Lipid alterations in renal membrane of stoke-prone spontaneously hypertensive rats.
Phospholipase A2 activity, phospholipids, and phospholipid fatty acids were investigated in renal membrane of male stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto rats. Renal phospholipase A2 activity increased and membranous phospholipids especially phosphatidylcholine and phosphatidylethanolamine, decreased with age in SHRSP. Arachidonate in phospholipid also decreased with age in SHRSP. To determine the effect of pressure load on the lipid alterations in renal membrane, SHRSP that received antihypertensive treatment with hydralazine, enalapril, or nicardipine for 5 weeks were compared with those without treatment. Antihypertensive treatments prevented phospholipid degradation and increased arachidonate in phospholipid relative to the control group. Phospholipase A2 activity in each group treated with antihypertensive drugs did not differ from that in the control group. These results suggest that the course of hypertension causes renal membranous phospholipid degradation and increases phospholipase A2 activity. Antihypertensive treatments may prevent these lipid alterations in SHRSP. These renal membranous structural changes may provide an explanation not only for functional abnormalities such as decreased membrane fluidity but also for the progress of hypertension.


Hypoglycemic mechanism of a novel proteoglycan, extracted from Ganoderma lucidum, in hepatocytes.
Protein tyrosine phosphatase 1 B (PTP1B) is one of main causes involved in type 2 diabetes, it dephosphorylates insulin receptor substrate (IRS) and dysregulates insulin signaling pathway, thus inducing insulin resistance. Our previous work first reported that FYGL, a neutral hyperbranched proteoglycan ingredient extracted from Ganoderma lucidum, has hypoglycemic activity in vivo and inhibitory potency on PTP1B in vitro, but the underlying mechanism was still unclear. In this study, we sought to investigate effects of FYGL on insulin signaling pathway involved with PTP1B as the targeting point in hepatocytes. We found that FYGL inhibited overexpression of PTP1B in liver tissues of ob/ob mice and HepG2 cells, significantly improved the phosphorylation of IRS1 on tyrosine residues, activated phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) cascades and increased phosphorylation of glycogen synthesis kinase-3β (GSK3β), finally enhanced insulin-stimulated glycogen synthesis in HepG2 cells and decreased blood glucose in insulin resistance model mice. Our study clearly illustrated the hypoglycemic mechanism of a novel proteoglycan possibly used in type 2 diabetes management in vivo.


Uranium reoxidation in previously bioreduced sediment by dissolved oxygen and nitrate.
Flow-through sediment column experiments examined the reoxidation of microbially reduced uranium with either oxygen or nitrate supplied as the oxidant. The uranium was reduced and immobilized via long-term (70 days) acetate biostimulation resulting in 62-92% removal efficiency of the 20 microM influent uranium concentration. Uranium reduction occurred simultaneously with iron reduction as the dominant electron accepting process. The columns were reoxidized by discontinuing the supply of acetate and either replacing the anaerobic gas used to purge the influent media with a gas mixture containing 20% oxygen (resulting in a dissolved oxygen concentration of 0.27 mM) or adding 1.6 mM nitrate to the influent media. Both oxygen and nitrate resolubilized the majority (88 and 97%, respectively) of the uranium precipitated during bioreduction within 54 days. Although oxygen is more thermodynamically favorable an oxidant than nitrate, nitrate-dependent uranium oxidation occurred significantly faster than oxygen-dependent uranium oxidation at the beginning of our experiment due, in part, to oxygen reacting more strongly with other reduced compounds. Nitrate breakthrough at the effluent of the column occurred within 12 h, which was significantly earlier than when oxygen was detected at the effluent (26 days). Although, over time, the majority of uranium was reoxidized by either oxidant, these results indicate that the type of oxidant and its reactivity with other reduced compounds will influence the fate of reduced uranium during a short-term oxidation event that may occur during a uranium bioremediation scenario.


A Swiss Longitudinal Study of the Prevalence of, and Overlap Between, Sexual Problems in Men and Women Aged 20 to 50 Years Old.
The aim of this study was to obtain data on the development and course of sexual problems and their interrelationships by investigating a representative sample of men and women over a period of 30 years. A representative sample of 299 women selected from the complete electoral register and 292 men selected from screening lists for military service in Zurich, Switzerland, answered questions about their sexuality as part of a series of seven interviews between ages 20 (1979) and 50 (2008). Of the initial sample of 591 participants, 43% (57% of them male) were lost to follow-up. Interviews were conducted using the Structured Psychopathological Interview and Rating of the Social Consequences of Psychological Disturbances for Epidemiology (SPIKE), a semistructured interview. Sexual problems were identified on the basis of the study participants' self-appraisal. One-year prevalence rates, lifetime risks, and overlap of functional, emotional, and sexual desire problems in men and women were evaluated. The findings confirmed higher lifetime risks in women than in men for any sexual problem (females 67.0%; males 46.0%) and for functional (39.3%; 22.1%), emotional (35.7%; 15.9%), and sexual desire problems (51.6%; 33.3%). While in general men's sexual problems increased with age, no such association was observed in women. The overlap of all three problems (functional, emotional, and sexual desire) was reported by 16.9% of women but only 5.0% of men. Although there are commonalities, the type but also the development and, in particular, the overlap of sexual problems in women and men are markedly different.


Canadian Public Health Laboratory Network laboratory guidelines for the use of serological tests (excluding point-of-care tests) for the diagnosis of syphilis in Canada.
Syphilis, caused by the bacterium Treponema pallidum subsp. pallidum, is an infection recognized since antiquity. It was first reported at the end of the 15th century in Europe. Infections may be sexually transmitted as well as spread from an infected mother to her fetus or through blood transfusions. The laboratory diagnosis of syphilis infection is complex. Because this organism cannot be cultured, serology is used as the principal diagnostic method. Some of the issues related to serological diagnoses are that antibodies take time to appear after infection, and serology screening tests require several secondary confirmatory tests that can produce complex results needing interpretation by experts in the field. Traditionally, syphilis screening was performed using either rapid plasma reagin or Venereal Disease Research Laboratory tests, and confirmed by treponemal tests such as MHA-TP, TPPA or FTA-Abs. Currently, that trend is reversed, ie, most of the laboratories in Canada now screen for syphilis using treponemal enzyme immunoassays and confirm the status of infection using rapid plasma reagin or Venereal Disease Research Laboratory tests; this approach is often referred to as the reverse algorithm. This chapter reviews guidelines for specimen types and sample collection, treponemal and non-treponemal tests utilized in Canada, the current status of serological tests for syphilis in Canada, the complexity of serological diagnosis of syphilis infection and serological testing algorithms. Both traditional and reverse sequence algorithms are recommended and the algorithm used should be based on a combination of local disease epidemiology, test volumes, performance of the proposed assays and available resources.


Marital status: association with social and economic circumstances, psychological state and outcomes of pregnancy.
We examined the association of marital status with economic, social and psychological factors and with the outcomes of pregnancy (defined as onset of labour, type of delivery, live and still births and birthweight). The study population was 1431 white women consecutively booking for antenatal care. Birth registrations were inspected. Of 278 women who were unmarried during pregnancy, 61 per cent were cohabiting, 26 per cent were living with adults other than the father and 13 per cent were living alone. Compared with the married women, unmarried women overall were, on average, younger, less educated, of lower social class, in poorer economic circumstances, more dependent on state support and less satisfied with their living arrangements. Irrespective of age and social class, they were less likely to have planned the pregnancy, more likely to smoke and drink, to book later for antenatal care and to miss more appointments. In general, unmarried women were more likely to have some indication of depression and to experience more serious life events during the pregnancy. Controlling for age and social class, the categories 'married', 'cohabiting' and 'on their own' showed significant trends from best to worst. Those living with adults other than the father showed intermediate results. There were no significant effects of marital status, controlled for age and social class, and associated social, economic and psychological circumstances on outcomes of pregnancy. Forty-one per cent of births to women on their own, 35 per cent to women living with other adults and 11 per cent to women cohabiting during pregnancy were registered by only one parent.(ABSTRACT TRUNCATED AT 250 WORDS)


A 10 mK scanning tunneling microscope operating in ultra high vacuum and high magnetic fields.
We present design and performance of a scanning tunneling microscope (STM) that operates at temperatures down to 10 mK providing ultimate energy resolution on the atomic scale. The STM is attached to a dilution refrigerator with direct access to an ultra high vacuum chamber allowing in situ sample preparation. High magnetic fields of up to 14 T perpendicular and up to 0.5 T parallel to the sample surface can be applied. Temperature sensors mounted directly at the tip and sample position verified the base temperature within a small error margin. Using a superconducting Al tip and a metallic Cu(111) sample, we determined an effective temperature of 38 ± 1 mK from the thermal broadening observed in the tunneling spectra. This results in an upper limit for the energy resolution of ΔE = 3.5 kBT = 11.4 ± 0.3 μeV. The stability between tip and sample is 4 pm at a temperature of 15 mK as demonstrated by topography measurements on a Cu(111) surface.


Evidence that halogenated furanones from Delisea pulchra inhibit acylated homoserine lactone (AHL)-mediated gene expression by displacing the AHL signal from its receptor protein.
Acylated homoserine lactone (AHL)-mediated gene expression controls phenotypes involved in colonization, often specifically of higher organisms, in both marine and terrestrial environments. The marine red alga Delisea pulchra produces halogenated furanones which resemble AHLs structurally and show inhibitory activity at ecologically realistic concentrations in AHL bioassays. Evidence is presented that halogenated furanones displace tritiated OHHL [N-3-(oxohexanoyl)-L-homoserine lactone] from Escherichia coli cells overproducing LuxR with potencies corresponding to their respective inhibitory activities in an AHL-regulated bioluminescence assay, indicating that this is the mechanism by which furanones inhibit AHL-dependent phenotypes. Alternative mechanisms for this phenomenon are also addressed. General metabolic disruption was assessed with two-dimensional PAGE, revealing limited non-AHL-related effects. A direct chemical interaction between the algal compounds and AHLs, as monitored by 1H NMR spectroscopy, was shown not to occur in vitro. These results support the contention that furanones, at the concentrations produced by the alga, can control bacterial colonization of surfaces by specifically interfering with AHL-mediated gene expression at the level of the LuxR protein.


