Effects of moderate and high glycemic index meals on metabolism and exercise performance.
The purpose of this study was to determine whether pre-exercise ingestion of meals with moderate and high glycemic indexes (GI) affects glucose availability during exercise and exercise performance time. Six male volunteers (22 +/- 1 years; 80.4 +/- 3.7 kg; VO(2peak), 54.3 +/- 1.2 ml. kg(-1). min(-1)) ingested 75 g of carbohydrate in the form of 2 different breakfast cereals, rolled oats (moderate GI, approximately 61; MOD-GI) or puffed rice (high GI, approximately 82; HI-GI), combined with 300 mL of water; or water alone (control). The trials were randomized, and the meals were ingested 45 minutes before the subjects performed cycling exercise (60% VO(2peak)) to exhaustion. Venous blood samples were drawn to measure glucose, free fatty acids (FFAs), glycerol, insulin (INS), epinephrine (EPI) and norepinephrine (NE) concentrations. A muscle biopsy specimen was obtained from the vastus lateralis before the meal and immediately after exercise for glycogen determination. Before exercise, both test meals elicited significant (P <.05) hyperglycemia and hyperinsulinemia compared with control. The glycemic response was higher (P <.05) at the start of exercise after the HI-GI meal than after the control. During exercise, plasma glucose levels were higher (P <.05) at 60 (5.2 +/- 0.1, 4.2 +/- 0.2, and 4.6 +/- 0.1 mmol. L(-1)) and 90 (4.8 +/- 0.1, 4.1 +/- 0.1, and 4.3 +/- 0.1 mmol. L(-1)) minutes after the MOD-GI meal than after either the HI-GI or control. Total carbohydrate oxidation was greater (P <.05) during the MOD-GI trial than in control and was directly correlated with exercise performance time (r =.95, P <.0001). Pre-exercise plasma FFA levels were suppressed (P <.05) 30 and 45 minutes after ingestion of the HI-GI meal and 45 minutes after the MOD-GI meal compared with control. At 30, 60, and 120 minutes of exercise, FFAs remained suppressed (P <.05) for both test meals compared with control. At exhaustion, plasma glucose, INS, FFA, glycerol, EPI, and NE levels and muscle glycogen use were not different for all trials. Exercise time was prolonged (P <.05) after the MOD-GI meal compared with control, but the HI-GI trial was not different from control (MOD-GI, 165 +/- 11; HI-GI, 141 +/- 8; control, 134 +/- 13 minutes). Thus, in contrast to the HI-GI meal or control, the MOD-GI breakfast cereal ingested 45 minutes before exercise enhanced performance time, maintained euglycemia for a longer period during exercise, and resulted in greater total carbohydrate oxidation during the exercise bout. We conclude that a MOD-GI meal provides a significant performance and metabolic advantage when consumed 45 minutes before exercise.


Successful weight management and health behaviour change using a health trainer model.
NHS Great Yarmouth and Waveney is an area of high deprivation and it is estimated that 49% of the adult population are overweight or obese. The health trainer model, which involves recruiting trainers from local communities, offers an innovative way of supporting individuals in managing their weight through one-to-one support. The aim of the current study was to evaluate the effectiveness of a health trainer-led intervention in terms of weight loss and behaviour change. Data were collected from all participants who visited a health trainer for the purpose of weight loss between February 2008 and March 2011. All participants were seen on a one-to-one basis, with the setting and length of the intervention varying according to individual requirements (median 21 weeks, IQR 12.4-29.6). Weight change was the primary outcome measure; secondary outcomes were blood pressure, fruit and vegetable intake and physical activity levels, measured using established health trainer data recording systems. Data on secondary outcomes were not available for all participants due to lack of compliance. Using intention-to-treat analysis, average weight change was -2.5 kg (95% CI - 2.7 - -2.1, n = 541, p < .001) and weight gain was prevented in 90% of participants (n = 487). The number of participants classified as hypertensive reduced from 60% (n = 66) to 41% (n = 45) over the period of the intervention. In terms of behaviour change, fruit and vegetable intake increased significantly by 2.4 portions per day (95% CI 2.1-2.7, n = 248, p < .001) with 46% (n = 115) of participants increasing their intake to five portions per day. 68% of participants for whom data were available (n = 227) reported an increase in moderate physical activity, with time increasing by 59.3 minutes per week (95% CI 46.3-72.4, p < .001). The health trainer service in Great Yarmouth and Waveney may be effective in helping participants to manage their weight and change their health-related behaviour. Although the degree of weight loss reported was moderate given the high levels of deprivation and the health needs of the local population, these were promising findings. To improve the current evidence base for the effectiveness of health trainer-led interventions, studies need to see if these findings are replicable in other population groups and in other settings.


Waking the undead: Implications of a soft explosive model for the timing of placental mammal diversification.
The explosive, long fuse, and short fuse models represent competing hypotheses for the timing of placental mammal diversification. Support for the explosive model, which posits both interordinal and intraordinal diversification after the KPg mass extinction, derives from morphological cladistic studies that place Cretaceous eutherians outside of crown Placentalia. By contrast, most molecular studies favor the long fuse model wherein interordinal cladogenesis occurred in the Cretaceous followed by intraordinal cladogenesis after the KPg boundary. Phillips (2016) proposed a soft explosive model that allows for the emergence of a few lineages (Xenarthra, Afrotheria, Euarchontoglires, Laurasiatheria) in the Cretaceous, but otherwise agrees with the explosive model in positing the majority of interordinal diversification after the KPg mass extinction. Phillips (2016) argues that rate transference errors associated with large body size and long lifespan have inflated previous estimates of interordinal divergence times, and further suggests that most interordinal divergences are positioned after the KPg boundary when rate transference errors are avoided through the elimination of calibrations in large-bodied and/or long lifespan clades. Here, we show that rate transference errors can also occur in the opposite direction and drag forward estimated divergence dates when calibrations in large-bodied/long lifespan clades are omitted. This dragging forward effect results in the occurrence of more than half a billion years of 'zombie lineages' on Phillips' preferred timetree. By contrast with ghost lineages, which are a logical byproduct of an incomplete fossil record, zombie lineages occur when estimated divergence dates are younger than the minimum age of the oldest crown fossils. We also present the results of new timetree analyses that address the rate transference problem highlighted by Phillips (2016) by deleting taxa that exceed thresholds for body size and lifespan. These analyses recover all interordinal divergence times in the Cretaceous and are consistent with the long fuse model of placental diversification. Finally, we outline potential problems with morphological cladistic analyses of higher-level relationships among placental mammals that may account for the perceived discrepancies between molecular and paleontological estimates of placental divergence times.


Strong-field-induced wave packet dynamics in carbon dioxide molecule.
Temporal evolution of electronic and nuclear wave packets created in strong-field excitation of the carbon dioxide molecule is studied employing momentum-resolved ion spectroscopy and channel-selective Fourier analysis. Combining the data obtained with two different pump-probe set-ups, we observed signatures of vibrational dynamics in both, ionic and neutral states of the molecule. We consider far-off-resonance two-photon Raman scattering to be the most likely mechanism of vibrational excitation in the electronic ground state of the neutral CO2. Using the measured phase relation between the time-dependent yields of different fragmentation channels, which is consistent with the proposed mechanism, we suggest an intuitive picture of the underlying vibrational dynamics. For ionic states, we found signatures of both, electronic and vibrational excitations, which involve the ground and the first excited electronic states, depending on the particular final state of the fragmentation. While our results for ionic states are consistent with the recent observations by Erattupuzha et al. [J. Chem. Phys.144, 024306 (2016)], the neutral state contribution was not observed there, which we attribute to a larger bandwidth of the 8 fs pulses we used for this experiment. In a complementary measurement employing longer, 35 fs pulses in a 30 ps delay range, we study the influence of rotational excitation on our observables, and demonstrate how the coherent electronic wave packet created in the ground electronic state of the ion completely decays within 10 ps due to the coupling to rotational motion.


Genetic network interactions among replication, repair and nuclear pore deficiencies in yeast.
The yeast RAD27 gene encodes a functional homolog of the mammalian FEN1 protein, a structure-specific endo/exonuclease which plays an important role in DNA replication and repair. Previous genetic interaction studies, including a synthetic genetic array (SGA) analysis, showed that the survival of rad27Delta cells requires several DNA metabolic processes, in particular those mediated by all members of the Rad52-dependent recombinational repair pathway. Here, we report the results of our SGA analysis of the collection of non-essential yeast genes against the rad27Delta mutation, which resulted in the identification of a novel synthetic lethal interaction conferred by mutations affecting the Nup84 nuclear pore subcomplex (nup133Delta, nup120Delta and nup84Delta). Additional screens showed that all Rad52 group genes are required for the survival of the nup133Delta and nup120Delta mutants, which are defective in nuclear pore distribution and mRNA export, but not of the nup133DeltaN mutant, which is solely defective in pore distribution. This requirement for the DNA double-strand break (DSB) repair pathway is consistent with the observation that, like rad27Delta, the nup133Delta, nup120Delta and nup84Delta mutants are sensitive to methyl methanesulfonate (MMS). Furthermore, nup133Delta cells exhibit an increased number of spontaneous DNA repair foci containing Rad52. Altogether, these data suggest that the pathological interactions between the rad27Delta and specific nupDelta mutations result from the accumulation of unrepaired DNA damages.


