Adverse outcomes were uncommon (<2%) and were not significantly different between the two length-of-stay groups. Higher-risk patients with acute PE and short length of stay more commonly received expedited follow up in our community setting than other groups of patients. These practice patterns are associated with low rates of 30-day adverse events.


Provider perceptions of colorectal cancer screening clinical decision support at three benchmark institutions.
Implementation of computerized clinical decision support (CDS), and its integration into workflow has not reached its potential. To better understand the use of CDS for colorectal cancer (CRC) screening at benchmark institutions for health information technology (HIT), we conducted direct observation, including opportunistic interviews of primary care providers, as well as key informant interviews and focus groups, to document current challenges to CRC screening and follow-up at clinics affiliated with the Veterans Heath Administration, Regenstrief Institute, and Partners HealthCare System. Analysis revealed six common barriers across institutions from the primary care providers' perspective: receiving and documenting "outside" exam results, inaccuracy of the CDS, compliance issues, poor usability, lack of coordination between primary care and gastroenterology, and the need to attend to more urgent patient issues. Strategies should be developed to enhance current HIT to address these challenges and better support primary care providers and staff.


Cigarette smoke induces nucleic-acid oxidation in lung fibroblasts.
Oxidative stress is widely proposed as a pathogenic mechanism for chronic obstructive pulmonary disease (COPD), but the molecular pathway connecting oxidative damage to tissue destruction remains to be fully defined. We suggest that reactive oxygen species (ROS) oxidatively damage nucleic acids, and this effect requires multiple repair mechanisms, particularly base excision pathway components 8-oxoguanine-DNA glycosylase (OGG1), endonuclease III homologue 1 (NTH1), and single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), as well as the nucleic acid-binding protein, Y-box binding protein 1 (YB1). This study was therefore designed to define the levels of nucleic-acid oxidation and expression of genes involved in the repair of COPD and in corresponding models of this disease. We found significant oxidation of nucleic acids localized to alveolar lung fibroblasts, increased levels of OGG1 mRNA expression, and decreased concentrations of NTH1, SMUG1, and YB1 mRNA in lung samples from subjects with very severe COPD compared with little or no COPD. Mice exposed to cigarette smoke exhibited a time-dependent accumulation of nucleic-acid oxidation in alveolar fibroblasts, which was associated with an increase in OGG1 and YB1 mRNA concentrations. Similarly, human lung fibroblasts exposed to cigarette smoke extract exhibited ROS-dependent nucleic-acid oxidation. The short interfering RNA (siRNA)-dependent knockdown of OGG1 and YB1 expression increased nucleic-acid oxidation at the basal state and after exposure to cigarette smoke. Together, our results demonstrate ROS-dependent, cigarette smoke-induced nucleic-acid oxidation in alveolar fibroblasts, which may play a role in the pathogenesis of emphysema.


Can the publication of guidelines change the management of early rheumatoid arthritis? An interrupted time series analysis from the United Kingdom.
To assess whether publication of national treatment guidelines improved the management of early RA in the UK. Incident diagnoses of RA in persons aged over 18 years from 1995 to 2010 were identified from the Clinical Practice Research Datalink. Using a natural experimental study design, interrupted time series analysis was used to assess whether trends in the proportion of patients receiving DMARDs, within 3 and 12 months of diagnosis, changed following publication of British Society for Rheumatology guidelines in 2006. Between 1995 and 2010, 11 772 incident cases of RA were identified. There was a progressive increase in the proportion of patients prescribed any DMARD within 12 months from 43.3% in 1995 to 78.5% in 2010. After publication of the British Society for Rheumatology guidelines, the proportion of patients prescribed any DMARD within 12 months increased by 4.2% (P = 0.053). Prior to the guidance, prescribing was increasing by 1.64% per year, compared with 3.55% per year after publication (P < 0.001). Guidelines published by a national body can improve the proportion of patients receiving DMARD treatment in the first year after diagnosis of RA.


Association between rs2294020 in X-linked CCDC22 and susceptibility to autoimmune diseases with focus on systemic lupus erythematosus.
Autoimmune diseases often share common susceptibility genes. Most genetic variants associated with susceptibility to systemic lupus erythematosus are also associated with other autoimmune diseases. The X-linked variant rs2294020 is positioned in exon 7 of the CCDC22 gene. The encoded protein functions in the regulation of NF-κB, a master regulator in immune response. The aim of this study is to investigate whether the rs2294020 polymorphism may be a general susceptibility factor for autoimmunity. We evaluated case-control association between the occurrence of rs2294020 and different autoimmune diseases, including new data for systemic lupus erythematosus and previous genome-wide association studies (GWAS) (though most did not analyse the X chromosome) of psoriasis, celiac disease, Crohn's disease, ulcerative colitis, multiple sclerosis, vitiligo, type-1 diabetes, rheumatoid arthritis, and ankylosing spondylitis. Cases from patients affected by amyotrophic lateral sclerosis and type-2 diabetes were also included in the study. We detected nominal significant associations of rs2294020 with systemic lupus erythematosus (additive model test: p=0.01), vitiligo (p=0.016), psoriasis (p=0.038), and in only one of two studies of multiple sclerosis (p=0.03). Our results suggest that rs2294020 is associated with the risk of several autoimmune diseases in European populations, specifically with diseases that present themselves, among else, in the skin.


Kidney stone risk following Roux-en-Y gastric bypass surgery.
Since the first report in 2005, Roux-en-Y gastric bypass (RYGB) surgery has been linked to a variety of metabolic changes that alter kidney stone risk. The studies with the highest level of evidence, performed in non-stone forming patients before and after RYGB, cite a number of kidney stone risk factors, including a 25% increase in urinary oxalate, a 30% decrease in urinary citrate, and reduction in urine volume by half a liter. In addition to these, recent clinical and experimental studies have contributed to our understanding of the pathophysiology of stone disease in this unique population. This review summarizes the current RYGB urinary chemistry profiles and epidemiological studies, outlines known and theoretical mechanisms of hyperoxaluria and hypocitrituria, and provides some standard recommendations for reducing stone risk in RYGB stone formers as well as some novel ones, including correction of metabolic acidosis and use of probiotics.