Rapid proton-detected NMR assignment for proteins with fast magic angle spinning.
Using a set of six (1)H-detected triple-resonance NMR experiments, we establish a method for sequence-specific backbone resonance assignment of magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectra of 5-30 kDa proteins. The approach relies on perdeuteration, amide (2)H/(1)H exchange, high magnetic fields, and high-spinning frequencies (ωr/2π ≥ 60 kHz) and yields high-quality NMR data, enabling the use of automated analysis. The method is validated with five examples of proteins in different condensed states, including two microcrystalline proteins, a sedimented virus capsid, and two membrane-embedded systems. In comparison to contemporary (13)C/(15)N-based methods, this approach facilitates and accelerates the MAS NMR assignment process, shortening the spectral acquisition times and enabling the use of unsupervised state-of-the-art computational data analysis protocols originally developed for solution NMR.


Marital status and head and neck cancer outcomes.
The objective of this study was to examine the effects of marital status on stage at presentation, receipt of treatment, and survival in patients with head and neck cancer (HNC). The Surveillance, Epidemiology, and End Results database was used to analyze 51,272 patients who were diagnosed with HNC from 2007 to 2010. The impact of marital status on cancer stage at presentation, receipt of definitive treatment, and HNC-specific mortality (HNCSM) was determined using multivariable logistic and Fine and Gray competing-risks regression models, as appropriate. Marriage had a protective effect against metastatic presentation of oral and laryngeal cancers (oral cancer: adjusted odds ratio [AOR], 0.72; 95% confidence interval [CI], 0.60-0.87; P < .001; laryngeal cancer: AOR, 0.53; 95% CI, 0.42-0.67; P < .001) but not against oropharyngeal, hypopharyngeal, or nasopharyngeal cancers. Among patients with nonmetastatic disease, married patients were more likely to receive definitive treatment (overall AOR, 1.77; 95% CI, 1.60-1.95; P < .001) and had a lower risk of HNCSM (overall adjusted hazard ratio, 0.72; 95% CI, 0.68-0.77; P < .001); these associations remained significant across all HNC sites. Among patients with oral and laryngeal cancers, those who are married are less likely to present with metastatic disease. In addition, married patients are more likely to receive definitive treatment and less likely to die from HNC across all HNC sites. This suggests that spousal support may have a role in the surveillance of visual and symptomatic HNC types and leads to higher rates of treatment and better survival across all HNC sites.


The specificity of naturally occurring heterophile antibodies in normal rabbit serum.
Rabbit sera used as a complement source contain cytotoxic antibodies which reacted with cultured human cells. This cytotoxic activity can be inhibited by human IgM. The capacity of IgM mu and L chains, and IgM glycopeptides to inhibit these heterospecific antibodies was determined. The inhibitory activity of several monosaccharides, bacterial polysaccharides and blood group substances was also determined. At least some of the heterospecific antibodies in normal rabbit sera are directed against carbohydrate determinants. Mannose, fucose, and bacterial polysaccharides containing mannose as the immunodominant sugar are particularly effective in inhibiting cytotoxic antibodies.


Carbon Nanostructures in Bone Tissue Engineering.
Recent advances in developing biocompatible materials for treating bone loss or defects have dramatically changed clinicians' reconstructive armory. Current clinically available reconstructive options have certain advantages, but also several drawbacks that prevent them from gaining universal acceptance. A wide range of synthetic and natural biomaterials is being used to develop tissue-engineered bone. Many of these materials are currently in the clinical trial stage. A selective literature review was performed for carbon nanostructure composites in bone tissue engineering. Incorporation of carbon nanostructures significantly improves the mechanical properties of various biomaterials to mimic that of natural bone. Recently, carbon-modified biomaterials for bone tissue engineering have been extensively investigated to potentially revolutionize biomaterials for bone regeneration. This review summarizes the chemical and biophysical properties of carbon nanostructures and discusses their functionality in bone tissue regeneration.


Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus.
To review the dose limits and standardize the three-dimenional (3D) radiographic definition for the organs at risk (OARs) for thoracic radiotherapy (RT), including the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. The present study was performed by representatives from the Radiation Therapy Oncology Group, European Organization for Research and Treatment of Cancer, and Soutwestern Oncology Group lung cancer committees. The dosimetric constraints of major multicenter trials of 3D-conformal RT and stereotactic body RT were reviewed and the challenges of 3D delineation of these OARs described. Using knowledge of the human anatomy and 3D radiographic correlation, draft atlases were generated by a radiation oncologist, medical physicist, dosimetrist, and radiologist from the United States and reviewed by a radiation oncologist and medical physicist from Europe. The atlases were then critically reviewed, discussed, and edited by another 10 radiation oncologists. Three-dimensional descriptions of the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus are presented. Two computed tomography atlases were developed: one for the middle and lower thoracic OARs (except for the heart) and one focusing on the brachial plexus for a patient positioned supine with their arms up for thoracic RT. The dosimetric limits of the key OARs are discussed. We believe these atlases will allow us to define OARs with less variation and generate dosimetric data in a more consistent manner. This could help us study the effect of radiation on these OARs and guide high-quality clinical trials and individualized practice in 3D-conformal RT and stereotactic body RT.


Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN).
Cardiovascular disease (CVD) risk is increased in type 2 diabetes. The purpose of this study was to assess the effect of 10 mg of atorvastatin versus placebo on CVD prevention in subjects with type 2 diabetes and LDL cholesterol levels below contemporary guideline targets. Subjects were randomly assigned to receive 10 mg of atorvastatin or placebo in a 4-year, double-blind, parallel-group study. The composite primary end point comprised cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization. A total of 2,410 subjects with type 2 diabetes were randomized. Mean LDL cholesterol reduction in the atorvastatin group over 4 years was 29% versus placebo (P < 0.0001). When we compared atorvastatin versus placebo, composite primary end point rates were 13.7 and 15.0%, respectively (hazard ratio 0.90 [95% CI 0.73-1.12]). In the subset of 1,905 subjects without prior myocardial infarction or interventional procedure, 10.4% of atorvastatin- and 10.8% of placebo-treated subjects experienced a primary end point (0.97 [0.74-1.28]). In the 505 subjects with prior myocardial infarction or interventional procedure, 26.2% of atorvastatin- and 30.8% of placebo-treated subjects experienced a primary end point (0.82 [0.59-1.15]). Relative risk reductions in fatal and nonfatal myocardial infarction were 27% overall (P = 0.10) and 19% (P = 0.41) and 36% (P = 0.11) for subjects without and with prior myocardial infarction or interventional procedure, respectively. Composite end point reductions were not statistically significant. This result may relate to the overall study design, the types of subjects recruited, the nature of the primary end point, and the protocol changes required because of changing treatment guidelines. For these reasons, the results of the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) did not confirm the benefit of therapy but do not detract from the imperative that the majority of diabetic patients are at risk of coronary heart disease and deserve LDL cholesterol lowering to the currently recommended targets.


Investigation of protein functions through data-mining on integrated human transcriptome database, H-Invitational database (H-InvDB).
H-Invitational Database (H-InvDB; ) is a human transcriptome database, containing integrative annotation of 41,118 full-length cDNA clones originated from 21,037 loci. H-InvDB is a product of the H-Invitational project, an international collaboration to systematically and functionally validate human genes by analysis of a unique set of high quality full-length cDNA clones using automatic annotation and human curation under unified criteria. Here, 19,574 proteins encoded by these cDNAs were classified into 11,709 function-known and 7865 function-unknown hypothetical proteins by similarity with protein databases and motif prediction (InterProScan). The proportion of "hypothetical proteins" in H-InvDB was as high as 40.4%. In this study, we thus conducted data-mining in H-InvDB with the aim of assigning advanced functional annotations to those hypothetical proteins. First, by data-mining in the H-InvDB version of GTOP, we identified 337 SCOP domains within 7865 H-Inv hypothetical proteins. Second, by data-mining of predicted subcellular localization by SOSUI and TMHMM in H-InvDB, we found 1032 transmembrane proteins within H-Inv hypothetical proteins. These results clearly demonstrate that structural prediction is effective for functional annotation of proteins with unknown functions. All the data in H-InvDB are shown in two main views, the cDNA view and the Locus view, and five auxiliary databases with web-based viewers; DiseaseInfo Viewer, H-ANGEL, Clustering Viewer, G-integra and TOPO Viewer; the data also are provided as flat files and XML files. The data consists of descriptions of their gene structures, novel alternative splicing isoforms, functional RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein 3D structure, mapping of SNPs and microsatellite repeat motifs in relation with orphan diseases, gene expression profiling, and comparisons with mouse full-length cDNAs in the context of molecular evolution. This unique integrative platform for conducting in silico data-mining represents a substantial contribution to resources required for the exploration of human biology and pathology.


Role of resistin in diet-induced hepatic insulin resistance.
Resistin is an adipose-derived hormone postulated to link adiposity to insulin resistance. To determine whether resistin plays a causative role in the development of diet-induced insulin resistance, we lowered circulating resistin levels in mice by use of a specific antisense oligodeoxynucleotide (ASO) directed against resistin mRNA and assessed in vivo insulin action by the insulin-clamp technique. After 3 weeks on a high-fat (HF) diet, mice displayed severe insulin resistance associated with an approximately 80% increase in plasma resistin levels. In particular, the rate of endogenous glucose production (GP) increased more than twofold compared with that in mice fed a standard chow. Treatment with the resistin ASO for 1 week normalized the plasma resistin levels and completely reversed the hepatic insulin resistance. Importantly, in this group of mice, the acute infusion of purified recombinant mouse resistin, designed to acutely elevate the levels of circulating resistin up to those observed in the HF-fed mice, was sufficient to reconstitute hepatic insulin resistance. These results provide strong support for a physiological role of resistin in the development of hepatic insulin resistance in this model.