Does preoperative rehabilitation for patients planning to undergo joint replacement surgery improve outcomes? A systematic review and meta-analysis of randomised controlled trials.
The clinical impact of preoperative physiotherapy on recovery after joint replacement remains controversial. This systematic review aimed to assess the clinical impact of prehabilitation before joint replacement. We searched PubMed, Embase and Cochrane CENTRAL up to November 2015 for randomised controlled trials comparing prehabilitation versus no prehabilitation before joint replacement surgery. Postoperative pain and function scores were converted to Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function subscales (0-100, high scores indicate worse outcome). Random effects meta-analysis was performed to calculate weighted mean differences (WMD, 95% CI), subgrouped by hip and knee surgery. Postoperative pain and function scores, time to resume activities of daily living, quality of life, length of hospital stay, total cost, patient satisfaction, postoperative complications, any adverse events and discontinuations. Of 22 studies (1492 patients), 18 had high risk of bias. Prehabilitation slightly reduced pain scores within 4 weeks postoperatively (WMD -6.1 points, 95% CI -10.6 to -1.6 points, on a scale of 0-100), but differences did not remain beyond 4 weeks. Prehabilitation slightly improved WOMAC function score at 6-8 and 12 weeks (WMD -4.0, 95% CI -7.5 to -0.5), and time to climbing stairs (WMD -1.4 days, 95% CI -1.9 to -0.8 days), toilet use (-0.9 days, 95% CI -1.3 to -0.5 days) and chair use (WMD -1.2 days, 95% CI -1.7 to -0.8 days). Effects were similar for knee and hip surgery. Differences were not found for SF-36 scores, length of stay and total cost. Other outcomes of interest were inadequately reported. Existing evidence suggests that prehabilitation may slightly improve early postoperative pain and function among patients undergoing joint replacement; however, effects remain too small and short-term to be considered clinically-important, and did not affect key outcomes of interest (ie, length of stay, quality of life, costs).


Self-assembly of repulsive interfacial particles via collective sinking.
Charged colloidal particles trapped at an air-water interface are well known to form an ordered crystal, stabilized by a long ranged repulsion; the details of this repulsion remain something of a mystery, but all experiments performed to date have confirmed a dipolar-repulsion, at least at dilute concentrations. More complex arrangements are often observed, especially at higher concentration, and these seem to be incompatible with a purely repulsive potential. In addition to electrostatic repulsion, interfacial particles may also interact via deformation of the surface: so-called capillary effects. Pair-wise capillary interactions are well understood, and are known to be too small (for these colloidal particles) to overcome thermal effects. Here we show that collective effects may significantly modify the simple pair-wise interactions and become important at higher density, though we remain well below close packing throughout. In particular, we show that the interaction of many interfacial particles can cause much larger interfacial deformations than do isolated particles, and show that the energy of interaction per particle due to this "collective sinking" grows as the number of interacting particles grows. Though some of the parameters in our simple model are unknown, the scaling behaviour is entirely consistent with experimental data, strongly indicating that estimating interaction energy based solely on pair-wise potentials may be too simplistic for surface particle layers.


Induction of Fc-Mediated Effector Functions Against a Stabilized Inner Domain of HIV-1 gp120 Designed to Selectively Harbor the A32 Epitope Region.
Recent clinical trials and studies using nonhuman primates (NHPs) suggest that antibody-mediated protection against HIV-1 will require α-HIV envelope humoral immunity beyond direct neutralization to include Fc-receptor (FcR) mediated effector functions such as antibody-dependent cellular cytotoxicity (ADCC). There is also strong evidence indicating that the most potent ADCC response in humans is directed toward transitional non-neutralizing epitopes associated with the gp41-interactive face of gp120, particularly those within the first and second constant (C1-C2) region (A32-like epitopes). These epitopes were shown to be major targets of ADCC responses during natural infection and have been implicated in vaccine-induced protective immunity. Here we describe the immunogenicity of ID2, an immunogen consisting of the inner domain of the clade A/E 93TH057 HIV-1 gp120 expressed independently of the outer domain (OD) and stabilized in the CD4-bound conformation to harbor conformational A32 region epitopes within a minimal structural unit of HIV-1 Env. ID2 induced A32-specific antibody responses in BALB/c mice when injected alone or in the presence of the adjuvants Alum or GLA-SE. Low α-ID2 titers were detected in mice immunized with ID2 alone whereas robust responses were observed with ID2 plus adjuvant, with the greatest ID2 and A32-specific titers observed in the GLA-SE group. Only sera from groups immunized in the presence of GLA-SE were capable of mediating significant ADCC using NKr cells sensitized with recombinant BaL gp120 as targets and human PBMCs as effectors. A neutralization response to a tier 2 virus was not observed. Altogether, our studies demonstrate that ID2 is highly immunogenic and elicits A32-specific ADCC responses in an animal host. The ID2 immunogen has significant translational value as it can be used in challenge studies to evaluate the role of non-neutralizing antibodies directed at the A32 subregion in HIV-1 protection.


Increased Epicardial Adipose Tissue Thickness is Associated With Angiographic Thrombus Burden in the Patients With Non-ST-Segment Elevation Myocardial Infarction.
We aimed to evaluate the relation among epicardial adipose tissue (EAT) thickness, angiographic presence of thrombus, and the no-reflow in the patients with non-ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. The study population consisted of 229 patients. The EAT thickness and neutrophil to lymphocyte ratio (NLR) were significantly higher in the patients with coronary thrombus than in those without coronary thrombus (6.1 ± 1.1 vs 5.1 ± 1.3 mm, P < .001 and 3.4 ± 0.9 vs 2.5 ± 0.7, P < .001, respectively) and in the patients with no-reflow compared to patients with reflow. The EAT thickness was found to be correlated positively with the degree of the thrombus burden, NLR, and waist circumference and negatively with high-density lipoprotein cholesterol. Multivariate logistic regression analysis demonstrated that EAT thickness and NLR independently predicted coronary thrombus formation and no-reflow. We have suggested that EAT can play an important role in the pathophysiology of coronary thrombus formation and the no-reflow.


Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept.
Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 μg/ml; n = 4). Bone formation was monitored using micro computed tomography (μCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via μCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration.


Populations of some molds in water-damaged homes may differ if the home was constructed with gypsum drywall compared to plaster.
Starting in the 1940s, gypsum drywall began replacing plaster and lathe in the U.S. home construction industry. Our goal was to evaluate whether some mold populations differ in water- damaged homes primarily constructed with gypsum drywall compared to plaster. The dust samples from the 2006 Department of Housing and Urban Development's (HUD) American Health Homes Survey (AHHS) were the subject of this analysis. The concentrations of the 36 Environmental Relative Moldiness Index (ERMI) molds were compared in homes of different ages. The homes (n=301) were built between 1878 and 2005. Homes with ERMI values >5 (n=126) were defined as water-damaged. Homes with ERMI values >5 were divided in the years 1976 to 1977 into two groups, i.e., older (n=61) and newer (n=65). Newer water-damaged homes had significantly (p=0.002) higher mean ERMI values than older water-damaged homes, 11.18 and 8.86, respectively. The Group 1 molds Aspergillus flavus, Ammophilus fumigatus, Aspergillus ochraceus, Cladosporium sphaerospermum and Trichoderma viride were found in significantly higher concentrations in newer compared to older high-ERMI homes. Some mold populations in water-damaged homes may have changed after the introduction of gypsum drywall.


Artificial Gene Amplification in Escherichia coli Reveals Numerous Determinants for Resistance to Metal Toxicity.
When organisms are subjected to environmental challenges, including growth inhibitors and toxins, evolution often selects for the duplication of endogenous genes, whose overexpression can provide a selective advantage. Such events occur both in natural environments and in clinical settings. Microbial cells-with their large populations and short generation times-frequently evolve resistance to a range of antimicrobials. While microbial resistance to antibiotic drugs is well documented, less attention has been given to the genetic elements responsible for resistance to metal toxicity. To assess which overexpressed genes can endow gram-negative bacteria with resistance to metal toxicity, we transformed a collection of plasmids overexpressing all E. coli open reading frames (ORFs) into naive cells, and selected for survival in toxic concentrations of six transition metals: Cd, Co, Cu, Ni, Ag, Zn. These selections identified 48 hits. In each of these hits, the overexpression of an endogenous E. coli gene provided a selective advantage in the presence of at least one of the toxic metals. Surprisingly, the majority of these cases (28/48) were not previously known to function in metal resistance or homeostasis. These findings highlight the diverse mechanisms that biological systems can deploy to adapt to environments containing toxic concentrations of metals.


The proteome of Toxoplasma gondii: integration with the genome provides novel insights into gene expression and annotation.
Although the genomes of many of the most important human and animal pathogens have now been sequenced, our understanding of the actual proteins expressed by these genomes and how well they predict protein sequence and expression is still deficient. We have used three complementary approaches (two-dimensional electrophoresis, gel-liquid chromatography linked tandem mass spectrometry and MudPIT) to analyze the proteome of Toxoplasma gondii, a parasite of medical and veterinary significance, and have developed a public repository for these data within ToxoDB, making for the first time proteomics data an integral part of this key genome resource. The draft genome for Toxoplasma predicts around 8,000 genes with varying degrees of confidence. Our data demonstrate how proteomics can inform these predictions and help discover new genes. We have identified nearly one-third (2,252) of all the predicted proteins, with 2,477 intron-spanning peptides providing supporting evidence for correct splice site annotation. Functional predictions for each protein and key pathways were determined from the proteome. Importantly, we show evidence for many proteins that match alternative gene models, or previously unpredicted genes. For example, approximately 15% of peptides matched more convincingly to alternative gene models. We also compared our data with existing transcriptional data in which we highlight apparent discrepancies between gene transcription and protein expression. Our data demonstrate the importance of protein data in expression profiling experiments and highlight the necessity of integrating proteomic with genomic data so that iterative refinements of both annotation and expression models are possible.