[Work and high-risk pregnancy due to diabetes: two incompatible circumstances].
In 1991 the prevalence of diabetes was 7.6% in women in nine Brazilian state capitals. This disease now ranks among the leading causes of death in the country and is becoming an increasingly alarming public health problem. In spite of advances in the treatment of diabetes and improved obstetric care, gestational diabetes puts a pregnant woman at high risk of spontaneous abortion, ketoacidosis, hypoglycemia, hypertension, and other serious disorders. This study used life histories to investigate the relationship between health, sexuality, and work in five working women who were diabetic and pregnant and who received care at the Prenatal Care Outpatient Clinic of the San Pablo Hospital. All these women had non-insulin-dependent diabetes mellitus, were between 26 and 43 years old, and earned from US$ 150 to 375 per month for working 8-hours days, with one day off each week. Two of the women's male partners were unemployed; all of the women performed household chores during their day off. Quotations taken directly from conversations with the five participants reveal: the difficulty of caring for children and working; the sexual harassment that some of them suffered; the conflict and dissatisfaction associated with work; the myth of the natural joy of motherhood; the sexual control exercised by males; the interference of working conditions and work activities with pregnancy; and the perception that they did not have legal protection owing to employers' lack of respect for workers' rights and for the maternity protection provisions of the Federal Constitutional of Brazil. It is concluded that health policies should pay greater attention to improving the quality of life of working women, especially if they suffer from diabetes and are pregnant.


Head and Neck Cancers, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.
Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.


Abnormally phosphorylated tau protein in senile dementia of Lewy body type and Alzheimer disease: evidence that the disorders are distinct.
The relationship between Alzheimer disease (AD) and dementia with Lewy bodies (senile dementia Lewy body type, or SDLT) and dementia in Parkinson's disease is unclear. AD pathology is characterised by both amyloid deposition and abnormal phosphorylation of tau in paired helical filaments (PHF-tau). In AD, abnormally phosphorylated PHF-tau is present in neurofibrillary tangles, in neuritic processes of senile plaques, and also in neuropil threads dispersed throughout the cerebral cortex. Cortical homogenates from 12 cases each of AD and SDLT, 13 cases of Parkinson's disease, and 11 normal controls were examined by Western blot analysis with antibodies that detect PHF-tau. No PHF-tau was found in Parkinson's disease or control cortex. No PHF-tau was found in SDLT cases without histological evidence of tangles. PHF-tau was detectable in SDLT cases with a low density of tangles, and large amounts of PHF-tau were present in AD cases. This study demonstrates that abnormally phosphorylated PHF-tau is only present where tangles are found and not in SDLT cases without tangles or with only occasional tangles. It is concluded that Lewy body dementias are distinct at a molecular level from AD.


Prediction and clinical utility of a liver cancer risk model in Chinese adults: A prospective cohort study of 0.5 million people.
China has made rapid progress in reducing the incidence of HBV infection in the past three decades, along with a rapidly changing lifestyle and aging population. We aimed to develop and validate an up-to-date liver cancer risk prediction model with routinely available predictors and evaluate its applicability for screening guidance. Using data from the China Kadoorie Biobank, we included 486 285 participants in this analysis. Fifteen risk factors were included in the model. Flexible parametric survival models were used to estimate the 10-year absolute risk of liver cancer. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. A total of 2706 participants occurred liver cancer over the 4 814 320 person-years of follow-up. Excellent discrimination of the model was observed in both development and validation datasets, with c-statistics (95% CI) of 0.80 (0.79-0.81) and 0.80 (0.78-0.82) respectively, as well as excellent calibration of observed and predicted risks. Decision curve analysis revealed that use of the model in selecting participants for screening improved benefit at a threshold of 2% 10-year risk, compared to current guideline of screening all HBsAg carriers. Our model was more sensitive than current guideline for cancer screening (28.17% vs 25.96%). We developed and validated a CKB-PLR (Prediction for Liver cancer Risk Based on the China Kadoorie Biobank Study) model to predict the absolute risk of liver cancer for both HBsAg seropositive and seronegative populations. Application of the model is beneficial for precisely identifying the high-risk groups among the general population.


Cardiomyopathy related to antimalarial therapy with illustrative case report.
The antimalarial agents, chloroquine (CQ) and hydroxychloroquine (HCQ) are used in long-term treatment of connective tissue diseases and dermatological disorders and are generally regarded as safe. We present one case of cardiotoxicity in a 59-year-old woman treated with antimalarials during 13 years for a discoid lupus erythematosus. She progressively developed conduction disturbances and congestive heart failure (CHF). When the diagnosis of antimalarials toxicity was suspected, CQ was withdrawn. However, heart transplantation had to be performed in the following 4 months for severe CHF. Indeed, rare but severe cardiotoxicity may develop following prolonged use of antimalarials with both conduction disturbances (45 patients) and CHF (25 patients). These cardiac toxic effects have been reported with CQ and less frequently with HCQ use alone. Diagnoses are often delayed since the toxicity of the drug might be misattributed to other factors in these patients. The endomyocardial biopsy, or in some cases the muscle biopsy, are essential to confirm the antimalarials toxicity. Antimalarials have been stopped in 12 cases of CHF, leading to improvement in 8 cases (within 3 months to 5 years) and to deaths or to heart transplantation in 4 cases (within 1 week to 3 months). In the latter cases, as in our patient, the lack of improvement may have been explained by the severity of the cardiomyopathy at diagnosis and the short delay since withdrawal. As a consequence, the potential for reversibility and the severity in undiagnosed cases of these toxic cardiomyopathies emphasize the importance of recognizing early signs of toxicity in order to withdraw antimalarials before the occurrence of life-threatening CHF.