Specimen-specific computational models of ankle sprains produced in a laboratory setting.
The use of computational modeling to predict injury mechanisms and severity has recently been investigated, but few models report failure level ligament strains. The hypothesis of the study was that models built off neutral ankle experimental studies would generate the highest ligament strain at failure in the anterior deltoid ligament, comprised of the anterior tibiotalar ligament (ATiTL) and tibionavicular ligament (TiNL). For models built off everted ankle experimental studies the highest strain at failure would be developed in the anterior tibiofibular ligament (ATiFL). An additional objective of the study was to show that in these computational models ligament strain would be lower when modeling a partial versus complete ligament rupture experiment. To simulate a prior cadaver study in which six pairs of cadaver ankles underwent external rotation until gross failure, six specimen-specific models were built based on computed tomography (CT) scans from each specimen. The models were initially positioned with 20 deg dorsiflexion and either everted 20 deg or maintained at neutral to simulate the cadaver experiments. Then each model underwent dynamic external rotation up to the maximum angle at failure in the experiments, at which point the peak strains in the ligaments were calculated. Neutral ankle models predicted the average of highest strain in the ATiTL (29.1 ± 5.3%), correlating with the medial ankle sprains in the neutral cadaver experiments. Everted ankle models predicted the average of highest strain in the ATiFL (31.2 ± 4.3%) correlating with the high ankle sprains documented in everted experiments. Strains predicted for ligaments that suffered gross injuries were significantly higher than the strains in ligaments suffering only a partial tear. The correlation between strain and ligament damage demonstrates the potential for modeling to provide important information for the study of injury mechanisms and for aiding in treatment procedure.


Common FTO rs9939609 variant and risk of type 2 diabetes in Palestine.
Genetic and environmental factors play a crucial role in the development of type 2 diabetes mellitus (T2DM) and obesity. This study aimed to investigate the association of the fat-mass and obesity-associated gene (FTO) rs9939609 variant with T2DM and body mass index (BMI) among Palestinian population. A total of 399 subjects were recruited, of whom 281 were type 2 diabetic patients and 118 normoglycemic subjects. All of them were unrelated, aged > 40 years and recruited within the period 2016-2017. The A allele of FTO rs9939609 was identified by PCR-RFLP. Significant association of the minor allele A of FTO rs9939609 and T2DM risk was observed with an allelic odd ratio of 1.92 (95% CI [1.09-3.29], p = 0.02) adjusted for age and gender, this association partly attenuated when adjusted for BMI with OR of 1.84, (95%CI [1.04-3.05], p = 0.03). Stratified data by glycemic status across FTO genotypes showed that A allele was marginally associated with increased BMI among diabetic group (p = 0.057) but not in control group (p = 0.7). Moreover, no significant association was observed between FTO genotypes and covariates of age, gender, T2DM complications or any tested metabolic trait in both diabetic and nondiabetic individuals (p > 0.05). The variant rs9939609 of the FTO gene was associated with T2DM in Palestine. This is the first study conducted on this gene in the Palestinian population and provides valuable information for comparison with other ethnic groups. Further analysis with larger sample size is required to elucidate the role of this variant on the predisposition to increased BMI in Palestinians.


Targeted and non-targeted forensic profiling of black powder substitutes and gunshot residue using gradient ion chromatography - high resolution mass spectrometry (IC-HRMS).
A novel and simplified gradient IC-HRMS approach is presented in this work for forensic profiling of ionic energetic material residues, including low-order explosives and gunshot residue (GSR). This new method incorporated ethanolic eluents to facilitate direct coupling of IC and HRMS without auxiliary post-column infusion pumps that are traditionally used to assist with gas phase transfer. Ethanolic eluents also enabled better integration with an in-service protocol for direct analysis of high-order organic explosives by IC-HRMS, without requiring solvent exchange before injection. Excellent method performance was achieved, enabling both full scan qualitative and quantitative analysis, as required. In particular, linearity for 19 targeted compounds yielded R2 > 0.99 across several orders of magnitude, with trace analysis possible at the low-mid pg level. Reproducibility and mass accuracies were also excellent, with peak area %RSDs <10%, tR %RSDs <0.4% and δm/z < 3 ppm. The method was applied to targeted analysis of latent fingermarks and swabbed hand sweat samples to determine contact with a black-powder substitute containing nitrate, benzoate and perchlorate. When combined with principal component analysis (PCA), the effect of time since handling on recorded signals could be interpreted further in order to support forensic investigations. In a second, non-targeted application, PCA using full scan IC-HRMS data enabled classification of GSR from three different types of ammunition. An additional 20 markers of GSR were tentatively identified in silico, in addition to the 15 anions detected during targeted analysis. This new approach therefore streamlines and adds consistency and flexibility to forensic analysis of ionic energetic material. Furthermore, it also has implications for targeted, non-targeted and suspect screening applications in other fields by expanding the separation space to low molecular weight inorganic and organic anions.


Sox8 is a critical regulator of adult Sertoli cell function and male fertility.
Sox8 encodes a high-mobility group transcription factor that is widely expressed during development. Sox8, -9 and -10 form group E of the Sox gene family which has been implicated in several human developmental disorders. In contrast to other SoxE genes, the role of Sox8 is unclear and Sox8 mouse mutants reportedly showed only idiopathic weight loss and reduced bone density. The careful analysis of our Sox8 null mice, however, revealed a progressive male infertility phenotype. Sox8 null males only sporadically produced litters of reduced size at young ages. We have shown that SOX8 protein is a product of adult Sertoli cells and its elimination results in an age-dependent deregulation of spermatogenesis, characterized by sloughing of spermatocytes and round spermatids, spermiation failure and a progressive disorganization of the spermatogenic cycle, which resulted in the inappropriate placement and juxtaposition of germ cell types within the epithelium. Those sperm that did enter the epididymides displayed abnormal motility. These data show that SOX8 is a critical regulator of adult Sertoli cell function and is required for both its cytoarchitectural and paracrine interactions with germ cells.


Chromosome Evolution in the Free-Living Flatworms: First Evidence of Intrachromosomal Rearrangements in Karyotype Evolution of Macrostomum lignano (Platyhelminthes, Macrostomida).
The free-living flatworm Macrostomum lignano is a hidden tetraploid. Its genome was formed by a recent whole genome duplication followed by chromosome fusions. Its karyotype (2n = 8) consists of a pair of large chromosomes (MLI1), which contain regions of all other chromosomes, and three pairs of small metacentric chromosomes. Comparison of MLI1 with metacentrics was performed by painting with microdissected DNA probes and fluorescent in situ hybridization of unique DNA fragments. Regions of MLI1 homologous to small metacentrics appeared to be contiguous. Besides the loss of DNA repeat clusters (pericentromeric and telomeric repeats and the 5S rDNA cluster) from MLI1, the difference between small metacentrics MLI2 and MLI4 and regions homologous to them in MLI1 were revealed. Abnormal karyotypes found in the inbred DV1/10 subline were analyzed, and structurally rearranged chromosomes were described with the painting technique, suggesting the mechanism of their origin. The revealed chromosomal rearrangements generate additional diversity, opening the way toward massive loss of duplicated genes from a duplicated genome. Our findings suggest that the karyotype of M. lignano is in the early stage of genome diploidization after whole genome duplication, and further studies on M. lignano and closely related species can address many questions about karyotype evolution in animals.


Temporal dynamics of real-world emotion are more strongly linked to prediction error than outcome.
Primarily based on laboratory studies, theories of affect propose that emotions are driven by the valence of outcomes as well as the difference between the outcome itself and the expected outcome (i.e., the prediction error [PE]). Yet no work has assessed the drivers of emotion using real-world, personally meaningful events on timescales over which human emotion unfolds. We developed an event-triggered, ecological momentary assessment procedure measuring positive and negative affect (PA and NA, respectively) in university students as they received exam grades for which they had made predictions. We split data into exploratory and confirmatory samples, and built computational models predicting the time course of PA and NA and demonstrate that a model incorporating both exam grade and grade PE accounted for the time course of PA and NA better than a model solely using exam grades. Further, grade PEs were stronger predictors of the time course of PA and NA than the grades themselves. Similarly, the effects of PEs also persisted longer for NA than PA. These data indicate that deviations from expectations are critical determinants of the temporal dynamics of real-world emotion. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Complete chloroplast genome sequence of MD-2 pineapple and its comparative analysis among nine other plants from the subclass Commelinidae.
Pineapple (Ananas comosus var. comosus) is known as the king of fruits for its crown and is the third most important tropical fruit after banana and citrus. The plant, which is indigenous to South America, is the most important species in the Bromeliaceae family and is largely traded for fresh fruit consumption. Here, we report the complete chloroplast sequence of the MD-2 pineapple that was sequenced using the PacBio sequencing technology. In this study, the high error rate of PacBio long sequence reads of A. comosus's total genomic DNA were improved by leveraging on the high accuracy but short Illumina reads for error-correction via the latest error correction module from Novocraft. Error corrected long PacBio reads were assembled by using a single tool to produce a contig representing the pineapple chloroplast genome. The genome of 159,636 bp in length is featured with the conserved quadripartite structure of chloroplast containing a large single copy region (LSC) with a size of 87,482 bp, a small single copy region (SSC) with a size of 18,622 bp and two inverted repeat regions (IRA and IRB) each with the size of 26,766 bp. Overall, the genome contained 117 unique coding regions and 30 were repeated in the IR region with its genes contents, structure and arrangement similar to its sister taxon, Typha latifolia. A total of 35 repeats structure were detected in both the coding and non-coding regions with a majority being tandem repeats. In addition, 205 SSRs were detected in the genome with six protein-coding genes contained more than two SSRs. Comparative chloroplast genomes from the subclass Commelinidae revealed a conservative protein coding gene albeit located in a highly divergence region. Analysis of selection pressure on protein-coding genes using Ka/Ks ratio showed significant positive selection exerted on the rps7 gene of the pineapple chloroplast with P less than 0.05. Phylogenetic analysis confirmed the recent taxonomical relation among the member of commelinids which support the monophyly relationship between Arecales and Dasypogonaceae and between Zingiberales to the Poales, which includes the A. comosus. The complete sequence of the chloroplast of pineapple provides insights to the divergence of genic chloroplast sequences from the members of the subclass Commelinidae. The complete pineapple chloroplast will serve as a reference for in-depth taxonomical studies in the Bromeliaceae family when more species under the family are sequenced in the future. The genetic sequence information will also make feasible other molecular applications of the pineapple chloroplast for plant genetic improvement.