Evaluation of incorporation characteristics of mitoxantrone into unilamellar liposomes and analysis of their pharmacokinetic properties, acute toxicity, and antitumor efficacy.
Mitoxantrone (MTO) was incorporated into small unilamellar liposomes by formation of a complex between the anticancer drug and negatively charged lipids. The complex was formed at a 2:1 molar ratio between the lipids and MTO, with phosphatidic acid (PA) being the strongest complex-forming lipid. Weaker complexes and lower incorporation rates of MTO resulted when liposomes containing dicetylphosphate, phosphatidyl inositol, phosphatidyl serine, phosphatidyl glycerol, oleic acid, and tridecylphosphate were used. Thus, all further experiments were performed with PA-MTO liposomes that contained 0.1-3 mg MTO/ml and had mean vesicle sizes of 40-150 nm, depending on the drug concentration and the method of liposome preparation. In vitro incubations of free and liposomal MTO with human plasma showed that the drug is slowly transferred from the liposome membranes to the plasma proteins. For liposomal MTO a transfer rate of 48% was determined, whereas 75.8% of free MTO was bound to the plasma proteins. The organ distribution of the two preparations in mice showed that higher and longer-lasting concentrations of liposomal MTO were found in the liver and spleen. The terminal elimination halflives in the liver were 77 h for liposomal MTO and 14.4 h for free MTO. In the blood, slightly higher concentrations were detected for liposomal MTO, which also had slower biphasic elimination kinetics as compared with the free drug. Drug distribution in the heart was not significantly different from that in the kidneys. The LD25 of PA-MTO liposomes in mice was 19.6 mg/kg and that of free MTO was 7.7 mg/kg. The antitumor effects of PA-MTO liposomes were evaluated in murine L1210 leukemia, in various xenografted human tumors, and in methylnitrosourea-induced rat mammary carcinoma. Generally, the liposomal application form was more effective and less toxic than the free drug. The cytostatic effects were dependent on the tumor model, the application schedule, and the drug concentration. At doses that were toxic when free MTO was used, the liposomal preparation produced strong antitumor effects in some cases. In summary, the incorporation of MTO into liposomes changes the drug's plasma-binding properties, alters its organ distribution, reduces its acute toxicity, and increases its cytostatic efficiency in various tumor models. The liposomal PA-MTO complex represents a new application form of MTO that has advantageous properties.


Gene profiling the window of implantation: Microarray analyses from human and rodent models.
Poor uterine receptivity leads to implantation defects or failure. Identification of uterine molecules crucial to uterine receptivity and/or embryo implantation provides the opportunity to design a diagnostic screening toolkit for uterine receptivity or targeted drug discovery for treating implantation-based infertility. In this regard, gene-profiling studies performed in humans and rodents have identified numerous genes involved in the transcriptional regulation of uterine receptivity and embryo implantation. In this article, we compared available uterine microarray datasets collected during the time of uterine receptivity and implantation in humans, mice and hamsters to uncover conserved gene sets. We also compared the transcriptome signature of women with unexplained infertility (UIF) and recurrent implantation failure (RIF) to gain insight into genes potentially dysregulated during endometrial receptivity or embryo implantation. Among numerous differentially expressed genes, few were revealed that might have molecular diagnostic screening potential for identifying the uterine receptive state during the time of implantation. Finally, functional annotation of gene sets uncovered altered uterine apoptosis or cell adhesion pathways in women with UIF and RIF, respectively. These conserved or divergent gene sets provide insights into the uterine receptive state for supporting blastocyst implantation.


Identification of a botanical inhibitor of intestinal diacylglyceride acyltransferase 1 activity via in vitro screening and a parallel, randomized, blinded, placebo-controlled clinical trial.
Diacylglyceride acyltransferase 1 (DGAT1) is the enzyme that adds the final fatty acid on to a diacylglyceride during triglyceride (TG) synthesis. DGAT1 plays a key role in the repackaging of dietary TG into circulating TG rich chylomicrons. A growing amount of research has indicated that an exaggerated postprandial circulating TG level is a risk indicator for cardiovascular and metabolic disorders. The aim of this research was to identify a botanical extract that inhibits intestinal DGAT1 activity and attenuates postprandial hypertriglyceridemia in overweight and obese humans. Twenty individual phytochemicals and an internal proprietary botanical extract library were screened with a primary cell-free DGAT1 enzyme assay that contained dioleoyl glycerol and palmitoleoyl Coenzyme A as substrates plus human intestinal microsomes as the DGAT1 enzyme source. Botanical extracts with IC50 values < 100 μg/mL were evaluated in a cellular DGAT1 assay. The cellular DGAT1 assay comprised the analysis of (14)C labeled TG synthesis in cells incubated with (14)C-glycerol and 0.3 mM oleic acid. Lead botanical extracts were then evaluated in a parallel, double-blind, placebo-controlled clinical trial. Ninety healthy, overweight and obese participants were randomized to receive 2 g daily of placebo or individual botanical extracts (the investigational product) for seven days. Serum TG levels were measured before and after consuming a high fat meal (HFM) challenge (0.354 L drink/shake; 77 g fat, 25 g carbohydrate and 9 g protein) as a marker of intestinal DGAT1 enzyme activity. Phenolic acids (i.e., gallic acid) and polyphenols (i.e., cyanidin) abundantly found in nature appeared to inhibit DGAT1 enzyme activity in vitro. Four polyphenolic rich botanical extracts were identified from in vitro evaluation in both cell-free and cellular model systems: apple peel extract (APE), grape extract (GE), red raspberry leaf extract (RLE) and apricot/nectarine extract (ANE) (IC50 = 1.4, 5.6, and 10.4 and 3.4 μg/mL, respectively). In the seven day clinical trial, compared to placebo, only GE significantly reduced the baseline subtracted change in serum TG AUC following consumption of the HFM (AUC = 281 ± 37 vs. 181 ± 30 mg/dL*h, respectively; P = 0.021). Chromatographic characterization of the GE revealed a large number of closely eluting components containing proanthocyanidins, catechins, anthocyanins and their secondary metabolites that corresponded with the observed DGAT1 enzyme inhibition in the cell-free model. These data suggest that a dietary GE has the potential to attenuate postprandial hypertriglyceridemia in part by the inhibition of intestinal DGAT1 enzyme activity without intolerable side effects. This trial was registered with ClinicalTrials.gov NCT02333461.


Hybrid LCA of a design for disassembly technology: active disassembling fasteners of hydrogen storage alloys for home appliances.
In the current recycling system of end-of-life (EoL) appliances, which is based on shredding, alloying elements tend to end up in the scrap of base metals. The uncontrolled mixing of alloying elements contaminates secondary metals and calls for dilution with primary metals. Active disassembling fastener (ADF) is a design for disassembly (DfD) technology that is expected to solve this problem by significantly reducing the extent of mixing. This paper deals with a life cycle assessment (LCA) based on the waste input-output (WIO) model of an ADF developed using hydrogen storage alloys. Special attention is paid to the issue of dilution of mixed iron scrap using pig iron in an electric arc furnace (EAF). The results for Japanese electrical and electronic appliances indicate superiority of the recycling system based on the ADF over the current system in terms of reduced emissions of CO(2). The superiority of ADF was found to increase with an increase in the requirement for dilution of scrap.


Reversal of the Ca2+ pump of blood platelets.
In this study, the endoplasmic Ca2+ transport ATPase of blood platelets was compared with the Ca2+ ATPase of sarcoplasmic reticulum skeletal muscle. Similar to the muscle enzyme, the Ca2+ ATPase from platelets was found to catalyse an ATP<-->P(i) exchange both in the presence and in the absence of a transmembrane Ca2+ gradient. When platelet vesicles are loaded with Ca2+ and diluted in medium containing ADP, P(i) and EGTA, the ATPase catalyses Ca2+ efflux coupled to synthesis of ATP. The stoichiometry between Ca2+ ion released and ATP synthesized by platelet Ca2+ ATPase is 1, while that of skeletal muscle is 2. Thapsigargin, a specific inhibitor of sarcoplasmic/endoplasmic reticulum Ca2+ ATPases, inhibited both the Ca(2+)-dependent ATPase activity and the reversal of the platelet Ca2+ pump. The possibility is discussed that the differences observed between the two transport systems is related to the distinct amino acid sequences of the enzymes.


Advanced Connectivity Analysis (ACA): a Large Scale Functional Connectivity Data Mining Environment.
Using resting-state functional magnetic resonance imaging (rs-fMRI) to study functional connectivity is of great importance to understand normal development and function as well as a host of neurological and psychiatric disorders. Seed-based analysis is one of the most widely used rs-fMRI analysis methods. Here we describe a freely available large scale functional connectivity data mining software package called Advanced Connectivity Analysis (ACA). ACA enables large-scale seed-based analysis and brain-behavior analysis. It can seamlessly examine a large number of seed regions with minimal user input. ACA has a brain-behavior analysis component to delineate associations among imaging biomarkers and one or more behavioral variables. We demonstrate applications of ACA to rs-fMRI data sets from a study of autism.


Carbodiimide EDC induces cross-links that stabilize RNase A C-dimer against dissociation: EDC adducts can affect protein net charge, conformation, and activity.
RNase A self-associates under certain conditions to form a series of domain-swapped oligomers. These oligomers show high catalytic activity against double-stranded RNA and striking antitumor actions that are lacking in the monomer. However, the dissociation of these metastable oligomers limits their therapeutic potential. Here, a widely used conjugating agent, 1-ethyl-3-(3-dimethylaminoisopropyl) carbodiimide (EDC), has been used to induce the formation of amide bonds between carboxylate and amine groups of different subunits of the RNase A C-dimer. A cross-linked C-dimer which does not dissociate was isolated and was found have augmented enzymatic activity toward double-stranded RNA relative to the unmodified C-dimer. Characterization using chromatography, electrophoresis, mass spectrometry, and NMR spectroscopy revealed that the EDC-treated C-dimer retains its structure and contains one to three novel amide bonds. Moreover, both the EDC-treated C-dimer and EDC-treated RNase A monomer were found to carry an increased number of positive charges (about 6 ± 2 charges per subunit). These additional positive charges are presumably due to adduct formation with EDC, which neutralizes a negatively charged carboxylate group and couples it to a positively charged tertiary amine. The increased net positive charge endowed by EDC adducts likely contributes to the heightened cleavage of double-stranded RNA of the EDC-treated monomer and EDC-treated C-dimer. Further evidence for EDC adduct formation is provided by the reaction of EDC with a dipeptide Ac-Asp-Ala-NH(2) monitored by NMR spectroscopy and mass spectrometry. To determine if EDC adduct formation with proteins is common and how this affects protein net charge, conformation, and activity, four well-characterized proteins, ribonuclease Sa, hen lysozyme, carbonic anhydrase, and hemoglobin, were incubated with EDC and the products were characterized. EDC formed adducts with all these proteins, as judged by mass spectrometry and electrophoresis. Moreover, all suffered conformational changes ranging from slight structural modifications in the case of lysozyme, to denaturation for hemoglobin as measured by NMR spectroscopy and enzyme assays. We conclude that EDC adduct formation with proteins can affect their net charge, conformation, and enzymatic activity.