Activity of cathepsin D and L in the heart muscle of coronary patients during coronary--aortal bypass graft operation.
During coronary--aortal bypass graft operation (CABG) the period of ischaemia with cardioplegia in coronaries, is followed by the phase of reperfusion. The role of lysosomal proteases in both ischaemic and reperfusion injuries of myocardium is not very well understood. Therefore, we decided to evaluate the changes in the activity of two lysosomal proteases: cathepsin D and L taking place in the heart muscle of the coronary sufferers during CABG. Small fragments of right atrium (SFRA) were taken out during CABG: 1) just before the injection of standard St. Thomas Hospital cold cardioplegic fluid (control) 2) just after completion of artificial circulation (peak of ischaemia) and 3) after 30-40 min. of reperfusion. Cathepsins were assayed in homogenates of SFRA at pH 3.6 with haemoglobin in the absence and presence of pepstatin (cathepsin D inhibitor). Some simple calculations allow for a better insight into what is going on with lysosomal enzymes of myocardium during CABG. Essentially, total and free activity of both cathepsin D and L in the myocardium of coronary patients did not undergo significant changes during CABG. However, the values of A expressing activation (A > 1) or inactivation (A < 1) of enzymes in intralysosomal (Ai) and extralysosomal (Ae) compartment varied to a large extent (regardless of the damage of lysosomes in vivo). During ischaemia Ai for both enzymes was 2.0-2.7 while Ae for cathepsin L was about 0.7. During reperfusion Ae and Ai values ranged between 0.5 and 0.7. During CABG ischaemia period the prominent activation of both cathepsin D and L in intralysosomal compartment and inactivation, especially of cathepsin L, outside the lysosomes (outside cells) takes place probably reflecting more intensive endocytosis into cardiomyocytes. During reperfusion, the inactivation of both enzymes in both compartments takes place. Some changes seem to be irreversible, especially for cathepsin L.


Interferon-inhibited human osteosarcoma xenografts induce host bone in nude mice.
The growth of human osteosarcoma xenografts in nude mice can be inhibited by human interferon-alpha (IFN-alpha). Histologic examination of growth-inhibited tumors has revealed mineralization and partial replacement of the tumor by normal bone tissue. We have investigated whether the normal bone tissue was formed by differentiated tumor cells or by induction of host stroma to differentiate into bone tissue. Employing antibodies to both murine and human type I collagen, it was found that the normal bone produced in IFN-inhibited osteosarcomas was host derived. These results suggest that IFN induced the osteosarcoma cells to produce a bone-inductive agent that interacts with the host cells, and leads to the formation of mature normal bone tissue in a heterotopic site.


Energy expenditure and body composition of chronically maintained decerebrate rats in the fed and fasted condition.
The contribution of the caudal brainstem to adaptation to starvation was tested using chronically maintained decerebrate (CD) and neurologically intact controls. All rats were gavage fed an amount of diet that maintained weight gain in controls. CD rats were subjected to a two-stage surgery to produce a complete transection of the neuroaxis at the mesodiencephalic juncture. One week later, the rats were housed in an indirect calorimeter, and 24 h energy expenditure was measured for 4 d. One half of each of the CD and control groups was then starved for 48 h. Fed CD rats maintained a lower body temperature (35 C), a similar energy expenditure per unit fat-free mass but an elevated respiratory quotient compared with controls. They gained less weight, had 20% less lean tissue, and had 60% more fat than controls. Circulating leptin, adiponectin, and insulin were elevated, glucose was normal, but testosterone was dramatically reduced. Responses to starvation were similar in CD and controls; they reduced energy expenditure, decreased respiratory quotient, indicating lipid utilization, defended body temperature, mobilized fat, decreased serum leptin and insulin, and regulated plasma glucose. These data clearly demonstrate that the isolated caudal brainstem is sufficient to mediate many aspects of the energetic response to starvation. In intact animals, these responses may be refined by a contribution by more rostral brain areas or by communication between fore- and hind-brain. In the absence of communication from the forebrain, the caudal brainstem is inadequate for maintenance of testosterone levels or lean tissue in fed or fasted animals.


Network clustering coefficient without degree-correlation biases.
The clustering coefficient quantifies how well connected are the neighbors of a vertex in a graph. In real networks it decreases with the vertex degree, which has been taken as a signature of the network hierarchical structure. Here we show that this signature of hierarchical structure is a consequence of degree-correlation biases in the clustering coefficient definition. We introduce a definition in which the degree-correlation biases are filtered out, and provide evidence that in real networks the clustering coefficient is constant or decays logarithmically with vertex degree.


Large-scale remodeling of a repressed exon ribonucleoprotein to an exon definition complex active for splicing.
Polypyrimidine-tract binding protein PTBP1 can repress splicing during the exon definition phase of spliceosome assembly, but the assembly steps leading to an exon definition complex (EDC) and how PTBP1 might modulate them are not clear. We found that PTBP1 binding in the flanking introns allowed normal U2AF and U1 snRNP binding to the target exon splice sites but blocked U2 snRNP assembly in HeLa nuclear extract. Characterizing a purified PTBP1-repressed complex, as well as an active early complex and the final EDC by SILAC-MS, we identified extensive PTBP1-modulated changes in exon RNP composition. The active early complex formed in the absence of PTBP1 proceeded to assemble an EDC with the eviction of hnRNP proteins, the late recruitment of SR proteins, and binding of the U2 snRNP. These results demonstrate that during early stages of splicing, exon RNP complexes are highly dynamic with many proteins failing to bind during PTBP1 arrest.