Age-related changes in the visual pathways: blame it on the axon.
The aging visual system is marked by a decline in some, but not all, key functions. Some of this decline is attributed to changes in the optics of the eye, but other aspects must have a neural basis. Across mammals, with aging there is remarkable persistence of central structures to which retinal ganglion cell (RGC) axons project with little or no loss of neurons. Similarly, RGC bodies in the retina are subject to variable age-related loss, with most mammals showing none over time. In contrast, the RGC axon itself is highly vulnerable. Across species, the rate of axon loss in the optic nerve is related inversely to the total number of axons at maturity and lifespan. The result of this scaling is approximately a 40% total decline in axon number. Evidence suggests that the consistent vulnerability of RGC axons to aging arises from their high metabolic demand combined with diminishing resources. Thus, therapeutic interventions that conserve bioenergetics may have potential to abate age-related decline in visual function.


Transcriptomic changes during TGF-β-mediated differentiation of airway fibroblasts to myofibroblasts.
Asthma is the most common chronic lung disease in children and young adults worldwide. Airway remodelling (including increased fibroblasts and myofibroblasts in airway walls due to chronic inflammation) differentiates asthmatic from non-asthmatic airways. The increase in airway fibroblasts and myofibroblasts occurs via epithelial to mesenchymal transition (EMT) where epithelial cells lose their tight junctions and are transdifferentiated to mesenchymal cells, with further increases in myofibroblasts occurring via fibroblast-myofibroblast transition (FMT). Transforming growth factor (TGF)-β is the central EMT- and FMT-inducing cytokine. In this study, we have used next generation sequencing to delineate the changes in the transcriptome induced by TGF-β treatment of WI-38 airway fibroblasts in both the short term and after differentiation into myofibroblasts, to gain an understanding of the contribution of TGF-β induced transdifferentiation to the asthmatic phenotype. The data obtained from RNAseq analysis was confirmed by quantitative PCR (qPCR) and protein expression investigated by western blotting. As expected, we found that genes coding for intermediates in the TGF-β signalling pathways (SMADs) were differentially expressed after TGF-β treatment, SMAD2 being upregulated and SMAD3 being downregulated as expected. Further, genes involved in cytoskeletal pathways (FN1, LAMA, ITGB1) were upregulated in myofibroblasts compared to fibroblasts. Importantly, genes that were previously shown to be changed in asthmatic lungs (ADAMTS1, DSP, TIMPs, MMPs) were similarly differentially expressed in myofibroblasts, strongly suggesting that TGF-β mediated differentiation of fibroblasts to myofibroblasts may underlie important changes in the asthmatic airway. We also identified new intermediates of signalling pathways (PKB, PTEN) that are changed in myofibroblasts compared to fibroblasts. We have found a significant number of genes that are altered after TGF-β induced transdifferentiation of WI-38 fibroblasts into myofibroblasts, many of which were expected or predicted. We also identified novel genes and pathways that were affected after TGF-β treatment, suggesting additional pathways are activated during the transition between fibroblasts and myofibroblasts and may contribute to the asthma phenotype.


Transcriptome signature in young children with acute otitis media due to Streptococcus pneumoniae.
Streptococcus pneumoniae (Spn) is the predominant causative organism of acute otitis media in children. To better understand the genes that are regulated at the onset of AOM caused by Spn infection in the middle ear, the transcriptome profile of peripheral blood mononuclear cells isolated from children prior to and during an AOM event was evaluated by microarray. We found that 1903 (6.2%) of 29,187 genes were differentially regulated greater than 2-fold at the onset of AOM compared to the pre-infection stage of the same children. The ontology of differentially regulated genes was dominated by those involved with the immune response. At onset of infection, genes associated with bacterial defenses were significantly up-regulated, including beta-defensin123, S100 protein A12, Toll-like receptor 5, IL-10, and those involved in the classical and alternative complement pathways. Genes associated with inhibition of bacterial entry through clathrin-dependent endocytosis were also up-regulated. In contrast, genes associated with cell-mediated immune responses were broadly down-regulated. The results provide the first human transcriptome data identifying genes differentially regulated at the onset of AOM in children.


A participatory assessment of dietary patterns and food behavior in Pohnpei, Federated States of Micronesia.
Non-communicable diseases are escalating rapidly within the Pacific region, including Pohnpei, Federated States of Micronesia. A shift in dietary patterns from indigenous, high fiber, healthy local food to energy-dense, imported food with low nutritional value, and increased sedentary lifestyles are expediting this process. Essential to counteract this trend is an understanding of how people make food decisions. This participatory assessment utilized a quantitative and qualitative approach to capture diet patterns and knowledge, attitudes, beliefs and practices of food consumption. A structured 7-day food frequency questionnaire (FFQ) was used to quantify the diets of 293 adult Pohnpeian women attending an island-wide education/disability screening program. An ethnographic approach, including in-depth interviews, informal focus groups and observations documented food behavior practices and contributed to the design of the FFQ. Of those responding to the FFQ, 96% reported eating rice frequently (3-7 days/week) whereas 75% reported eating locally grown carbohydrate foods frequently. Factors associated with culture change, including availability, affordability, convenience, and status of food items were found to determine food decisions. Food-based, culturally sensitive and innovative strategies that utilize existing resources are required to promote local food production and consumption. Prevention programs with an information, education and communication (IEC) approach are needed to provide accurate and available health and nutrition knowledge and to increase the demand for local foods. Behavior modification requires the continued collaboration of the national, state, and community organizations that partnered on this research to strategize programs in order to target individual food choices and to transform the environment to support these decisions.


Quantum features in the orthogonality of optical modes for structured and plane-wave light.
A fundamental photon creation-annihilation commutation relation underpins the familiar quantum formulation of optics. However, an internal inconsistency becomes apparent in the pursuit of structured light applications. This requires the relationship between operator commutation and mode orthogonality to be recast in a form ensuring full consistency with the precepts of quantum theory. A suitable reformulation, shown to register correctly an intrinsic quantum uncertainty in the associated interactions, has special relevance to optical vortex physics-particularly with regard to information content-through its connection to the degrees of freedom in the associated radiation modes.


An ionic coordination hybrid hydrogel for bioseparation.
An ionic coordination hybrid hydrogel is formed with ionic and covalent crosslinked networks via one-step copolymation. It is demonstrated that the hybrid crosslinker gel is used as a separation matrix for bioseparation, showing high separation efficiency, in contrast to traditional polyacrylamide gels. The hydrogel might serve as a novel matrix for bioseparation.


TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation.
The bile acid-responsive G protein-coupled receptor TGR5 is involved in several metabolic processes, and recent studies suggest that TGR5 activation may promote pathways that are protective against diet-induced diabetes. Here, we investigated the role of macrophage-specific TGR5 signaling in protecting adipose tissue from inflammation and associated insulin resistance. Examination of adipose tissue from obese mice lacking macrophage Tgr5 revealed enhanced inflammation, increased chemokine expression, and higher macrophage numbers compared with control obese animals. Moreover, macrophage-specific deletion of Tgr5 exacerbated insulin resistance in obese animals. Conversely, pharmacological activation of TGR5 markedly decreased LPS-induced chemokine expression in primary macrophages. This reduction was mediated by AKT-dependent activation of mTOR complex 1, which in turn induced the differential translation of the dominant-negative C/EBPβ isoform, liver inhibitory protein (LIP). Overall, these studies reveal a signaling pathway downstream of TGR5 that modulates chemokine expression in response to high-fat diet and suggest that targeting this pathway has the potential to be therapeutically exploited for prevention of chronic inflammatory diseases and type 2 diabetes mellitus.


Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family.
Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 45 genes. Recently, the FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. We performed a clinical and molecular genetic study of a consanguineous Palestinian family with two three siblings affected with retinitis pigmentosa. DNA samples were collected from the index patient, his father, his affected sister, and two non-affected brothers. DNA sample from the index was subjected to high resolution genome-wide SNP array. Assuming identity-by-descent in this consanguineous family we applied homozygosity mapping to identify disease causing genes. The index patient reported night blindness since the age of 20 years, followed by moderate disease progression with decrease of peripheral vision, the development of photophobia and later on reduced central vision. At the age of 40 his visual acuity was counting fingers (CF) for both eyes, color discrimination was not possible and his visual fields were severely constricted. Funduscopic examination revealed a typical appearance of advanced RP with optic disc pallor, narrowed retinal vessels, bone-spicule like pigmentary changes in the mid-periphery and atrophic changes in the macula. His younger affected brother (37 years) was reported with overall milder symptoms, while the youngest sister (21 years) reported problems only with night vision. Applying high-density SNP arrays we identified several homozygous genomic regions one of which included the recently identified FAM161A gene mutated in RP28-linked autosomal recessive RP. Sequencing analysis revealed the presence of a novel homozygous nonsense mutation, c.1003C>T/p.R335X in the index patient and the affected sister. We identified an RP28-linked RP family in the Palestinian population caused by a novel nonsense mutation in FAM161A. RP in this family shows a typical disease onset with moderate to rapid progression into severe visual impairment including central vision in the index and overall milder symptoms in the younger brother and sister.


Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer.
Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%-25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62L(lo)CD54(hi)) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses.


Design of the Coordinated Anxiety Learning and Management (CALM) study: innovations in collaborative care for anxiety disorders.
Despite a marked increase in the number of persons seeking help for anxiety disorders, the care provided may not be evidence based, especially when delivered by nonspecialists. Since anxiety disorders are most often treated in primary care, quality improvement interventions, such as the Coordinated Anxiety Learning and Management (CALM) intervention, are needed in primary care. This study is a randomized controlled trial of a collaborative care effectiveness intervention for anxiety disorders. Approximately 1040 adult primary care patients with at least one of four anxiety disorders (generalized anxiety disorder, panic disorder, posttraumatic stress disorder or social anxiety disorder) will be recruited from four national sites. Anxiety clinical specialists (ACSs) deliver education and behavioral activation to intervention patients and monitor their symptoms. Intervention patients choose cognitive-behavioral therapy, antianxiety medications or both in "stepped-care" treatment, which varies according to clinical needs. Control patients receive usual care from their primary care clinician. The innovations of CALM include the following: flexibility to treat any one of the four anxiety disorders, co-occurring depression, alcohol abuse or both; use of on-site clinicians to conduct initial assessments; and computer-assisted psychotherapy delivery. Anxiety symptoms, functioning, satisfaction with care and health care utilization are assessed at 6-month intervals for 18 months. CALM was designed for clinical effectiveness and easy dissemination in a variety of primary care settings.