Abnormal uterine cervical cytology in a large tertiary hospital in Bangkok metropolis: Prevalence, management, and outcomes.
To determine the prevalence of abnormal cervical cytology, management, and association with clinical significant histopathology including cervical intraepithelial neoplasia II or adenocarcinoma in situ and more severe lesions. Women with abnormal cervical cytology from January 2005 to December 2009 were identified from the archives of Department of Anatomical Pathology and Department of Obstetrics and Gynecology. Demographic data, type of abnormal cytology, management, and their associated histopathology were collected. During the study period: 2533/54,179 women (4.7%) had abnormal cervical Pap test. Squamous lesions were more common than glandular lesions: 2309 (4.3%) compared to 224 (0.4%). Atypical squamous cell (ASC) was most commonly found (1449 or 2.7%), whereas low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intra-epithelial lesion (HSIL), or squamous cell carcinoma (SCC) were found in 648 (1.2%) and 212 (0.4%), respectively. Among abnormal glandular cytology, atypical glandular cell (AGC) was most commonly found (199 women or 0.4%) whereas adenocarcinoma and endometrial cell in woman aged >40 year were found in only 14 (0.02%) and 11 women (0.02%), respectively. Majority (77.3%) underwent further investigations. We found that 13.0% of ASC, 20.3% of LSIL, and 78.7% of HSIL and SCC had clinical significant histopathology. In glandular abnormalities: 14.9% of AGC, 33.3% of women aged >40 years with endometrial cell, and 66.7% of adenocarcinoma were histologically proven to be of clinical significant. ASC was the most common abnormal cervical cytology. Cytology abnormalities of HSIL and SCC had the highest association with clinical significant histopathology.


Abstracts from the 2016 Annual Louisiana American College of Physicians Associates Meeting.
Each year medical students in Louisiana and residents from the eight Internal Medicine training programs in Louisiana are invited to submit abstracts for the Annual Louisiana American College of Physicians (ACP) Associates Meeting. The content of these abstracts includes clinical case vignettes or research activities. The abstracts have all identifying features removed (i.e., names, institutional affiliations, etc.) before being sent to physician judges. Each judge scores each abstract independently and then the scores from all judges are averaged and ranked. This year we are excited to be able to publish most highly ranked abstracts presented at this year's competition. These abstracts (17 oral; 14 poster) were presented at the Associates Meeting held at LSU Health Sciences Center in Baton Rouge on January 19, 2016. We would like to thank the Journal of the Louisiana State Medical Society and appreciate its efforts to publicize the hard work of these trainees.


Rupture characteristics of the deep bolivian earthquake of 9 june 1994 and the mechanism of deep-focus earthquakes.
The M(w) = 8.3 deep (636 kilometers) Bolivian earthquake of 9 June 1994 was the largest deep-focus earthquake ever recorded. Seismic data from permanent stations plus portable instruments in South America show that rupture occurred on a horizontal plane and extended at least 30 by 50 kilometers. Rupture proceeded at 1 to 3 kilometers per second along the down-dip azimuth of the slab and penetrated through more than a third of the slab thickness. This extent is more than three times that expected for a metastable wedge of olivine at the core of the slab, and thus appears to be incompatible with an origin by transformational faulting. These large events may instead represent slip on preserved zones of weakness established in oceanic lithosphere at the Earth's surface.


Protocol for a feasibility study of a self-help cognitive behavioural therapy resource for the reduction of dental anxiety in young people.
Childhood dental anxiety is very common, with 10-20 % of children and young people reporting high levels of dental anxiety. It is distressing and has a negative impact on the quality of life of young people and their parents as well as being associated with poor oral health. Affected individuals may develop a lifelong reliance on general anaesthetic or sedation for necessary dental treatment thus requiring the support of specialist dental services. Children and young people with dental anxiety therefore require additional clinical time and can be costly to treat in the long term. The reduction of dental anxiety through the use of effective psychological techniques is, therefore, of high importance. However, there is a lack of high-quality research investigating the impact of cognitive behavioural therapy (CBT) approaches when applied to young people's dental anxiety. The first part of the study will develop a profile of dentally anxious young people using a prospective questionnaire sent to a consecutive sample of 100 young people referred to the Paediatric Dentistry Department, Charles Clifford Dental Hospital, in Sheffield. The second part will involve interviewing a purposive sample of 15-20 dental team members on their perceptions of a CBT self-help resource for dental anxiety, their opinions on whether they might use such a resource with patients, and their willingness to recruit participants to a future randomised controlled trial (RCT) to evaluate the resource. The third part of the study will investigate the most appropriate outcome measures to include in a trial, the acceptability of the resource, and retention and completion rates of treatment with a sample of 60 dentally anxious young people using the CBT resource. This study will provide information on the profile of dentally anxious young people who could potentially be helped by a guided self-help CBT resource. It will gain the perceptions of dental care team members of guided self-help CBT for dental anxiety in young people and their willingness to recruit participants to a trial. Acceptability of the resource to participants and retention and completion rates will also be investigated to inform a future RCT.


Efficacy and tolerability of mono-compound topical treatments for reduction of intraocular pressure in patients with primary open angle glaucoma or ocular hypertension: an overview of reviews.
To evaluate the existing evidence on relative efficacy and tolerability of topical mono-compound intraocular pressure (IOP)-lowering drugs in treatment of primary open angle glaucoma (POAG) and ocular hypertension (OHT). In this systematic review of systematic reviews/meta-analyses of randomized controlled trials a thorough and sensitive search of PubMed, Embase and Cochrane Databases was performed. Individual study methodological quality and quality of evidence were assessed using the AMSTAR checklist and the GRADE system, respectively. The relationships between individual drugs were evaluated based on the best available evidence. Of the 133 initial non-duplicate records, 16 studies met the inclusion criteria. Five achieved an overall "moderate" (none achieved "high") quality of evidence and evaluated prostaglandin analogues (PGAs) - latanoprost, travoprost, and bimatoprost; timolol; "other beta-blockers;" carbonic anhydrase inhibitors (CAI) as a group or dorzolamide separately; and brimonidine. "Moderate quality" refers to efficacy and incidence of conjunctival hyperemia. Quality of evidence regarding other tolerability aspects was low. PGAs should be considered equivalent regarding efficacy, but latanoprost was relevantly better tolerated than the other two. Non-PGA compounds did not relevantly differ between each other in either efficacy or safety. Timolol and brimonidine were relevantly less effective than all PGAs. The same was true for CAI vs bimatoprost. Regarding tolerability, timolol was superior to all PGAs and brimonidine and CAI were superior to bimatoprost. No high quality evidence on relative efficacy and tolerability of the most commonly used mono-compound IOP-lowering drugs for POAG/OHT exists. Moderate quality evidence indicates latanoprost as a treatment with the most favorable trade-off between benefits and harms.


Dynamic estimation of task-relevant variance in movement under risk.
Humans take into account their own movement variability as well as potential consequences of different movement outcomes in planning movement trajectories. When variability increases, planned movements are altered so as to optimize expected consequences of the movement. Past research has focused on the steady-state responses to changing conditions of movement under risk. Here, we study the dynamics of such strategy adjustment in a visuomotor decision task in which subjects reach toward a display with regions that lead to rewards and penalties, under conditions of changing uncertainty. In typical reinforcement learning tasks, subjects should base subsequent strategy by computing an estimate of the mean outcome (e.g., reward) in recent trials. In contrast, in our task, strategy should be based on a dynamic estimate of recent outcome uncertainty (i.e., squared error). We find that subjects respond to increased movement uncertainty by aiming movements more conservatively with respect to penalty regions, and that the estimate of uncertainty they use is well characterized by a weighted average of recent squared errors, with higher weights given to more recent trials.


Cdk1 is sufficient to drive the mammalian cell cycle.
Unicellular organisms such as yeasts require a single cyclin-dependent kinase, Cdk1, to drive cell division. In contrast, mammalian cells are thought to require the sequential activation of at least four different cyclin-dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6, to drive cells through interphase, as well as Cdk1 to proceed through mitosis. This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks. Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks. Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type and E-type cyclins. Here we show that mouse embryos lacking all interphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. We also report that embryos fail to develop to the morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.


A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis.
Peripherin is a neuronal intermediate filament associated with inclusion bodies in motor neurons of patients with amyotrophic lateral sclerosis (ALS). A possible peripherin involvement in ALS pathogenesis has been suggested based on studies with transgenic mouse overexpressors and with a toxic splicing variant of the mouse peripherin gene. However, the existence of peripherin gene mutations in human ALS has not yet been documented. Therefore, we screened for sequence variants of the peripherin gene (PRPH) in a cohort of ALS patients including familial and sporadic cases. We identified 18 polymorphic variants of PRPH detected in both ALS and age-matched control populations. Two additional PRPH variants were discovered in ALS cases but not in 380 control individuals. One variant consisted of a nucleotide insertion in intron 8 (PRPH(IVS8)(-36insA)), whereas the other one consisted of a 1-bp deletion within exon 1 (PRPH(228delC)), predicting a truncated peripherin species of 85 amino acids. Remarkably, expression of this frameshift peripherin mutant in SW13 cells resulted in disruption of neurofilament network assembly. These results suggest that PRPH mutations may be responsible for a small percentage of ALS, cases and they provide further support of the view that neurofilament disorganization may contribute to pathogenesis.