Complementary and alternative medicine for treatment of irritable bowel syndrome.
To review the evidence supporting selected complementary and alternative medicine approaches used in the treatment of irritable bowel syndrome (IBS). MEDLINE (from January 1966), EMBASE (from January 1980), and the Cochrane Database of Systematic Reviews were searched until March 2008, combining the terms irritable bowel syndrome or irritable colon with complementary therapies, alternative medicine, acupuncture, fiber, peppermint oil, herbal, traditional, yoga, massage, meditation, mind, relaxation, probiotic, hypnotherapy, psychotherapy, cognitive therapy, or behavior therapy. Results were screened to include only clinical trials, systematic reviews, and meta-analyses. Level I evidence was available for most interventions. Soluble fibre improves constipation and global IBS symptoms. Peppermint oil alleviates IBS symptoms, including abdominal pain. Probiotic trials show overall benefit for IBS but there is little evidence supporting the use of any specific strain. Hypnotherapy and cognitive-behavioural therapy are also effective therapeutic options for appropriate patients. Certain herbal formulas are supported by limited evidence, but safety is a potential concern. All interventions are supported by systematic reviews or meta-analyses. Several complementary and alternative therapies can be recommended as part of an evidence-based approach to the treatment of IBS; these might provide patients with satisfactory relief and improve the therapeutic alliance.


Effects of antagonists and heat on TRPM8 channel currents in dorsal root ganglion neuron activated by nociceptive cold stress and menthol.
Transient receptor potential ion channel melastatin subtype 8 (TRPM8) is activated by cold temperature and cooling agents, such as menthol and icilin. Compounds containing peppermint are reported to reduce symptoms of environmental cold stress such as cold allodynia in dorsal root ganglion (DRG) neuron; however, the underlying mechanisms of action are unclear. We tested the effects of physiological heat (37°C), anthralic acid (ACA and 0.025 mM), 2-aminoethyl diphenylborinate (2-APB and 0.05) on noxious cold (10°C) and menthol (0.1 mM)-induced TRPM8 cation channel currents in the DRG neurons of rats. DRG neurons were freshly isolated from rats. In whole-cell patch clamp experiments, TRPM8 currents were consistently induced by noxious cold or menthol. TRPM8 channels current densities of the neurons were higher in cold and menthol groups than in control. When the physiological heat is introduced by chamber TRPM8 channel currents were inhibited by the heat. Noxious cold-induced Ca(2+) gates were blocked by the ACA although menthol-induced TRPM8 currents were not blocked by ACA and 2-APB. In conclusion, the results suggested that activation of TRPM8 either by menthol or nociceptive cold can activate TRPM8 channels although we observed the protective role of heat, ACA and 2-APB through a TRPM8 channel in nociceptive cold-activated DRG neurons. Since cold allodynia is a common feature of neuropathic pain and diseases of sensory neuron, our findings are relevant to the etiology of neuropathology in DRG neurons.


Automatically visualise and analyse data on pathways using PathVisioRPC from any programming environment.
Biological pathways are descriptive diagrams of biological processes widely used for functional analysis of differentially expressed genes or proteins. Primary data analysis, such as quality control, normalisation, and statistical analysis, is often performed in scripting languages like R, Perl, and Python. Subsequent pathway analysis is usually performed using dedicated external applications. Workflows involving manual use of multiple environments are time consuming and error prone. Therefore, tools are needed that enable pathway analysis directly within the same scripting languages used for primary data analyses. Existing tools have limited capability in terms of available pathway content, pathway editing and visualisation options, and export file formats. Consequently, making the full-fledged pathway analysis tool PathVisio available from various scripting languages will benefit researchers. We developed PathVisioRPC, an XMLRPC interface for the pathway analysis software PathVisio. PathVisioRPC enables creating and editing biological pathways, visualising data on pathways, performing pathway statistics, and exporting results in several image formats in multiple programming environments. We demonstrate PathVisioRPC functionalities using examples in Python. Subsequently, we analyse a publicly available NCBI GEO gene expression dataset studying tumour bearing mice treated with cyclophosphamide in R. The R scripts demonstrate how calls to existing R packages for data processing and calls to PathVisioRPC can directly work together. To further support R users, we have created RPathVisio simplifying the use of PathVisioRPC in this environment. We have also created a pathway module for the microarray data analysis portal ArrayAnalysis.org that calls the PathVisioRPC interface to perform pathway analysis. This module allows users to use PathVisio functionality online without having to download and install the software and exemplifies how the PathVisioRPC interface can be used by data analysis pipelines for functional analysis of processed genomics data. PathVisioRPC enables data visualisation and pathway analysis directly from within various analytical environments used for preliminary analyses. It supports the use of existing pathways from WikiPathways or pathways created using the RPC itself. It also enables automation of tasks performed using PathVisio, making it useful to PathVisio users performing repeated visualisation and analysis tasks. PathVisioRPC is freely available for academic and commercial use at http://projects.bigcat.unimaas.nl/pathvisiorpc.