Differential effects of D1 and D2 dopamine-receptor agonists and antagonists on appetitive and consummatory aspects of male sexual behavior in Japanese quail.
Pharmacological studies in Japanese quail based on behavioral tests with a variety of dopaminergic compounds suggest that the activation of D2 dopamine receptors inhibits, and the activation of D1 dopamine receptors enhances, appetitive and consummatory components of male sexual behavior. This hypothesis was tested by studying the behavioral effects of specific D1 and D2 dopaminergic-receptor agonists and antagonists in castrated male Japanese quail chronically treated with exogenous testosterone (subcutaneous Silastic implants). The effects of 5 compounds were tested: 1 D1 (SKF38393) and 2 D2 (PPHT and quinpirole) agonists, and 1 D1 (SCH23390) and 1 D2 (Spiperone) antagonist. All compounds were tested at a low and a high dose (0.1 and 1 mg/kg, respectively, for all drugs, except spiperone where the doses were 2 and 10 mg/kg). A consistent effect of all drugs on consummatory sexual behavior was observed: it was stimulated by the D1 agonist and the D2 antagonist, but inhibited by the D1 antagonist and the D2 agonists. Far fewer effects of the treatments were detected on the measures of appetitive behavior. Measures of appetitive behavior were decreased by the 2 D2 agonists, but not affected by the other treatments. These data suggest that male copulatory behavior in quail is stimulated by dopamine acting on D1 receptors, but inhibited by activation of the D2 receptor subtype. The partial dissociation observed between the effects of the same treatments on appetitive and consummatory aspects of sexual behavior also suggests that these 2 behavioral systems may be controlled by the action of dopamine on different neuronal systems.


Proximate determinants of telomere length in sand lizards (Lacerta agilis).
Telomeres are repeat sequences of non-coding DNA that cap the ends of chromosomes and contribute to their stability and the genomic integrity of cells. In evolutionary ecology, the main research target regarding these genomic structures has been their role in ageing and as a potential index of age. However, research on humans shows that a number of traits contribute to among-individual differences in telomere length, in particular traits enhancing cell division and genetic erosion, such as levels of free radicals and stress. In lizards, tail loss owing to predation attempts results in a stress-induced shift to a more cryptic lifestyle. In sand lizard (Lacerta agilis) males, telomere length was compromised by tail regrowth in a body size-related manner, so that small males, which already exhibit more cryptic mating tactics, were less affected than larger males. Tail regrowth just fell short of having a significant relationship with telomere length in females, and so did age in males. In females, there was a significant positive relationship between age and telomere length. We conclude that the proximate effect of compromised antipredation and its associated stress seems to have a more pronounced effect in males than in females and that age-associated telomere dynamics differ between the sexes.


Health, happiness and eating together: what can a large Thai cohort study tell us?
Our research investigates the significance of frequent solo consumption of main meals and the association with a holistic wellbeing measure of happiness using data from 39820 Thai Cohort Study members who completed 8-year follow-up in 2013. This nationwide cohort has been under study since 2005 to analyse the dynamics and determinants of the health-risk transition from infectious to chronic diseases. Here we analyse data from the 2009 and 2013 follow-ups. Approximately 11% reported eating more than half of the main meals per week alone. Sociodemographic attributes associated with eating alone were being male, older age, unmarried, smaller household, lower income, and urban residence. Dissatisfaction with amount of spare time (ie 'busyness') was also linked to eating alone. In the multivariate cross-sectional model, reporting being unhappy was associated with frequent solo eating (Adjusted Odds Ratio - AOR 1.54, 95% Confidence Intervals 1.30-1.83). Stratified by age and sex groups, the effects were strongest among females (AOR 1.90 1.52-2.38). A monotonic relationship linked frequent eating alone and 4-year longitudinal unhappiness. The larger the dose of unhappiness the greater the odds of eating alone - AOR 1.29, 1.31, 1.72 after controlling for potential covariates. Having a meal is not only important for nutritional and health outcomes; it is also a vital part of daily social interaction. Our study provided empirical evidence from a non-Western setting that sharing meals could contribute to increasing happiness.


Geographic variations in the cost of treating condition-specific episodes of care among Medicare patients.
To measure geographic variations in treatment costs for specific conditions, explore the consistency of these patterns across conditions, and examine how service mix and population health factors are associated with condition-specific and total area costs. Medicare claims for 1.5 million elderly beneficiaries from 60 community tracking study (CTS) sites who received services from 5,500 CTS Physician Survey respondents during 2004-2006. Episodes of care for 10 costly and common conditions were formed using Episode Treatment Group grouper software. Episode and total annual costs were calculated, adjusted for price, patient demographics, and comorbidities. We correlated episode costs across sites and examined whether episode service mix and patient health were associated with condition-specific and total per-beneficiary costs. Adjusted episode costs varied from 34 to 68 percent between the most and least expensive site quintiles. Area mean costs were only weakly correlated across conditions. Hospitalization rates, surgery rates, and specialist involvement were associated with site episode costs, but local population health indicators were most related to site total per-beneficiary costs. Population health appears to drive local per-beneficiary Medicare costs, whereas local practice patterns likely influence condition-specific episode costs. Reforms should be flexible to address local conditions and practice patterns.


When should surgical cytoreduction in advanced ovarian cancer take place?
Initial surgical management is commonly accepted to date as paramount in the treatment of women presenting with epithelial ovarian cancer and permits the assessment of the disease (staging), the histological confirmation of disease type and grade, and the practice of maximal debulking preceding platinum-based chemotherapy. Many studies have shown that the volume of residual disease after initial surgical cytoreduction inversely correlates with survival. Thus, women with optimal debulking performed by a trained specialist have improved median survival. In this review, we will focus on the answers gleaned from clinical trials on primary and interval surgery, which prompts the question on the timing of surgery in respect to chemotherapy. Interval debulking surgery (IDS) is secondary cytoreduction following primary debulking and is carried out in between the courses of chemotherapy. The major clinical trials and the latest systematic reviews seem unable to give any definitive guidance or recommendation for clinical practice. The choice of aggressive primary cytoreduction or upfront chemotherapy followed by second line surgical cytoreduction seems among others to have to be individualized according to tumour load, prediction of its resectability, and response to chemotherapy. The role of tumour biology must also be kept in mind. Finally, concrete answers are awaited on the timing of surgery from the ongoing prospective randomized control trials (CHORUS and EORTC 55971) though preliminary data from the latter have already been presented at major meetings (IGCS 2008; SGO 2009) and ignited strong debate.


Consumption of extra-virgin olive oil rich in phenolic compounds improves metabolic control in patients with type 2 diabetes mellitus: a possible involvement of reduced levels of circulating visfatin.
Phenolic compounds naturally contained in extra-virgin olive oil (EVOO) have demonstrated anti-inflammatory and antioxidant properties. The present study aimed at evaluating the effects of a polyphenol-rich extra-virgin olive oil (EVOO) (high-polyphenol EVOO, HP-EVOO) on the metabolic control and the production of specific pro-/anti-inflammatory adipokines in overweight patients with type 2 diabetes mellitus (T2D). Eleven overweight T2D patients not in treatment with insulin were invited to follow their habitual diet for a total of 8 weeks. During the first 4 weeks (wash-out period), they were asked to consume refined olive oil (ROO, polyphenols not detectable) and then to replace ROO with HP-EVOO (25 mL/day, 577 mg of phenolic compounds/kg) for the remaining 4 weeks. Anthropometric parameters, fasting glycaemia, glycated haemoglobin (HbA1c), high-sensitive C-reactive protein, plasma lipid profile, liver function and serum levels of TNF-α, IL-6, adiponectin, visfatin and apelin were assessed at the end of each 4-week period. HP-EVOO consumption significantly reduced fasting plasma glucose (P = 0.023) and HbA1c (P = 0.039) levels as well as BMI (P = 0.012) and body weight (P = 0.012). HP-EVOO ingestion determined a reduction in serum level of aspartate aminotransferase (AST, P = 0.0056) and alanine aminotransferase (ALT, P = 0.024). Serum visfatin levels strongly decreased after HP-EVOO ingestion (P = 0.0021). Daily consumption of polyphenol-rich EVOO might improve metabolic control and circulating inflammatory adipokines profile in overweight T2D patients.


The protective effects of thymoquinone on lung damage caused by cigarette smoke.
Chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation that usually is caused by exposure to noxious particles or gases. Thymoquinone (TQ) prevents the production of inflammatory mediators, such as thromboxane B2 and leukotriene, by altering arachidonic acid metabolism. We investigated the preventive and curative effects of TQ on lung damage in rats caused by cigarette smoke (CS). We used 50 adult male rats, 30 of which were exposed to CS every day for 3 months. TQ in dimethylsulfoxide (DMSO) was administered intraperitoneally (i.p.) every day to ten animals to investigate the protective effects of TQ, and to ten other animals during the last 21 days to investigate the curative effect. Ten rats received saline for the last 21 days. Ten subjects were untreated controls. Ten controls that were not exposed to CS received TQ for the last ten days. Serum IL-8, IL-6, IL-1β and MMP-9 levels were measured using ELISA. IL-1β and IL-8 levels were elevated in the group exposed to CS compared to controls. IL-8 levels were decreased in the group that received only TQ compared to controls, which indicated the anti-inflammatory effect of TQ. The apoptotic index (AI) was increased in all groups that were exposed to CS compared to controls. The AI index was decreased in the group that received TQ for the last 21 days compared to the other CS groups. AI was increased in the group that received TQ daily compared to the other CS groups. Our findings indicate that TQ exerts curative effects for the inflammation caused by CS and may prevent apoptosis if administered in appropriate doses; however, long term TQ or DMSO exposure may produce cumulative toxic effects.