Inhalation of Hydrogen Attenuates Progression of Chronic Heart Failure via Suppression of Oxidative Stress and P53 Related to Apoptosis Pathway in Rats.
Background: Continuous damage from oxidative stress and apoptosis are the important mechanisms that facilitate chronic heart failure (CHF). Molecular hydrogen (H2) has potentiality in the aspects of anti-oxidation. The objectives of this study were to investigate the possible mechanism of H2 inhalation in delaying the progress of CHF. Methods and Results: A total of 60 Sprague-Dawley (SD) rats were randomly divided into four groups: Sham, Sham treated with H2, CHF and CHF treated with H2. Rats from CHF and CHF treated with H2 groups were injected isoprenaline subcutaneously to establish the rat CHF model. One month later, the rat with CHF was identified by the echocardiography. After inhalation of H2, cardiac function was improved vs. CHF (p < 0.05), whereas oxidative stress damage and apoptosis were significantly attenuated (p < 0.05). In this study, the mild oxidative stress was induced in primary cardiomyocytes of rats, and H2 treatments significantly reduced oxidative stress damage and apoptosis in cardiomyocytes (p < 0.05 or p < 0.01). Finally, as a pivotal transcription factor in reactive oxygen species (ROS)-apoptosis signaling pathway, the expression and phosphorylation of p53 were significantly reduced by H2 treatment in this rat model and H9c2 cells (p < 0.05 or p < 0.01). Conclusion: As a safe antioxidant, molecular hydrogen mitigates the progression of CHF via inhibiting apoptosis modulated by p53. Therefore, from the translational point of view and speculation, H2 is equipped with potential therapeutic application as a novel antioxidant in protecting CHF in the future.


The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1).
The Age-Related Eye Disease Study (AREDS) demonstrated beneficial effects of oral supplementation with antioxidant vitamins and minerals on the development of advanced age-related macular degeneration (AMD) in persons with at least intermediate AMD (bilateral large drusen with or without pigment changes). Observational data suggest that other oral nutrient supplements might further reduce the risk of progression to advanced AMD. The primary purpose of the Age-Related Eye Disease Study 2 (AREDS2) is to evaluate the efficacy and safety of lutein plus zeaxanthin (L+Z) and/or ω-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation in reducing the risk of developing advanced AMD. The study also assesses the reduction in zinc and the omission of β-carotene from original AREDS formulation. Multicenter, phase III, randomized, controlled clinical trial. Persons aged 50 to 85 with bilateral intermediate AMD or advanced AMD in 1 eye. All participants were randomly assigned to placebo (n = 1012), L+Z (10 mg/2 mg; n = 1044), ω-3 LCPUFAs (eicosapentaenoic acid + docosahexaenoic acid [650 mg/350 mg]; n = 1069), or the combination of L+Z and ω-3 LCPUFAs (n = 1078). All participants were offered a secondary randomization to 1 of 4 variations of the original AREDS formulation keeping vitamins C (500 mg) and E (400 IU) and copper (2 mg) unchanged while varying zinc and β-carotene as follows: Zinc remains at the original level (80 mg), lower only zinc to 25 mg, omit β-carotene only, or lower zinc to 25 mg and omit β-carotene. Progression to advanced AMD determined by centralized grading of annual fundus photographs. We enrolled 4203 participants at 82 clinical centers located in the United States. Population characteristics at baseline were as follows: Mean age, 74 years; 57% female; 97% white; 7% current smokers; 19% with prior cardiovascular disease; and 44% and 50% taking statin-class cholesterol-lowering drugs and aspirin, respectively. Ocular characteristics include 59% with bilateral large drusen, 32% with advanced AMD in 1 eye and mean visual acuity of 20/32 in eyes without advanced AMD. This report presents the AREDS2 study design and the participants' baseline demographic and ocular characteristics.


Compassion training in healthcare: what are patients' perspectives on training healthcare providers?
The purpose of this qualitative study was to investigate advanced cancer patients' perspectives on the importance, feasibility, teaching methods, and issues associated with training healthcare providers in compassionate care. This study utilized grounded theory, a qualitative research method, to develop an empirical understanding of compassion education rooted in direct patient reports. Audio-recorded semi-structured interviews were conducted to obtain an in-depth understanding of compassion training from the perspectives of hospitalized advanced cancer patients (n = 53). Data were analyzed in accordance with grounded theory to determine the key elements of the underlying theory. Three overarching categories and associated themes emerged from the data: compassion aptitude, cultivating compassion, and training methods. Participants spoke of compassion as an innate quality embedded in the character of learners prior to their healthcare training, which could be nurtured through experiential learning and reflective practices. Patients felt that the innate qualities that learners possessed at baseline were further fashioned by personal and practice experiences, and vocational motivators. Participants also provided recommendations for compassion training, including developing an interpersonal relationship with patients, seeing the patient as a person, and developing a human connection. Teaching methods that patients suggested in compassion training included patient-centered communication, self-reflection exercises, and compassionate role modeling. This study provides insight on compassion training for both current and future healthcare providers, from the perspectives of the end recipients of healthcare provider training - patients. Developing a theoretical base for patient centred, evidence-informed, compassion training is a crucial initial step toward the further development of this core healthcare competency.


Dependence of electron transfer dynamics on the number of graphene layers in π-stacked 2D materials: insights from ab initio nonadiabatic molecular dynamics.
Recent time-resolved transient absorption studies demonstrated that the rate of photoinduced interfacial charge transfer (CT) from Zn-phthalocyanine (ZnPc) to single-layer graphene (SLG) is faster than to double-layer graphene (DLG), in contrast to the expectation from Fermi's golden rule. We present the first time-domain non-adiabatic molecular dynamics (NA-MD) study of the electron injection process from photoexcited ZnPc molecules into SLG and DLG substrates. Our calculations suggest that CT occurs faster in the ZnPc/SLG system than in the ZnPc/DLG system, with 580 fs and 810 fs being the fastest components of the observed CT timescales, respectively. The computed timescales are in close agreement with those reported in the experiment. The computed CT timescales are determined largely by the magnitudes of the non-adiabatic couplings (NAC), which we find to be 4 meV and 2 meV, for the ZnPc/SLG and ZnPc/DLG systems, respectively. The transitions are driven mainly by the ZnPc out-of-plane bending mode at 1100 cm-1 and an overtone of fundamental modes in graphene at 2450 cm-1. We find that dephasing occurs on the timescale of 20 fs and is similar in both systems, so decoherence does not notably change the qualitative trends in the CT timescales. We highlight the importance of proper energy level alignment for capturing the qualitative trends in the CT dynamics observed in experiment. In addition, we illustrate several methodological points that are important for accurately modeling nonadiabatic dynamics in the ZnPc/FLG systems, such as the choice of surface hopping methodology, the use of phase corrections, NAC scaling, and the inclusion of Hubbard terms in the density functional and molecular dynamics calculations.


A descriptive study on street children living in a southern city of Turkey.
We aimed to determine the social-demographic characteristics and rate of occurrence of hepatitis B infection of children living/working in the streets in Adana, southern city of Turkey. The application forms of 52 children were assessed. Physical examination could be performed for 39 children. The median age was 14 years. The educational status of the children and parents was low. Shoe polishing (22%), selling different goods (22%) and scavenging (33%) were the most common type of work activities. Eighteen (35%) pointed out that they were exposed to beating and attack, three (6%) were sexually abused. Twenty-one (40%) of them were involved in physical fighting and two (4%) were involved in fights resulting in stabbing. Twenty-four (67%) of the children were under 50 percentile for height. Nineteen percent of the children were heavy or medium smokers. Among the 38 children whose hepatitis B markers were checked, HbsAg was positive in 2 (5%), anti-HbcAg in 12 (32%), and anti-HbsAg in 9 (24%). Fifteen (39%) blood samples had negative results. A more nationwide, institutional approach to the problem must be created and maintained.


The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer.
Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.


Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial.
The aim of this study was to test the effects of treatment with ivabradine on exercise capacity and left ventricular filling in patients with heart failure with preserved ejection fraction (HFpEF). Because symptoms of HFpEF are typically exertional, optimization of diastolic filling time by controlling heart rate may delay the onset of symptoms. Sixty-one patients with HFpEF were randomly assigned to ivabradine 5 mg twice daily (n = 30) or placebo (n = 31) for 7 days in this double-blind trial. Cardiopulmonary exercise testing with echocardiographic assessment of myocardial function and left ventricular filling were undertaken at rest and after exercise. The ivabradine group demonstrated significant improvement between baseline and follow-up exercise capacity (4.2 ± 1.8 METs vs. 5.7 ± 1.9 METs, p = 0.001) and peak oxygen uptake (14.0 ± 6.1 ml/min/kg vs. 17.0 ± 3.3 ml/min/kg, p = 0.001), with simultaneous reduction in exercise-induced increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (3.1 ± 2.7 vs. 1.3 ± 2.0, p = 0.004). Work load-corrected chronotropic response (the difference in heart rate at the same exercise time at the baseline and follow-up tests) showed a slower increase in heart rate during exercise than in the placebo-treated group. Therapy with ivabradine (β = 0.34, p = 0.04) and change with treatment in exertional increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (β = -0.30, p = 0.02) were independent correlates of increase in exercise capacity, and therapy with ivabradine (β = 0.32, p = 0.007) was independently correlated with increase in peak oxygen uptake. In patients with HFpEF, short-term treatment with ivabradine increased exercise capacity, with a contribution from improved left ventricular filling pressure response to exercise as reflected by the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity. Because this patient population is symptomatic on exertion, therapeutic treatments targeting abnormal exercise hemodynamic status may prove useful. (Use of Exercise and Medical Therapies to Improve Cardiac Function Among Patients With Exertional Shortness of Breath Due to Lung Congestion; ACTRN12610001087044).