Hyperbaric oxygen for carbon monoxide poisoning : a systematic review and critical analysis of the evidence.
Poisoning with carbon monoxide (CO) is an important cause of unintentional and intentional injury worldwide. Hyperbaric oxygen (HBO) enhances CO elimination and has been postulated to reduce the incidence of neurological sequelae. These observations have led some clinicians to use HBO for selected patients with CO poisoning, although there is considerable variability in clinical practice. This article assesses the effectiveness of HBO compared with normobaric oxygen (NBO) for the prevention of neurological sequelae in patients with acute CO poisoning. The following databases were searched: MEDLINE (1966 to present), EMBASE (1980 to present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognised content experts. All randomised controlled trials involving people acutely poisoned with CO, regardless of severity, were examined. The primary analysis included all trials from which data could be extracted. Sensitivity analysis examined trials with better validity (defined using the validated instrument of Jadad) and those enrolling more severely poisoned patients. Two reviewers independently extracted from each trial, including information on the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurological sequelae at follow-up. A pooled odds ratio (OR) for the presence of neurological symptoms at 1-month follow-up was calculated using a random effects model. Bayesian models were also investigated to illustrate the degree of certainty about clinical effectiveness. Eight randomised controlled trials were identified. Two had no evaluable data and were excluded. The remaining trials were of varying quality and two have been published only as abstracts. The severity of CO poisoning varied among trials. At 1-month follow-up after treatment, sequelae possibly related to CO poisoning were present in 242 of 761 patients (36.1%) treated with NBO, compared with 259 of 718 patients (31.8%) treated with HBO. Restricting the analysis to the trials with the highest quality scores or those that enrolled all patients regardless of severity did not change the lack of statistical significance in the outcome of the pooled analysis. We found empiric evidence of multiple biases that operated to inflate the benefit of HBO in two positive trials. In contrast, the interpretation of negative trials was hampered by low rates of follow-up, unusual interventions for control patients and inclusion of less severely poisoned patients. Collectively, these limitations may have led negative trials to overlook a real and substantial benefit of HBO (type II error). There is conflicting evidence regarding the efficacy of HBO treatment for patients with CO poisoning. Methodological shortcomings are evident in all published trials, with empiric evidence of bias in some, particularly those that suggest a benefit of HBO. Bayesian analysis further illustrates the uncertainty about a meaningful clinical benefit. Consequently, firm guidelines regarding the use of HBO for patients with CO poisoning cannot be established. Further research is needed to better define the role of HBO, if any, in the treatment of CO poisoning. Such research should not exclude patients with severe poisoning, have a primary outcome that is clinically meaningful and have oversight from an independent data monitoring and ethics committee.


Recent infection with human immunodeficiency virus and possible rapid loss of CD4 T lymphocytes.
To assess a hypothesized trend that persons recently infected with the human immunodeficiency virus (HIV) may have more rapid declines in absolute CD4 T-lymphocyte (CD4+ cell) counts than those who were HIV-infected in earlier years, sequential CD4+ cell counts in three groups who had definable dates of HIV seroconversion between 1978 and 1992 were reviewed. The CD4+ cell counts examined were from some of the longest extant studies in the United States: 100 homosexual and bisexual men engaged in ongoing observational cohort studies in San Francisco, Denver, and Chicago since 1978 (Group 1); 89 persons in South Carolina infected after 1986 (Group 2); and 155 injecting drug users participating in an observational cohort study in Baltimore since 1988 (Group 3). For all groups, individually and in the aggregate, mean CD4+ cell counts declined rapidly in the first year after HIV infection and then stabilized. However, there was no clear trend for lower (or higher) CD4+ cell counts by fixed time after HIV seroconversion among those seroconverting in recent compared with earlier calendar years. These data do not support a hypothesized trend for more rapid loss of CD4 T lymphocytes--and, by implication, more pathogenic strains of HIV-1--among persons acquiring HIV infection in recent years.


Circulating proteins and risk of pancreatic cancer: a case-subcohort study among Chinese adults.
Pancreatic cancer has a very poor prognosis. Biomarkers that may help predict or diagnose pancreatic cancer may lead to earlier diagnosis and improved survival. The prospective China Kadoorie Biobank (CKB) recruited 512 891 adults aged 30-79 years during 2004-08, recording 702 incident cases of pancreatic cancer during 9 years of follow-up. We conducted a case-subcohort study measuring 92 proteins in 610 cases and a subcohort of 623 individuals, using the OLINK immuno-oncology panel in stored baseline plasma samples. Cox regression with the Prentice pseudo-partial likelihood was used to estimate adjusted hazard ratios (HRs) for risk of pancreatic cancer by protein levels. Among 1233 individuals (including 610 cases), several chemokines, interleukins, growth factors and membrane proteins were associated with risk of pancreatic cancer, with adjusted HRs per 1 standard deviation (SD) of 0.86 to 1.86, including monocyte chemotactic protein 3 (MCP3/CCL7) {1.29 [95% CI (confidence interval) (1.10, 1.51)]}, angiopoietin-2 (ANGPT2) [1.27 (1.10, 1.48)], interleukin-18 (IL18) [1.24 (1.07, 1.43)] and interleukin-6 (IL6) [1.21 (1.06, 1.38)]. Associations between some proteins [e.g. matrix metalloproteinase-7 (MMP7), hepatocyte growth factor (HGF) and tumour necrosis factor receptor superfamily member 9 [TNFRSF9)] and risk of pancreatic cancer were time-varying, with higher levels associated with higher short-term risk. Within the first year, the discriminatory ability of a model with known risk factors (age, age squared, sex, region, smoking, alcohol, education, diabetes and family history of cancer) was increased when several proteins were incorporated (weighted C-statistic changed from 0.85 to 0.99; P for difference = 4.5 × 10-5), although only a small increase in discrimination (0.77 to 0.79, P = 0.04) was achieved for long-term risk. Several plasma proteins were associated with subsequent diagnosis of pancreatic cancer. The potential clinical utility of these biomarkers warrants further investigation.


Motivations for firearm possession and storage practices among urban young adults: differences between parents and non-parents.
To evaluate motivations for firearm possession among urban young adults and determine if differences emerge between parents and non-parents, and to identify if storage practices differed according to motivation for firearm possession and parenting status. We used cross-sectional data among young adults seeking urban emergency department treatment at Hurley Medical Center between 2017 and 2018. Our analyses, completed in 2020, included 194 firearm-possessing young adults, 95 of whom were young parents. Firearm-possessing parents were more likely to have a firearm for protection, than for any other motivation, compared with firearm-possessing non-parents (OR: 2.38, 95% CI 1.06 to 5.46). A significant interaction between parenting status and motivation for possession indicated the association between protective motivations and locked storage was significantly different between parents and non-parents, whereby there was a decreased odds of locked storage among non-parents who were motivated to possess a firearm for protection compared with any other motivation, but this association did not exist for parents (interaction OR=10.57, p<0.05). Parental motivation for possessing a firearm most often lies in the desire to protect families. This motivation, however, does not necessitate unsafe storage.