Time-of-Day Could Affect Cognitive Screening Performance in Older Patients with TIA and Stroke.
The impact of time-of-day on the cognitive performance of older patients with limited cognitive reserve after a transient ischemic attack (TIA) or stroke, and on short cognitive tests, such as the Montreal Cognitive Assessment (MoCA), is unknown. We retrospectively studied whether morning versus afternoon assessment might affect the classification of patients aged 70 or older as severe (SCI), mild (MCI), and no (NCI) cognitive impairment by the MoCA. Morning (12 p.m. or earlier) versus afternoon (later than 12 p.m.) proportions of SCI (MoCA score <20), MCI (MoCA score 25-20) and NCI (MoCA score ≥26) were compared in a cohort of patients aged ≥70, attending a rapid-access TIA/stroke clinic. Of 278 patients, 113 (40.6%) were tested in the morning and 165 (59.4%) in the afternoon. The proportion with SCI was greater in the afternoon than in the morning (10.9 vs. 1.8%, respectively, p = 0.004), with no difference in age, education, diagnosis, disability, or vascular risk factors. Time-of-day appears to affect cognitive performance of older patients after they undergo TIA and minor stroke. If our cross-sectional findings are confirmed in cross-over studies with repeated testing, timing of assessments should be considered in clinical practice and in research studies.


The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stem cells.
Mitochondrial biogenesis and activation of both oxidative phosphorylation, as well as transcription and replication of the mitochondrial genome, are key regulatory events in cell differentiation. Mitochondrial DNA transcription and replication are highly dependent on the interaction with nuclear-encoded transcription factors translocated from the nucleus. Using a human embryonic stem cell line, HSF 6, we analyzed the proliferation of mitochondria and the expression of mtDNA-specific transcription factors in undifferentiated, migratory embryonic stem cells and spontaneously derived cardiomyocytes. Mitochondrial proliferation and mtDNA transcription are initiated in human embryonic stem cells as they undergo spontaneous differentiation in culture into beating cardiomyocytes. Undifferentiated, pluripotent human embryonic stem cells have few mitochondria, and, as they differentiate, they polarize to one extremity of the cell and then bipolarize the differentiating cell. The differentiated cell then adopts the cytoplasmic configuration of a somatic cell as evidenced in differentiating cardiomyocytes. Transcription and replication of the extranuclear mitochondrial genome is dependent on nuclear encoded factors exported to the mitochondrion. However, the differentiating cardiomyocytes have reduced or absent levels of these transcription and replication factors, namely mitochondrial transcription factors A, B1, B2, and nuclear respiratory factor 1 and polymerase gamma. Therefore, final embryonic stem cell commitment may be influenced by mitochondrial proliferation and mtDNA transcription. However, it is likely that differentiating cardiomyocytes are in mitochondrial arrest, awaiting commitment to a final cell fate.


A series of N-terminal epitope tagged Hdh knock-in alleles expressing normal and mutant huntingtin: their application to understanding the effect of increasing the length of normal Huntingtin's polyglutamine stretch on CAG140 mouse model pathogenesis.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that is caused by the expansion of a polyglutamine (polyQ) stretch within Huntingtin (htt), the protein product of the HD gene. Although studies in vitro have suggested that the mutant htt can act in a potentially dominant negative fashion by sequestering wild-type htt into insoluble protein aggregates, the role of the length of the normal htt polyQ stretch, and the adjacent proline-rich region (PRR) in modulating HD mouse model pathogenesis is currently unknown. We describe the generation and characterization of a series of knock-in HD mouse models that express versions of the mouse HD gene (Hdh) encoding N-terminal hemaglutinin (HA) or 3xFlag epitope tagged full-length htt with different polyQ lengths (HA7Q-, 3xFlag7Q-, 3xFlag20Q-, and 3xFlag140Q-htt) and substitution of the adjacent mouse PRR with the human PRR (3xFlag20Q- and 3xFlag140Q-htt). Using co-immunoprecipitation and immunohistochemistry analyses, we detect no significant interaction between soluble full-length normal 7Q- htt and mutant (140Q) htt, but we do observe N-terminal fragments of epitope-tagged normal htt in mutant htt aggregates. When the sequences encoding normal mouse htt's polyQ stretch and PRR are replaced with non-pathogenic human sequence in mice also expressing 140Q-htt, aggregation foci within the striatum, and the mean size of htt inclusions are increased, along with an increase in striatal lipofuscin and gliosis. In mice, soluble full-length normal and mutant htt are predominantly monomeric. In heterozygous knock-in HD mouse models, substituting the normal mouse polyQ and PRR with normal human sequence can exacerbate some neuropathological phenotypes.


Blood pressure, cholesterol and cardiovascular disease in Thailand.
Although associations between risk factors such as hypertension and hypercholesterolaemia, and cardiovascular disease (CVD) are well-established it is not known to what extent these associations are similar in people from different ethnicities or regions. This study aims to measure the contributions of systolic blood pressure (SBP) and total cholesterol (TC) to ischaemic heart disease (IHD) and stroke in the Thai population. Data from a Thai cohort study were used for analyses. Participants were 2702 males and 797 females aged between 35 and 54 years at the start of study in 1985. Cox Proportional Hazards Models were used to assess RRs of IHD or stroke associated with SBP or TC stratified by age at the time of an event of 30-44, 45-59, and 60-69 years. During the 17 years of follow-up, 96 IHD (40 non-fatal, 56 fatal), 69 strokes (32 non-fatal and 37 fatal) occurred. Each 1 mmol/l increase in TC was associated with a fivefold increase in IHD risk in people aged 30-44 years, but not with significant increase in stroke risk in any age group. The RRs (95% CIs) of IHD per 10 mm Hg increase in SBP were 1.31 (1.04 to 1.64) and 1.46 (1.15 to 1.87), and of stroke, 1.40 (1.10 to 1.79) and 1.85 (1.40 to 2.45) in people aged 45-59 and 60-69 years, respectively. Increases in IHD and stroke risks associated with these two risk factors observed in Thailand are comparable with those in the Asia Pacific and western populations.


Inactivation of cytochrome P-450 by the drug methoxsalen.
Administration of methoxsalen (50 mumol X kg-1 i.p.) increased 4-fold the hexobarbital sleeping time in rats; at this low dose, SKF 525-A, piperonyl butoxide and cimetidine had little or no effect. In vitro, the concentration of methoxsalen inhibiting by 50% monooxygenase activities ranged from 10 microM (for benzo(a)-pyrene and hexobarbital hydroxylases] to 25 microM for 7-ethoxy-coumarin deethylase and aminopyrine demethylase); these values were in the range of those observed with SKF 525-A (1-50 microM) or piperonyl butoxide (10-100 microM) but much lower than those for cimetidine (100-500 microM). Methoxsalen (25-1000 microM) decreased cytochrome P-450 in vitro, in the presence of EDTA; this effect required NADPH and oxygen, was decreased by piperonyl butoxide and was increased by phenobarbital pretreatment. Similarly, administration of methoxsalen (125 mumol X kg-1 i.p.) decreased cytochrome P-450 and monooxygenase activities in vivo; the decrease in cytochrome P-450 was enhanced by phenobarbital pretreatment and was prevented by piperonyl butoxide. There was no evidence for lipid peroxidation, denaturation into cytochrome P-420, formation of cytochrome P-450-metabolite complexes, destruction of heme or formation of green pigments. In contrast, a reactive metabolite of methoxsalen covalently bound to microsomal proteins; covalent binding required NADPH and oxygen, was decreased by piperonyl butoxide and was increased by phenobarbital pretreatment. We conclude that methoxsalen is activated into a metabolite which destroys cytochrome P-450.


Phase 1 study of concurrent sunitinib and image-guided radiotherapy followed by maintenance sunitinib for patients with oligometastases: acute toxicity and preliminary response.
To determine the safety and maximum-tolerated dose of concurrent sunitinib and image-guided radiotherapy (IGRT) followed by maintenance sunitinib in oligometastastic patients. Eligible patients had 1 to 5 sites of metastatic cancer measuring<or=6 cm. The most common treatment sites were bone, liver, and lung. Patients were treated with concurrent sunitinib (Day 1 through Day 28) and IGRT (40-50 Gy in 10 fractions starting on Day 8) followed by maintenance sunitinib (50 mg daily, 4 weeks on/2 weeks off starting on Day 43). The starting dose was sunitinib 25 mg and IGRT 40 Gy. Doses were escalated in a ping-pong design with incremental increases in either sunitinib or IGRT. Twenty-one patients with 36 metastatic lesions were enrolled, with a median follow-up of 10 months. No dose limiting toxicities (DLT) were noted at dose levels 1 or 2 (SU 37.5 mg/RT 40 Gy). One of 10 patients at dose level 3 (SU 37.5 mg/RT 50 Gy) and 2 of 5 patients at dose level 4 (SU 50 mg/RT 50 Gy) experienced DLTs comprising grade 4 myelosuppression and grade 3 nausea. At last follow-up, 8 patients are alive without evidence of progression. The 1-year local, progression-free, and overall survival were 85%, 44%, and 75%, respectively. Addition of SU (25 to 37.5 mg) to IGRT is tolerable in patients with oligometastases, without potentiation of RT toxicity. On the basis of promising antitumor responses observed with this novel combination, a multi-institutional phase 2 trial using SU 37.5 mg/RT 50 Gy is ongoing.


Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder.
Patients with anxiety disorders exhibit excessive neural reactivity in the amygdala, which can be normalized by effective treatment like cognitive behavior therapy (CBT). Mechanisms underlying the brain's adaptation to anxiolytic treatments are likely related both to structural plasticity and functional response alterations, but multimodal neuroimaging studies addressing structure-function interactions are currently missing. Here, we examined treatment-related changes in brain structure (gray matter (GM) volume) and function (blood-oxygen level dependent, BOLD response to self-referential criticism) in 26 participants with social anxiety disorder randomly assigned either to CBT or an attention bias modification control treatment. Also, 26 matched healthy controls were included. Significant time × treatment interactions were found in the amygdala with decreases both in GM volume (family-wise error (FWE) corrected P(FWE) = 0.02) and BOLD responsivity (P(FWE) = 0.01) after successful CBT. Before treatment, amygdala GM volume correlated positively with anticipatory speech anxiety (P(FWE)=0.04), and CBT-induced reduction of amygdala GM volume (pre-post) correlated positively with reduced anticipatory anxiety after treatment (P(FWE) ⩽ 0.05). In addition, we observed greater amygdala neural responsivity to self-referential criticism in socially anxious participants, as compared with controls (P(FWE) = 0.029), before but not after CBT. Further analysis indicated that diminished amygdala GM volume mediated the relationship between decreased neural responsivity and reduced social anxiety after treatment (P=0.007). Thus, our results suggest that improvement-related structural plasticity impacts neural responsiveness within the amygdala, which could be essential for achieving anxiety reduction with CBT.


Globalization of gerontology education: current practices and perceptions for graduate gerontology education in the United States.
The purpose of this study is to document current practices and understandings about globalization of gerontology education in the United States. Better understanding of aging requires international perspectives in global communities. However, little is known about how globalization of gerontology education is practiced in U.S. graduate-level degree programs. The authors conducted qualitative interviews with representatives of the Association for Gerontology in Higher Education, the major national organization supporting higher education in gerontology, graduate program directors, and students. Although all respondents expressed their interest in globalizing gerontology education, actual practices are diverse. The authors discuss suggested conceptualization and strategies for globalizing gerontology education.


Remaining Mysteries of Molecular Biology: The Role of Polyamines in the Cell.
The polyamines (PAs) spermidine, spermine, putrescine and cadaverine are an essential class of metabolites found throughout all kingdoms of life. In this comprehensive review, we discuss their metabolism, their various intracellular functions and their unusual and conserved regulatory features. These include the regulation of translation via upstream open reading frames, the over-reading of stop codons via ribosomal frameshifting, the existence of an antizyme and an antizyme inhibitor, ubiquitin-independent proteasomal degradation, a complex bi-directional membrane transport system and a unique posttranslational modification-hypusination-that is believed to occur on a single protein only (eIF-5A). Many of these features are broadly conserved indicating that PA metabolism is both concentration critical and evolutionary ancient. When PA metabolism is disrupted, a plethora of cellular processes are affected, including transcription, translation, gene expression regulation, autophagy and stress resistance. As a result, the role of PAs has been associated with cell growth, aging, memory performance, neurodegenerative diseases, metabolic disorders and cancer. Despite comprehensive studies addressing PAs, a unifying concept to interpret their molecular role is missing. The precise biochemical function of polyamines is thus one of the remaining mysteries of molecular cell biology.


Activation of a latent nuclear localization signal in the NH2 terminus of γ-ENaC initiates feedback regulation of channel activity.
Proteolytic enzymes cleave the epithelial Na(+) channel (ENaC) at several positions releasing, in part, the NH(2) terminus of the γ-subunit. Cleavage increases ENaC activity by increasing open probability; however, the role of polypeptides cleaved from the channel core remains unclear. We find that the cytosolic NH(2) terminus of γ-ENaC unexpectedly targets to the nucleus being particularly strong in nucleoli. In contrast, the cytosolic COOH terminus targets to the cytoplasm and plasma membrane in a manner similar to full-length subunits. Targeting of the cytosolic NH(2) terminus of γ-ENaC to the nucleus has functional consequences for coexpression of eGFP-fusion proteins containing this segment of the channel, but not the COOH terminus, decrease ENaC activity in a dose-dependent manner. The mechanism of this negative regulation is associated with a decrease in the functional half-life of ENaC at the plasma membrane. Inspection of the primary amino acid sequence of γ-ENaC reveals possible nuclear localization signals (NLS) conserved at the extreme NH(2) terminus and just preceding the first transmembrane domain. Disruption of the putative NLS preceding the first transmembrane domain in γ-ENaC but not that at the extreme NH(2) terminus abolishes both targeting to the nucleus and negative regulation of ENaC activity. These findings are consistent with the release of the NH(2) terminus of γ-ENaC following cleavage being functionally important for signaling to the nucleus in a manner similar to Notch signaling and release of the cytosolic COOH-terminal tail of polycystin-1.


Alpha-adrenergic control of blood flow during exercise: effect of sex and menstrual phase.
Sex differences exist in autonomic control of the cardiovascular system. This study was designed to directly test sex or female menstrual phase-related differences in α-adrenergic control of blood flow during exercise. We hypothesized that women would exhibit reduced α-adrenergic vasoconstriction compared with men during exercise; in addition, women would constrict less during the early luteal than the early follicular phase of the female menses. Young men (n = 10) were studied once and women (n = 9) studied twice, once during the early follicular phase and once during the early luteal phase of female menses. We measured forearm blood flow (FBF; Doppler ultrasound of the brachial artery) during rest and steady-state dynamic exercise (15 and 30% of maximal voluntary contraction, 20 contractions/min). A brachial artery catheter was inserted for the local administration of α-adrenergic agonists [phenylephrine (PE; α(1)) or clonidine (CL; α(2))]. Blood flow responses to exercise [forearm vascular conductance (FVC)] were similar between all groups. At rest, infusion of PE or CL decreased FVC in all groups (40-60% reduction). Vasoconstriction to PE was abolished in all groups at 15 and 30% exercise intensity. Vasoconstriction to CL was reduced at 15% and abolished at 30% intensity in all groups; women had less CL-induced constriction during the early luteal than early follicular phase (P < 0.017, 15% intensity). These results indicate that vasodilator responses to forearm exercise are comparable between men and women and are achieved through similar paths of α-adrenergic vascular control at moderate intensities; this control may differ at low intensities specific to the female menstrual phase.


Smoking and health-related quality of life in English general population: implications for economic evaluations.
Little is known as to how health-related quality of life (HRQoL) when measured by generic instruments such as EQ-5D differ across smokers, ex-smokers and never-smokers in the general population; whether the overall pattern of this difference remain consistent in each domain of HRQoL; and what implications this variation, if any, would have for economic evaluations of tobacco control interventions. Using the 2006 round of Health Survey for England data (n = 13,241), this paper aims to examine the impact of smoking status on health-related quality of life in English population. Depending upon the nature of the EQ-5D data (i.e. tariff or domains), linear or logistic regression models were fitted to control for biology, clinical conditions, socio-economic background and lifestyle factors that an individual may have regardless of their smoking status. Age- and gender-specific predicted values according to smoking status are offered as the potential 'utility' values to be used in future economic evaluation models. The observed difference of 0.1100 in EQ-5D scores between never-smokers (0.8839) and heavy-smokers (0.7739) reduced to 0.0516 after adjusting for biological, clinical, lifestyle and socioeconomic conditions. Heavy-smokers, when compared with never-smokers, were significantly more likely to report some/severe problems in all five domains--mobility (67%), self-care (70%), usual activity (42%), pain/discomfort (46%) and anxiety/depression (86%). 'Utility' values by age and gender for each category of smoking are provided to be used in the future economic evaluations. Smoking is significantly and negatively associated with health-related quality of life in English general population and the magnitude of this association is determined by the number of cigarettes smoked. The varying degree of this association, captured through instruments such as EQ-5D, may need to be fed into the design of future economic evaluations where the intervention being evaluated affects (e.g. tobacco control) or is affected (e.g. treatment for lung cancer) by individual's (or patients') smoking status.


Computed tomography of the breast: a valuable adjunct to mammography in selected cases.
Computed tomography (CT) is not often used for the further assessment of a mass in the breast. In the case presented it proved to be invaluable in demonstrating a very posterior breast mass previously suboptimally demonstrated on mammography, not palpable clinically, and not visualized on ultrasound examination. The predicament of a very posterior breast mass is highlighted and it is suggested that present-day routine craniocaudal and oblique views may not be adequate to show such a mass even if meticulous attention to radiographic technique is given. If the supine-oblique view with balloon compression cannot be obtained, CT in the prone position with the breasts dependent may be the best alternative. Fine needle aspiration biopsy can be performed under CT guidance in such cases.


A novel lymphocyte function-associated antigen (LFA-1): cellular distribution, quantitative expression, and structure.
We have previously described a monoclonal antibody (MAb), M7/14, which blocks a variety of T cell functions, including CTL-mediated killing, the mixed lymphocyte response, and antigen-specific proliferation. The antigen defined by M7/14 has been designated lymphocyte function-associated antigen one (LFA-1). In this report, LFA-1 has been studied as to cell distribution, surface abundance, structure, and in comparison to other CTL surface antigens, LFA-1 is expressed on lymphoid cells of both the T and the B lineages and on a large fraction of bone marrow cells, but not on exudate macrophages or nonlymphoid tissues. T cells express more LFA-1 than B cells, both in the unstimulated and stimulated states. Compared with unstimulated spleen cells, cytolytic T lymphocyte cell preparations (CTLP) and Con A blasts, but not LPS blasts, show increased LFA-1 expression relative to H-2, and for T cell-containing populations, Lyt-2. M7/14 MAb binds to about 1.5 X 10(4) and 7 X 10(4) LFA-1 sites per average spleen cell or CTLP cell, respectively. M7/14 Mab binds to cTLP in quantitites of 2.5-fold and ies 10.4-fold less than H-2 and Thy-1 Mab, respectively; since the latter have little or no effect on CTL function, inhibition of killing by M7/14 MAb is specific for the LFA-1 surface site. M7/14 MAb and a blocking Lyt-2 MAb are bound in similar quantities of CTLP. LFA-1 is a glycoprotein and consists of 2 noncovalently linked polypeptide chains of 180,000 and 95,000 Mr. The same molecular species as on CTL is present on other T cells and on B cells. The molecular structure and cell distribution of LFA-1 clearly distinguishes it from Lyt-2,3, Ly-5, T145, and T11, which were previously suggested to be either associated with the function of and/or present on the surface of CTL.


Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells.
Cancer stem cells (CSC) may take advantage of the Warburg effect-induced siphoning of metabolic intermediates into de novo fatty acid biosynthesis to increase self-renewal growth. We examined the anti-CSC effects of the antifungal polyketide soraphen A, a specific inhibitor of the first committed step of lipid biosynthesis catalyzed by acetyl-CoA carboxylase (ACACA). The mammosphere formation capability of MCF-7 cells was reduced following treatment with soraphen A in a dose-dependent manner. MCF-7 cells engineered to overexpress the oncogene HER2 (MCF-7/HER2 cells) were 5-fold more sensitive than MCF-7 parental cells to soraphen A-induced reductions in mammosphere-forming efficiency. Soraphen A treatment notably decreased aldehyde dehydrogenase (ALDH)-positive CSC-like cells and impeded the HER2's ability to increase the ALDH+-stem cell population. The following results confirmed that soraphen A-induced suppression of CSC populations occurred throughACACA-driven lipogenesis: a.) exogenous supplementation with supraphysiological concentrations of oleic acid fully rescued mammosphere formation in the presence of soraphen A and b.) mammosphere cultures of MCF-7 cells with stably silenced expression of the cytosolic isoform ACACA1, which specifically participates in de novo lipogenesis, were mostly refractory to soraphen A treatment. Our findings reveal for the first time that ACACA may constitute a previously unrecognized target for novel anti-breast CSC therapies.


Impact of multimodal treatment on prognosis for patients with metastatic upper urinary tract urothelial cancer: Subanalysis of the multi-institutional nationwide case series study of the Japanese Urological Association.
To describe the nature of metastatic upper urinary tract urothelial cancer and determine the prognostic predictors or treatment modality associated with all-cause mortality. Within the nationwide case series study of the Japanese Urological Association, consisting of 1509 patients with urinary tract urothelial cancer diagnosed in 2005, we identified 102 patients with metastatic urinary tract urothelial cancer. Univariate and multivariate survival analyses identified prognostic outcome variables. Predominant sites of distant metastasis at diagnosis were the lungs (54.9%), distant lymph nodes (37.3%), bone (32.4%) and liver (19.6%). Of 102 patients, 70 patients (68.6%) died during the median follow-up period of 6 months, and the 2-year overall survival rate was estimated at 22%. The median survival time to all-cause mortality was 8.5 months (95% confidence interval 6.4-10.7 months). On multivariate analysis, independent predictive factors for all-cause mortality were age (hazard ratio 2.36, P = 0.015) and liver metastasis (hazard ratio 2.35, P = 0.037). Patients who received multimodal treatment including chemotherapy and surgery showed significantly better prognosis (median survival time 25.8 months) compared with patients treated with chemotherapy alone (median survival time 7.3 months) or best supportive care (median survival time 4.3 months). Age at diagnosis and the presence of liver metastasis seem to have an impact on survival of metastatic urinary tract urothelial cancer patients. Multimodal treatment including systemic chemotherapy and surgery might result in better prognosis in some of these patients.


Did dinosaurs invent flowers? Dinosaur-angiosperm coevolution revisited.
Angiosperms first appeared in northern Gondwana during the Early Cretaceous, approximately 135 million years ago. Several authors have hypothesised that the origin of angiosperms, and the tempo and pattern of their subsequent radiation, was mediated by changes in the browsing behaviour of large herbivorous dinosaurs (sauropods and ornithischians). Moreover, the taxonomic and ecological radiation of angiosperms has been associated with the evolution of complex jaw mechanisms among ornithischian dinosaurs. Here, we review critically the evidence for dinosaur-angiosperm interactions during the Cretaceous Period, providing explicit spatiotemporal comparisons between evolutionary and palaeoecological events in both the dinosaur and angiosperm fossil records and an assessment of the direct and indirect evidence for dinosaur diets. We conclude that there are no strong spatiotemporal correlations in support of the hypothesis that dinosaurs were causative agents in the origin of angiosperms; however, dinosaur-angiosperm interactions in the Late Cretaceous may have resulted in some coevolutionary interactions, although direct evidence of such interactions is scanty at present. It is likely that other animal groups (insects, arboreal mammals) had a greater impact on angiosperm diversity during the Cretaceous than herbivorous dinosaurs. Elevated levels of atmospheric CO2 might have played a critical role in the initial stages of the angiosperm radiation.


An Energy-Efficient and Secure Data Inference Framework for Internet of Health Things: A Pilot Study.
Privacy protection in electronic healthcare applications is an important consideration, due to the sensitive nature of personal health data. Internet of Health Things (IoHT) networks that are used within a healthcare setting have unique challenges and security requirements (integrity, authentication, privacy, and availability) that must also be balanced with the need to maintain efficiency in order to conserve battery power, which can be a significant limitation in IoHT devices and networks. Data are usually transferred without undergoing filtering or optimization, and this traffic can overload sensors and cause rapid battery consumption when interacting with IoHT networks. This poses certain restrictions on the practical implementation of these devices. In order to address these issues, this paper proposes a privacy-preserving two-tier data inference framework solution that conserves battery consumption by inferring the sensed data and reducing data size for transmission, while also protecting sensitive data from leakage to adversaries. The results from experimental evaluations on efficiency and privacy show the validity of the proposed scheme, as well as significant data savings without compromising data transmission accuracy, which contributes to energy efficiency of IoHT sensor devices.


Magnetic resonance T1-mapping evaluates the degree of thyroid destruction in patients with autoimmune thyroiditis.
Autoimmune thyroiditis (AIT) is the most common autoimmune thyroid disease. Longitudinal relaxation time mapping (T1-mapping) measured by MRI is a new technique for assessing interstitial fibrosis of some organs, such as heart and liver. This study aimed to evaluate the relationship between T1-mapping value and thyroid function and determine the usefulness of T1-mapping in identifying thyroid destruction in AIT patients. This case-control study recruited 57 drug-naïve AIT patients and 17 healthy controls. All participants were given thyroid MRI, and T1-mapping values were measured using a modified look-locker inversion-recovery sequence. AIT patients had significantly higher thyroid T1-mapping values than the healthy controls (1.077 ± 177 vs 778 ± 82.9 ms; P < 0.01). A significant increase in thyroid T1-mapping values was presented along with the increased severity of thyroid dysfunction (P < 0.01). Correlation analyses showed that increased thyroid T1-mapping values were associated with higher TSH and lower FT3 and FT4 levels (TSH: r = 0.75; FT3: r = -0.47; FT4: r = -0.72; all P < 0.01). Receiver-operating characteristic curve analysis revealed a high diagnostic value of T1-mapping values for the degree of thyroid destruction (area under the curve was 0.95, 95% CI: 0.90-0.99, P < 0.01). AIT patients have higher thyroid T1-mapping values than the healthy controls, and the T1-mapping values increased with the progression of thyroid dysfunction. Thyroid T1-mapping value might be a new index to quantitatively evaluate the degree of thyroid destruction in AIT patients.


First Report of Hop stunt viroid Infecting Japanese Plum, Cherry Plum, and Peach in Greece.
Dapple plum and peach fruit is a widely distributed disorder of plum and peach resulting in significant economic losses (4). During a survey for the presence of Hop stunt viroid (HSVd) on stone fruit trees in Greece, samples from 30 European plums (Prunus domestica L., cvs. President, Tuleu Grass), 45 Japanese plums (Prunus salicina Lindl., cvs. Angeleno, Diamond, Santa Rosa), 12 cherry plums (Prunus domestica L. var. insititia (L.) Fiori & Paoletti of unknown cultivar), and 107 peaches (Prunus persica (L.) Batsch, cvs. Red Haven, Elberta, June Gold, Spring Crest, Lemonato) were collected in several orchards around Greece. Their fruit skin symptomatology indicated viroid infection (reddish dappling blotches and cracks in European and Japanese plum, green dappling in cherry plum, and light colored blotches and lines in peach). Samples were screened with tissue-print hybridization (TPH) for HSVd using a full length DIG-labelled riboprobe deriving from in vitro transcription of the positive control, a citrus isolate of HSVd (G. Vidalakis, CCPP, University of California, Riverside). In total, 44 out of the 194 trees surveyed were HSVd-positive with TPH. For a small number (40) of TPH-positive field samples, TNA phenol extraction from fruit skin, leaves, and bark and one-tube two-step reverse transcription (RT)-PCR assays followed, using a standardized protocol (3) with two different primer pairs, one new primer pair (this study) and a previously reported primer pair (2). RT-PCR analysis showed the presence of HSVd in peach and Japanese plum in prefectures Pella (Central Macedonia), Achaia, and Korinthia (Peloponnesus) and in cherry plum in Achaia (Peloponnesus). Six of 11 Japanese plums (cvs. Angeleno, Santa Rosa), 2 of 12 cherry plums, and 8 of 12 peaches (cvs. Spring Crest, Red Haven) examined were found HSVd-infected, but none of the five European plums were. Nucleotide sequence analyses of purified and cloned amplicons from peaches and Japanese and cherry plums revealed sizes of 297 to 308 nt and similarity to sequence variants of other HSVd isolates previously characterized: 95 to 97% identity with the Moroccan isolates apr.9, apr.10, apr.11, and apr.12 and the Spanish isolate apr.4 from apricot (1) (GenBank Accession Nos. AJ297825 to AJ297828 and Y09346, respectively). For confirmation of HSVd presence in field trees, 10 Japanese plums cv. Angeleno, 10 peaches cv. June Gold, and 10 peaches cv. Spring Crest, HSVd-negative (TPH), were bud- or chip-grafted from two of the aforementioned Japanese plums cv. Angeleno and two of the aforementioned peaches cv. Red Haven. Two years later, five Japanese plum trees (cv. Angeleno) and five peach trees (three cv. Spring Crest and two cv. June Gold) were found HSVd-positive with TPH; no fruits were observed to produce fruit symptoms as the grafted trees were kept in an insect-proof greenhouse (no bees for cross-pollination). To our knowledge, our investigation reports for the first time the occurrence of HSVd infecting Japanese plum, cherry plum, and peach in Greece, emphasizing the need for a certification program for the prevention of spreading stone fruit tree viroids in this country. References: (1) K. Amari et al. J. Gen. Virol. 82:953, 2001. (2) N. Astruc et al. Eur. J. Plant Pathol. 102:837, 1996. (3). F. Faggioli et al. Acta. Hort. 550:59, 2001. (4) T. Sano et al. J. Gen. Virol. 70:1311, 1989.