Cytochrome P450 side-chain cleavage enzyme in the cerebellar Purkinje neuron and its neonatal change in rats.
Neurosteroids are de novo synthesized in the nervous system through mechanisms at least partly independent of peripheral steroidogenic glands. However, the concept of neurosteroidogenesis in neurons is not clear in mammalian brains. The present study identified the presence of cytochrome P450scc in the rat Purkinje cell, a typical cerebellar neuron. Immunohistochemical analysis with the antibody against the purified bovine adrenal P450scc showed an immunoreaction restricted to somata and dendrites of the Purkinje cells in adult cerebella. Preadsorbing the antibody with P450scc resulted in a complete absence of the immunoreaction. The antibody against inositol triphosphate receptor, a marker of the Purkinje cell, recognized P450scc-immunoreactive cerebellar cells that showed no immunoreaction with glial fibrillary acidic protein, a specific marker of glial cells. Expression of the P450scc-like protein in the cerebellum was verified by Western blot analysis, and cerebellar P450scc messenger RNA, by RT-PCR analysis in adulthood. On the other hand, P450scc-immunoreactive cells were found to scatter throughout the cerebellum at 0 day of age, before the differentiation of the first Purkinje cells, while the site of expression of this protein was localized only in somata of Purkinje cells at 3 days of age. Immunoreactive dendrites of the Purkinje cell spread into the molecular layer during neonatal development concurrently with its maturation. The intensity of the immunoreaction did not change during neonatal life. Expression of the cerebellar P450scc messenger RNA was also detected after birth, and the level was almost constant during neonatal life. A specific RIA indicated that the pregnenolone concentration was unexpectedly high at 0 day and decreased until 7 days. The total amount of pregnenolone in the cerebellum was almost constant from 0-7 days and increased during 7-21 days concurrently with the cerebellar development. In contrast, the pregnenolone sulfate ester level was low and did not significantly change among the developmental stages. These results suggest that steroidogenic enzyme P450scc appears in the rat Purkinje cell immediately after its differentiation. The expression of this enzyme may remain during neonatal development and in adulthood.


Cisplatin and 5-fluorouracil as neoadjuvant chemotherapy: predicting response in head and neck squamous cell cancer.
In order to prospectively evaluate the efficacy, toxicity and predictive factors of response to neoadjuvant chemotherapy, a total of 120 patients with head and neck squamous cell cancer diagnosed from January 1992 to November 1993 were enrolled in this study. There were 118 male and 2 female patients, with a median age of 51 years (range 30-74 years). The primary sites were the oral cavity (77), oropharynx (15), hypopharynx (25) and larynx (3). Betel quid chewing was habitual in 91% of patients. All patients were previously untreated, and 94% had stage III or IV disease. Chemotherapy was given in two or three courses to 96 patients who were then assessed for response rate and predictive factors. The chemotherapy regimen consisted of cisplatin 100 mg/m2/day on day 1 and 5-fluorouracil (5-FU) 1 g/m2/day intravenous infusion continuously for 4 to 5 days for 4 weeks. The overall chemotherapy response rate was 56%, with a 3% complete response. By univariate analysis, both the T-stage and tumor volume were significant for predicting the response of the primary site. The age, histologic differentiation, tumor location and N-stage were unpredictive for response. The nodal response (43%) was less than that of the primary site (68%). By multivariate analysis, only the tumor volume (> or = 50 cm3) and the presence of nodal metastases were predictive for the combined TN response. Based on the World Health Organization toxicity criteria, 49 patients experienced grade 3 to 4 mucositis, and 24 patients had grade 3 to 4 vomiting.(ABSTRACT TRUNCATED AT 250 WORDS)


Synthetic brain imaging: grasping, mirror neurons and imitation.
The article contributes to the quest to relate global data on brain and behavior (e.g. from PET, Positron Emission Tomography, and fMRI. functional Magnetic Resonance Imaging) to the underpinning neural networks. Models tied to human brain imaging data often focus on a few "boxes" based on brain regions associated with exceptionally high blood flow, rather than analyzing the cooperative computation of multiple brain regions. For analysis directly at the level of such data, a schema-based model may be most appropriate. To further address neurophysiological data, the Synthetic PET imaging method uses computational models of biological neural circuitry based on animal data to predict and analyze the results of human PET studies. This technique makes use of the hypothesis that rCBF (regional cerebral blood flow) is correlated with the integrated synaptic activity in a localized brain region. We also describe the possible extension of the Synthetic PET method to fMRI. The second half of the paper then exemplifies this general research program with two case studies, one on visuo-motor processing for control of grasping (Section 3 in which the focus is on Synthetic PET) and the imitation of motor skills (Sections 4 and 5, with a focus on Synthetic fMRI). Our discussion of imitation pays particular attention to data on the mirror system in monkey (neural circuitry which allows the brain to recognize actions as well as execute them). Finally, Section 6 outlines the immense challenges in integrating models of different portions of the nervous system which address detailed neurophysiological data from studies of primates and other species; summarizes key issues for developing the methodology of Synthetic Brain Imaging; and shows how comparative neuroscience and evolutionary arguments will allow us to extend Synthetic Brain Imaging even to language and other cognitive functions for which few or no animal data are available.


Opinion and practice survey about the use of prognostic models in acute pulmonary embolism.
Methods for prognosis assessment and patient management in acute pulmonary embolism (PE) are much debated among physicians. We conducted an online survey to determine physician's attitudes and barriers towards the use of prognostic models when treating patients with acute PE. Physicians members of the French and the European scientific societies for emergency medicine or of a French thrombosis research network were reached by their respective scientific societies and invited to participate via email. The questionnaire was a mixture of close-ended with yes-no or multiple-choice options and a small number of open-ended questions. The survey included 461 respondents. The most commonly used prognostic tools were clinical judgment (36%) and prognostic models (29.5%). Prognostic models were used by 57% of respondents in more than half of all cases and prognostic indicators by 62% in addition to prognostic models. Affiliation group and type of hospital emerged as independent predictors for choosing prognostic models. Many (52%) reported lack of familiarity with the models and reported clinical judgment (60%) or hospital checklists (73%) as being as good as or better than prognostic models. The highest acceptable 30-day mortality rate limit for early discharge or outpatient management was deemed to be 1%, but few patients are discharged early or completely managed on an outpatient basis. This survey provides new information for implementing knowledge translation strategies to improve prognostic risk assessment for acute PE patients, and highlights the need for considering the use of clinical judgment and hospital checklists in future clinical research.


HDR VolVis: high dynamic range volume visualization.
In this paper, we present an interactive high dynamic range volume visualization framework (HDR VolVis) for visualizing volumetric data with both high spatial and intensity resolutions. Volumes with high dynamic range values require high precision computing during the rendering process to preserve data precision. Furthermore, it is desirable to render high resolution volumes with low opacity values to reveal detailed internal structures, which also requires high precision compositing. High precision rendering will result in a high precision intermediate image (also known as high dynamic range image). Simply rounding up pixel values to regular display scales will result in loss of computed details. Our method performs high precision compositing followed by dynamic tone mapping to preserve details on regular display devices. Rendering high precision volume data requires corresponding resolution in the transfer function. To assist the users in designing a high resolution transfer function on a limited resolution display device, we propose a novel transfer function specification interface with nonlinear magnification of the density range and logarithmic scaling of the color/ opacity range. By leveraging modern commodity graphics hardware, multiresolution rendering techniques and out-of-core acceleration, our system can effectively produce an interactive visualization of large volume data, such as 2,048(3).


Perioperative atrial fibrillation and the long-term risk of ischemic stroke.
Clinically apparent atrial fibrillation increases the risk of ischemic stroke. In contrast, perioperative atrial fibrillation may be viewed as a transient response to physiological stress, and the long-term risk of stroke after perioperative atrial fibrillation is unclear. To examine the association between perioperative atrial fibrillation and the long-term risk of stroke. Retrospective cohort study using administrative claims data on patients hospitalized for surgery (as defined by surgical diagnosis related group codes), and discharged alive and free of documented cerebrovascular disease or preexisting atrial fibrillation from nonfederal California acute care hospitals between 2007 and 2011. Patients undergoing cardiac vs other types of surgery were analyzed separately. Previously validated diagnosis codes were used to identify ischemic strokes after discharge from the index hospitalization for surgery. The primary predictor variable was atrial fibrillation newly diagnosed during the index hospitalization, as defined by previously validated present-on-admission codes. Patients were censored at postdischarge emergency department encounters or hospitalizations with a recorded diagnosis of atrial fibrillation. Of 1,729,360 eligible patients, 24,711 (1.43%; 95% CI, 1.41%-1.45%) had new-onset perioperative atrial fibrillation during the index hospitalization and 13,952 (0.81%; 95% CI, 0.79%-0.82%) experienced a stroke after discharge. At 1 year after hospitalization for cardiac surgery, cumulative rates of stroke were 0.99% (95% CI, 0.81%-1.20%) in those with perioperative atrial fibrillation and 0.83% (95% CI, 0.76%-0.91%) in those without atrial fibrillation. At 1 year after noncardiac surgery, cumulative rates of stroke were 1.47% (95% CI, 1.24%-1.75%) in those with perioperative atrial fibrillation and 0.36% (95% CI, 0.35%-0.37%) in those without atrial fibrillation. In a Cox proportional hazards analysis accounting for potential confounders, perioperative atrial fibrillation was associated with subsequent stroke both after cardiac surgery (hazard ratio, 1.3; 95% CI, 1.1-1.6) and noncardiac surgery (hazard ratio, 2.0; 95% CI, 1.7-2.3). The association was significantly stronger for perioperative atrial fibrillation after noncardiac vs cardiac surgery (P < .001 for interaction). Among patients hospitalized for surgery, perioperative atrial fibrillation was associated with an increased long-term risk of ischemic stroke, especially following noncardiac surgery.