Prospective study of blunt aortic injury: Multicenter Trial of the American Association for the Surgery of Trauma.
Blunt aortic injury is a major cause of death from blunt trauma. Evolution of diagnostic techniques and methods of operative repair have altered the management and posed new questions in recent years. This study was a prospectively conducted multi-center trial involving 50 trauma centers in North America under the direction of the Multi-institutional Trial Committee of the American Association for the Surgery of Trauma. There were 274 blunt aortic injury cases studied over 2.5 years, of which 81% were caused by automobile crashes. Chest computed tomography and transesophageal echocardiography were applied in 88 and 30 cases, respectively, and were 75 and 80% diagnostic, respectively. Two hundred seven stable patients underwent planned thoracotomy and repair. Clamp and sew technique was used in 73 (35%) and bypass techniques in 134 (65%). Overall mortality was 31%, with 63% of deaths being attributable to aortic rupture; mortality was not affected by method of repair. Paraplegia occurred postoperatively in 8.7%. Logistic regression analysis demonstrated clamp and sew (p = 0.002) and aortic cross clamp time of > or = 30 minutes (p = 0.01) to be associated with development of postoperative paraplegia. Rupture after hospital admission remains a major problem. Although newer diagnostic techniques are being applied, at this time aortography remains the diagnostic standard. Aortic cross clamp time beyond 30 minutes was associated with paraplegia; bypass techniques, which provide distal aortic perfusion, produced significantly lower paraplegia rates than the clamp and sew approach.


Metabolic changes after repetitive transcranial magnetic stimulation (rTMS) of the left prefrontal cortex: a sham-controlled proton magnetic resonance spectroscopy (1H MRS) study of healthy brain.
Rapid transcranial magnetic stimulation is being increasingly used in the treatment of psychiatric disorders, especially major depression. However, its mechanisms of action are still unclear. The aim of this study was to assess metabolic changes by proton magnetic resonance spectroscopy following high-frequency rapid transcranial magnetic stimulation (20 Hz), both immediately after a single session and 24 h after a series of five consecutive sessions. Twelve healthy volunteers were enrolled in a prospective single-blind, randomized study [sham (n = 5) vs. real (n = 7)]. Three brain regions were investigated (right, left dorsolateral prefrontal cortex, left anterior cingulate cortex). A single as well as a series of consecutive rapid transcranial magnetic stimulations affected cortical glutamate/glutamine levels. These effects were present not only close to the stimulation site (left dorsolateral prefrontal cortex), but also in remote (right dorsolateral prefrontal cortex, left cingulate cortex) brain regions. Remarkably, the observed changes in glutamate/glutamine levels were dependent on the pre-transcranial magnetic stimulation glutamate/glutamine concentration, i.e. the lower the pre-stimulation glutamate/glutamine level, the higher the glutamate/glutamine increase observed after short- or long-term stimulation (5 days). In general, the treatment was well tolerated and no serious side-effects were reported. Neither transient mood changes nor significant differences in the outcome of a series of neuropsychological test batteries after real or sham transcranial magnetic stimulation occurred in our experiment. In summary, these data indicate that rapid transcranial magnetic stimulation may act via stimulation of glutamatergic prefrontal neurons.


Effects of Quetiapine on Neural Tube Development in the Early Stage of Chicken Embryos.
To investigate the effects of quetiapine exposure on neural tube development in early stage chicken embryos. Eighty-four fertilised specific pathogen-free chicken eggs were divided into four equal groups (groups 1?4). Three experimental groups (groups 2, 3 and 4) and a single control group (group 1) were used. Each egg in group 2 (n=21) was injected with 20 ?L of saline after 30 hours of incubation. Eggs in groups 3 and 4 were injected with 0.02 ml of a solution containing 400 and 800 ?g of quetiapine dose, respectively. Incubation was continued until the end of 72 hours. All embryos were then removed from the eggs and histopathologically examined. Normal development and the closed neural tubes were shown in 18, 16, 13 and 9 embryos in groups 1 2, 3 and 9, respectively, of the 84 embryos incubated. Open neural tubes were found in one, three and five embryos in groups 2, 3 and 5, respectively. Also, developmental anomalies were found in three, four, five and seven embryos in groups 1, 2, 3 and 4, respectively. Moreover, no significant relationship between NTD and quetiapine exposure had been found. Quetiapine has no significant effect on the occurrence of neural tube defects in the chicken embryo model.


Temporal analysis of neural differentiation using quantitative proteomics.
The ability to derive neural progenitors, differentiated neurons and glial cells from human embryonic stem cells (hESCs) with high efficiency holds promise for a number of clinical applications. However, investigating the temporal events is crucial for defining the underlying mechanisms that drive this process of differentiation along different lineages. We carried out quantitative proteomic profiling using a multiplexed approach capable of analyzing eight different samples simultaneously to monitor the temporal dynamics of protein abundance as human embryonic stem cells differentiate into motor neurons or astrocytes. With this approach, a catalog of approximately 1200 proteins along with their relative quantitative expression patterns was generated. The differential expression of the large majority of these proteins has not previously been reported or studied in the context of neural differentiation. As expected, two of the widely used markers of pluripotency, alkaline phosphatase (ALPL) and LIN28, were found to be downregulated during differentiation, while S-100 and tenascin C were upregulated in astrocytes. Neurofilament 3 protein, doublecortin and CAM kinase-like 1 and nestin proteins were upregulated during motor neuron differentiation. We identified a number of proteins whose expression was largely confined to specific cell types, embryonic stem cells, embryoid bodies and differentiating motor neurons. For example, glycogen phosphorylase (PYGL) and fatty acid binding protein 5 (FABP5) were enriched in ESCs, while beta spectrin (SPTBN5) was highly expressed in embryoid bodies. Karyopherin, heat shock 27 kDa protein 1 and cellular retinoic acid binding protein 2 (CRABP2) were upregulated in differentiating motor neurons but were downregulated in mature motor neurons. We validated some of the novel markers of the differentiation process using immunoblotting and immunocytochemical labeling. To our knowledge, this is the first large-scale temporal proteomic profiling of human stem cell differentiation into neural cell types highlighting proteins with limited or undefined roles in neural fate.