The role of apoptosis proteins and complement components in the etiopathogenesis of systemic lupus erythematosus.
Systemic lupus erythematosus is a prototypical autoimmune disease characterized by the deregulation of T and B cells, tissue infiltration by mononuclear cells, tissue damage and the production of autoantibodies. There is a consensus that accelerated apoptosis of circulating lymphocytes and/or impaired clearance of apoptotic bodies may increase the amount of nuclear antigens presented to T lymphocytes. This process is accompanied by autoimmune responses that can lead to the development of lupus. The dysfunction of apoptosis may be a direct consequence of alterations in proteins/genes such as Fas, Bcl-2 and C1q. Increased expression of Fas antigen could intensify the exposure of hidden antigens. The overexpression of Bcl-2 protein might inhibit the removal of auto-reactive cells, and the lack of C1q could impair the clearance of self-antigens. The complete knowledge of the role of apoptosis components in the etiopathogenesis of lupus could lead to the development of new therapies targeting the apoptotic threshold, which could result in a more specific and effective disease response compared to global immunosuppression. This review summarizes the role of each component of the apoptotic process in the pathogenesis of lupus.


CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP.
To determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP). We compared the ability of baseline CSF β-amyloid1-42, tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients. Higher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS (p = 0.004, false discovery rate-corrected) and SEADL (p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS (p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL (p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau (p = 0.003) or NfL (p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively). Both CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease.


The role of exosomes contents on genetic and epigenetic alterations of recipient cancer cells.
Exosomes, as a mediator of cell-to-cell transfer of genetic information, act an important role in intercommunication between tumor cells and their niche including fibroblasts, endothelial cells, adipocytes and monocytes. Several studies have shown that tumor cells can influence their neighboring cells by releasing exosomes. These exosomes provide signaling cues for stimulation, activation, proliferation and differentiation of cells. Exosomes contain mRNAs, microRNAs (miRNA), and proteins that could be transferred to target cells inducing genetic and epigenetic changes. By facilitating the horizontal transfer of bioactive molecules such as proteins, RNAs and microRNAs, they are now thought to have vital roles in tumor invasion and metastases, inflammation, coagulation, and stem cell renewal and expansion. The aim of this review article is to discuss the significance of exosome-mediated intercellular communication within the tumor biology.


Early discharge hospital at home.
'Early discharge hospital at home' is a service that provides active treatment by health care professionals in the patient's home for a condition that otherwise would require acute hospital in-patient care. If hospital at home were not available then the patient would remain in an acute hospital ward. To determine, in the context of a systematic review and meta-analysis, the effectiveness and cost of managing patients with early discharge hospital at home compared with in-patient hospital care. We searched the Cochrane Effective Practice and Organisation of Care (EPOC) Group Register , MEDLINE (1950 to 2008), EMBASE (1980 to 2008), CINAHL (1982 to 2008) and EconLit through to January 2008. We checked the reference lists of articles identified for potentially relevant articles. Randomised controlled trials recruiting patients aged 18 years and over. Studies comparing early discharge hospital at home with acute hospital in-patient care. Evaluations of obstetric, paediatric and mental health hospital at home schemes are excluded from this review. Two authors independently extracted data and assessed study quality. Our statistical analyses were done on an intention-to-treat basis. We requested individual patient data (IPD) from trialists, and relied on published data when we did not receive trial data sets or the IPD did not include the relevant outcomes. For the IPD meta-analysis, where at least one event was reported in both study groups in a trial, Cox regression models were used to calculate the log hazard ratio and its standard error for mortality and readmission separately for each data set. The calculated log hazard ratios were combined using fixed-effect inverse variance meta-analysis. Twenty-six trials were included in this review [n = 3967]; 21 were eligible for the IPD meta-analysis and 13 of the 21 trials contributed data [1899/2872; 66%]. For patients recovering from a stroke and elderly patients with a mix of conditions there was insufficient evidence of a difference in mortality between groups (adjusted HR 0.79, 95% CI 0.32 to 1.91; N = 494; and adjusted HR 1.06, 95% CI 0.69 to 1.61; N = 978). Readmission rates were significantly increased for elderly patients with a mix of conditions allocated to hospital at home (adjusted HR 1.57; 95% CI 1.10 to 2.24; N = 705). For patients recovering from a stroke and elderly patients with a mix of conditions respectively, significantly fewer people allocated to hospital at home were in residential care at follow up (RR 0.63; 95% CI 0.40 to 0.98; N = 4 trials; RR 0.69, 95% CI 0.48 to 0.99; N =3 trials). Patients reported increased satisfaction with early discharge hospital at home. There was insufficient evidence of a difference for readmission between groups in trials recruiting patients recovering from surgery. Evidence on cost savings was mixed. Despite increasing interest in the potential of early discharge hospital at home services as a cheaper alternative to in-patient care, this review provides insufficient objective evidence of economic benefit or improved health outcomes.


Topographic independent component analysis.
In ordinary independent component analysis, the components are assumed to be completely independent, and they do not necessarily have any meaningful order relationships. In practice, however, the estimated "independent" components are often not at all independent. We propose that this residual dependence structure could be used to define a topographic order for the components. In particular, a distance between two components could be defined using their higher-order correlations, and this distance could be used to create a topographic representation. Thus, we obtain a linear decomposition into approximately independent components, where the dependence of two components is approximated by the proximity of the components in the topographic representation.


Endoscopic diagnosis of cytomegalovirus gastritis after allogeneic hematopoietic stem cell transplantation.
To clarify the endoscopic and clinical findings of cytomegalovirus (CMV) gastritis after allogeneic hematopoietic stem cell transplantation (allo-SCT). Between 1999 and 2005, 523 patients underwent allo-SCT at our hospital, and 115 of these patients with gastrointestinal symptoms underwent esophagogastroduodenoscopy. CMV gastritis was diagnosed pathologically in seven patients (1.3%) with the other 108 patients serving as controls. Six of the seven patients developed positive CMV antigenemia, and five complained of abdominal pain. Development of abdominal pain preceded CMV antigenemia in four of the five patients. Endoscopic examination showed oozing (n = 2), erosion (n = 6), and redness (n = 5) in the seven patients with CMV gastritis, while the control patients showed oozing (n = 3), erosion (n = 24), and redness (n = 100). Erosion and oozing were more frequently documented in patients with CMV gastritis compared with the controls, and the differences were statistically significant (P = 0.0012 and 0.029, respectively). CMV inclusion bodies were documented in 12 of 14 biopsy specimens obtained from erosive lesions, while they were identified in 4 of 15 biopsy specimens obtained from lesions other than erosions (P = 0.0025). This study suggests that erosion and oozing, as well as abdominal pain, are useful indicators in the diagnosis of CMV gastritis following allo-SCT.


Randomized, double-blinded, placebo-controlled crossover trial of treating erectile dysfunction with sildenafil after radiotherapy and short-term androgen deprivation therapy: results of RTOG 0215.
Erectile dysfunction (ED) may be the most commonly observed adverse event (AE) associated with the combination of radiation therapy (RT) and androgen deprivation therapy (ADT). A significant number of men are trying phosphodiesterase type 5 inhibitors (PDE5s) such as sildenafil to treat ED, yet sildenafil studies to date shed little light on the response to ED after ADT. The purpose of this trial was to evaluate sildenafil in the treatment of ED in prostate cancer patients previously treated with external beam RT and neoadjuvant and concurrent ADT. In this randomized, double-blinded crossover trial, eligible patients received RT/ADT for intermediate risk prostate cancer and currently had ED as defined by the International Index of Erectile Function (IIEF). Patients were randomized to 12 weeks of sildenafil or placebo followed by 1 week of no treatment then 12 weeks of the alternative. Treatment differences were evaluated using a marginal model for binary crossover data. The primary end point was improved erectile function, as measured by the IIEF. The study accrued 115 patients and 61 (55%) completed all three IIEF assessments. Sildenafil effect was significant (P = 0.009) with a difference in probabilities of erectile response of 0.17 (95% confidence interval: 0.06, 0.29), and 0.21 (0.06, 0.38) for patients receiving ≤ 120 days of ADT. However, as few as 21% of patients had a treatment-specific response, only improving during sildenafil but not during the placebo phase. This is the first controlled trial to suggest a positive sildenafil response for ED treatment in patients previously treated with RT/ADT, however, only a minority of patients responded to treatment. ADT duration may be associated with response and requires further study. The overall low response rate suggests the need for study of additional or preventative strategies for ED after RT/ADT for prostate cancer.