3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions.
A fine balance between bone resorption by osteoclasts and bone formation by osteoblasts maintains bone homeostasis. In patients with cherubism, gain-of-function mutations in 3BP2, which is encoded by SH3-domain binding protein 2 (SH3BP2), cause cystic lesions with activated osteoclasts that lead to craniofacial abnormalities. However, little is known about the function of wild-type 3BP2 in regulating bone homeostasis. Here we have shown that 3BP2 is required for the normal function of both osteoblasts and osteoclasts. Initial analysis showed that Sh3bp2-/-mice developed osteoporosis as a result of reduced bone formation despite the fact that bone resorption was impaired. We demonstrated using reciprocal bone marrow chimeras, a cell-intrinsic defect of the osteoblast and osteoclast compartments in vivo. Further, Sh3bp2-/- osteoblasts failed to mature and form mineralized nodules in vitro, while Sh3bp2-/- osteoclasts spread poorly and were unable to effectively degrade dentine matrix in vitro. Finally, we showed that 3BP2 was required for Abl activation in osteoblasts and Src activation in osteoclasts, and demonstrated that the in vitro defect of each cell type was restored by the respective expression of activated forms of these kinases. These findings reveal an unanticipated role for the 3BP2 adapter protein in osteoblast function and in coordinating bone homeostatic signals in both osteoclast and osteoblast lineages.


Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status.
Melatonin (MLT) has been proven to counteract chemotherapy toxicity, by acting as an anti-oxidant agent, and to promote apoptosis of cancer cells, so enhancing chemotherapy cytotoxicity. The aim of this study was to evaluate the effects of concomitant MLT administration on toxicity and efficacy of several chemotherapeutic combinations in advanced cancer patients with poor clinical status. The study included 250 metastatic solid tumour patients (lung cancer, 104; breast cancer, 77; gastrointestinal tract neoplasms, 42; head and neck cancers, 27), who were randomized to receive MLT (20 mg/day orally every day) plus chemotherapy, or chemotherapy alone. Chemotherapy consisted of cisplatin (CDDP) plus etoposide or gemcitabine alone for lung cancer, doxorubicin alone, mitoxantrone alone or paclitaxel alone for breast cancer, 5-FU plus folinic acid for gastro-intestinal tumours and 5-FU plus CDDP for head and neck cancers. The 1-year survival rate and the objective tumour regression rate were significantly higher in patients concomitantly treated with MLT than in those who received chemotherapy (CT) alone (tumour response rate: 42/124 CT + MLT versus 19/126 CT only, P < 0.001; 1-year survival: 63/124 CT + MLT versus 29/126 CT only, P < 0.001). Moreover, the concomitant administration of MLT significantly reduced the frequency of thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis and asthenia. This study indicates that the pineal hormone MLT may enhance the efficacy of chemotherapy and reduce its toxicity, at least in advanced cancer patients of poor clinical status.


Interactive collision detection for deformable models using streaming AABBs.
We present an interactive and accurate collision detection algorithm for deformable, polygonal objects based on the streaming computational model. Our algorithm can detect all possible pairwise primitive-level intersections between two severely deforming models at highly interactive rates. In our streaming computational model, we consider a set of axis aligned bounding boxes (AABBs) that bound each of the given deformable objects as an input stream and perform massively-parallel pairwise, overlapping tests onto the incoming streams. As a result, we are able to prevent performance stalls in the streaming pipeline that can be caused by expensive indexing mechanism required by bounding volume hierarchy-based streaming algorithms. At runtime, as the underlying models deform over time, we employ a novel, streaming algorithm to update the geometric changes in the AABB streams. Moreover, in order to get only the computed result (i.e., collision results between AABBs) without reading back the entire output streams, we propose a streaming en/decoding strategy that can be performed in a hierarchical fashion. After determining overlapped AABBs, we perform a primitive-level (e.g., triangle) intersection checking on a serial computational model such as CPUs. We implemented the entire pipeline of our algorithm using off-the-shelf graphics processors (GPUs), such as nVIDIA GeForce 7800 GTX, for streaming computations, and Intel Dual Core 3.4G processors for serial computations. We benchmarked our algorithm with different models of varying complexities, ranging from 15K up to 50K triangles, under various deformation motions, and the timings were obtained as 30 approximately 100 FPS depending on the complexity of models and their relative configurations. Finally, we made comparisons with a well-known GPU-based collision detection algorithm, CULLIDE [4] and observed about three times performance improvement over the earlier approach. We also made comparisons with a SW-based AABB culling algorithm [2] and observed about two times improvement.


The effects of calcium channel blockers on nephropathy and pigment epithelium-derived factor in the treatment of hypertensive patients with type 2 diabetes mellitus.
The aim of this study was to compare the effects of a dihidropiridin calcium channel blocker amlodipin and a non-dihidropiridin calcium channel blocker verapamil on nephropathy and serum pigment epithelium-derived factor (PEDF) levels of type 2 diabetic patients with hypertension. Forty-one type 2 diabetic patients with uncontrolled hypertension in spite of using angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) were enrolled in the study. The patients were randomized in two groups. First group received amlodipin (5-10 mg/d) and second group verapamil (120-240 mg/d) for 6 weeks. The difference between two calcium channel blocker treatments was investigated by analyzing urinary albumin excretion and plasma PEDF levels of patients at the end of 6 weeks. Urinary microalbumin/creatinine values were decreased in both amlodipin and verapamil groups but it was not statistically significant. Plasma PEDF levels also decreased significantly in both groups at the end of the treatment (p < 0.001 and p < 0.001, respectively). At the end of the treatment there was no significant difference between changes in values of systolic BP, diastolic BP, microalbumin/creatinine and PEDF percentage in both groups (p = 0.788, p = 0.926, p = 0.908, p = 0.140, respectively). PEDF values showed a positive correlation with microalbumin/creatinine, hb A1c, FBS, systolic and diastolic BP levels. It was observed that both of the drugs have similar effects on nefhropathy and PEDF at the end of the treatment. In this study, we suggest that calcium channel blockers may have renoprotective effects by different mechanisms except their antihypertensive effects and this may be important to determine the selection of antihypertensive drug combinations in diabetic nephropathy.


Staging and response assessment in lymphomas: the new Lugano classification.
Staging and response criteria were initially developed for Hodgkin lymphoma (HL) over 60 years ago, but not until 1999 were response criteria published for non-HL (NHL). Revisions to these criteria for both NHL and HL were published in 2007 by an international working group, incorporating PET for response assessment, and were widely adopted. After years of experience with these criteria, a workshop including representatives of most major international lymphoma cooperative groups and cancer centers was held at the 11(th) International Conference on Malignant Lymphoma (ICML) in June, 2011 to determine what changes were needed. An Imaging Task Force was created to update the relevance of existing imaging for staging, reassess the role of interim PET-CT, standardize PET-CT reporting, and to evaluate the potential prognostic value of quantitative analyses using PET and CT. A clinical task force was charged with assessing the potential of PET-CT to modify initial staging. A subsequent workshop was help at ICML-12, June 2013. Conclusions included: PET-CT should now be used to stage FDG-avid lymphomas; for others, CT will define stage. Whereas Ann Arbor classification will still be used for disease localization, patients should be treated as limited disease [I (E), II (E)], or extensive disease [III-IV (E)], directed by prognostic and risk factors. Since symptom designation A and B are frequently neither recorded nor accurate, and are not prognostic in most widely used prognostic indices for HL or the various types of NHL, these designations need only be applied to the limited clinical situations where they impact treatment decisions (e.g., stage II HL). PET-CT can replace the bone marrow biopsy (BMBx) for HL. A positive PET of bone or bone marrow is adequate to designate advanced stage in DLBCL. However, BMBx can be considered in DLBCL with no PET evidence of BM involvement, if identification of discordant histology is relevant for patient management, or if the results would alter treatment. BMBx remains recommended for staging of other histologies, primarily if it will impact therapy. PET-CT will be used to assess response in FDG-avid histologies using the 5-point scale, and included in new PET-based response criteria, but CT should be used in non-avid histologies. The definition of PD can be based on a single node, but must consider the potential for flare reactions seen early in treatment with newer targeted agents which can mimic disease progression. Routine surveillance scans are strongly discouraged, and the number of scans should be minimized in practice and in clinical trials, when not a direct study question. Hopefully, these recommendations will improve the conduct of clinical trials and patient management.


The effect of pre-injury physical fitness on the initial severity and recovery from whiplash injury, at six-month follow-up.
To evaluate the effect of pre-injury physical fitness on the initial severity and recovery of motor vehicle-induced neck injury (whiplash injury). A quantitative experimental design using both retrospective and prospective data. Metropolitan Police physiotherapy and rehabilitation department in the UK. One-hundred and two patients with neck pain following whiplash injury. Patients were divided into three groups based on pre-injury physical fitness (low, medium and high). Recovery was compared between the three groups initially then again at three and six months. Three measurement scales were used: the Neck Disability Index, the Problem Percentage, and the Physical Activity Scale. Pre-injury physical fitness had a marked effect on recovery at three and six months, with the medium and high fitness groups having significantly better recovery than the low fitness group. At three months the Neck Disability Index score for the low fitness group was 12 compared with 7 and 7.5 for the medium and high fitness groups respectively (P = 0.009). At six months the Neck Disability Index score was 9 for the low fitness group compared with 0 and 3 for the medium and high fitness groups (P = 0.002). In addition, the return to work rate was almost twice as high for individuals with medium/high fitness. Early recovery from whiplash injury was significantly more likely for individuals with medium to high levels of pre-injury physical fitness than for individuals with low levels of pre-injury physical fitness.


Determinants of anti-predator tactics in hatchling grass snakes (Natrix natrix).
Many organisms exhibit diverse anti-predator tactics, influenced by genetics and prior experience. In ectothermic taxa, offspring phenotypes are often sensitive to developmental temperatures. If the effectiveness of alternative anti-predator responses depends on thermally sensitive traits, then the temperatures experienced during embryonic life should also affect how offspring respond to an approaching predator. We incubated 16 clutches of Swedish grass snakes (Natrix natrix) at a range of developmental temperatures, and scored body size, colour pattern, locomotor performance and anti-predator responses of 213 hatchlings from those clutches. A hatchling snake's size and locomotor abilities were affected by its clutch of origin, its developmental temperature, and by an interaction between these two factors. Anti-predator tactics were strongly linked to locomotor ability, such that slower snakes tended to rely upon aggressive displays rather than flight. Incubation temperatures that generated slow (and thus aggressive) snakes also modified the colour of the snake's nuchal spot. Temperatures in the low to medium range generated mostly cream, white and orange spots, whereas medium to high temperatures generated more yellow spots. Incubation effects, and gene X environment interactions, thus may generate complex correlations between morphology, locomotor ability, and anti-predator tactics.