Leishmania major infection in the fat sand rat Psammomys obesus in Tunisia: interaction of host and parasite populations.
The causative agent of cutaneous leishmaniasis, Leishmania major, was studied in a Tunisian population of the fat sand rat, Psammomys obesus. Seasonal changes in the abundances of parasite and host were monitored in a longitudinal field survey lasting 21 months. Overall, 566 P. obesus, collected during 10 trapping sessions between May 1995 and January 1997, were examined. Analysis of prevalence, using logistic regression, revealed that extrinsic factors, such as season and climatic conditions, and intrinsic factors, such as host age, have a combined effect. Leishmania major showed a seasonal pattern, with most transmission occurring in late summer and in autumn, when prevalences were 7.5- and 6.6-fold higher, respectively, than in spring. Prevalence peaked, at 70%, in September 1995 and then decreased to 0% in June 1996. The same temporal fluctuation was observed during the second study year, albeit among prevalences that were relatively low because of unusually dry conditions. Prevalence was highly dependent on the age of the P. obesus, and season and age acted in synergy so that the rodents were highly infected in late summer and in autumn. Prevalence was not correlated with the relative density of the P. obesus and also appeared independent of gender. Although the ear lesions observed on 378 sand rats during a 1-year survey were closely associated with Leishmania infection, such lesions were not good predictors of infection, as 35% of the rodents found to be infected had no visible lesions on their ears. The prevalences of Leishmania infection observed in this study, among P. obesus living in monospecific colonies, were generally lower than those observed in other studies of P. obesus. It seems possible that P. obesus living in monospecific colonies could have a lesser role in propagating the parasite than those living in plurispecific colonies of rodents, and act as an 'epidemiological sink'.


Evaluating the consumption of chemical products and articles as proxies for diffuse emissions to the environment.
In this study we have evaluated the use of consumption of manufactured products (chemical products and articles) in the EU as proxies for diffuse emissions of chemicals to the environment. The content of chemical products is relatively well known. However, the content of articles (products defined by their shape rather than their composition) is less known and currently has to be estimated from chemicals that are known to occur in a small set of materials, such as plastics, that are part of the articles. Using trade and production data from Eurostat in combination with product composition data from a database on chemical content in materials (the Commodity Guide), we were able to calculate trends in the apparent consumption and in-use stocks for 768 chemicals in the EU for the period 2003-2016. The results showed that changes in the apparent consumption of these chemicals over time are smaller than in the consumption of corresponding products in which the chemicals are present. In general, our results suggest that little change in chemical consumption has occurred over the timespan studied, partly due to the financial crisis in 2008 which led to a sudden drop in the consumption, and partly due to the fact that each of the chemicals studied is present in a wide variety of products. Estimated in-use stocks of chemicals show an increasing trend over time, indicating that the mass of chemicals in articles in the EU, that could potentially be released to the environment, is increasing. The quantitative results from this study are associated with large uncertainties due to limitations of the available data. These limitations are highlighted in this study and further underline the current lack of transparency on chemicals in articles. Recommendations on how to address these limitations are also discussed.


Does strengthening the abdominal muscles prevent low back pain--a randomized controlled trial.
To investigate the effects of abdominal muscle strengthening exercise on low back pain (LBP) risk reduction. We compared the effects of abdominal muscle strength (AMS) exercise and back education with back education only on 402 asymptomatic subjects with weak AMS. The primary outcome was the percentage of subjects with at least one episode of LBP at 24 months. A diary was used to monitor compliance. There were no statistically significant differences between experimental (E) and control (C) subjects at 24 months for LBP episodes (E: 34.7%, C: 30.4%; C-E = 4.2%, P2 = 0.481; 95% CI -16.1%, 7.6%). The LBP episodes were also not statistically significantly different at 6 months (E: 13.2%, C: 16.1%; C-E: 2.9%, P2 = 0.493; 95% CI -5.3%, 11.0%) or at 12 months (E: 24.8%, C: 23.6%; C-E = -1.2%, P2 = 0.818; 95% CI -11.6%, 9.2%). Adjusting the data for strata and baseline AMS did not alter the findings. Imputed results for LBP episodes at 6 months (C-E: 4.8%, P2 = 0.191; 95% CI -2.4%, 12.0%), 12 months (C-E: -1.0%, P2 = 0.821; 95% CI -9.5%, 7.6%), and 24 months (C-E: -3.3%, P2 = 0.483; 95% CI -12.6%, 5.9%) were also not statistically significantly different. Back education and abdominal exercise instructions are similar to back education alone. There were no group differences in LBP episodes, possibly due to noncompliance with the exercise program. While the estimated benefit of 2.9% at 6 months from the complete data and 4.8% from the imputed data were not statistically significant, a larger study or future metaanalyses may be needed to confirm whether there is a clinical benefit or whether these results should be considered a chance finding.


Collaborative care for depression in UK primary care: a randomized controlled trial.
Collaborative care is an effective intervention for depression which includes both organizational and patient-level intervention components. The effect in the UK is unknown, as is whether cluster- or patient-randomization would be the most appropriate design for a Phase III clinical trial. We undertook a Phase II patient-level randomized controlled trial in primary care, nested within a cluster-randomized trial. Depressed participants were randomized to 'collaborative care' - case manager-coordinated medication support and brief psychological treatment, enhanced specialist and GP communication - or a usual care control. The primary outcome was symptoms of depression (PHQ-9). We recruited 114 participants, 41 to the intervention group, 38 to the patient randomized control group and 35 to the cluster-randomized control group. For the intervention compared to the cluster control the PHQ-9 effect size was 0.63 (95% CI 0.18-1.07). There was evidence of substantial contamination between intervention and patient-randomized control participants with less difference between the intervention group and patient-randomized control group (-2.99, 95% CI -7.56 to 1.58, p=0.186) than between the intervention and cluster-randomized control group (-4.64, 95% CI -7.93 to -1.35, p=0.008). The intra-class correlation coefficient for our primary outcome was 0.06 (95% CI 0.00-0.32). Collaborative care is a potentially powerful organizational intervention for improving depression treatment in UK primary care, the effect of which is probably partly mediated through the organizational aspects of the intervention. A large Phase III cluster-randomized trial is required to provide the most methodologically accurate test of these initial encouraging findings.


The work ability index and single-item question: associations with sick leave, symptoms, and health--a prospective study of women on long-term sick leave.
This study investigated the association between the work ability index (WAI) and the single-item question on work ability among women working in human service organizations (HSO) currently on long-term sick leave. It also examined the association between the WAI and the single-item question in relation to sick leave, symptoms, and health. Predictive values of the WAI, the changed WAI, the single-item question and the changed single-item question were investigated for degree of sick leave, symptoms, and health. This cohort study comprised 324 HSO female workers on long-term (>60 days) sick leave, with follow-ups at 6 and 12 months. Participants responded to questionnaires. Data on work ability, sick leave, health, and symptoms were analyzed with regard to associations and predictability. Spearman correlation and mixed-model analysis were performed for repeated measurements over time. The study showed a very strong association between the WAI and the single-item question among all participants. Both the WAI and the single-item question showed similar patterns of associations with sick leave, health, and symptoms. The predictive value for the degree of sick leave and health-related quality of life (HRQoL) was strong for both the WAI and the single-item question, and slightly less strong for vitality, neck pain, both self-rated general and mental health, and behavioral and current stress. This study suggests that the single-item question on work ability could be used as a simple indicator for assessing the status and progress of work ability among women on long-term sick leave.


Cognitive functioning enhancement in older adults: is there an advantage of multicomponent training over Nordic walking?
We compared Nordic walking training (NW) to a multicomponent training (MCT) program of an equivalent intensity, in older adults. Our main hypothesis was that MCT would result in larger effects on cognitive processes than NW. Thirty-nine healthy older adults, divided into two groups (NW and MCT), took part in the study (17 males, 22 females, mean age =70.8±0.8 years). They were tested for cardiovascular fitness, motor fitness and cognitive performance during the two weeks preceding and following the 12-week training session (3 times/week), respectively. For both the NW and MCT interventions, the training sessions were supervised by a trainer. Heart rate of participants was monitored during the sessions and then used to make training loads as similar as possible between the two groups (TRaining IMPulse method). Results showed that training resulted in better performance for cardiovascular and motor fitness tests. Among these tests, only two revealed a significant difference between the two groups. The NW group progressed more than the MCT group in the 30 Seconds Chair Stand test, while in the One Leg Stance test, the MCT group progressed more. For the cognitive assessment, a significant effect of training was found for executive functions, spatial memory score, and information processing speed response time, with no differences between the two groups. The study confirmed that physical exercise has a positive impact on cognitive processes with no advantage of MCT intervention over NW training. A possible reason is that NW intervention not only improved cardiovascular capacities, but also motor fitness, including coordination capacities.


Effect of a high fat, high sucrose diet on the promotion of non-alcoholic fatty liver disease in male rats: the ameliorative role of three natural compounds.
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease with a complex pathophysiology. The clinical features of NAFLD include obesity, insulin resistance (IR) and dyslipidemia. Consumption of a diet high in saturated fats and sucrose is an important factor in the increasing occurrence of these metabolic disorders, primarily NAFLD and IR. We sought to assess the role of a high-fat, high-sucrose (HFS) diet in the promotion of NAFLD and to evaluate the effects of quercetin (Q), berberine (BB) and o-coumaric acid (CA) on modulation of these disorders. Fifty male rats were divided into 2 main groups as follows: group 1 comprised 10 rats fed a standard diet (SD), and group 2 comprised 40 rats fed an HFS diet for 6 weeks and then subdivided equally into 4 groups; one of these groups served as the HFS diet and each of the other three groups received daily supplementation with either Q, CA or BB for 6 weeks. In the present study, several metabolic disorders were induced in our laboratory animal model, as evidenced by histological and biochemical changes. These alterations included serum and hepatic dyslipidemia (i.e., increased triglyceride, total cholesterol and low-density lipoprotein levels and decreased high-density lipoprotein levels), alterations in metabolic enzyme activities (lipase, glycerol-3-phosphate dehydrogenase, and glucose-6-phosphate dehydrogenase), histological changes in the liver (micro- and macrovesicular steatosis) and the downregulation of peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue and the liver. Daily oral supplementation with Q, CA or BB for 6 weeks after NAFLD induction had a hypolipidemic action and modulated metabolic markers. We showed that an HFS diet is able to promote NAFLD, and our results suggest that CA and BB are promising complementary supplements that can ameliorate the metabolic disorders associated with an HFS diet; however, Q requires further investigation.